Krazati (adagrasib)

If adverse effects occur during adagrasib therapy, temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug may be necessary.

Consult Table 1 for recommended dosage reductions for adverse reactions for use of adagrasib as a single agent or in combination with cetuximab. If an adverse reaction occurs, a maximum of 2 dosage reductions are allowed; permanently discontinue adagrasib in patients who are unable to tolerate 600 mg once daily.

Please refer to the cetuximab prescribing information for dose modifications for cetuximab-related adverse reactions. If adagrasib is withheld or permanently discontinued, withhold or permanently discontinue cetuximab. If cetuximab is permanently discontinued, monotherapy with adagrasib may be continued.

Table 1. Recommended Adagrasib Dosage Reductions for Adverse Reactions.

Dosage Reduction Recommended Dosage First dose reduction 400 mg twice daily Second dose reduction 600 mg once daily

Consult Table 2 for recommended dosage adjustments for specific adverse reactions based on severity.

Table 2. Recommended Adagrasib Dosage Adjustments for Adverse Reactions.

Adverse Reaction Severity Recommended Dosage Adjustment Nausea or vomiting Grade 3 or 4 Withhold until recovery despite appropriate to grade 1 or lower or supportive care, return to baseline; including antiemetic resume at the next lower therapy dosage level Diarrhea despite Grade 3 or 4 Withhold until recovery appropriate supportive to grade 1 or lower or care, including return to baseline; antidiarrheal therapy resume at the next lower dosage level QTc interval Absolute QTc value >500 Withhold until QTc prolongation ms OR an increase of >60 interval is <481 ms or ms from baseline returns to baseline; resume at the next lower dosage level Torsade de pointes, Permanently discontinue polymorphic ventricular tachycardia, or signs or symptoms of serious or life-threatening arrhythmia Hepatotoxicity Grade 2, AST or ALT Decrease dosage to the next lower dosage level Grade 3 or 4, AST or ALT Withhold until recovery to grade 1 or lower or return to baseline; resume at the next lower dosage level AST or ALT >3 times ULN Permanently discontinue with total bilirubin >2 times ULN in the absence of alternative causes Interstitial lung Any grade Withhold if interstitial disease or pneumonitis lung disease/pneumonitis is suspected; permanently discontinue if confirmed Other adverse reactions Grade 3 or 4 Withhold until recovery to grade 1 or lower or return to baseline; resume at the next lower dosage level

ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal.

Adagrasib is administered orally twice daily when given as a single agent or in combination with cetuximab. Administer at the same time every day, with or without food.

Swallow tablets whole; do not chew, crush, or split the tablets.

If vomiting occurs after taking a dose of adagrasib, do not take an additional dose; resume dosing at the next scheduled time.

If a dose of adagrasib is missed, skip the dose if more than 4 hours have elapsed from the expected dosing time; resume dosing at the next scheduled time.

Store tablets at 20-25oC (excursions permitted between 15-30oC).

No dosing information is available for this tab.

Adagrasib is a cytochrome P-450 (CYP) isoenzyme 3A4 substrate. Adagrasib is an inhibitor of CYP isoenzymes 3A, 2C9, and 2D6, and the efflux transporter P-glycoprotein (P-gp).

In vitro studies indicate that adagrasib may inhibit CYP isoenzyme 2B6, multidrug and toxin extrusion (MATE)-1, and MATE-2K, and may be a substrate of breast cancer resistance protein (BCRP).

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Adagrasib/Cyclosporine; Sirolimus

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Adagrasib may decrease the metabolism and increase the absorption of cyclosporine and sirolimus by inhibiting CYP3A4 and P-glycoprotein (P-gp).(1)

CLINICAL EFFECTS: Concurrent use of adagrasib may result in elevated levels of and toxicity from cyclosporine and sirolimus.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of adagrasib states that concurrent administration of sensitive narrow therapeutic index P-glycoprotein substrates or sensitive CYP3A4 substrates (e.g. cyclosporine, sirolimus) with adagrasib should be avoided.(1)

DISCUSSION: Concurrent adagrasib (600 mg twice daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of digoxin by 1.5-fold and 1.9-fold, respectively.(1) In a study, adagrasib (400 mg twice daily) increased the AUC and Cmax of a single dose of midazolam by 21-fold and 4.8-fold, respectively. In a study, adagrasib (600 mg twice daily) increased the AUC and Cmax of a single dose of midazolam by 31-fold and 3.1-fold, respectively.(1)

Adagrasib/Desipramine; Imipramine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Adagrasib is a moderate inhibitor of CYP2D6 and is expected to inhibit the metabolism of agents through this pathway.(1)

CLINICAL EFFECTS: Concurrent use of adagrasib may result in elevated levels of and toxicity from agents metabolized by CYP2D6.(1)

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(2)

PATIENT MANAGEMENT: Avoid the concurrent use of adagrasib with CYP2D6 substrates with a narrow therapeutic index (e.g. desipramine, imipramine). If concurrent use is warranted, monitor patients for toxicity.(1)

DISCUSSION: In a study, adagrasib (400 mg twice daily) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of dextromethorphan (a sensitive CYP2D6 substrate) by 1.9-fold and 1.8-fold, respectively. Adagrasib (600 mg twice daily) is predicted to increase the Cmax and AUC of a single dose of dextromethorphan by 1.7-fold and 2.4-fold, respectively.(1)

Adagrasib/Digoxin; Etoposide

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Adagrasib may increase the absorption of digoxin and etoposide by inhibiting P-glycoprotein (P-gp).(1)

CLINICAL EFFECTS: Concurrent use of adagrasib may result in elevated levels of and toxicity from digoxin and etoposide.(1) Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias. Etoposide toxicity may include hematologic and gastrointestinal toxicities.

PREDISPOSING FACTORS: The interaction magnitude may be greater in patients receiving oral etoposide, or with impaired renal or hepatic function.

PATIENT MANAGEMENT: The US manufacturer of adagrasib states that concurrent administration of sensitive narrow therapeutic index P-glycoprotein substrates (e.g. digoxin, etoposide) with adagrasib should be avoided.(1)

DISCUSSION: Concurrent adagrasib (600 mg twice daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of digoxin by 1.5-fold and 1.9-fold, respectively.(1)

Adagrasib/Haloperidol

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Haloperidol is metabolized via many metabolic pathways. The contributions of CYP2D6, CYP3A4 and possibly CYP1A2 pathways are most clearly defined. Concomitant use of haloperidol with inhibitors of one or more of these pathways may lead to clinically significant increases in haloperidol levels and result in additive QT effects of the QTc interval. Adagrasib is a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor.(1,2)

CLINICAL EFFECTS: The concurrent administration of adagrasib may result in elevated levels of haloperidol and lead to toxicities such as orthostatic hypotension, akathisia, acute dystonia, or Parkinsonism. Concurrent use may also result in additive QTc prolongation, which may lead to life-threatening cardiac arrhythmias like torsade de pointes.(1,2)

PREDISPOSING FACTORS: Elderly patients, particularly those with a history of falls or swallowing disorders, and patients with Parkinson Disease, Lewy Body Disease, or other dementias are more sensitive to antipsychotics and have a greater risk for adverse effects. Younger patients, patients on low doses of haloperidol, or on a dose targeted to lower-therapeutic serum levels, have a lower interaction risk. The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: The manufacturer of adagrasib states that concurrent use with QT prolonging agents, sensitive CYP2D6 substrates with a narrow therapeutic window, or sensitive CYP3A4 substrates should be avoided.(2) Monitor patient for extrapyramidal side effects and orthostatic hypotension if adagrasib is added to haloperidol therapy and lower haloperidol dose if needed.(1) When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If patients develop QTc prolongation >500 msec or >60 msec from baseline, withhold adagrasib until QTc interval less than 481 msec or QTc interval returns to baseline. Resume adagrasib at the next lower dose level. If patients develop torsade de pointes, polymorphic ventricular tachycardia, or signs and symptoms of serious or life-threatening arrhythmia, permanently discontinue adagrasib.(1)

DISCUSSION: Although it is an older agent, the complex pharmacokinetics of haloperidol are not yet fully understood. Adagrasib has been associated with QTc interval prolongation. Adagrasib increased QTc in a concentration-dependent manner. In patients administered adagrasib 600 mg twice daily, the mean QTcF change from baseline was 18 msec. In the pooled safety population, 6% of 366 patients with at least one post-baseline ECG had an average QTc greater than 501 msec and 11% of patients had a increase from baseline QTc greater than 60 msec.(1)

Adagrasib/Levoketoconazole

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Levoketoconazole is a strong inhibitor of CYP3A4 that prolongs the QTc interval and may inhibit the CYP3A4 metabolism of adagrasib. This combination may also have additive effects on the QTc interval.(1,2)

CLINICAL EFFECTS: Concurrent use of levoketoconazole, a strong inhibitor of CYP3A4 that prolongs the QTc interval, may result in elevated levels and increased effects of adagrasib, such as hepatotoxicity, intersitial lung disease or pneumonitis, or gastrointestinal adverse reactions.(1,2) Symptoms can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue. Concurrent use may also result in additive QTc prolongation, which may lead to life-threatening cardiac arrhythmias like torsade de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)

PATIENT MANAGEMENT: The US manufacturer of levoketoconazole states that levoketoconazole is contraindicated with other agents that prolong the QT interval.(2) Levoketoconazole is also contraindicated in patients with a prolonged QTcF interval of greater than 470 msec at baseline, history of torsades de pointes, ventricular tachycardia, ventricular fibrillation, or long QT syndrome (including first-degree family history). Use caution in patients with other risk factors for QT prolongation including congestive heart failure, bradyarrhythmias, and uncorrected electrolyte abnormalities. Consider more frequent ECG monitoring. Prior to starting levoketoconazole, obtain a baseline ECG and correct hypokalemia or hypomagnesemia. If a patient develops QT prolongation with a QTc interval greater than 500 msec, temporarily discontinue levoketoconazole. After resolution of prolonged QTc interval, levoketoconazole may be resumed at a lower dose. If QTc interval prolongation recurs, permanently discontinue levoketoconazole.(1) If patients develop QTc prolongation >500 msec or >60 msec from baseline, withhold adagrasib until QTc interval less than 481 msec or QTc interval returns to baseline. Resume adagrasib at the next lower dose level. If patients develop torsade de pointes, polymorphic ventricular tachycardia, or signs and symptoms of serious or life-threatening arrhythmia, permanently discontinue adagrasib.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. Monitor liver tests, including AST, ALT, total bilirubin, according to the recommendations in the adagrasib package insert. Advise patients to immediately report any symptoms of hepatotoxicity. Monitor for new or worsening respiratory symptoms indicative of interstitial lung disease or pneumonitis.

DISCUSSION: Coadministration of itraconazole (strong CYP3A4 inhibitor) increased adagrasib (single dose 200 mg) maximum concentration (Cmax) and area-under-the-curve (AUC) by 2.4-fold and 4-fold. No clinically significant differences in the pharmacokinetics of adagrasib at steady state were predicted when used concomitantly with itraconazole.(1) Adagrasib has been associated with QTc interval prolongation. Adagrasib increased QTc in a concentration-dependent manner. In patients administered adagrasib 600 mg twice daily, the mean QTcF change from baseline was 18 msec. In the pooled safety population, 6% of 366 patients with at least one post-baseline ECG had an average QTc greater than 501 msec and 11% of patients had a increase from baseline QTc greater than 60 msec.(1) During phase 1 and 2 studies with levoketoconazole, which excluded patients with baseline QTcF interval greater than 470 msec, 4 (2.4%) patients experienced QTcF > 500 msec, and 23 (14.7%) patients experienced change-from-baseline QTcF > 60 msec.(2) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(5)

Adagrasib/Sel Sensitive 3A4 Substrates That Prolong Qt

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Adagrasib is a strong inhibitor of CYP3A4 and may decrease the metabolism of drugs metabolized by the CYP3A4 enzyme and result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: Concurrent use of adagrasib may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(1) Concurrent use may also result in additive QTc prolongation, which may lead to life-threatening cardiac arrhythmias like torsade de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of adagrasib states that coadministration of CYP3A4 substrates should be avoided.(1) If patients develop QTc prolongation >500 msec or >60 msec from baseline, withhold adagrasib until QTc interval is less than 481 msec or QTc interval returns to baseline. Resume adagrasib at the next lower dose level. If patients develop torsade de pointes, polymorphic ventricular tachycardia, or signs and symptoms of serious or life-threatening arrhythmia, permanently discontinue adagrasib.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study, adagrasib (400 mg twice daily) increased the area-under-the-curve (AUC) and maximum concentration (Cmax) of a single dose of midazolam by 21-fold and 4.8-fold, respectively. In a study, adagrasib (600 mg twice daily) increased the AUC and Cmax of a single dose of midazolam by 31-fold and 3.1-fold, respectively.(1) Adagrasib has been associated with QTc interval prolongation. Adagrasib increased QTc in a concentration-dependent manner. In patients administered adagrasib 600 mg twice daily, the mean QTcF change from baseline was 18 msec. In the pooled safety population, 6% of 366 patients with at least one post-baseline ECG had an average QTc greater than 501 msec and 11% of patients had a increase from baseline QTc greater than 60 msec.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(4) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: lopinavir, saquinavir, and terfenadine.(1,3-4)

Adagrasib/Selected Sensitive Cyp3a4 Substrates

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Adagrasib is a strong inhibitor of CYP3A4 and may decrease the metabolism of drugs metabolized by the CYP3A4 enzyme.(1)

CLINICAL EFFECTS: Concurrent use of adagrasib may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of adagrasib states that coadministration of CYP3A4 substrates should be avoided.(1)

DISCUSSION: In a study, adagrasib (400 mg twice daily) increased the area-under-the-curve (AUC) and maximum concentration (Cmax) of a single dose of midazolam by 21-fold and 4.8-fold, respectively. In a study, adagrasib (600 mg twice daily) increased the AUC and Cmax of a single dose of midazolam by 31-fold and 3.1-fold, respectively.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: atazanavir, atorvastatin, brotizolam, darunavir, ebastine, eletriptan, indinavir, nisoldipine, paritaprevir, and tipranavir.(1-3)

Adagrasib/Strong Cyp3a4 Inducers

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inducers of CYP3A4 may increase the metabolism of adagrasib.(1)

CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of adagrasib.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of adagrasib states that the concurrent use of strong CYP3A4 inducers should be avoided, and that alternative treatments with less CYP3A4 induction should be considered.(1)

DISCUSSION: In a study with healthy subjects, co-administration of rifampin (strong 3A4 inducer) with a single dose of adagrasib (600 mg), decreased adagrasib area-under-curve (AUC) by 95% and maximum concentration (Cmax) by 88%.(1) Co-administration of rifampin (strong 3A4 inducer) with multiple doses of adagrasib (600 mg) is predicted to decrease adagrasib AUC by greater than 61% and Cmax by greater than 66%. Strong inducers of CYP3A4 linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(3-4)

Adagrasib/Warfarin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Adagrasib is a moderate CYP2C9 inhibitor(1) which may decrease the metabolism of the S-enantiomer of warfarin.(1,2)

CLINICAL EFFECTS: Concurrent use of adagrasib may result in elevated levels of warfarin and increased INR.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: The US manufacturer of adagrasib states that concurrent administration with sensitive CYP2C9 substrates should be avoided.(1) Monitor INRs more frequently until stable in patients who start adagrasib therapy.(1,2) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. Discontinue anticoagulation in patients with active pathologic bleeding.

DISCUSSION: In clinical studies, coadministration of adagrasib 600 mg twice daily increased the area-under-the-curve (AUC) and maximum concentration (Cmax) of S-warfarin by 2.9-fold and 1.1-fold, respectively.(1)

Cyp3a4 Substrates That Prolong Qt/Posaconazole

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Posaconazole is a strong inhibitor of CYP3A4 and may inhibit the metabolism of CYP3A4 substrates. Use of posaconazole with agents that prolong the QTc interval may result in an additive effect on the QTc interval.(1,2)

CLINICAL EFFECTS: Concurrent administration may result in elevated levels of the CYP3A4 substrate and/or prolongation of the QTc interval, which may result in life-threatening cardiac arrhythmias, including torsades de pointes.(1,2)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The US manufacturer of posaconazole states that the concurrent use of agents that prolong the QTc interval that are metabolized by CYP3A4 is contraindicated.(1) The UK manufacturer of posaconazole states that CYP3A4 substrates that are known to prolong the QTc interval must not be coadministered.(2) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Posaconazole has been shown to inhibit CYP3A4. Elevated levels of CYP3A4 substrates that are known to prolong the QTc interval may have an additive effect on the QTc interval.(1,2) CYP3A4 substrates that prolong the QTc interval and that are linked to this monograph include: aclarubicin, adagrasib, amiodarone, artemether-lumefantrine, bepridil, clarithromycin, dofetilide, erythromycin, fexinidazole, levomethadyl, lonafarnib, mobocertinib, quizartinib, revumenib, savolitinib, taletrectinib, and telithromycin.

P-Glycoprotein (P-Gp) Inhibitors/Topotecan

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibitors of P-glycoprotein may increase the absorption of topotecan.(1)

CLINICAL EFFECTS: The concurrent administration of topotecan with an inhibitor of P-glycoprotein may result in elevated levels of topotecan and signs of toxicity. These signs may include but are not limited to anemia, diarrhea, and thrombocytopenia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of topotecan states that the use of topotecan and P-glycoprotein inhibitors should be avoided. If concurrent use is warranted, carefully monitor patients for adverse effects.(1) For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(2)

DISCUSSION: In clinical studies, the combined use of elacridar (100 mg to 1000 mg) increased the area-under-curve (AUC) of topotecan approximately 2.5-fold.(1) Oral cyclosporine (15 mg/kg) increased the AUC of topotecan lactone and total topotecan to 2-fold to 3-fold of the control group, respectively.(1) P-gp inhibitors linked to this monograph include: adagrasib, amiodarone, asciminib, asunaprevir, aumolertinib, azithromycin, belumosudil, bosutinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan, daraxonrasib, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, erythromycin, flibanserin, ginseng, hydroquinidine, imlunestrant, isavuconazonium, itraconazole, ivacaftor, josamycin, ketoconazole, ledipasvir, lonafarnib, mavorixafor, neratinib, osimertinib, pibrentasvir/glecaprevir, posaconazole, propafenone, quinidine, ranolazine, selpercatinib, sotorasib, tepotinib, tucatinib, valbenazine, velpatasvir, vemurafenib, vepdegestrant, verapamil, vimseltinib, and voclosporin.(3,4)

P-Gp And Strong Cyp3a4 Inhibitors/Rivaroxaban

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Adagrasib, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, paritaprevir, posaconazole, telaprevir, telithromycin, and tucatinib may inhibit the metabolism of rivaroxaban by CYP3A4 and by P-glycoprotein.(1-3)

CLINICAL EFFECTS: Concurrent use of an agent that is both an inhibitor of P-gp and a strong inhibitor of CYP3A4 may result in elevated levels of and clinical effects of rivaroxaban,(1-3) including an increased risk of bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The Canadian manufacturer of rivaroxaban states that the concurrent use of agents that are both an inhibitor of P-gp and a strong inhibitor of CYP3A4 with rivaroxaban is contraindicated.(1) The US manufacturer states that concurrent use of these agents should be avoided.(2) The UK manufacturer states that concurrent use is not recommended.(3) The US manufacturer of itraconazole states concurrent use with rivaroxaban is not recommended during and two weeks after itraconazole treatment.(5) Agents that are not strong inhibitors of both CYP3A4 and P-glycoprotein, including fluconazole, are expected to increase rivaroxaban levels to a lesser extent and can be used with rivaroxaban with caution(3) in patients with normal renal function.(6) If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Concurrent use of rivaroxaban with ketoconazole (400 mg daily) increased rivaroxaban AUC and Cmax by 2.6-fold and 1.7-fold, respectively. There were also significant increases in pharmacodynamic effects.(1-3) Clarithromycin increased the Cmax and AUC of a single dose of rivaroxaban by 40% and 50%, respectively and is not expected to affect bleeding risk.(2) Agents that are not strong inhibitors of both CYP3A4 and P-glycoprotein, including fluconazole, are expected to increase rivaroxaban levels to a lesser extent and can be used with rivaroxaban with caution(2) in patients with normal renal function.(3)

Qt Prolonging Agents/Anagrelide

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent use of anagrelide with agents that prolong the QTc interval may result in additive effects on the QTc interval.(1-4)

CLINICAL EFFECTS: The concurrent use of anagrelide with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1-4)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(5) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(5)

PATIENT MANAGEMENT: The US manufacturer of anagrelide states that anagrelide should not be used in patients taking medications known to prolong the QT interval.(1) The Australian, Canadian, and UK manufacturers of anagrelide state use of anagrelide should be approached with caution in patients taking medications that can prolong the QTc interval.(2-4) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a thorough QT study, dose-related QT changes were observed with anagrelide. The maximum mean change in QTcI (95% CI) in comparison to placebo was 7.0 (9.8) ms and 13.0 (15.7) msec following doses of 0.5 mg and 2.5mg, respectively.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(6) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Qt Prolonging Agents/Bepridil

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Bepridil has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of bepridil with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: Hypokalemia, the use of potassium wasting diuretics, and the presence of antecedent bradycardia may increase the risk of torsades de pointes.(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibitors its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The manufacturer of bepridil states under contraindications that bepridil is contraindicated in patients taking other drugs that prolong the QT interval.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Qt Prolonging Agents/Droperidol

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Droperidol has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of droperidol with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: Congestive heart failure, bradycardia, use of a diuretic, cardiac hypertrophy, hypokalemia, hypomagnesemia, age over 65 years, alcohol abuse, and the use of agents such as benzodiazepines, volatile anesthetics, and intravenous opiate may predispose patients to the development of prolonged QT syndrome.(1) Risk may also be increased in patients with other cardiovascular diseases (e.g. myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypocalcemia, or female gender.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The manufacturer of droperidol states under precautions drug interactions that drugs known to have the potential to prolong the QT interval should not be used together with droperidol.(1)

DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Qt Prolonging Agents/Halofantrine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Halofantrine has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of halofantrine with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction.(3)

PATIENT MANAGEMENT: The manufacturer of halofantrine states in a black box warning that halofantrine is not recommended for use in combination with drugs known to prolong the QTc interval. Under precautions, drug interactions, the manufacturer states that halofantrine should not be administered with drugs known to prolong the QTc interval.(1)

DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Qt Prolonging Agents/Levomethadyl

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Levomethadyl has been shown to prolong the QTc interval and induce torsade de pointes. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of levomethadyl with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: Congestive heart failure, bradycardia, diuretic use, cardiac hypertrophy, hypokalemia, or hypomagnesemia may increase the risk of torsade de pointes and/or sudden death.(1) The risk of QT prolongation may also be increased in patients with other cardiovascular diseases (e.g. myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypocalcemia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The manufacturer of levomethadyl states under contraindications that levomethadyl is contraindicated in patients being treated concomitantly with other drug products known to prolong the QT interval.(1)

DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Qt Prolonging Agents/Sertindole

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Sertindole has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of sertindole with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The manufacturer of sertindole states that sertindole is contraindicated in patients receiving drugs known to prolong the QT interval.(1)

DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)

Qt Prolonging Agents/Sparfloxacin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Sparfloxacin has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of sparfloxacin with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The manufacturer of sparfloxacin states under contraindications that sparfloxacin is contraindicated in patients being treated concomitantly with medications known to produce an increase in the QTc interval and/or torsade de pointes.(1)

DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)

Selected Cyp3a4 Inhibitors/Oral Midazolam

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The metabolism of midazolam by CYP3A4 may be inhibited by strong CYP3A4 inhibitors.(1)

CLINICAL EFFECTS: The concurrent administration of strong CYP3A4 inhibitors may result in elevated levels of midazolam, which may result in increased adverse effects including profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturers of boceprevir,(1) cobicistat,(2) and telaprevir(3) state that concurrent use of oral midazolam is contraindicated. The US manufacturers of adagrasib,(4) idelalisib,(5) and relacorilant(6) state that concurrent use of oral midazolam should be avoided. Patients receiving intravenous midazolam should be closely monitored. Consideration should be given to lowering the dose of intravenous midazolam in patients maintained on strong CYP3A4 inhibitors. If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: Boceprevir (800 mg 3 times daily for 6 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single oral dose of midazolam (4mg) by 2.77-fold and 5.30-fold, respectively.(1) In a study in 21 subjects, telaprevir (750mg every 8 hours for 11 days) increased the Cmax and AUC of a single oral dose of midazolam (2 mg) by 2.86-fold and 8.96-fold, respectively.(3) In a study in 22 subjects, telaprevir (750mg every 8 hours for 9 days) increased the Cmax and AUC of a single intravenous dose of midazolam (0.5 mg) by 2% and 3.40-fold, respectively.(3,7) Coadministration of adagrasib 400 mg twice daily and 600 mg twice daily with midazolam increased the Cmax of midazolam by 4.8-fold and 3.1-fold, respectively, and increased the AUC of midazolam by 21-fold and 31-fold, respectively.(4) Coadministration of idelalisib with midazolam increased the Cmax and AUC of midazolam by 2.4-fold and 5.4-fold, respectively.(5) Coadministration of relacorilant with midazolam increased the Cmax and AUC of midazolam by 3.1-fold and 8.9-fold, respectively.(6) Selected CYP3A4 inhibitors linked include: adagrasib, boceprevir, cobicistat, idelalisib, relacorilant, and telaprevir.

Selected Strong And Moderate Cyp3a4 Inhibitors/Cisapride

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong and moderate CYP3A4 inhibitors impair the CYP3A4 mediated metabolism of cisapride.(1)

CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inhibitors may result in elevated levels of and toxicity from cisapride, including life-threatening cardiac arrhythmias such as torsades de pointes.(1-2)

PREDISPOSING FACTORS: In general, the risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: Concurrent use of strong or moderate CYP3A4 inhibitors with cisapride is contraindicated. Use alternative antiemetics, or an alternative to the strong or moderate CYP3A4 inhibitor, whichever is more clinically appropriate. The US manufacturer of itraconazole states that concurrent administration with cisapride is contraindicated during and two weeks after itraconazole treatment.(4) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(5) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, atazanavir, avacopan, ciprofloxacin, clofazimine, conivaptan, darunavir, erythromycin, fosamprenavir, rilzabrutinib, and treosulfan.(5)

Selected Strong And Moderate Cyp3a4 Inhibitors/Domperidone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong and moderate CYP3A4 inhibitors impair the CYP3A4 mediated metabolism of domperidone.(1)

CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inhibitors may result in elevated levels of and toxicity from domperidone, including life-threatening cardiac arrhythmias such as torsades de pointes.(1-2)

PREDISPOSING FACTORS: In epidemiologic studies and post-market safety data, domperidone was associated with an increased risk for serious ventricular arrhythmias in patients > 60 years of age, using more than 30 mg of domperidone daily, and having other risk factors for QT prolongation.(1) In general, the risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Concurrent use of strong or moderate CYP3A4 inhibitors with domperidone is contraindicated. Use alternative antiemetics, or an alternative to the strong or moderate CYP3A4 inhibitor, whichever is more clinically appropriate. If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. The manufacturer of itraconazole states that concurrent use of domperidone during and 2 weeks after itraconazole treatment is contraindicated.(3,4)

DISCUSSION: In a study in 24 healthy subjects, ketoconazole (200 mg twice daily) tripled plasma levels of domperidone (10 mg four times daily). In male subjects, the combination significantly increased QTc interval greater than either agent alone. In females, there were no significant changes in QTc intervals, but QTc intervals were correlated with domperidone levels.(5) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole. Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, atazanavir, clofazimine, darunavir, dronedarone, erythromycin, fluconazole, and fosamprenavir. One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Selected Strong Cyp3a4 Inhibitors/Alprazolam; Triazolam

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of alprazolam and triazolam.(1,2)

CLINICAL EFFECTS: The concurrent administration of alprazolam or triazolam with strong CYP3A4 inhibitors may result in elevated levels of alprazolam or triazolam, which may result in increased adverse effects including profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturers of alprazolam and triazolam state that concurrent use with strong CYP3A4 inhibitors is contraindicated.(1,2) The Australian manufacturer of alprazolam states the coadministration of alprazolam with ketoconazole, itraconazole or other azole antifungals is not recommended.(3)

DISCUSSION: Many of the strong CYP3A4 inhibitors linked to this monograph have not been studied in combination with alprazolam or triazolam. However, other strong CYP3A4 have been well studied and are expected to cause a similar effect. In a study coadministration with ketoconazole increased alprazolam area-under-curve (AUC) by 3.98-fold.(1) In a study of 12 healthy volunteers, clarithromycin (500 mg twice daily for 2 days) increased the AUC of triazolam by 5-fold.(4) In a randomized, cross-over study in 10 healthy subjects, itraconazole ingested simultaneously, or 3, 12, or 24 hours before triazolam increased triazolam AUC by 3.1-fold, 4.8-fold, 4.6-fold, and 3.8-fold, respectively. The increase in triazolam Cmax ranged from 1.4-fold to 1.8-fold. Subjects noted increased triazolam effects.(5) In a double-blind cross-over study in 9 subjects, itraconazole increased triazolam AUC by 27-fold.(6) In a double-blind cross-over study in 9 subjects, ketoconazole increased triazolam AUC by 22-fold.(4) In a double-blind cross-over study, concurrent ketoconazole decreased triazolam clearance by 91%. Triazolam half-life and Cmax increased 5.1-fold and 1.1-fold, respectively.(7) Serum concentrations and the half-life of triazolam were increased by troleandomycin by as much as 258%.(8) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, grapefruit, idelalisib, josamycin, lonafarnib, mibefradil, posaconazole, relacorilant, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(9)

Selected Strong Cyp3a4 Inhibitors/Conivaptan

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of conivaptan.(1) Toxicity may result from an overly rapid correction of serum sodium. Conivaptan may also increase levels of levoketoconazole.(4)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels of conivaptan.(1) Elevated levels of these agents may lead to increased clinical effects such as hypotension, hypovolemia, and thirst, as well as toxicity in the form of neurologic sequelae such as osmotic demyelination syndrome (ODS). ODS can lead to coma and death. Symptoms of ODS include dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, and coma.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of conivaptan and strong CYP3A4 inhibitors is contraindicated.(1) The US manufacturer of itraconazole states that concurrent use with conivaptan is contraindicated during and two weeks after itraconazole treatment.(2)

DISCUSSION: Conivaptan is a substrate of CYP3A4. Coadministration of conivaptan (10mg) and ketoconazole (a strong CYP3A4 inhibitor, 200 mg) resulted in a 4-fold increase in the AUC and an 11-fold increase in the Cmax of conivaptan.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(3)

Selected Strong Cyp3a4 Inhibitors/Ensartinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Ensartinib is primarily metabolized by CYP3A4. Ensartinib metabolism may be inhibited by strong CYP3A4 inhibitors.(1)

CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from ensartinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of ensartinib states that concurrent use of strong CYP3A4 inhibitors should be avoided.(1)

DISCUSSION: Ensartinib is predominately metabolized by CYP3A4.(1) Strong CYP3A4 inhibitors include: adagrasib, ceritinib, ensitrelvir, grapefruit, idelalisib, relacorilant, ribociclib, troleandomycin, and voriconazole.(2,3)

Selected Strong Cyp3a4 Inhibitors/Ergot Alkaloids

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the hepatic metabolism of ergot alkaloids.(1-4)

CLINICAL EFFECTS: Concurrent use may result in increased levels of ergot alkaloids, which may result in clinical signs of ergotism, including vasospasm, dysesthesia, renal ischemia, and peripheral ischemia.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of dihydroergotamine,(1,2) ergotamine,(2,3) or methylergonovine(2,4) and strong inhibitors of CYP3A4 is contraindicated. It would be prudent to avoid the concurrent use of all ergot alkaloids and strong inhibitors of CYP3A4. Patients receiving concurrent therapy should be monitored for clinical signs of ergotism. One or both agents may need to be discontinued. Patients should be treated symptomatically for ergotism.

DISCUSSION: Case reports have documented clinical signs of ergotism following concomitant therapy with various ergot alkaloids and strong inhibitors of CYP3A4 such as clarithromycin, erythromycin, indinavir, nelfinavir, ritonavir, and troleandomycin. Selected strong CYP3A4 inhibitors linked include: adagrasib, ceritinib, cobicistat, grapefruit, idelalisib, josamycin, levoketoconazole, lonafarnib, mibefradil, nefazodone, relacorilant, ribociclib, and tucatinib.

Selected Strong Cyp3a4 Inhibitors/Isavuconazonium

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent use of strong CYP3A4 inhibitors may inhibit the metabolism of isavuconazonium.(1)

CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inhibitor may result in elevated levels and toxicity from isavuconazonium, leading to antifungal discontinuation. Adverse reactions may include headache, dizziness, paresthesia, somnolence, disturbance in attention, dysgeusia, dry mouth, diarrhea, oral hypoesthesia, vomiting, hot flush, anxiety, restlessness, palpitations, tachycardia, photophobia and arthralgia.(1)

PREDISPOSING FACTORS: Patients with familial short QT syndrome may be at increased risk of heart arrhythmias.(1)

PATIENT MANAGEMENT: The concurrent use of isavuconazonium with strong inhibitors of CYP3A4 is contraindicated.(1) The US manufacturer of itraconazole states that administration of isavuconazonium is contraindicated during and two weeks after itraconazole treatment. If concurrent therapy is deemed medically necessary, monitor patients for isavuconazonium toxicity, including headache, dizziness, paresthesia, somnolence, disturbance in attention, dysgeusia, dry mouth, diarrhea, oral hypoesthesia, vomiting, hot flush, anxiety, restlessness, palpitations, tachycardia, photophobia and arthralgia. Isavuconazonium or the CYP3A4 inhibitor may need to be discontinued.

DISCUSSION: Ketoconazole (200 mg BID) increased the maximum concentration (Cmax) and area-under-curve (AUC) of isavuconazole (from a single dose of isavuconazonium equivalent to 200 mg isavuconazole) by 9% and 422%, respectively.(1) Lopinavir/ritonavir (400 mg/100 mg BID) increased the Cmax and AUC of isavuconazole by 74% and 96%, respectively.(1) Supratherapeutic doses of isavuconazonium (three times the recommended dosage) used in a study resulted in 17.9% of patients discontinuing isavuconazonium therapy.(1) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, mibefradil, mifepristone, nefazodone, nelfinavir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.

Selected Strong Cyp3a4 Inhibitors/Lovastatin; Simvastatin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of lovastatin and simvastatin by CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in elevated levels of lovastatin and simvastatin and increase the risk of rhabdomyolysis.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of strong CYP3A4 inhibitors with lovastatin or simvastatin is contraindicated.(1,2) Therapy with lovastatin or simvastatin should be suspended during ribociclib therapy. In patients requiring long-term therapy with ribociclib, consider the use of pravastatin or reduced dosages of atorvastatin or fluvastatin, using the lowest dose possible.(3) Patients should be carefully monitored for and instructed to report any signs of myopathy.

DISCUSSION: In a study in healthy subjects, concomitant administration of ribociclib (400 mg once daily for 8 days) with midazolam increased the midazolam maximum concentration (Cmax) and area under the curve (AUC) by 2.1-fold and 3.8-fold, respectively. Administration of ribociclib 600 mg once daily is predicted to increase the midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.(3) Strong CYP3A4 inhibitors linked include: adagrasib, ceritinib, grapefruit, idelalisib, relacorilant, and ribociclib.(4,5)

Selected Strong Cyp3a4 Inhibitors/Lurasidone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of lurasidone.(1) Sensitive substrates will have at least a 5-fold increase in area-under-curve (AUC) when given with a strong inhibitor of the enzyme.(2)

CLINICAL EFFECTS: Concomitant use of lurasidone with strong inhibitors of CYP3A4 may lead to orthostatic hypotension, akathisia, acute dystonia, Parkinsonism, confusion, postural instability or other lurasidone toxicities.(1)

PREDISPOSING FACTORS: Elderly patients, particularly those with a history of falls, swallowing disorders, Parkinson Disease, Lewy Body Disease, or other dementias are more sensitive to antipsychotics and have a greater risk for adverse effects.(1)

PATIENT MANAGEMENT: The US manufacturer of lurasidone states that concurrent use of strong CYP3A4 inhibitors is contraindicated.(1) If a patient is maintained on lurasidone and requires a strong CYP3A4 inhibitor for treatment, then the patient should be converted to another antipsychotic prior to initiation of the strong CYP3A4 inhibitor therapy.

DISCUSSION: Pretreatment with ketoconazole (400 mg daily for 5 days), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of lurasidone (10 mg) by 6.9-fold and 9.0-fold, respectively.(1) Agents linked to this monograph include adagrasib, ceritinib, idelalisib, josamycin, levoketoconazole, lonafarnib, mibefradil, mifepristone, nefazodone, relacorilant, troleandomycin, and tucatinib.(2)

Selected Strong Cyp3a4 Inhibitors/Orforglipron (>9 Mg)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Orforglipron is metabolized via CYP3A4. Strong inhibitors of CYP3A4 may inhibit the metabolism of orforglipron.(1)

CLINICAL EFFECTS: Concurrent use of orforglipron with strong CYP3A4 inhibitors may increase the levels and toxicities of orforglipron, including severe gastrointestinal adverse effects.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of orforglipron states that when used concomitantly with strong CYP3A4 inhibitors, the orforglipron maximum dosage is 9 mg once daily.(1)

DISCUSSION: In a clinical study, coadministration of orforglipron with clarithromycin 500 mg twice daily, a strong CYP3A4 inhibitor, resulted in a 3.5-fold increase in orforglipron area-under-curve (AUC) and a 1.9-fold increase in maximum concentration (Cmax).(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, mibefradil, mifepristone, nefazodone, nelfinavir, posaconazole, relacorilant, ribociclib, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(2,3)

Str 3A4 Inhib;Atazan;Darun/Colchicine (For Cardioprotection)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of colchicine.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from colchicine. Symptoms of colchicine toxicity include muscle weakness or pain; numbness or tingling in the fingers or toes; myelosuppression; abdominal pain; nausea; severe diarrhea or vomiting; feeling weak or tired; increased infections; and pale or gray color of the lips, tongue, or palms of hands.(1,2)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with renal or hepatic impairment.(1,2)

PATIENT MANAGEMENT: The manufacturer of colchicine used for cardiovascular risk reduction states that concurrent use of colchicine with strong CYP3A4 inhibitors is contraindicated.(1)

DISCUSSION: There are several reports of colchicine toxicity(4-6) and death(7,8) following the addition of clarithromycin to therapy. In a retrospective review of 116 patients who received clarithromycin and colchicine during the same hospitalization, 10.2% (9/88) of patients who received simultaneous therapy died, compared to 3.6% (1/28) of patients who received sequential therapy.(9) An FDA review of 117 colchicine-related deaths that were not attributable to overdose found that 60 deaths (51%) involved concurrent use of clarithromycin.(2) In a study in 23 subjects, pretreatment with clarithromycin (250 mg twice daily for 7 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by 227.2% (range 65.7% to 591.1%) and by 281.5% (range 88.7% to 851.6%), respectively.(1) In a study in 24 subjects, pretreatment with ketoconazole (200 mg twice daily for 5 days) increased the Cmax and AUC of a single dose of colchicine (0.6 mg) by 101.7% (range 19.6% to 219%) and by 212.2% (range 76.7% to 419.6%), respectively.(1) In a study in 18 subjects, pretreatment with ritonavir (100 mg twice daily for 5 days) increased the Cmax and AUC of a single dose of colchicine (0.6 mg) by 184.4% (range 79.2% to 447.4%) and by 296% (range 53.8% to 924.4%), respectively.(1) Colchicine toxicity has been reported with concurrent use of CYP3A4 and P-gp inhibitors such as clarithromycin, cyclosporine, diltiazem, erythromycin, and verapamil.(1,2) Strong inhibitors of CYP3A4 include: adagrasib, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(1,10)

Str Cyp3a4 Inhibitors That Prolong Qt/Aumolertinib (>55 Mg)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Aumolertinib is a CYP3A4 substrate and has been shown to prolong the QTc interval. Strong inhibitors of CYP3A4 may inhibit the metabolism of aumolertinib.(1) Concurrent use of agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors that prolong QT may result in increased levels and toxicities of aumolertinib, including an additive risk of potentially life-threatening arrhythmias like torsades de pointes, cardiac failure, rhabdomyolysis, thrombosis, elevated LFTs, hyponatremia, and hematologic toxicity.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Patients with risk factors for thrombosis may be at higher risk of adverse events, including those with advanced age, obesity (BMI >30), smoking, prolonged immobilization, heart failure, hypercoagulable state, history of venous thromboembolism, malignancy, and major surgery. The risk for rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of rhabdomyolysis.

PATIENT MANAGEMENT: The manufacturer of aumolertinib states that concurrent use with strong CYP3A4 inhibitors should be avoided. If concurrent use of a strong CYP3A4 inhibitor cannot be avoided, the dose of aumolertinib should be reduced from 110 mg to 55 mg daily.(1) The manufacturer of aumolertinib states that concurrent use of other drugs that are known to prolong the QTc interval should be avoided. If a suitable alternative is not available, consider increasing the frequency of ECG and electrolyte monitoring.(1) Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If QTc prolongation occurs, follow recommended dose modifications: - Grade 2 (QTc interval >480 to 500 ms): Withhold aumolertinib for up to 2 weeks. If QTc interval has not recovered to <= 480 ms, permanently discontinue aumolertinib. If QTc interval recovers to <= 480 ms or within 30 ms of baseline, resume aumolertinib treatment at 110 mg. Monitor ECGs at least weekly for 2 weeks following return to <= 480 ms. Monitor and correct electrolytes and/or change concomitant medications. - Grade 3 (QTc interval > 500 ms or QTc interval increase of > 60 ms from baseline): Withhold aumolertinib for up to 2 weeks. If QTc interval has not recovered to <= 480 ms or within 30 ms of baseline, permanently discontinue aumolertinib. If QTc interval recovers to <= 480 ms and it is the first occurrence, resume treatment at 110 mg dose. If QTc interval recovers to <= 480 ms and it is the second occurrence or the first occurrence in patients with risk factors, resume treatment at 55 mg dose. Permanently discontinue aumolertinib if signs or symptoms recur at any time on the 55 mg dose. Monitor ECGs at least weekly for 2 weeks following return to <= 480 ms. Monitor and correct electrolytes and/or change concomitant medications. - QT interval prolongation associated with torsade de pointes, polymorphic ventricular tachycardia, or signs/symptoms of other serious arrhythmia: permanently discontinue aumolertinib.(1)

DISCUSSION: In a clinical study, itraconazole (strong CYP3A inhibitor) increased aumolertinib area-under-curve (AUC) by 3.7-fold.(1) A concentration-QT analysis predicted a QTc interval prolongation at 110 mg aumolertinib of 9.06 ms (upper confidence interval = 11.01 ms) in 49 subjects.(1) In clinical studies (n=545), QT prolongation was reported in 51 patients (9.4%) treated with aumolertinib 110 mg. Seven patients (1.3%) had symptomatic events, including cardiac arrest, syncope, and ventricular arrhythmia. One patient with cardio-respiratory arrest and one patient with sudden cardiac death died. QTcF increase >60 ms occurred in 4.2% of patients, and increase in QTcF to >500 ms occurred in 0.9% of patients.(1) Strong inhibitors of CYP3A4 that prolong QT include: adagrasib, ceritinib, ribociclib, and saquinavir.(3,4)

Str Cyp3a4 Inhibitors That Prolong Qt/Panobinostat (> 10 Mg)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of panobinostat.

CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP3A4 may result in elevated levels of and toxicity from panobinostat,(1) including increased risk of bleeding and prolongation of the QT interval which may result in life-threatening arrhythmia and death.

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Reduce the dose of panobinostat to 10 mg when coadministered with strong CYP3A4 inhibitors. Limit the starting dose of panobinostat to 10 mg in patients taking strong CYP3A4 inhibitors.(1) If concurrent therapy is warranted, continue standard monitoring of complete blood counts, ECG, and serum electrolytes. Instruct patients to report any irregular heartbeat, dizziness, or fainting; nausea, vomiting, or diarrhea; unusual tiredness, shortness of breath, paleness; unusual or unexplained bleeding or bruising; signs of infection such as fever, cough, or flu-like symptoms. If panobinostat toxicity occurs, panobinostat or the CYP3A4 inhibitor may need to be discontinued.(1) Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In 14 patients with advanced cancer, ketoconazole (a strong CYP3A4 inhibitor, 200 mg twice daily for 14 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of panobinostat by 62% and 73%, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(1,3-4)

Strong & Mod Cyp3a4 Inhibitor That Prolong Qt/Oral Lefamulin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibitors of CYP3A4 that prolong the QT interval may inhibit the metabolism of oral lefamulin and may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of oral lefamulin with inhibitors of CYP3A4 that prolong the QTc interval may result in elevated levels of and effects from lefamulin, including potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Avoid the concurrent use of lefamulin with medications that prolong the QT interval and inhibit CYP3A4.(1) When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a thorough QT study, intravenous lefamulin increased the QTcF 13.6 msec (90% CI = 15.5 msec) and oral lefamulin increased the QTcF by 9.3 msec (90% CI = 10.9 msec).(1) Coadministration of ketoconazole (strong CYP3A4 inhibitor) with lefamulin tablets increased lefamulin maximum concentration (Cmax) and area-under-the-curve (AUC) by 165% and 58%.(1) In a study, oral lefamulin tablets administered concomitantly with and at 2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200% and 100%, respectively. No clinically significant effect on midazolam pharmacokinetics was observed when co-administered with lefamulin injection.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3) Strong and moderate CYP3A4 inhibitors linked to this monograph include: adagrasib, ceritinib, clarithromycin, clofazimine, crizotinib, erythromycin, fluconazole, levoketoconazole, nilotinib, posaconazole, ribociclib, telithromycin, and voriconazole.(4)

Strong & Moderate 3A4 Inhibitor That Prolong Qt/Fexinidazole

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibitors of CYP3A4 that prolong the QT interval may inhibit the metabolism of fexinidazole to its active metabolites. Fexinidazole may increase the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of fexinidazole with inhibitors of CYP3A4 that prolong the QTc interval may result in decreased levels of its active metabolites, resulting in decreased efficacy. Concurrent administration of fexinidazole with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Avoid the concurrent use of fexinidazole with medications that prolong the QT interval and inhibit CYP3A4. If coadministration cannot be avoided, monitor for lack of efficacy of fexinidazole.(1) Avoid use of fexinidazole in patients who have a baseline QTcF interval greater than 470 msec, a history of torsades de pointes, congenital long QT syndrome, cardiac arrhythmias, uncompensated heart failure, or family history of sudden death, or uncorrected hypokalemia.(1) If patients are, or need to be, treated with drugs known to prolong the QTcF interval or to induce bradycardia, either do not initiate therapy with fexinidazole until such drugs are eliminated from the body (allow a washout period of 5 half-lives for such other drugs). Do not start such drugs until fexinidazole therapy is eliminated (allow a washout period of 7 days).(1) When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In clinical studies, fexinidazole was associated with a concentration-dependent QTcF prolongation. At recommended therapeutic doses, the mean (upper 90% confidence interval) increase in QTcF is predicted to be 19.0 msec (23.3 msec). The observed increase in QTcF appears to be associated with the M2 (sulfone) metabolite of fexinidazole.(1) Although no clinical drug interaction studies were performed with CYP3A4 inhibitors, the formation of the M1 and M2 metabolites may be decreased.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3) Strong and moderate CYP3A4 inhibitors that prolong QT included: adagrasib, ceritinib, clofazimine, dronedarone, erythromycin, fluconazole, levoketoconazole, lopinavir, nilotinib, ribociclib, saquinavir, telithromycin, and voriconazole.

Strong And Moderate Cyp3a4 Inhibitors/Asunaprevir

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of asunaprevir.(1)

CLINICAL EFFECTS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may result in increased levels of and effects from asunaprevir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use strong or moderate CYP3A4 inhibitors with asunaprevir is contraindicated.(1)

DISCUSSION: Asunaprevir is a sensitive CYP3A4 substrate. Sensitive substrates would be expected to have an area-under-curve (AUC) ratio of at least 5-fold.(1,2) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, clarithromycin, ceritinib, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir/ritonavir, lonafarnib, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(2)

Strong And Moderate Cyp3a4 Inhibitors/Elacestrant

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of elacestrant.(1)

CLINICAL EFFECTS: Concomitant use of a strong or moderate CYP3A4 inhibitor increases elacestrant plasma concentrations, which may increase the incidence and severity of adverse reactions.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of elacestrant states avoid concomitant use of strong or moderate CYP3A4 inhibitors with elacestrant.(1) The US manufacturer of elacestrant does not provide dose modification recommendations with strong and moderate CYP3A4 inhibitors. The Australian and UK manufacturers state concomitant use of strong or moderate CYP3A4 inhibitors should be avoided and an alternative concomitant medicinal product with no or minimal potential to inhibit CYP3A4 should be considered. If concomitant use of a strong CYP3A4 inhibitor is unavoidable, the elacestrant dose should be reduced to 172 mg once daily with careful monitoring of tolerability. Subsequent dose reduction to 86 mg once daily may be considered with moderate CYP3A4 inhibitors based on tolerability. If the CYP3A4 inhibitor is discontinued, the elacestrant dose should be increased to the dose used prior to the initiation of the CYP3A4 inhibitor (after 5 half-lives of the CYP3A4 inhibitor).(2,3)

DISCUSSION: Coadministration of itraconazole (a strong CYP3A4 inhibitor) increased elacestrant area-under-curve (AUC) and maximum concentration (Cmax) by 5.3-fold and 4.4-fold, respectively.(1) Coadministration of fluconazole (a moderate CYP3A4 inhibitor) is predicted to increase elacestrant AUC and Cmax by 2.3-fold and 1.6-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(4,5) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(4,5)

Strong And Moderate Cyp3a4 Inhibitors/Infigratinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of infigratinib.(1)

CLINICAL EFFECTS: Concomitant use of a strong or moderate CYP3A4 inhibitor increases infigratinib plasma concentrations, which may increase the incidence and severity of adverse reactions.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant use of strong or moderate CYP3A4 inhibitors with infigratinib.(1)

DISCUSSION: Coadministration of multiple doses of itraconazole (a strong CYP3A4 inhibitor) increased infigratinib area-under-curve (AUC) and maximum concentration (Cmax) by 622% and 164%, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2)

Strong And Moderate Cyp3a4 Inhibitors/Lemborexant

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of lemborexant.(1)

CLINICAL EFFECTS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may result in increased levels of and effects from lemborexant, including somnolence, fatigue, CNS depressant effects, daytime impairment, headache, and nightmare or abnormal dreams.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of strong or moderate CYP3A4 inhibitors with lemborexant should be avoided.(1)

DISCUSSION: Lemborexant is a CYP3A4 substrate. In a PKPB model, concurrent use of lemborexant with itraconazole increased area-under-curve (AUC) and concentration maximum (Cmax) by 3.75-fold and 1.5-fold, respectively. Concurrent use of lemborexant with fluconazole increased AUC and Cmax by 4.25-fold and 1.75-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(2)

Strong And Moderate Cyp3a4 Inhibitors/Nirogacestat

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of nirogacestat.(1)

CLINICAL EFFECTS: Concomitant use of a strong or moderate CYP3A4 inhibitor increases nirogacestat plasma concentrations, which may increase the incidence and severity of adverse reactions, including hepatotoxicity, diarrhea, hypokalemia, and hypophosphatemia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant use of strong or moderate CYP3A4 inhibitors with nirogacestat.(1)

DISCUSSION: In a study, itraconazole (a strong CYP3A4 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of nirogacestat by 8.2-fold and 2.5-fold, respectively, following a single 100 mg dose of nirogacestat. In a PKPB model, nirogacestat AUC was predicted to increase by 6.33-, 5.19-, and 3.46-fold following coadministration of multiple doses of nirogacestat (150 mg BID) with itraconazole, ketoconazole and clarithromycin (strong CYP3A inhibitors), respectively.(1) In a PKPB model, nirogacestat AUC was predicted to increase 2.73-and 3.18-fold following coadministration of multiple doses of nirogacestat (150 mg BID) with erythromycin (moderate CYP3A inhibitor) and fluconazole (moderate CYP3A inhibitor), respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2)

Strong And Moderate Cyp3a4 Inhibitors/Repotrectinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of repotrectinib.(1)

CLINICAL EFFECTS: Concomitant use of a strong or moderate CYP3A4 inhibitor increases repotrectinib plasma concentrations, which may increase the incidence and severity of adverse reactions, including CNS effects (dizziness, ataxia, cognitive disorders), interstitial lung disease/pneumonitis, hepatotoxicity, and myalgia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant use of strong or moderate CYP3A4 inhibitors with repotrectinib. Discontinue CYP3A4 inhibitors for 3 to 5 half lives of the inhibitor prior to initiating repotrectinib.(1)

DISCUSSION: In a study, itraconazole (a strong CYP3A4 and P-gp inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of repotrectinib by 5.9-fold and 1.7-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, letermovir, netupitant, nilotinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2)

Strong Cyp3a4 Inhib That Prolong Qt/Artemether;Lumefantrine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Potent inhibitors of CYP3A4 that prolong the QTc interval may inhibit the metabolism of artemether and lumefantrine and result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: Concurrent use of potent CYP3A4 inhibitors that prolong the QTc interval with artemether-lumefantrine may result in elevated levels of the antimalarial agents and increased risk of toxicities, including additive prolongation of the QTc interval, which may result in life threatening arrhythmia and death.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of artemether-lumefantrine states that the use of artemether-lumefantrine should be avoided in patients taking drugs that are known to prolong the QTc interval. Concurrent use with potent CYP3A4 inhibitors should be approached with caution.(1) The US manufacturer of adagrasib states that it should be avoided with sensitive CYP3A4 substrates and with other drugs known to prolong the QTc interval.(3) The US manufacturer of levoketoconazole states that levoketoconazole is contraindicated with other agents that prolong the QT interval. Avoid the use of strong CYP3A4 inhibitors two weeks before and during levoketoconazole treatment.(4) Levoketoconazole is also contraindicated in patients with a prolonged QTcF interval of greater than 470 msec at baseline, history of torsades de pointes, ventricular tachycardia, ventricular fibrillation, or long QT syndrome (including first-degree family history). Use caution in patients with other risk factors for QT prolongation including congestive heart failure, bradyarrhythmias, and uncorrected electrolyte abnormalities. Consider more frequent ECG monitoring.(4) Prior to starting levoketoconazole, obtain a baseline ECG and correct hypokalemia or hypomagnesemia. If a patient develops QT prolongation with a QTc interval greater than 500 msec, temporarily discontinue levoketoconazole. After resolution of prolonged QTc interval, levoketoconazole may be resumed at a lower dose. If QTc interval prolongation recurs, permanently discontinue levoketoconazole.(4) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study in 13 healthy subjects, administration of ketoconazole (400 mg Day 1, 200 mg Days 2-5, a potent inhibitor of CYP3A4) with a single dose of artemether-lumefantrine (20 mg/120 mg) increased the area-under-curve (AUC) of artemether and lumefantrine by 2.3-fold and 1.6-fold, respectively.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(5) During phase 1 and 2 studies of levoketoconazole, which excluded patients with baseline QTcF interval greater than 470 msec, 4 (2.4%) patients experienced QTcF > 500 msec, and 23 (14.7%) patients experienced change-from-baseline QTcF > 60 msec.(4) Strong CYP3A4 inhibitors that prolong the QTc interval linked to this monograph include: adagrasib, levoketoconazole, and lonafarnib.(6,7)

Strong Cyp3a4 Inhib That Prolong Qt/Mavorixafor (>200 Mg)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors that prolong the QTc interval may inhibit the metabolism of mavorixafor and result in additive risk of QT prolongation.(1) Mavorixafor is also a substrate of P-glycoprotein (P-gp). P-gp inhibitors may increase mavorixafor exposure.(1) Many CYP3A4 inhibitors also inhibit P-glycoprotein (P-gp), including adagrasib, clarithromycin, lopinavir/ritonavir, saquinavir, and telithromycin.(2)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors that prolong QT may increase the levels and effects of mavorixafor including additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: Reduce the dose of mavorixafor to 200 mg once daily when used concomitantly with strong CYP3A4 inhibitors.(1) If concurrent use is warranted, monitor ECG prior to initiation, during concurrent therapy, and as clinically indicated.(1) When concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If QT prolongation occurs, a dose reduction or discontinuation of mavorixafor may be required.(1)

DISCUSSION: In a study with healthy subjects, itraconazole 200 mg daily (a strong CYP3A4 and P-gp inhibitor) increased the exposure to single-dose mavorixafor 200 mg similar to that from single-dose mavorixafor 400 mg alone. This suggests that itraconazole increased mavorixafor exposure by about 2-fold.(1) A study in healthy volunteers found that ritonavir 100 mg twice daily (a strong CYP3A4 inhibitor and P-gp inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose mavorixafor 200 mg by 60% and 39%, respectively.(4) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(5) Strong inhibitors of CYP3A4 that prolong QT include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir/ritonavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(2,6)

Strong Cyp3a4 Inhib; Protease Inhib/Lumateperone (>10.5 Mg)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 and protease inhibitors may inhibit the metabolism of lumateperone.(1,2)

CLINICAL EFFECTS: Concurrent use of lumateperone with strong CYP3A4 inhibitors or protease inhibitors increases lumateperone exposure, which may increase the risk of adverse reactions.(1,2)

PREDISPOSING FACTORS: Patients with moderate or severe hepatic impairment (Child-Pugh class B or C) may be at higher risk of increased lumateperone exposure.(1)

PATIENT MANAGEMENT: The manufacturer of lumateperone recommends decreasing the dosage of lumateperone to 10.5 mg once daily in patients receiving strong CYP3A4 inhibitors.(1) The US Department of Health and Human Services HIV guidelines state that protease inhibitors should not be coadministered with lumateperone.(2)

DISCUSSION: Coadministration of lumateperone with itraconazole, a strong CYP3A4 inhibitor, resulted in a 4-fold and 3.5-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively.(1) Coadministration of lumateperone with diltiazem, a moderate CYP3A4 inhibitor, resulted in a 2.5-fold and 2-fold increase AUC and Cmax, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, amprenavir, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, ensitrelvir, fosamprenavir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2-4)

Strong Cyp3a4 Inhib;Atazanav;Darunavir/Saxagliptin (>2.5 Mg)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of saxagliptin.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in elevated levels and increased effects of saxagliptin.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of saxagliptin states that the dose of saxagliptin should be limited to 2.5 mg daily in patients taking strong inhibitors of CYP3A4.(1)

DISCUSSION: Pretreatment with ketoconazole (200 mg every 12 hours for 9 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of saxagliptin (100 mg) by 62% and 2.5-fold, respectively. The Cmax and AUC of the active metabolite of saxagliptin decreased 95% and 91%, respectively. The Cmax and AUC of ketoconazole decreased 16% and 13%, respectively.(1,2) Pretreatment with ketoconazole (200 mg every 12 hours for 7 days) increased the Cmax and AUC of a single dose of saxagliptin (100 mg) by 2.4-fold and 3.7-fold, respectively. The Cmax and AUC of the active metabolite of saxagliptin decreased 96% and 90%, respectively.(1) Inhibitors of CYP3A4 linked to this monograph include: adagrasib, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(1,3,4)

Strong Cyp3a4 Inhibit That Prolong Qt/Pimavanserin (> 10 Mg)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong the QTc interval may inhibit the metabolism of pimavanserin and result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors that prolong the QTc interval may increase systemic exposure and the risk for pimavanserin toxicities such as peripheral edema, confusion, or additive QTc prolongation and life-threatening cardiac arrhythmias like torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of pimavanserin recommends avoiding use with agents that prolong the QTc interval.(1) The US Department of Health and Human Services HIV guidelines state that pimavanserin should not be coadministered with saquinavir or lopinavir due to the risk of QTc prolongation.(3) If concomitant use of pimavanserin and a strong CYP3A4 inhibitor is needed, the pimavanserin dose should be reduced to 10 mg once daily.(1) During concomitant therapy with a strong CYP3A4 inhibitor, monitor patients closely for prolongation of the QT interval. Obtain serum calcium, magnesium, and potassium levels and monitor ECG at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a drug interaction study, ketoconazole increased pimavanserin maximum concentration (Cmax) 1.5-fold and area-under-curve(AUC) 3-fold. A thorough QTc study performed in 252 subjects found a mean maximum change from baseline of 13.5 msec (upper bound of the 90% confidence interval was 16.6 msec) at twice the therapeutic dose.(1) Thus, coadministration of pimavanserin and a QT prolonging agent, even at a reduced dose, may increase the risk for significant QT prolongation. Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(4)

Strong Cyp3a4 Inhibitors That Prolong Qt/Alfuzosin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors decrease the metabolism of alfuzosin. Concurrent use of alfuzosin with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: Coadministration of strong CYP3A4 inhibitors that prolong the QTc interval may cause an increase in alfuzosin levels and effects, including severe hypotension. Coadministration may lead to additive risk of potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of alfuzosin states that concurrent use of strong CYP3A4 inhibitors is contraindicated.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Repeated administration of ketoconazole (400 mg, a strong inhibitor of CYP3A4) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of alfuzosin (10 mg) by 2.3-fold and 3.2-fold, respectively.(1) Administration of ketoconazole (200 mg daily) increased the Cmax and AUC of a single dose of alfuzosin (10 mg) by 2.1-fold and 2.5-fold, respectively.(1) Strong inhibitors of CYP3A4 that prolong the QTc interval include: adagrasib, ceritinib, clarithromycin, lonafarnib, posaconazole, ribociclib, telithromycin, and voriconazole.(3)

Strong Cyp3a4 Inhibitors That Prolong Qt/Anamorelin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of anamorelin and result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase the levels and effects of anamorelin, including hyperglycemia, hepatotoxicity, and additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of anamorelin states that concomitant use with strong CYP3A4 inhibitors is contraindicated.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study of 12 healthy volunteers, concomitant use of anamorelin 25 mg with ketoconazole 200 mg every 12 hours for 3 doses (a strong CYP3A4 inhibitor) increased anamorelin maximum concentration (Cmax) and area-under-curve (AUC) by 3.12-fold and 3.22-fold, respectively.(1) Anamorelin blocks sodium channels and may suppress cardiac conduction, resulting in prolongation of the QRS width or QT interval. A study of 7 healthy volunteers receiving single-dose anamorelin 400 mg found that 1 patient experienced QRS width prolongation. In 60 healthy adults, the maximum difference (upper limit of 95% one-sided confidence interval) in the change from baseline in QTcF interval compared to placebo was 6.16 (7.73) msec in patients on 100 mg and 7.38 (10.31) msec in patients on 300 mg.(1) The Japanese pharmacovigilance database was reviewed to evaluate disproportionality of conduction defects related to anamorelin. Out of 537 cases of adverse reactions, there were 51 cases of conduction defects (36 cases of prolonged QT, 5 cases of prolonged QRS complex, 2 cases of long QT syndrome). When adjusted for concomitant use of QT prolonging agents, the reporting odds ratio (ROR) of anamorelin-related conduction defects was 20.00 (95% CI 14.86-26.91).(3) There have been several case reports of widened QRS complexes following anamorelin exposure, usually accompanied by worsening hepatic function.(4-6) Strong CYP3A4 inhibitors that prolong the QT interval linked to this monograph include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir-ritonavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(7-8)

Strong Cyp3a4 Inhibitors That Prolong Qt/Bosutinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong the QTc interval may inhibit the metabolism of bosutinib and result in additive risk of QT prolongation.(1)

CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP3A4 that prolong QT may result in elevated levels of and toxicity from bosutinib, including additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1) Other toxicities include nausea, vomiting, diarrhea, abdominal pain, myelosuppression, transaminitis, renal toxicity, and cardiac failure.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors that prolong QT in patients undergoing therapy with bosutinib.(1) Consider alternatives with no or minimal enzyme inhibition and with no effect on the QTc interval. Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and bosutinib should be monitored for prolongation of the QTc interval. When concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a randomized, phase I, double-blind, placebo-controlled, sequential group study, 48 healthy adults received a single dose of bosutinib 100, 200, 300, 400, 500, or 600 mg with ketoconazole 400 mg days -1 and days 1-4. Bosutinib area-under-curve (AUC) and maximum concentration (Cmax) increased 7.3-fold and 7.7-fold.(3) In an open-label, randomized, 2-period, crossover study, healthy subjects received a single dose of bosutinib 100 mg alone and with multiple doses of ketoconazole 400 mg. Bosutinib Cmax and AUC increased 5.2-fold and 8.6-fold, respectively.(4) A retrospective review of 618 cancer patients treated with 902 administrations of tyrosine kinase inhibitors were evaluated for rate and incidence of QTc prolongation. In patients who received bosutinib, QTc prolongation was identified in 8 patients(38.1%), with 5 patients (62.5%) having Grade 1 (QTc 450-480 ms) and 3 patients(37.5%) having Grade 2 (QTc 480-500 ms) events. Grade 3 events occurred in 1 (12.5%) patient having QTc greater than or equal to 500 ms. No patients had a QTc change greater than or equal to 60 ms, ventricular tachycardia (VT), sudden cardiac death (SCD), or TdP.(5) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(6) Strong inhibitors of CYP3A4 that prolong QT include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lopinavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(7,8)

Strong Cyp3a4 Inhibitors That Prolong Qt/Disopyramide

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors that prolong the QTc interval may inhibit the metabolism of disopyramide and result in additive effects on the QTc interval.(1,2)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors that prolong the QT interval with disopyramide may result in elevated levels of disopyramide and serious and/or life-threatening effects, including QT prolongation.(1,2)

PREDISPOSING FACTORS: Renal and hepatic impairment may increase risk for excessive QTc prolongation as disopyramide is eliminated renally and hepatically. To prevent increased serum levels and risk for ventricular arrhythmias, disopyramide must be dose adjusted in renal and hepatic insufficiency. The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The US labeling states coadministration of disopyramide with QT prolonging agents is not advised and coadministration of strong CYP3A4 inhibitors that prolong the QT interval with disopyramide should be avoided. If use of the combination is warranted, clinical monitoring is recommended.(1) The Australian manufacturer of disopyramide states that concurrent use with agents liable to produce torsades de pointes is contraindicated.(2) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Strong CYP3A4 inhibitors may inhibit the metabolism and increase levels of disopyramide by inhibition of CYP3A4.(1,2) Selected CYP3A4 inhibitors that prolong QT linked to this monograph include: adagrasib, clarithromycin, levoketoconazole and lonafarnib.(4,5)

Strong Cyp3a4 Inhibitors That Prolong Qt/Dronedarone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors that prolong the QTc interval may inhibit the metabolism of dronedarone and result in additive risk of QTc prolongation. Dronedarone is a CYP3A4 substrate.(1)

CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inhibitor that prolongs QT may increase the levels and effects of dronedarone, including additive QTc prolongation, which may result in life-threatening cardiac arrhythmias like torsades de pointes( TdP).(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of dronedarone states that concurrent administration of strong CYP3A4 inhibitors is contraindicated. Concurrent use of drugs that prolong the QT interval is also contraindicated. Treatment with drugs that prolong QTc or are strong CYP3A4 inhibitors must be stopped before starting dronedarone.(1) If alternatives are not available and concurrent therapy is deemed medically necessary, obtain serum calcium, magnesium, and potassium levels and monitor ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If the QTc interval is >500 msec, discontinue dronedarone.(1)

DISCUSSION: Concurrent use of ketoconazole 200 mg once daily and dronedarone (dosage not stated) increased the area-under-curve (AUC) and maximum concentration (Cmax) of dronedarone by 17-fold and 9-fold, respectively.(1) Dronedarone causes dose-dependent increases in QTc, with 400 mg twice daily taken with food causing an estimated 15 msec increase in QTcF.(1) Strong CYP3A4 inhibitors that prolong QT linked to this monograph include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.

Strong Cyp3a4 Inhibitors That Prolong Qt/Entrectinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong the QT interval may inhibit the metabolism of entrectinib(1,2) and result in additive effects on the QT interval.(1)

CLINICAL EFFECTS: The concurrent use of entrectinib with strong inhibitors of CYP3A4 that prolong the QTc interval may result in elevated levels of and effects from entrectinib, including potentially life-threatening cardiac arrhythmias, including torsades de pointes, hepatotoxicity, CNS effects, hyperuricemia, anemia, or neutropenia.(1,2) Symptoms of hepatotoxicity can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Avoid the concurrent use of entrectinib with medications that inhibit CYP3A4 and prolong the QT interval.(1) When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Monitor liver tests, including AST and ALT. For adult and pediatric patients 2 years and older, reduce the entrectinib dose as follows: -If the starting dose is 600 mg, reduce the entrectinib dose to 100 mg daily. -If the starting dose is 400 mg, reduce the entrectinib dose to 50 mg daily. -If the starting dose is 300 mg, reduce the entrectinib dose to 50 mg daily. -If the starting dose is 200 mg, reduce the entrectinib dose to 50 mg on alternate days.(1) For pediatric patients less than 2 years old, avoid coadministration with strong CYP3A4 inhibitors.(1) If concomitant use is discontinued, increase the entrectinib dose to the dose that was used before starting the inhibitor after three to five plasma half-lives of the strong CYP3A4 inhibitor. Advise patients to immediately report any symptoms of hepatotoxicity and any irregular heartbeat, dizziness, or fainting. If QTc prolongation develops: ---Monitor and supplement electrolytes as clinically indicated ---Review and adjust concomitant QT prolonging medications ---Interrupt entrectinib therapy for QTc interval greater than 500 ms. ---Follow labeling recommendations regarding restarting entrectinib.(1) If torsade de pointes, polymorphic ventricular tachycardia, and/or signs/symptoms of serious arrhythmia occur, permanently discontinue entrectinib.(1) The Australian manufacturer of entrectinib states avoid the concurrent use of entrectinib with medications that inhibit CYP3A4 and prolong the QT interval. If concurrent therapy with a strong CYP3A4 inhibitor that prolong QT cannot be avoided, reduce the dose of entrectinib to 100 mg once daily.(3) If concomitant use of a strong CYP3A4 inhibitor that prolong QT is discontinued, increase the entrectinib dose to the dose that was used before starting the inhibitor after three to five plasma half-lives of the strong CYP3A4 inhibitor that prolong QT.(3)

DISCUSSION: In clinical trials, 3.1% of patients with at least one post-baseline ECG experienced QTcF prolongation of greater than 60 msec after starting entrectinib.(1) Coadministration of itraconazole (strong CYP3A4 inhibitor) with a single 100 mg entrectinib dose increased entrectinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 1.7-fold and 6-fold.(1) Coadministration of a moderate CYP3A4 inhibitor with entrectinib is predicted to increase entrectinib Cmax and AUC by 2.9-fold and 3-fold. Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(4)

Strong Cyp3a4 Inhibitors That Prolong Qt/Gepirone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong the QTc interval may inhibit the metabolism of gepirone and result in additive risk of QT prolongation.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors that prolong QT may increase the levels and effects of gepirone including additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1) Serotonin syndrome may also result. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The use of strong CYP3A4 inhibitors is contraindicated in patients undergoing therapy with gepirone.(1) If coadministration with a strong CYP3A4 inhibitor is unavoidable, monitor for prolongation of the QTc interval more frequently.(1) When concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If QTcF is > 450 msec at baseline, do not initiate gepirone. If QTc increases to > 450 msec during treatment, monitor ECGs more frequently and do not increase the dose of gepirone.(1)

DISCUSSION: In a study, ketoconazole (200 mg twice daily), a strong CYP3A4 inhibitor, increased the maximum concentration (Cmax) and area-under-curve (AUC) of gepirone 36.3 mg by about 5.25-fold and 5.5-fold, respectively.(1) In a thorough QT study, 100 mg per day of immediate-release gepirone increased the mean QTc by 18.4 msec (upper 90% CI = 22.7 msec) on day 1 and 16.1 msec (upper 90% CI = 20.7) on day 7. The dose of gepirone was 2-fold the exposure of the recommended maximum daily dose.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3) Strong inhibitors of CYP3A4 that prolong QT include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(4,5)

Strong Cyp3a4 Inhibitors That Prolong Qt/Gepotidacin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong QT may inhibit the metabolism of gepotidacin and result in additive effects on the QTc interval.(1,2)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in increased levels and toxicity from gepotidacin,(1) including diarrhea, nausea, abdominal pain and prolongation of the QT interval, which may result in life-threatening arrhythmia and death. Concurrent use may also result in additive QTc prolongation, which may lead to life-threatening cardiac arrhythmias like torsade de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of gepotidacin states to avoid concurrent administration with strong CYP3A4 inhibitors.(1) The manufacturer of gepotidacin states that the concurrent use of QT prolonging agents should be avoided. If concurrent use cannot be avoided, obtain ECGs prior to initiating gepotidacin, during concomitant use, and as clinically indicated.(1) If concurrent therapy is warranted, correct any electrolyte abnormalities and instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Gepotidacin is primarily metabolized by CYP3A4.(1) Concomitant administration of a strong inhibitor of CYP3A4 (itraconazole; 200 mg per day for 3 days), and a single 1500 mg dose of gepotidacin resulted in a increase in gepotidacin maximum concentration (Cmax) of 1.4-fold and area under the curve (AUC) of 1.5-fold.(1) The effect of gepotidacin on the QTc interval was evaluated in a randomized, active (moxifloxacin 400 mg) and placebo-controlled, double-blind cross-over trial in healthy subjects who received single intravenous (IV) infusions of gepotidacin over 2 hours. A dose- and concentration-dependent QTc prolongation effect of gepotidacin was observed. The mean placebo-corrected change from baseline QTcF values around Tmax were 12 msec at 1,000 mg IV and 22 msec at 1,800 mg IV (not approved dosing regimens and route of administration). Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3) Strong CYP3A4 inhibitors that prolong the QT interval linked to this monograph include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir-ritonavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(3,4)

Strong Cyp3a4 Inhibitors That Prolong Qt/Ivabradine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong the QTc interval may inhibit the metabolism of ivabradine and result in additive risk of QT prolongation.(1,2)

CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP3A4 that prolong QT may result in elevated levels of and toxicity from ivabradine including an additive reduction in heart rate which can contribute to QT prolongation or torsades de pointes.(1,2)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The manufacturer of ivabradine states that concurrent use with strong CYP3A4 inhibitors is contraindicated.(1,2,4,5) Guideline recommendations state ivabradine should not be used with protease inhibitors.(6) If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for bradycardia (heart rate less than 50 bpm), dizziness, fatigue, hypotension, and/or symptoms of atrial fibrillation (heart palpitations, chest pressure, shortness of breath).

DISCUSSION: Concurrent use of potent CYP3A4 inhibitors ketoconazole (200 mg daily) and josamycin (1000 mg twice daily) increased mean ivabradine plasma exposure by 7- to 8-fold.(1) Strong CYP3A4 inhibitors that prolong QT linked to this monograph include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir/ritonavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.

Strong Cyp3a4 Inhibitors That Prolong Qt/Lonafarnib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors that prolong the QTc interval may inhibit the metabolism of lonafarnib and cause an additive risk of QTc prolongation.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors that prolong QT may increase the levels and effects of lonafarnib including additive QTc prolongation and potentially life-threatening cardiac arrhythmias like torsades de pointes. Concurrent use may also result in severe nausea and vomiting, increased liver enzymes, myelosuppression, and hypertension.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The use of lonafarnib with strong CYP3A4 inhibitors is contraindicated.(1) The manufacturer of lonafarnib states that the concurrent use of QT prolonging agents should be avoided. If concurrent use cannot be avoided, obtain ECGs when initiating, during concurrent use, and as clinically indicated.(1) Lonafarnib dose modification recommendation: if the QTc interval is greater than or equal to 500 msec, withhold lonafarnib until the QTc interval is less than 470 msec, then resume lonafarnib at the same dosage.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: With coadministration of a single oral dose of 50 mg lonafarnib following 200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, the area-under-curve (AUC) and maximum concentration (Cmax) were increased by 425% and 270%, respectively.(1) In a thorough QT study, lonafarnib 200 mg twice daily for 9 consecutive days and a single 200 mg dose on day 10 increased the mean QTc interval by 19 msec (upper bound of 90% confidence interval = 27 msec) on day 10 at 48 hours after administration of the morning dose of lonafarnib 200 mg. The Cmax on Day 10 was 2233 ng/ml, which is similar to the mean Cmax of 2695 ng/ml observed in the Hutchinson-Gilford Progeria Syndrome patient population.(1) Strong inhibitors of CYP3A4 that prolong QT include: adagrasib, clarithromycin, lopinavir/ritonavir, telithromycin, and voriconazole.(3)

Strong Cyp3a4 Inhibitors That Prolong Qt/Mobocertinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong the QTc interval may inhibit the metabolism of mobocertinib and result in additive risk of QT prolongation.(1)

CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP3A4 that prolong QT may result in elevated levels of and toxicity from mobocertinib including additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors that prolong QT in patients undergoing therapy with mobocertinib.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Increase the frequency of ECG monitoring in patients with risk factors for QTc prolongation, including congenital long QT syndrome, heart disease, or electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If patients develop QTc prolongation during mobocertinib therapy, dose modifications are recommended: - If Grade 2 (QTc interval 481-500 msec) and first occurrence: hold mobocertinib until QTc returns to <= Grade 1 or baseline. Upon recovery, resume mobocertinib at the same dose. - If Grade 2 and recurrence: hold mobocertinib until QTc returns to <= Grade 1 or baseline. Upon recovery, resume mobocertinib at the next lower dose or permanently discontinue. - If Grade 3 (QTc interval >= 501 msec or QTc interval increase of > 60 msec from baseline) and first occurrence: hold mobocertinib until QTc returns to <= Grade 1 or baseline. Upon recovery, resume mobocertinib at the next lower dose or permanently discontinue. - If Grade 3 and recurrence: permanently discontinue mobocertinib. - If Grade 4 (Torsades de pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrhythmia): permanently discontinue mobocertinib.

DISCUSSION: Coadministration of mobocertinib with multiple doses of itraconazole or ketoconazole (strong CYP3A inhibitors) is predicted to increase the steady-state combined molar area-under curve (AUC) of mobocertinib and its active metabolites by 374 to 419%.(1) In a clinical study, mobocertinib 160 mg once daily was associated with a concentration-dependent increase in QTc, with the largest mean increase in QTc of 23 msec.(1) In clinical studies, patients were excluded if baseline QTc was greater than 470 msec. In a subset of 250 patient with scheduled and unscheduled electrocardiograms (ECGs), 1.2% of patients had a QTc interval >500 msec and 11% of patients had a change-from-baseline QTc interval >60 msec. Grade 4 Torsades de Pointes occurred in 1 patient (0.4%).(1) Strong inhibitors of CYP3A4 that prolong QT include: adagrasib, ceritinib, clarithromycin, lonafarnib, lopinavir, ribociclib, saquinavir, telithromycin, and voriconazole.(3,4)

Strong Cyp3a4 Inhibitors That Prolong Qt/Pacritinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong the QTc interval may inhibit the metabolism of pacritinib and result in additive risk of QT prolongation.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors that prolong the QTc interval may increase the levels and effects of pacritinib, including additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1) Other toxicities include bleeding, diarrhea, thrombocytopenia, major adverse cardiovascular events, thrombosis, and infection.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The use of strong CYP3A4 inhibitors that prolong the QTc interval is contraindicated in patients undergoing therapy with pacritinib.(1) Consider alternatives with no or minimal enzyme inhibition and with no effect on the QTc interval. If coadministration is unavoidable, monitor for prolongation of the QTc interval.(1) When concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If patients develop QTc prolongation >500 msec or >60 msec from baseline, hold pacritinib. If QTc prolongation resolves to <=480 msec or to baseline within 1 week, resume pacritinib at the same dose. If time to resolution of the QTc interval takes greater than 1 week to resolve, reduce the pacritinib dose according to labeling.(1)

DISCUSSION: Clarithromycin (500 mg twice daily for 5 days) increased maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of pacritinib (400 mg) by 30% and 80%, respectively.(1) In a 24 week clinical study, patients treated with pacritinib 200 mg twice daily had a change in QTc from baseline of 11 msec (90% CI: 5-17).(1) Pacritinib has been associated with QTc interval prolongation. In clinical trials, patients with QTc prolongation >500 msec occurred in 1.4% of patients in the treatment arm compared to 1% in the control arm. The treatment arm had a greater incidence of an increase in QTc > 60 msec from baseline than the control arm (1.9% vs 1%, respectively). QTc prolongation adverse reactions were higher in the treatment arm than the control group (3.8% vs 2%, respectively).(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(5) Strong inhibitors of CYP3A4 that prolong QT include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lopinavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(3,4)

Strong Cyp3a4 Inhibitors That Prolong Qt/Pimozide

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors that prolong the QTc interval may inhibit the metabolism of pimozide and cause an additive risk of QTc prolongation.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors that prolong QT may increase the levels and effects of pimozide including additive QTc prolongation and potentially life-threatening cardiac arrhythmias like torsades de pointes. Concurrent use may also result in extrapyramidal symptoms such as akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, and oculogyric crisis.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3)

PATIENT MANAGEMENT: The use of pimozide with strong CYP3A4 inhibitors that prolong QT is contraindicated, especially when other risk factors for QT prolongation are present. The manufacturer of pimozide states that concomitant treatment with strong CYP3A4 inhibitors is contraindicated and treatment with less potent inhibitors of CYP3A4 should also be avoided.(1) If concurrent use cannot be avoided, then correct or minimize QT prolonging risk factors, use the lowest effective dose of pimozide, and discontinue other concurrent QT prolonging agents or CYP3A4 inhibitors if possible. If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Pimozide is metabolized at CYP3A. Elevated levels of pimozide may prolong the QTc interval resulting in life-threatening ventricular arrhythmias.(1) Strong inhibitors of CYP3A4 that prolong QT include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(5,6)

Strong Cyp3a4 Inhibitors That Prolong Qt/Ranolazine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong the QTc interval may inhibit the metabolism of ranolazine and result in additive effects on the QTc interval.(1,2)

CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP3A4 that prolong the QTc interval may result in elevated levels of and clinical effects from ranolazine, including additive QTc prolongation and life-threatening cardiac arrhythmia like torsades de pointes.(1,2)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The concurrent use of ranolazine with strong CYP3A4 inhibitors is contraindicated.(1,2) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Concurrent use of ketoconazole (200 mg twice daily), a strong CYP3A4 inhibitor, increased plasma levels of ranolazine (1000 mg twice daily) by 220%.(1) Ranolazine-induced QTc prolongation is dose and concentration-related.(1,2) Strong inhibitors of CYP3A4 that prolong the QTc interval include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(1,2,4,5)

Strong Cyp3a4 Inhibitors That Prolong Qt/Sebetralstat

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong QT may inhibit the metabolism of sebetralstat and result in additive effects on the QTc interval.(1,2)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in increased levels and effects of sebetralstat including additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)

PREDISPOSING FACTORS: Child-Pugh class B or C hepatic impairment may increase the risk for increased exposure to sebetralstat. Sebetralstat should be avoided in patients with severe hepatic impairment (Child-Pugh class C).(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of sebetralstat states that concomitant use with strong CYP3A4 inhibitors should be avoided.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Concomitant use of sebetralstat with itraconazole (200 mg once daily for 6 days), a strong CYP3A4 inhibitor, increased sebetralstat maximum concentration (Cmax) and area-under-curve (AUC) by 2.4-fold and 5.2-fold, respectively.(1) In a study in healthy subjects, the largest mean increase in QTc interval was 10.4 msec (upper confidence interval = 15.3 msec) after administration of sebetralstat (2.5 times the maximum recommended dose). The increase in the QTc interval was concentration dependent.(1) Strong CYP3A4 inhibitors that prolong the QT interval linked to this monograph include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir-ritonavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(3,4)

Strong Cyp3a4 Inhibitors That Prolong Qt/Taletrectinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong QT may inhibit the metabolism of taletrectinib and result in additive effects on the QTc interval.(1,2)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in increased levels and toxicity from taletrectinib including hepatotoxicity and myalgia. Concurrent use may also result in additive QTc prolongation, which may lead to life-threatening cardiac arrhythmias like torsade de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Taletrectinib should be taken on an empty stomach. Administration with food may increase the risk of QT prolongation or torsade de pointes.

PATIENT MANAGEMENT: Avoid concurrent administration with strong CYP3A4 inhibitors that prolong the QTc interval. If concurrent therapy cannot be avoided, adjust the frequency of monitoring as recommended in the prescribing information. Withhold taletrectinib if the QTc interval is >500 msec or the change from baseline is >60 msec.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Taletrectinib is primarily metabolized by CYP3A4.(1) Concomitant administration of itraconazole 200 mg daily (a strong inhibitor of CYP3A4) and taletrectinib resulted in a increase in taletrectinib maximum concentration (Cmax) of 1.8-fold and area under the curve (AUC) of 3.3-fold.(1) In a pooled safety population, 351 patients had at least one post baseline ECG assessment. Of those patients, 13% experienced an increase in QTcF of >60 msec compared to baseline after receiving taletrectinib and 2.6% had an increase in QTcF to >500 msec. Overall, 3.4% of patients had Grade 3 or greater QTc interval prolongation. The median time from the first dose of taletrectinib to the onset of ECG QT prolongation was 22 days (range: 1 day to 38.7 months). QTc prolongation led to dose interruption and dose reduction, each in 2.8% of patients treated with taletrectinib.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3) Strong CYP3A4 inhibitors that prolong the QT interval linked to this monograph include: adagrasib, ceritinib, clarithromycin, lonafarnib, lopinavir-ritonavir, ribociclib, saquinavir, telithromycin, and voriconazole.(4,5)

Strong Cyp3a4 Inhibitors That Prolong Qt/Zidesamtinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors that prolong the QTc interval may inhibit the metabolism of zidesamtinib and cause an additive risk of QTc prolongation.(1)

CLINICAL EFFECTS: Concurrent use of zidesamtinib with strong CYP3A4 inhibitors that prolong QT may result in elevated zidesamtinib levels and toxicities, including interstitial lung disease, pneumonitis, pancreatitis, myalgias, and additive QT prolongation, which may lead to potentially life-threatening cardiac arrhythmias like torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, and advanced age.(1,2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of zidesamtinib states that concurrent use of strong CYP3A4 inhibitors should be avoided.(1) The manufacturer of zidesamtinib also states that concurrent use of other drugs that are known to prolong the QTc interval should be monitored more frequently.(1) If concurrent use is warranted, monitor ECG and electrolytes when initiating zidesamtinib, during concurrent use, and as clinically indicated. Consider increasing the frequency of ECG and electrolyte monitoring. Withhold, then resume at same or reduced dose, or permanently discontinue zidesamtinib based on severity.(1) If QTc prolongation occurs, follow recommended dose modifications: - Grade 2 (QTc interval 481-500 ms): Withhold zidesamtinib until recovery to Grade <= 1 or baseline; correct electrolytes and/or change concomitant medications; and resume at same dose. - Grade 3 (QTc interval >= 501 ms or QTc interval increase of > 60 ms from baseline): Withhold zidesamtinib until recovery to Grade <= 1 or baseline; correct electrolytes and/or change concomitant medications; and resume at reduced dose. - Grade 4 (Torsades de pointes; polymorphic ventricular tachycardia; or signs/symptoms of serious arrhythmia): Permanently discontinue zidesamtinib. Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Zidesamtinib is a CYP3A4 substrate. In a study, itraconazole 200 mg daily (a strong CYP3A4 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of zidesamtinib by 2.6-fold and 1.8-fold, respectively.(1) Zidesamtinib 100 mg once daily increased the QTc by 13 ms (upper confidence interval = 19 ms) in patients with advanced ROS1-positive NSCLC and other advanced ROS1-positive solid tumors.(1) In a pooled safety study, QTc increase >60 ms occurred in 2% of patients and 0.2% of patients had an increase in QTcF > 500 ms.(1) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(3,4)

Strong Cyp3a4 Inhibitors/Abemaciclib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Abemaciclib is a substrate of CYP3A4. Strong inhibitors of CYP3A4 may inhibit the metabolism of abemaciclib.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels and toxicity from abemaciclib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Recommendations for management of this interaction vary in different regions. The US manufacturer of abemaciclib states to avoid concurrent administration with ketoconazole, a strong CYP3A4 inhibitor.(1) The US manufacturer of abemaciclib recommends a dose reduction of abemaciclib if concurrent use with other strong CYP3A4 inhibitors (other than ketoconazole). In patients on the recommended starting dose of abemaciclib 200 mg twice daily or 150 mg twice daily, reduce the abemaciclib dose to 100 mg twice daily. In patients who have had a dose reduction of abemaciclib to 100 mg twice daily due to adverse reactions, further reduce the dose to 50 mg twice daily with concurrent use of a strong CYP3A4 inhibitor.(1) The Australian manufacturer of abemaciclib recommends specific dose recommendations based on the concomitant strong CYP3A4 inhibitor. If given with ketoconazole, the recommended abemaciclib dose is 50 mg once daily. If given with itraconazole, the recommended abemaciclib dose is 50 mg twice daily. If given with clarithromycin, the recommended abemaciclib dose is 100 mg twice daily. For other strong CYP3A4 inhibitors, the recommended abemaciclib dose is 50 mg twice daily.(2) If the concurrent strong CYP3A4 inhibitor is discontinued, increase the abemaciclib dose after 3-5 half-lives of the inhibitor to the dose that was used prior to starting the strong inhibitor.(1,2) Monitor patient for signs and symptoms of abemaciclib toxicity with concurrent use.

DISCUSSION: Abemaciclib is a substrate of CYP3A4.(1) Concurrent administration of ketoconazole (a strong CYP3A4 inhibitor) is predicted to increase the area-under-curve (AUC) of abemaciclib up to 16-fold.(1) Concurrent administration of itraconazole (a strong CYP3A4 inhibitor) is predicted to increase the relative potency adjusted unbound AUC of abemaciclib and its active metabolites (M2, M18, and M20) by 2.2-fold.(1) Concurrent administration of clarithromycin (500 mg twice daily, a strong CYP3A4 inhibitor) with a single dose of 50 mg of abemaciclib increased the relative potency adjusted unbound AUC of abemaciclib and its active metabolites (M2, M18, and M20) by 1.7-fold.(1) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, levoketoconazole, lonafarnib, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, tucatinib, troleandomycin, and voriconazole.(3,4)

Strong Cyp3a4 Inhibitors/Acalabrutinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Agents which inhibit the CYP3A4 enzyme may inhibit the metabolism of acalabrutinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase systemic exposure and the risk for acalabrutinib toxicities such as neutropenia, anemia, or thrombocytopenia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant use of acalabrutinib and strong CYP3A inhibitors. Consider an alternative concomitant medication with less potential for CYP3A4 inhibition. If a CYP3A inhibitor will be used short-term (such as anti-infective for up to 7 days), interrupt acalabrutinib therapy.

DISCUSSION: In a drug interaction study in healthy subjects, coadministration of itraconazole (200mg once daily for 5 days) with acalabrutinib increased acalabrutinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 3.9 and 5.1-fold, respectively. Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib and voriconazole.(3)

Strong Cyp3a4 Inhibitors/Avutometinib-Defactinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Avutometinib and defactinib are CYP3A4 substrates. Strong CYP3A4 inhibitors may inhibit the metabolism of defactinib. Avutometinib also undergoes non-enzymatic degradation is not affected by CYP3A4 inhibitors.(1)

CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 inhibitor may result in elevated levels of defactinib and toxicity from avutometinib-defactinib, including hepatotoxicity, rhabdomyolysis, ocular toxicities, and skin toxicities.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of avutometinib-defactinib and strong CYP3A4 inhibitors should be avoided.(1)

DISCUSSION: Defactinib maximum concentration (Cmax) increased by 2.2-fold and area-under-curve (AUC) by 3.9-fold following concomitant use with itraconazole (strong CYP3A4 inhibitor) 200 mg daily for 10 days. The AUC of M4, a major active metabolite of defactinib, increased by 2.2-fold and Cmax decreased by 6.8%.(1) No clinically significant differences in avutometinib pharmacokinetics were observed when used concomitantly with itraconazole.(1) Strong CYP3A4 inhibitors include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2-3)

Strong Cyp3a4 Inhibitors/Cobimetinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of cobimetinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from cobimetinib, including hemorrhage, cardiomyopathy, dermatologic reactions, retinopathy, hepatotoxicity, or rhabdomyolysis.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with cobimetinib.(1) Consider alternatives with no or minimal enzyme inhibition. The manufacturer of cobimetinib states an alternative to a strong or moderate CYP3A4 inhibitor in patients taking cobimetinib 20 mg or 40 mg daily is recommended.(1) The manufacturer of itraconazole states avoid concomitant use during and 2 weeks after itraconazole treatment.(2,3)

DISCUSSION: In a study, itraconazole 200 mg once daily for 14 days followed by a single dose of cobimetinib 10 mg increased mean cobimetinib area-under-curve (AUC) 6.7-fold (90% CI 5.6, 8.0).(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(4,5)

Strong Cyp3a4 Inhibitors/Dabrafenib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of dabrafenib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from dabrafenib, including hemorrhage, cardiomyopathy, uveitis, skin toxicities, or hyperglycemia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with dabrafenib.(1) Consider alternatives with no or minimal enzyme inhibition. If concomitant use is unavoidable, monitor patients closely for toxicity. The manufacturer of itraconazole states avoid concomitant use during and 2 weeks after itraconazole treatment.(2,3)

DISCUSSION: Ketoconazole (400 mg daily for 4 days) increased the area-under-curve (AUC) of dabrafenib (75 mg BID) by 71%. The AUC of hydroxy-dabrafenib and desmethyl-dabrafenib increased by 82% and 68%, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, indinavir, itraconazole, josamycin, ketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(4,5)

Strong Cyp3a4 Inhibitors/Dapagliflozin-Saxagliptin-Metformin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of saxagliptin.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in elevated levels and increased effects of saxagliptin.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of the combination product containing dapagliflozin-saxagliptin-metformin states that this combination should not be coadministered with strong inhibitors of CYP3A4.(1)

DISCUSSION: Pretreatment with ketoconazole (200 mg every 12 hours for 9 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of saxagliptin (100 mg) by 62% and 2.5-fold, respectively. The Cmax and AUC of the active metabolite of saxagliptin decreased 95% and 91%, respectively. The Cmax and AUC of ketoconazole decreased 16% and 13%, respectively.(1,2) Pretreatment with ketoconazole (200 mg every 12 hours for 7 days) increased the Cmax and AUC of a single dose of saxagliptin (100 mg) by 2.4-fold and 3.7-fold, respectively. The Cmax and AUC of the active metabolite of saxagliptin decreased 96% and 90%, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(1,3)

Strong Cyp3a4 Inhibitors/Dapoxetine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of dapoxetine.(1-3)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in elevated levels and increased effects of dapoxetine.(1-3)

PREDISPOSING FACTORS: If the patient is a CYP2D6 poor metabolizer, dapoxetine metabolism can be further inhibited.(1-3)

PATIENT MANAGEMENT: Concurrent use of dapoxetine at any dose is contraindicated in patients taking strong inhibitors of CYP3A4.(1-3) Monitor patients receiving concurrent therapy for agitation, hallucinations, muscle twitching/stiffness/tightness, rapid heartbeat, high or low blood pressure, sweating or fever, nausea or vomiting, diarrhea, abnormal bleeding or bruising, difficulty urinating or the inability to urinate, seizures or convulsions, signs of mania (greatly increased energy, trouble sleeping, racing thoughts, reckless behavior, unusually grand ideas, excessive happiness or irritability, talking more or faster than usual). The manufacturer of itraconazole states that concurrent use of dapoxetine during and 2 weeks after itraconazole treatment is contraindicated.(4,5)

DISCUSSION: Ketoconazole (200 mg twice daily for 7 days), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of dapoxetine (30 mg) by 35% and 99%, respectively. The Cmax and AUC of the active fraction are expected to increase by 25% and 2-fold, respectively, with strong inhibitors of CYP3A4.(1-3) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(1-7)

Strong Cyp3a4 Inhibitors/Daraxonrasib (>150 Mg)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Daraxonrasib is a substrate of CYP3A4. Strong CYP3A4 inhibitors may inhibit the metabolism of daraxonrasib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase the levels and toxicities of daraxonrasib, including dermatologic toxicity, stomatitis, GI perforation, and interstitial lung disease/pneumonitis.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: For patients taking agents that are strong CYP3A4 inhibitors, reduce the dose of daraxonrasib to 150 mg once daily. If the inhibitor is discontinued, resume the previous dose of daraxonrasib after 5 days or 3 to 5 half-lives of the inhibitor, whichever is longer.(1)

DISCUSSION: In a pharmacokinetic model, voriconazole 200 mg twice daily (a strong CYP3A inhibitor) increased the area under curve (AUC) of daraxonrasib by 2-fold.(1) Strong CYP3A4 inhibitors include: adagrasib, boceprevir, ceritinib, ensitrelvir, idelalisib, mibefradil, nefazodone, nelfinavir, relacorilant, ribociclib, troleandomycin, and voriconazole.(2-3)

Strong Cyp3a4 Inhibitors/Daridorexant

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of daridorexant.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels of and effects from daridorexant including somnolence, fatigue, CNS depressant effects, daytime impairment, or headache.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Canadian and UK manufacturers of daridorexant state that concurrent use of strong CYP3A4 inhibitors is contraindicated.(2-3) The US manufacturer of daridorexant states that concurrent use of strong CYP3A4 inhibitors with daridorexant should be avoided.(1)

DISCUSSION: Daridorexant is a CYP3A4 substrate. In a PKPB model, concurrent use of daridorexant with itraconazole, a strong CYP3A4 inhibitor, increased daridorexant area-under-curve (AUC) by 400%.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(4)

Strong Cyp3a4 Inhibitors/Doxorubicin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of doxorubicin.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from doxorubicin, including cardiomyopathy, myelosuppression, or hepatic impairment.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with doxorubicin.(1) Consider alternatives with no or minimal enzyme inhibition.

DISCUSSION: Doxorubicin is a substrate of CYP3A4.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Finerenone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of finerenone.(1)

CLINICAL EFFECTS: Concurrent use of finerenone with a strong inhibitor of CYP3A4 increases finerenone concentrations and may increase the risk of toxicity (e.g. hyperkalemia, hypotension).(1)

PREDISPOSING FACTORS: Severe renal disease increases the risk for hyperkalemia.

PATIENT MANAGEMENT: The manufacturer of finerenone states that the concurrent use of strong CYP3A4 inhibitors is contraindicated.(1) The manufacturer of itraconazole states that concurrent use of finerenone during and 2 weeks after itraconazole treatment is contraindicated.(2,3) In all patients taking finerenone with a moderate or weak CYP3A4 inhibitor, monitor serum potassium during drug initiation or dosage adjustment of either finerenone or the moderate or weak CYP3A4 inhibitor. Dose adjustment may be necessary.(1)

DISCUSSION: Concurrent use of finerenone with itraconazole, a strong CYP3A4 inhibitor, increased finerenone area-under-curve (AUC) by greater than 400%.(1) Concurrent use of finerenone with erythromycin, a moderate CYP3A4 inhibitor, increased finerenone mean AUC by 248% and concentration maximum (Cmax) by 88%.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(4,5)

Strong Cyp3a4 Inhibitors/Futibatinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Futibatinib is primarily metabolized by CYP3A4. Agents that are strong CYP3A4 inhibitors may inhibit the metabolism of futibatinib.(1)

CLINICAL EFFECTS: Concurrent use with inhibitors of CYP3A4 may result in elevated systemic levels and toxicity from futibatinib including hyperphosphatemia, retinal pigment epithelial detachment and elevated liver enzymes.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of futibatinib states concurrent use with strong CYP3A4 inhibitors should be avoided.(1)

DISCUSSION: In an interaction study, multiple doses of itraconazole (an inhibitor of CYP3A4) increased the mean maximum concentration (Cmax) and area-under-curve (AUC) of futibatinib by 51% and 41%, respectively.(1) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Leniolisib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of leniolisib.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels of and effects from leniolisib including neutropenia.(1) Common side effects may also include sinusitis.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of strong CYP3A4 inhibitors with leniolisib should be avoided.(1)

DISCUSSION: Leniolisib exposure was increased 2-fold when coadministered with itraconazole, a strong CYP3A4 inhibitor.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2)

Strong Cyp3a4 Inhibitors/Levomilnacipran (>80Mg)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of levomilnacipran.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in elevated levels and increased effects of levomilnacipran.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The dose of levomilnacipran should not exceed 80 mg daily in patients taking strong inhibitors of CYP3A4.(1) Monitor patients receiving concurrent therapy for agitation, hallucinations, muscle twitching/stiffness/tightness, rapid heartbeat, high or low blood pressure, sweating or fever, nausea or vomiting, diarrhea, abnormal bleeding or bruising, difficulty urinating or the inability to urinate, seizures or convulsions, signs of mania (greatly increased energy, trouble sleeping, racing thoughts, reckless behavior, unusually grand ideas, excessive happiness or irritability, talking more or faster than usual).

DISCUSSION: Pretreatment with ketoconazole, a strong inhibitor of CYP3A4, increased the Cmax and AUC of levomilnacipran between 1.25 and 1.50-fold and between 1.50 and 1.75-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(1-3)

Strong Cyp3a4 Inhibitors/Macitentan

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of macitentan.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in elevated levels and increased effects of macitentan.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of macitentan states that use of strong inhibitors of CYP3A4 should be avoided. When strong CYP3A4 inhibitors are required (e.g. protease inhibitors in the treatment of HIV), use other treatment options for pulmonary arterial hypertension.(1) The Journal of American College of Cardiology (JACC) states concurrent use of macitentan and nirmatrelvir-ritonavir is not advised. JACC recommends discontinuing macitentan for at least 36 hours before initiation of nirmatrelvir-ritonavir.(2)

DISCUSSION: Pretreatment with ketoconazole increased the area-under-curve (AUC) and maximum concentration (Cmax) of macitentan approximately 2.3 and 1.3-fold respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3)

Strong Cyp3a4 Inhibitors/Mitapivat

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of mitapivat.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels of and effects from mitapivat including decreased estrone and estradiol levels in males, increased urate, back pain, and arthralgias.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of strong CYP3A4 inhibitors with mitapivat should be avoided.(1)

DISCUSSION: Mitapivat is a CYP3A4 substrate. In a pharmacokinetic study with mitapivat 20 mg single dose, itraconazole increased mitapivat area-under-curve (AUC) and concentration maximum (Cmax) by 4.9-fold and 1.7-fold, respectively. In a pharmacokinetic study with mitapivat 50 mg twice daily, itraconazole increased mitapivat AUC and Cmax by 3.6-fold and 2.2-fold, respectively. With ketoconazole, mitapivat doses of 5, 20, or 50 mg twice daily had an AUC and Cmax increased by 3.9-fold and 2.4-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2)

Strong Cyp3a4 Inhibitors/Naloxegol

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of naloxegol.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels of naloxegol, which may precipitate opioid withdrawal symptoms.(1)

PREDISPOSING FACTORS: Patients taking methadone may be more likely to experience gastrointestinal side effects such as abdominal pain and diarrhea as a result of opioid withdrawal.(1)

PATIENT MANAGEMENT: The concurrent use of naloxegol and strong CYP3A4 inhibitors is contraindicated.(1) The US manufacturer of itraconazole states that concurrent administration with naloxegol is contraindicated during and two weeks after itraconazole treatment.(5) If concurrent use is deemed medically necessary, monitor patients for signs of opioid withdrawal such as sweating, chills, diarrhea, stomach pain, anxiety, irritability, yawning, restlessness, muscle/joint aches, increased lacrimation, running nose, and piloerection. Monitor patients taking methadone for abdominal pain and diarrhea as well.(1)

DISCUSSION: Ketoconazole (400 mg daily for 5 days), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of naloxegol by 9.58-fold and 12.85-fold, respectively.(2) Diltiazem (240 mg XR daily), a moderate inhibitor of CYP3A4, increased the Cmax and AUC of a single dose of naloxegol by 2.85 and 3.41, respectively.(2) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(1,3,4)

Strong Cyp3a4 Inhibitors/Nimodipine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Nimodipine is metabolized by CYP3A4. Strong inhibitors of CYP3A4 may decrease the metabolism of nimodipine.(1-3)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in increased levels of and toxicity from nimodipine.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of nimodipine capsules states that the concurrent use of strong CYP3A4 inhibitors is contraindicated due to the risk of significant hypotension.(1) The US manufacturer of nimodipine solution states that strong CYP3A4 inhibitors should generally be avoided.(2) The US manufacturers of some strong CYP3A4 inhibitors, including cobicistat(4) and ritonavir,(5) state that concurrent use of CYP3A4 substrates for which increased levels may cause serious or life-threatening events are contraindicated. If coadministration is necessary, monitor the patient closely and adjust the dose of nimodipine as needed.(3)

DISCUSSION: In 7 healthy volunteers, cimetidine (a moderate CYP3A4 inhibitor) 200 mg 3 times daily with meals and 400 mg at bedtime increased the area-under-curve (AUC) and maximum concentration (Cmax) of nimodipine (30 mg 3 times daily) by 82% and 54%, respectively. There was no change in blood pressure, heart rate, or tolerability of nimodipine, and no dose adjustment was required.(6) The combination of nimodipine with strong CYP3A4 inhibitors has not been studied, but a more marked effect is expected. Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(7-8)

Strong Cyp3a4 Inhibitors/Olaparib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of olaparib.(1,2)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from olaparib, including myelodysplastic syndrome, pneumonitis, thromboembolic events, anemia, neutropenia or thrombocytopenia.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with olaparib.(1,2) Consider alternatives with no or minimal enzyme inhibition. If concomitant use with olaparib cannot be avoided, reduce the olaparib dose. Dosage adjustments are specific to the formulation of olaparib (CAPsules or TABlets).(1,2) -Reduce the dosage of the CAPsule formulation to 150 mg (3 CAPsules) taken twice daily.(1) -Reduce the dosage of the TABlet formulation to 100 mg (one 100 mg TABlet) twice daily).(2) If the CYP3A4 inhibitor is discontinued, resume the dose of olaparib taken prior to initiation of the CYP3A4 inhibitor after 3 to 5 half-lives.(1,2)

DISCUSSION: In an interaction study, the area-under-curve (AUC) and concentration maximum (Cmax) of olaparib was increased 2.7- and 1.4-fold, respectively when it was administered with itraconazole (dose not specified), a strong CYP3A4 inhibitor.(1,2,3) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(4,5)

Strong Cyp3a4 Inhibitors/Olverembatinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Olverembatinib is metabolized via CYP3A4. Strong inhibitors of CYP3A4 may inhibit the metabolism of olverembatinib.(1)

CLINICAL EFFECTS: Concurrent use of olverembatinib with strong CYP3A4 inhibitors may increase the levels and toxicities of olverembatinib, including myelosuppression, bleeding, and hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of olverembatinib states coadministration with strong CYP3A4 inhibitors should be avoided.(1)

DISCUSSION: In a clinical study of 16 healthy subjects, coadministration of olverembatinib 20 mg with itraconazole 200 mg daily, a strong CYP3A4 inhibitor, resulted in a 2.59-fold increase in olverembatinib's area-under-curve (AUC) and a 1.76-fold increase in olverembatinib's maximum concentration (Cmax).(2) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3,4)

Strong Cyp3a4 Inhibitors/Oveporexton

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Oveporexton is metabolized by CYP3A4. Strong CYP3A4 inhibitors may inhibit the metabolism of oveporexton.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase the levels and toxicities of oveporexton, including insomnia, urinary frequency and urgency, and CPK elevation.(1)

PREDISPOSING FACTORS: Adverse reactions from oveporexton may be more likely in patients with Child-Pugh class C hepatic impairment and in patients with severe renal impairment on dialysis.

PATIENT MANAGEMENT: Concomitant use of oveporexton with strong CYP3A4 inhibitors is contraindicated.(1)

DISCUSSION: In a study, itraconazole (a strong CYP3A inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of oveporexton by 7.4-fold and 1.7-fold, respectively. Oveporexton half-life was increased by about 5-fold.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2-3)

Strong Cyp3a4 Inhibitors/Palovarotene

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of palovarotene.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inhibitor may result in increased levels of and effects from palovarotene including rash, alopecia, skin exfoliation, photosensitivity, reduction in bone mass, hyperostosis, and night blindness.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of strong CYP3A4 inhibitors with palovarotene should be avoided.(1,2)

DISCUSSION: In a clinical trial, ketoconazole, a strong CYP3A4 inhibitor, increased the maximum concentration (Cmax) and area-under-curve (AUC) of palovarotene by 121% and 212%, respectively.(1,2) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3)

Strong Cyp3a4 Inhibitors/Plitidepsin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of plitidepsin.(1)

CLINICAL EFFECTS: Concurrent administration of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from plitidepsin.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration with strong CYP3A4 inhibitors should be avoided. Strong CYP3A4 inhibitors should be discontinued at least 1 week prior to starting treatment and while on treatment with plitidepsin.

DISCUSSION: In vitro studies indicate that CYP3A4 is the main enzyme involved in the metabolism of plitidepsin. The Australian manufacturer of plitidepsin states that coadministration with strong CYP3A4 inhibitors should be avoided.(1) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, tipranavir, troleandomycin, tucatinib, and voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Pyrotinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Pyrotinib is metabolized via CYP3A4. Strong inhibitors of CYP3A4 may inhibit the metabolism of pyrotinib.(1)

CLINICAL EFFECTS: Concurrent use of pyrotinib with strong CYP3A4 inhibitors may increase the levels and toxicities of pyrotinib, including hepatotoxicity, decreased left ventricular ejection fraction, bone marrow suppression and gastrointestinal adverse effects.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of pyrotinib states coadministration with strong CYP3A4 inhibitors should be avoided.(1)

DISCUSSION: In a clinical study of healthy subjects, coadministration of pyrotinib with itraconazole, a strong CYP3A4 inhibitor, resulted in a 11.8-fold increase in area-under-curve (AUC) and a 3.78-fold increase in maximum concentration (Cmax).(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Remibrutinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Remibrutinib is metabolized via CYP3A4. Strong inhibitors of CYP3A4 may inhibit the metabolism of remibrutinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from remibrutinib, including bleeding.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in older patients (65 years and over) and patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients taking remibrutinib.(1)

DISCUSSION: In a clinical study, remibrutinib maximum concentration (Cmax) increased by 3.3-fold and area-under-curve (AUC) increased by 4.3-fold following concomitant administration with ritonavir (a strong CYP3A4 inhibitor) 100 mg twice daily for 4 days.(1) Strong inhibitors of CYP3A4 linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Rilzabrutinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Rilzabrutinib is metabolized via CYP3A4. Strong inhibitors of CYP3A4 may inhibit the metabolism of rilzabrutinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from rilzabrutinib, including hepatotoxicity and immunosuppression.(1)

PREDISPOSING FACTORS: Patients with moderate to severe hepatic impairment (Child-Pugh class B-C) may be more susceptible to the effects of this drug interaction due to the potential for increased rilzabrutinib exposure.(1)

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients taking rilzabrutinib. If concurrent use cannot be avoided and the CYP3A4 inhibitor will be used short term (i.e., less than 7 days), interrupt treatment with rilzabrutinib.(1)

DISCUSSION: In a clinical study, ritonavir (a strong CYP3A4 inhibitor) increased the maximum concentration (Cmax) of rilzabrutinib by 5-fold and the area-under-curve (AUC) by 8-fold at steady state.(1) Strong inhibitors of CYP3A4 linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Rimegepant

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Rimegepant is primarily metabolized by CYP3A4. Strong inhibitors of CYP3A4 may decrease the metabolism of rimegepant.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in increased levels of and toxicity from rimegepant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of rimegepant recommends avoiding concomitant use of agents that are strong CYP3A4 inhibitors due to a significant increase in exposure to rimegepant.(1)

DISCUSSION: In a drug interaction study, itraconazole, a strong CYP3A4 inhibitor, increased the area-under-curve (AUC) and maximum concentration (Cmax) of rimegepant (75 mg) by 4-fold and 1.5-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2-3)

Strong Cyp3a4 Inhibitors/Silodosin; Tamsulosin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of silodosin and tamsulosin.(1,2)

CLINICAL EFFECTS: Coadministration of a strong CYP3A4 inhibitor may cause an increase in silodosin and tamsulosin levels and effects, including severe hypotension.(1,2)

PREDISPOSING FACTORS: In patients receiving tamsulosin, the interaction may be worse in patients who are CYP2D6 poor metabolizers because tamsulosin also undergoes metabolism by this pathway.(2)

PATIENT MANAGEMENT: The US manufacturer of silodosin states that concurrent use of strong CYP3A4 inhibitors is contraindicated.(1) The US manufacturer of tamsulosin states that tamsulosin should not be used with strong CYP3A4 inhibitors.(2) The US manufacturer of itraconazole states that silodosin or tamsulosin should not be administered until at least 2 weeks after itraconazole treatment.(3)

DISCUSSION: Administration of ketoconazole (200 mg daily for 4 days) increased the Cmax and AUC of a single dose of silodosin (4 mg) by 3.7-fold and 2.9-fold, respectively.(1) Administration of ketoconazole (400 mg daily for 4 days) increased the Cmax and AUC of a single dose of silodosin (8 mg) by 3.8-fold and 3.2-fold, respectively.(1) In a study in 24 healthy male subjects, administration of ketoconazole (400 mg daily for 5 days) increased the Cmax and AUC of a single dose of tamsulosin (0.4 mg) by 2.2-fold (90% CI 1.96, 2.45) and 2.8-fold (90% CI 2.56, 3.07), respectively. No serous adverse events were reported when subjects took tamsulosin with ketoconazole.(2,4) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, itraconazole, josamycin, ketoconazole, lonafarnib, mibefradil, mifepristone, nefazodone, posaconazole, relacorilant, ribociclib, telaprevir, telithromycin, troleandomycin, tucatinib and voriconazole.(5,6)

Strong Cyp3a4 Inhibitors/Slt High Strength Antimuscarinics

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of darifenacin(1) and fesoterodine.(2)

CLINICAL EFFECTS: The concurrent administration of a strong inhibitor of CYP3A4 may result in elevated levels of and signs of toxicity from darifenacin(1) and fesoterodine.(2)

PREDISPOSING FACTORS: The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3)

PATIENT MANAGEMENT: The US manufacturer of darifenacin states that the daily dose of darifenacin should not exceed 7.5 mg in patients receiving potent CYP3A4 inhibitors.(1) The US manufacturer of fesoterodine states that the daily dose of fesoterodine should not exceed 4 mg in adult patients receiving potent CYP3A4 inhibitors. In pediatric patients, the daily dose of fesoterodine in patients taking strong CYP3A4 inhibitors should be reduced to 4 mg in patients weighing greater than 35 kilograms. Use of fesoterodine in pediatric patients weighing greater than 25 kilograms and up to 35 kilograms is not recommended.(2) The US manufacturer of itraconazole states that concurrent use with fesoterodine is contraindicated in patients with severe renal or hepatic impairment during and two weeks after itraconazole treatment.(4)

DISCUSSION: In a study in 10 extensive CYP2D6 metabolizers and 1 poor CYP2D6 metabolizer, concurrent administration of ketoconazole (400 mg) increased the area-under-curve (AUC) and maximum concentration (Cmax) of darifenacin (7.5 mg daily) by 3.9-fold and 4.6-fold, respectively, in extensive metabolizers and by 12.9-fold and 12-fold, respectively, in the poor metabolizer, compared to historical controls. The concurrent administration of ketoconazole (400 mg) and darifenacin (15 mg daily) increased darifenacin AUC and Cmax by 11.5-fold and 10.73-fold, respectively, in extensive metabolizers and by 4.9-fold and 4.9-fold, respectively, in the poor metabolizer, compared to historical controls.(1) Concurrent administration of darifenacin (30 mg daily) and erythromycin, a moderate CYP3A4 inhibitor, increased darifenacin AUC and Cmax by 128% and 95%, respectively. Administration of darifenacin (30 mg daily) and fluconazole, another moderate CYP3A4 inhibitor, increased darifenacin AUC and Cmax by 84% and 88%, respectively. No dosage adjustment is recommended during concurrent therapy with moderate inhibitors of CYP3A4.(1) In a study, co-administration of ketoconazole (200 mg twice a day) increased the Cmax and AUC of the active metabolite of fesoterodine 2.0 and 2.3-fold in CYP2D6 extensive metabolizers and 2.1 and 2.5-fold in CYP2D6 poor metabolizers, respectively. Fesoterodine Cmax and AUC were 4.5-fold and 5.7-fold higher in subjects who were CYP2D6 poor metabolizers and taking ketoconazole when compared to extensive CYP2D6 metabolizers not taking ketoconazole.(2) In another study, ketoconazole (200 mg daily) increased the Cmax and AUC of the active metabolite of fesoterodine 2.2-fold in CYP2D6 extensive metabolizers and 1.5-fold and 1.9-fold in CYP P-450-2D6 poor metabolizers, respectively.(1,2) Fesoterodine Cmax and AUC were 3.4-fold and 4.2-fold higher in subjects who were CYP2D6 poor metabolizers and taking ketoconazole when compared to extensive CYP2D6 metabolizers not taking ketoconazole.(2) Based on a controlled randomized study in 28 healthy adults, oral fluconazole (200 mg daily) taken with oral fesoterodine (8 mg daily) was generally well tolerated in patients. A slightly non-clinically significant rise in plasma fesoterodine levels did occur. No clinically significant side effects were reported. The most common side effects reported by patients include: dizziness, blurred vision and abdominal distension when fluconazole was taken with fesoterodine.(5) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(6)

Strong Cyp3a4 Inhibitors/Solifenacin (> 5 Mg)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of solifenacin.(1-3)

CLINICAL EFFECTS: The concurrent administration of a strong inhibitor of CYP3A4 may result in elevated levels of and signs of toxicity from solifenacin.(1-3)

PREDISPOSING FACTORS: The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: The US and Swedish manufacturers of solifenacin state the daily dose should be limited to 5 mg in adults and should not exceed the starting dose in children and adolescents when administered with strong CYP3A4 inhibitors. The starting dose of solifenacin is 2 mg for patients weighing up to 15 kg, 3 mg for patients over 15 kg to 45 kg, 4 mg for patients over 45 kg to 60 kg, and 5 mg for patients over 60 kg.(1,24) The Swedish manufacturer of the combination product of tamsulosin-solifenacin states that the daily dose of solifenacin should not exceed 6 mg in patients receiving potent CYP3A4 inhibitors.(3) The US manufacturer of itraconazole states that concurrent use with solifenacin is contraindicated in patients with severe renal or hepatic impairment during and two weeks after itraconazole treatment.(5)

DISCUSSION: Concurrent use of ketoconazole (400 mg daily for 21 days) increased the Cmax and AUC of solifenacin (10 mg) by 1.5-fold and 2.7-fold,respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(6)

Strong Cyp3a4 Inhibitors/Sonidegib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of sonidegib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from sonidegib, including musculoskeletal adverse reactions (elevated creatine kinase) or rhabdomyolysis.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with sonidegib.(1) Consider alternatives with no or minimal enzyme inhibition.

DISCUSSION: In a study, 15 healthy subjects received a single sonidegib 800 mg alone or after ketoconazole 200 mg twice daily for 14 days. Mean area-under-curve (AUC) and concentration maximum (Cmax) increased by 2.2-fold and 1.5-fold respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Sparsentan

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of sparsentan.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels of and effects from sparsentan including hepatotoxicity, hypotension, hyperkalemia, and renal impairment.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of strong CYP3A4 inhibitors with sparsentan should be avoided. If concurrent use cannot be avoided, interrupt therapy with sparsentan. When resuming sparsentan, consider dose titration.(1)

DISCUSSION: Co-administration of a single dose of sparsentan with itraconazole (a strong CYP3A4 inhibitor) increased concentration maximum (Cmax) and area-under-curve (AUC) of sparsentan by 25% and 174%, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2)

Strong Cyp3a4 Inhibitors/Suzetrigine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Suzetrigine and M6-SUZ (active metabolite of suzetrigine) are CYP3A4 substrates. Strong CYP3A4 inhibitors increase suzetrigine and M6-SUZ exposures, which may cause suzetrigine adverse reactions.(1)

CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from suzetrigine including pruritis, muscle spasms, increased blood creatine phosphokinase, and rash.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of suzetrigine and strong CYP3A4 inhibitors is contraindicated.(1)

DISCUSSION: Concomitant administration of itraconazole (a strong CYP3A4 inhibitor) with a single dose of suzetrigine increased the area-under-curve (AUC) of suzetrigine and active metabolite M6-SUZ by 4.8-fold and 4.4-fold, respectively, while the maximum concentration (Cmax) of suzetrigine increased by 1.5-fold and Cmax of M6-SUZ decreased by 32%.(1) Strong CYP3A4 inhibitors include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2-3)

Strong Cyp3a4 Inhibitors/Tolvaptan

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of tolvaptan.(1) Toxicity may result from an overly rapid correction of serum sodium.

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels of tolvaptan.(1) Elevated levels of tolvaptan may lead to increased clinical effects such as hypotension, hypovolemia, and thirst, as well as toxicity in the form of neurologic sequelae such as osmotic demyelination syndrome (ODS). ODS can lead to coma and death. Symptoms of ODS include dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, and coma.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of tolvaptan and strong CYP3A4 inhibitors is contraindicated.(1) The Australian manufacturer of tolvaptan provides different recommendations with strong CYP3A4 inhibitors based on the indication for tolvaptan. Refer to product labeling for recommendations with strong CYP3A4 inhibitors.(2,3) The US manufacturer of itraconazole states that concurrent use with tolvaptan is contraindicated during and two weeks after itraconazole treatment.(4)

DISCUSSION: Tolvaptan is a substrate of CYP3A4. Concurrent administration of ketoconazole (200 mg daily) increased tolvaptan exposure by 5-fold. Administration of ketoconazole at dosages of 400 mg daily would be expected to produce greater increases, as would concurrent administration with other strong CYP3A4 inhibitors.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(5)

Strong Cyp3a4 Inhibitors/Trabectedin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Agents which strongly inhibit the CYP3A4 enzyme may impede the metabolism of trabectedin.

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase systemic exposure and the risk for adverse effects from trabectedin.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When possible, avoid the use of strong CYP3A4 inhibitors in patients receiving trabectedin.(1) The US manufacturer of itraconazole states that concomitant administration with trabectedin is not recommended during and two weeks after itraconazole treatment.(3) If short term use (i.e. less than 14 days) of a CYP3A4 inhibitor is required, administer the strong CYP3A4 inhibitor one week after trabectedin infusion and discontinue it prior to the next trabectedin infusion.(1) Monitor closely for adverse effects and decrease dosage if required.

DISCUSSION: In an interaction study, a single dose of trabectedin with ketoconazole 200 mg orally twice daily for 7.5 days increased trabectedin exposure (AUC, area-under-curve) 66% compared with a single dose of trabectedin given alone.(1) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, itraconazole, josamycin, ketoconazole, lonafarnib, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, ritonavir, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(2)

Strong Cyp3a4 Inhibitors/Trastuzumab Emtansine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Trastuzumab emtansine is a conjugate of trastuzumab and emtansine, a complex of MCC-DM1. DM1 is a microtubule inhibitor and is metabolized by CYP3A4. Strong inhibitors of CYP3A4 are expected to inhibit the metabolism of DM1.(1-4)

CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP3A4 are expected to increase exposure to and toxicity from DM1, an active metabolite of trastuzumab emtansine, including hepatotoxicity, pneumonitis, hemorrhage, thrombocytopenia, or neurotoxicity.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US, UK, and Canadian manufacturers recommend avoiding the use of strong CYP3A4 inhibitors in patients undergoing therapy with trastuzumab emtansine. Consider alternatives with no or minimal enzyme inhibition.(1-4) If concurrent use with trastuzumab emtansine is unavoidable, consider delaying trastuzumab emtansine treatment until the strong CYP3A4 inhibitor has cleared from circulation (approximately 3 half-lives of the inhibitor). If strong CYP3A4 inhibitors are used concurrently with trastuzumab emtansine, patients should be closely monitored for toxicity.(1-3) The Australian manufacturer recommends patients receiving strong CYP3A4 inhibitors concomitantly with trastuzumab emtansine should be closely monitored for adverse reactions.(4)

DISCUSSION: Trastuzumab emtansine is a conjugate of trastuzumab and emtansine, a complex of MCC-DM1. DM1 is a microtubule inhibitor. In vitro studies in human liver microsomes indicate that DM1 is metabolized by CYP3A4 and inhibition of this isoenzyme is expected to result in elevated levels of and toxicity from DM1.(1-4) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(5,6)

Strong Cyp3a4 Inhibitors/Ubrogepant

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of ubrogepant.(1)

CLINICAL EFFECTS: Concurrent use of ubrogepant with strong CYP3A4 inhibitors may result in a significant increase in exposure of ubrogepant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of ubrogepant states coadministration with strong CYP3A4 inhibitors is contraindicated.(1)

DISCUSSION: Coadministration of ubrogepant with ketoconazole, a strong CYP3A4 inhibitor, resulted in a 9.7-fold and 5.3-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Valbenazine (> 40 Mg)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Agents which inhibit the CYP3A4 enzyme may inhibit the metabolism of valbenazine.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase systemic exposure and the risk for valbenazine toxicities such as QT prolongation.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Concurrent use of strong CYP2D6 inhibitors may further increase levels of valbenazine.(1)

PATIENT MANAGEMENT: Reduce the valbenazine dose to 40 mg once daily when valbenazine is coadministered with a strong CYP3A4 inhibitor.(1) During concomitant therapy with a strong CYP3A4 inhibitor, monitor patients closely for prolongation of the QT interval. Obtain serum calcium, magnesium, and potassium levels and monitor ECG at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a drug interaction study in healthy subjects, coadministration of ketoconazole with valbenazine increased valbenazine maximum concentration (Cmax) and area-under-the-curve (AUC) by 2 and 1.5-fold, respectively. Cmax and AUC for the active metabolite of valbenazine (alpha-HTBZ) increased by approximately 2 and 1.6-fold, respectively. Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3)

Strong Cyp3a4 Inhibitors/Vardenafil (>2.5 Mg)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of vardenafil.(1-3)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in increased levels, clinical effects, and side effects of vardenafil.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of vardenafil states that a maximum dose of 2.5 mg of vardenafil every 24 hours should not be exceeded in patients taking strong CYP3A4 inhibitors.(1) Note that other countries have different warnings. The Canadian(3) and UK(3) manufacturer of vardenafil state that vardenafil should not exceed 5 mg in patients taking clarithromycin. The UK manufacturer of vardenafil states that the concurrent use of vardenafil with strong CYP3A4 inhibitors should be avoided.(3) The US manufacturer of cobicistat states that a maximum dose of 2.5 mg of vardenafil every 72 hours should not be exceeded in patients taking cobicistat.(4)

DISCUSSION: Concurrent use of ketoconazole (200 mg, a strong inhibitor of CYP3A4) with vardenafil (5 mg) increased the vardenafil area-under-curve (AUC) and maximum concentration (Cmax) by 10-fold and 4-fold, respectively.(1-3) Concurrent administration of erythromycin (500 mg three times daily, a moderate inhibitor of CYP3A4) with vardenafil (5 mg) increased the AUC and Cmax of vardenafil by 4-fold and 3-fold, respectively.(1-3)

Strong Cyp3a4 Inhibitors/Vilazodone (>20 Mg)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of vilazodone.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in elevated levels and increased effects of vilazodone.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The dose of vilazodone should be reduced to 20 mg daily when coadministered with strong inhibitors of CYP3A4.(1) Monitor patients receiving concurrent therapy for agitation, hallucinations, muscle twitching/stiffness/tightness, rapid heartbeat, high or low blood pressure, sweating or fever, nausea or vomiting, diarrhea, abnormal bleeding or bruising, difficulty urinating or the inability to urinate, seizures or convulsions, signs of mania (greatly increased energy, trouble sleeping, racing thoughts, reckless behavior, unusually grand ideas, excessive happiness or irritability, talking more or faster than usual).

DISCUSSION: Ketoconazole increased vilazodone concentrations by 50%.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(1-3)

Strong Cyp3a4 Inhibitors/Vincristine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of vincristine.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from vincristine, including myelosuppression, neurologic toxicity, tumor lysis syndrome, hepatotoxicity, constipation, or bowel obstruction.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with vincristine.(1) Consider alternatives with no or minimal enzyme inhibition. The US manufacturer of vincristine states that concomitant use of strong CYP3A4 inhibitors should be avoided.(1) The manufacturer of lopinavir/ritonavir states that patients who develop significant hematological or gastrointestinal toxicity on concomitant vincristine should temporarily hold lopinavir/ritonavir, or use alternative medications that do not inhibit CYP3A4 or P-gp.(2) The Australian manufacturer of vincristine states coadministration of vincristine with strong CYP3A4 inhibitors should be used with caution.(19) The Australian manufacturer of voriconazole recommends that a dose adjustment of vincristine be considered when coadministered with voriconazole.(20)

DISCUSSION: Vincristine is a substrate of CYP3A4. Inhibitors of CYP3A4 may increase toxicity of vincristine.(1) There are several case reports of neurotoxicity with concurrent administration of vincristine and itraconazole (6,12-16), posaconazole (8), and voriconazole.(11) There is a case report of neurotoxicity with concurrent administration of lopinavir-ritonavir with vincristine.(9) In a retrospective study of 29 adults with acute lymphoplastic leukemia (ALL) receiving concurrent vincristine and azole therapy (fluconazole, voriconazole, or posaconazole), patients were more likely to have a dose modification (dose reduction or discontinue drug, 58.6% vs. 23.8%, p = 0.02) and more likely to have symptoms of decreased peristalsis (65.5% vs. 28.6%, p = 0.019). A mean dose reduction of vincristine when combined with an azole was 46.5%. Six patients had to withhold treatment with vincristine because of the severity of the neurotoxicity.(10) In a prospective study in 22 children receiving various chemotherapy with prophylactic itraconazole oral solution (0.5 ml/kg per day), two children receiving vincristine developed non-alcoholic steatohepatitis (NASH) and one child developed syndrome of inappropriate anti-diuretic hormone secretion (SIADH).(17) In a retrospective review, 8 ALL patients on vincristine and voriconazole prophylaxis (200 mg twice a day) did not show any signs of neurotoxicity.(18) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, fusidic acid, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(3,4)

Strong Cyp3a4 Inhibitors/Vinflunine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of vinflunine.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from vinflunine, including neutropenia, thrombocytopenia, anemia, constipation, stomatitis, diarrhea, or alopecia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with vinflunine.(1) Consider alternatives with no or minimal enzyme inhibition. The manufacturer of vinflunine states that concomitant use with strong CYP3A4 inhibitors should be avoided.(1)

DISCUSSION: In a phase I study, concurrent use of ketoconazole (400 mg orally daily for 8 days) increased the exposure to vinflunine and DVFL by 30% and 50%, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Voclosporin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of voclosporin.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from voclosporin, including infection, neurotoxicity, nephrotoxicity, hypertension, or hyperkalemia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The prescribing information for voclosporin states the use of strong CYP3A4 inhibitors in patients undergoing therapy with voclosporin is contraindicated.(1) Consider alternatives with no or minimal enzyme inhibition. The manufacturer of itraconazole states that concurrent use of voclosporin during and 2 weeks after itraconazole treatment is contraindicated.(2,3)

DISCUSSION: Concurrent use of voclosporin and ketoconazole 400 mg daily (strong CYP3A4 inhibitor)for 9 days increased the concentration maximum (Cmax) and area-under-curve (AUC) by 6.45-fold and 18.55-fold, respectively.(1) Concurrent use of voclosporin and verapamil 80 mg three times a day for 10 days (moderate CYP3A4 inhibitor and P-gp inhibitor) increased Cmax and AUC by 2.08-fold and 2.71-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(4,5)

Strong Cyp3a4 Inhibitors/Zilurgisertib (>50 Mg)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Zilurgisertib is primarily metabolized by CYP3A4. Strong CYP3A4 inhibitors may inhibit the metabolism of zilurgisertib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase the levels and toxicities of zilurgisertib including headaches, arthralgias, and upper respiratory infections.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When used concomitantly with a strong CYP3A4 inhibitor, reduce zilurgisertib dose to 50 mg once daily.(1)

DISCUSSION: In a clinical study, itraconazole increased zilurgisertib area-under-curve (AUC) by 2.13-fold and maximum concentration (Cmax) by 1.28-fold.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2-3)

Strong Cyp3a4 Inhibitors; Atazanavir; Darunavir/Avanafil

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of avanafil.(1-2)

CLINICAL EFFECTS: The concurrent administration of a CYP3A4 inhibitor may result in elevated levels of avanafil, which may result in increased adverse effects such as hypotension, visual changes, and priapism.(1-2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of avanafil states that the concurrent use of strong inhibitors of CYP3A4 is contraindicated.(1) The US Department of Health and Human Services HIV guidelines state that boosted atazanavir or darunavir should not be coadministered with avanafil. Unboosted atazanavir may be coadministered with avanafil doses not exceeding 50 mg every 24 hours.(2) The US manufacturer of itraconazole states that concurrent use of avanafil is contraindicated during and two weeks after itraconazole treatment.(3)

DISCUSSION: Ketoconazole (400 mg daily), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of avanafil (50 mg) by 3-fold and 13-fold, respectively. The half-life of avanafil increased from 5 hours to 9 hours.(1) Ritonavir (600 mg BID), a strong inhibitor of CYP3A4 and an inhibitor of CYP2C19, increased the Cmax and AUC of a single dose of avanafil (50 mg) by 2.4-fold and 13-fold, respectively. The half-life of avanafil increased from 5 hours to 9 hours.(1) Erythromycin (500 mg BID), a moderate inhibitor of CYP3A4, increased the Cmax and AUC of a single dose of avanafil (200 mg) by 2-fold and 3-fold, respectively. The half-life of avanafil increased from 5 hours to 8 hours.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, elvitegravir, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(4-5)

Strong Cyp3a4 Inhibitors; Atazanavir; Darunavir/Suvorexant

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibitors of CYP3A4 impair the metabolism of suvorexant.(1)

CLINICAL EFFECTS: Concurrent use of suvorexant with a CYP3A4 inhibitor may result in an increase in hypnotic levels and clinical adverse effects such as confusion, memory loss, sleep-walking or sleep-driving behaviors, thought or behavioral changes, or excessive daytime drowsiness, as well as toxic effects such as profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Systemic exposure may also be increased in patients with severe hepatic impairment. Elderly and debilitated patients are more likely to have impaired motor or cognitive performance when treated with hypnotics.

PATIENT MANAGEMENT: The US manufacturer of suvorexant states that concurrent use with strong inhibitors of CYP3A4 is not recommended. Consider alternative agents with less CYP3A4 inhibition when possible.(1) The US Department of Health and Human Services HIV guidelines state that suvorexant should not be coadministered with protease inhibitors.(2) Patients requiring concurrent therapy will need a substantially lower dose of suvorexant. Patients should be counseled that concurrent use of a strong CYP3A4 inhibitor with suvorexant may result in an increase in side effects such as confusion, memory loss, sleep-walking or sleep-driving behaviors, or daytime drowsiness. With moderate inhibitors of CYP3A4, the manufacturer recommends a starting dose of 5 mg daily and a maximum dose of 10 mg daily.(1)

DISCUSSION: Ketoconazole increased suvorexant AUC and Cmax by approximately 2.75-fold and 1.25-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, clarithromycin, cobicistat, elvitegravir, ensitrelvir, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, and voriconazole.(3,4)

Strong Cyp3a4 Inhibitors; Atazanavir;Darunavir/Lercanidipine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of lercanidipine.(1)

CLINICAL EFFECTS: Concomitant use of lercanidipine with strong inhibitors of CYP3A4 may lead to increased lercanidipine effects.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of lercanidipine states that concurrent use of strong CYP3A4 inhibitors is contraindicated.(1)

DISCUSSION: In a study, concurrent administration of ketoconazole increased lercanidipine's area-under-the-curve (AUC) and maximum concentration (Cmax) by 15-fold and 8-fold, respectively.(1) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, ensitrelvir, erythromycin, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(2-4)

Strong Cyp3a4 Inhibitors; Darunavir/Irinotecan

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of SN-38, the active metabolite of irinotecan. Strong CYP3A4 inhibitors and darunavir may prevent the breakdown of SN-38 to its inactive metabolites APC, NPC, M2, M3, and M4.(1,2)

CLINICAL EFFECTS: Coadministration of irinotecan with a strong CYP3A4 inhibitor may result in increased irinotecan plasma concentration, and therefore increased exposure to its active metabolite SN-38. Increased SN-38 exposure may lead to serious toxicity, including severe neutropenia, interstitial pulmonary disease, and even death.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of irinotecan and strong CYP3A4 inhibitors or darunavir is contraindicated.(2-4) Strong CYP3A4 inhibitors should be discontinued at least 1 week prior to starting irinotecan.(4) The US manufacturer of itraconazole states that concomitant administration with irinotecan is contra-indicated during and two weeks after itraconazole treatment.(5) If concurrent therapy is warranted, consider a four-fold reduction in irinotecan dose.(3) Patients receiving concurrent therapy should be closely monitored for toxicity.

DISCUSSION: A randomized cross-over study involving seven patients was performed in which each was given irinotecan 350 mg/m2 IV alone for 90 minutes and followed 3 weeks later by irinotecan 100 mg/m2 given with ketoconazole 200 mg orally 1 hour before or 23 hours after the infusion of irinotecan, or both cycles were given vice versa. With ketoconazole coadministration, the conversion of irinotecan to its inactive metabolite was reduced by 87%, whereas the relative exposure to the active prodrug was increased by 109%. Both hematologic (degree of myelosuppression; percent decrease in neutrophil count) and nonhematologic (nausea, vomiting, and diarrhea) parameters were similar between the courses, despite a 3.5 fold reduced irinotecan dose when given in combination with ketoconazole. The authors concluded that the coadministration of various CYP3A4 inhibitors could potentiate a fatal outcome.(3) A prospective, open-label, randomized study was conducted to determine the pharmacokinetics of lopinavir (LPV)/ritonavir (RTV) administration with irinotecan (CPT11). Eight HIV-infected, Caucasian male patients with Kaposi's sarcoma, stage IV (according to New York University classification) were administered highly active antiretroviral therapy (HAART). HAART consisted of 400 mg lopinavir/ 100 mg ritonavir (Kaletra) twice daily (b.i.d) in association with NRTIs b.i.d. for at least 1 month before the start of anticancer chemotherapy. Patients were then treated with irinotecan as a single agent (150 mg/m2) over a 90 min infusion at days 1 and 10, every 3 weeks. Concomitant LPV/RTV treatment reduced the irinotecan clearance from 21.3 +/- 6.3 to 11.3 +/- 3.5 l/h/m2 (P=0.0008) causing an 89% increase of CPT11 AUC (P=0.001) and a 20% increase in the Cmax of CPT11 (p=0.02). The LPV/RTV treatment increased the AUC of SN38 by 204% (p=0.0001) and AUC of SN38G by 94% (P=0.002). Conversely, LPV/RTV treatment caused an 81% reduction in AUC of APC (p=0.02). Overall, the authors concluded that CYP3A4 inhibitors like LPV/RTV decrease CPT11 clearance and increase SN-38 exposure, potentially leading to CPT11 toxicity if not monitored closely.(7) Strong CYP3A4 Inhibitors include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(8) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Strong Cyp3a4 Inhibitors; Protease Inhibitors/Eplerenone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 and protease inhibitors may inhibit the metabolism of eplerenone.(1-3)

CLINICAL EFFECTS: Concurrent use of eplerenone with a strong inhibitor of CYP3A4 or a protease inhibitor may result in 5-fold increases in eplerenone concentrations and toxicity (e.g. hyperkalemia, hypotension).(1-3)

PREDISPOSING FACTORS: Severe renal disease increases the risk for hyperkalemia.

PATIENT MANAGEMENT: The manufacturer of eplerenone states that the concurrent use of strong CYP3A4 inhibitors is contraindicated.(1) The US Department of Health and Human Services HIV guidelines state that protease inhibitors are contraindicated with eplerenone.(3) The US manufacturer of itraconazole states that concurrent use of eplerenone is contraindicated during and two weeks after itraconazole treatment.(4) The starting dose of eplerenone for hypertension should be reduced to 25 mg in patients receiving moderate CYP3A4 inhibitors.(1) In all patients taking eplerenone who start taking a moderate CYP3A4 inhibitor, check serum potassium and creatinine levels after 3-7 days of concurrent therapy.(1)

DISCUSSION: Ketoconazole (200 mg BID) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of eplerenone (100 mg) by 1.7-fold and 5.4-fold, respectively.(1) The concurrent use of eplerenone with less potent CYP3A4 inhibitors (erythromycin 500 mg BID, fluconazole 200 mg daily, saquinavir 1200 mg TID, and verapamil 240 mg daily) increased the Cmax of eplerenone by 1.4-fold to 1.6-fold and the AUC of eplerenone by 2.0-fold and 2.9-fold.(1) Strong inhibitors of CYP3A4 and protease inhibitors linked to this monograph include: adagrasib, amprenavir, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, ensitrelvir, fosamprenavir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(1,2)

Strong Cyp3a4 Inhibitors; Protease Inhibitors/Ticagrelor

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of ticagrelor.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in a substantial increase in exposure to and effects from ticagrelor, including increased risk of bleeding.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The UK manufacturer of ticagrelor states that concurrent use of strong CYP3A4 inhibitors is contraindicated.(1) The US manufacturer of ticagrelor states that concurrent use of strong CYP3A4 inhibitors should be avoided.(2) The US manufacturer of itraconazole states that concurrent use of ticagrelor is contraindicated during and two weeks after itraconazole treatment.(3)

DISCUSSION: Concurrent ketoconazole increased ticagrelor maximum concentration (Cmax) and area-under-curve (AUC) by 2.4-fold and 7.3-fold, respectively. The Cmax and AUC of the active ticagrelor metabolite decreased by 89% and 56%, respectively.(1) Strong CYP3A4 inhibitors linked include: adagrasib, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, ensitrelvir, fosamprenavir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir/ritonavir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tucatinib, and voriconazole.(4,5)

Strong Cyp3a4 Inhibitors; Protease Inhibitors/Vorapaxar

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of vorapaxar.(1-3)

CLINICAL EFFECTS: Concurrent use of an agent that is a strong inhibitor of CYP3A4 or a protease inhibitor may result in elevated levels of and clinical effects of vorapaxar,(1) including an increased risk of bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The US manufacturer of vorapaxar states that concurrent use with strong inhibitors of CYP3A4 should be avoided.(1) The US Department of Health and Human Services HIV guidelines state that protease inhibitors should not be coadministered with vorapaxar.(4) The US manufacturer of itraconazole states that concurrent use with vorapaxar is not recommended during and two weeks after itraconazole treatment.(5) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In a study in 12 healthy subjects, ketoconazole (400 mg daily for 28 days) increased exposure to vorapaxar (20 mg on Day 7, 2.5 mg on Days 8-28) by 2-fold.(1,2) Strong inhibitors of CYP3A4 and protease inhibitor linked to this monograph include: adagrasib, atazanavir, ceritinib, clarithromycin, cobicistat, darunavir, ensitrelvir, fosamprenavir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(6)

Strong Or Moderate Cyp3a4 Inhibitors/Flibanserin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Flibanserin is primarily metabolized by CYP3A4, though CYP2C19 also plays a role in metabolism.(1)

CLINICAL EFFECTS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may result in high to very high levels of and toxicity from flibanserin, including severe hypotension or syncope.(1)

PREDISPOSING FACTORS: Patients with any degree of hepatic impairment, who are poor CYP2C19 metabolizers, or who also receive concomitant therapy with strong CYP2C19 inhibitors are expected to have increased systemic concentrations of flibanserin, adding to the risk for hypotension or syncopal episodes.(1) Hypotensive or syncopal episodes are more common when flibanserin is taken during waking hours.(1)

PATIENT MANAGEMENT: The concomitant use of flibanserin with moderate or strong CYP3A4 inhibitors significantly increases flibanserin concentrations which may lead to hypotension and syncope. The manufacturer of flibanserin states moderate or strong CYP3A4 inhibitors are contraindicated.(1) If the benefit of initiating a CYP3A4 inhibitor within 2 days of stopping flibanserin clearly outweighs the risk flibanserin-associated hypotension or syncope, monitor and counsel the patient regarding symptoms of hypotension or syncope. Discontinue moderate or strong CYP3A4 inhibitors for 2 weeks before initiating or restarting flibanserin therapy.(1)

DISCUSSION: In a drug interaction study with 15 healthy subjects, the combination of flibanserin (100 mg on day 6) and fluconazole (a moderate CYP3A4 and strong CYP2C19 inhibitor, 400 mg once then 200 mg daily for 5 days) resulted in an increased flibanserin exposure of 7-fold. Hypotension or syncope requiring supine placement with leg elevation occurred in 3 subjects (20%). One patient became unresponsive with a blood pressure of 64/41 mm Hg and required emergency room treatment where she required intravenous saline.(1) Though the combination has not been studied, a similar result is plausible with voriconazole, a strong CYP3A4 inhibitor and moderate CYP2C19 inhibitor.(1) In a drug interaction study with flibanserin 50 mg (one-half of the recommended dose) and ketoconazole 400 mg, flibanserin exposure increased 4.5-fold. One of 24 patients(4%) developed syncope.(1) A study of 12 healthy men and women on itraconazole (400 mg once then 200 mg daily for 4 days) with flibanserin 50 mg given 2 hours after itraconazole found that flibanserin exposure was increased 2.6-fold.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(1-3) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir/ritonavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole (also a CYP2C19 inhibitor), fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, ledipasvir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(1-3)

Strong Or Moderate Cyp3a4 Inhibitors/Lomitapide

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Lomitapide is primarily metabolized via CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may result in high to very high levels of and toxicity from lomitapide.(1)

PREDISPOSING FACTORS: The interaction may be more severe in patients with hepatic impairment or with end-stage renal disease.(1)

PATIENT MANAGEMENT: Given the magnitude of this interaction and the potential toxicity of lomitapide, moderate and strong CYP3A4 inhibitors are contraindicated.(1) When possible use an alternative to the CYP3A4 inhibitor. If a moderate or strong CYP3A4 inhibitor is required, discontinue lomitapide. Due to its long half-life, it will take 1 to 2 weeks for remaining lomitapide to be eliminated; thus lomitapide adverse effects could occur after discontinuation. The US manufacturer of itraconazole states that concurrent use with lomitapide is contraindicated during and two weeks after itraconazole treatment.(4)

DISCUSSION: Concurrent administration with ketoconazole (a strong inhibitor of CYP3A4) increased lomitapide area-under-curve (AUC) by 27-fold.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(1-3,5) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir/ritonavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole (also a CYP2C19 inhibitor), fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, lefamulin, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(1-3)

Strong&Mod 3A4 Inhib That Prolong Qt/Cilostazol (>50 Mg Bid)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong and moderate inhibitors of CYP3A4 may inhibit the metabolism of cilostazol at CYP3A4.(1) Both agents have been shown to prolong the QT interval.(1,2)

CLINICAL EFFECTS: The concurrent use of cilostazol and strong and moderate inhibitors of CYP3A4 may result in elevated levels of cilostazol, which may produce increased effects of cilostazol and adverse effects.(1) Concurrent use may also result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(2)

PREDISPOSING FACTORS: In general, the risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(1) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(1) This interaction may also be more severe in patients taking inhibitors of CYP2C19.(1)

PATIENT MANAGEMENT: The dose of cilostazol should be limited to 50 mg twice daily in patients receiving concurrent therapy with strong and moderate inhibitors of CYP3A4.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study in 16 healthy males, the administration of a single dose of cilostazol (10 mg) with erythromycin (500 mg every eight hours) increased the maximum concentration (Cmax) and area-under-curve (AUC) of cilostazol by 47% and 73%, respectively. The Cmax and AUC of 4'-trans-hydroxy-cilostazol were increased by 29% and 141%, respectively.(3) Analysis of population pharmacokinetics indicated that the concurrent administration of diltiazem with cilostazol increased cilostazol concentrations by 53%.(1) Concurrent administration of diltiazem and cilostazol decreased cilostazol clearance by 30%, increased the Cmax by 30%, and increased AUC by 40%. In a study, the administration of a single dose of cilostazol (10 mg) with erythromycin (500 mg every eight hours) increased the Cmax and AUC of cilostazol by 47% and 73%, respectively. The AUC of 4'-trans-hydroxy-cilostazol was increased by 141%.(1) In an vitro study in human liver microsomes, ketoconazole inhibited the metabolism of cilostazol.(4) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Adagrasib/Ivosidenib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ivosidenib, a strong CYP3A4 inducer(1), may induce the CYP3A4 isoenzyme and increase the metabolism of adagrasib.(2) Strong inhibitors of the CYP3A4 enzyme may inhibit the metabolism of ivosidenib.(3) Adagrasib is a strong CYP3A4 inhibitor.(1) Concurrent use of adagrasib and ivosidenib may also result in additive effects on the QTc interval.

CLINICAL EFFECTS: Concurrent use of adagrasib with ivosidenib, a strong CYP3A4 inducer, may decrease the levels and effectiveness of adagrasib and may cause additive effects on the QTc interval, which may result in life-threatening cardiac arrhythmias including torsades de pointes.(2) In addition, systemic exposure to ivosidenib may increase and elevate the risk for ivosidenib toxicities such as QT prolongation.(3)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The manufacturer of adagrasib states that the concurrent use of strong CYP3A4 inducers should be avoided, and that alternative treatments with less CYP3A4 induction should be considered.(2) If patients develop QTc prolongation >500 msec or >60 msec from baseline, withhold adagrasib until QTc interval less than 481 msec or QTc interval returns to baseline. Resume adagrasib at the next lower dose level. If patients develop torsade de pointes, polymorphic ventricular tachycardia, or signs and symptoms of serious or life-threatening arrhythmia, permanently discontinue adagrasib.(2) Avoid the concurrent use of strong CYP3A4 inducers like ivosidenib in patients receiving therapy with adagrasib. Consider the use of alternative agents with less enzyme induction potential and less potential to affect the QTc interval.(3) The US manufacturer of ivosidenib recommends considering an alternative concomitant medication with less potential for CYP3A4 inhibition.(3) Although the manufacturer of ivosidenib provides recommendations for dose modification of ivosidenib when used with strong CYP3A4 inhibitors, it has not been studied in dual-directional interactions such as with adagrasib. Thus, this dose modification recommendation is for information only. The US manufacturer of ivosidenib states when concomitant use of ivosidenib and a strong CYP3A4 inhibitor is needed, the ivosidenib dose should be reduced to 250 mg once daily. If the strong CYP3A4 inhibitor is discontinued, increase the ivosidenib dose to the recommended dose of 500 mg once daily after at least 5 half-lives of the strong 3A4 inhibitor.(3) If concurrent therapy is warranted, monitor patients closely for prolongation of the QT interval. Obtain serum calcium, magnesium, and potassium levels and monitor ECG at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study with healthy subjects, co-administration of rifampin (strong 3A4 inducer) with a single dose of adagrasib (600 mg), decreased adagrasib area-under-curve (AUC) by 95% and maximum concentration (Cmax) by 88%.(2) Co-administration of rifampin (strong 3A4 inducer) with multiple doses of adagrasib (600 mg) is predicted to decrease adagrasib AUC by greater than 61% and Cmax by greater than 66%.(2) Adagrasib has been associated with QTc interval prolongation. Adagrasib increased QTc in a concentration-dependent manner. In patients administered adagrasib 600 mg twice daily, the mean QTcF change from baseline was 18 msec. In the pooled safety population, 6% of 366 patients with at least one post-baseline ECG had an average QTc greater than 501 msec and 11% of patients had a increase from baseline QTc greater than 60 msec.(2) In a drug interaction study in healthy subjects, coadministration of itraconazole (200 mg once daily for 18 days) with a single dose of ivosidenib (250 mg) increased ivosidenib AUC by 269%. No change was seen in ivosidenib's Cmax.(3)

Adagrasib/Qt Prolonging Agents

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Adagrasib has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1-3)

CLINICAL EFFECTS: The concurrent use of adagrasib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1-3)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of adagrasib states that the concurrent use of QT prolonging agents should be avoided.(1) When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If patients develop QTc prolongation >500 msec or >60 msec from baseline, withhold adagrasib until QTc interval less than 481 msec or QTc interval returns to baseline. Resume adagrasib at the next lower dose level. If patients develop torsade de pointes, polymorphic ventricular tachycardia, or signs and symptoms of serious or life-threatening arrhythmia, permanently discontinue adagrasib.(1)

DISCUSSION: Adagrasib has been associated with QTc interval prolongation. Adagrasib increased QTc in a concentration-dependent manner. In patients administered adagrasib 600 mg twice daily, the mean QTcF change from baseline was 18 msec. In the pooled safety population, 6% of 366 patients with at least one post-baseline ECG had an average QTc greater than 501 msec and 11% of patients had a increase from baseline QTc greater than 60 msec.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)

Adagrasib/Strong Cyp3a4 Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of adagrasib.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in elevated levels and increased effects of adagrasib, such as hepatotoxicity, intersitial lung disease or pneumonitis, or gastrointestinal adverse reactions.(1,2) Symptoms can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue. Concurrent use may also result in increased risk of QTc prolongation, which may lead to life-threatening cardiac arrhythmias like torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)

PATIENT MANAGEMENT: The US manufacturer of adagrasib states that adagrasib coadministration with strong inhibitors of CYP3A4 should be avoided until adagrasib concentrations have reached steady state (approximately 8 days).(1) Monitor liver tests, including AST, ALT, total bilirubin, according to the recommendations in the Krazati package insert. Advise patients to immediately report any symptoms of hepatotoxicity. Monitor for new or worsening respiratory symptoms indicative of interstitial lung disease or pneumonitis. If patients develop QTc prolongation >500 msec or >60 msec from baseline, withhold adagrasib until QTc interval less than 481 msec or QTc interval returns to baseline. Resume adagrasib at the next lower dose level. If patients develop torsade de pointes, polymorphic ventricular tachycardia, or signs and symptoms of serious or life-threatening arrhythmia, permanently discontinue adagrasib.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Coadministration of itraconazole (a strong CYP3A4 inhibitor) increased adagrasib (single dose 200 mg) maximum concentration (Cmax) and area-under-the-curve (AUC) by 2.4-fold and 4-fold. No clinically significant differences in the pharmacokinetics of adagrasib at steady state were predicted when used concomitantly with itraconazole.(1) Adagrasib has been associated with QTc interval prolongation. Adagrasib increased QTc in a concentration-dependent manner. In patients administered adagrasib 600 mg twice daily, the mean QTcF change from baseline was 18 msec. In the pooled safety population, 6% of 366 patients with at least one post-baseline ECG had an average QTc greater than 501 msec and 11% of patients had a increase from baseline QTc greater than 60 msec.(1) Strong inhibitors of CYP3A4 linked to this monograph include: boceprevir, cobicistat, ensitrelvir, itraconazole, josamycin, ketoconazole, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, relacorilant, telaprevir, and tucatinib.(1,3)

Adagrasib/Strong Cyp3a4 Inhibitors That Prolong Qt

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong the QTc interval may inhibit the metabolism of adagrasib and result in additive effects on the QTc interval.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 that prolongs the QTc interval may result in elevated levels and increased effects of adagrasib, such as hepatotoxicity, intersitial lung disease or pneumonitis, or gastrointestinal adverse reactions.(1,2) Symptoms can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue. Concurrent use may also result in additive QTc prolongation, which may lead to life-threatening cardiac arrhythmias like torsade de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)

PATIENT MANAGEMENT: The US manufacturer of adagrasib states that the concurrent use of QT prolonging agents should be avoided.(1) The US manufacturer of adagrasib states that adagrasib coadministration with strong inhibitors of CYP3A4 should be avoided until adagrasib concentrations have reached steady state (approximately 8 days).(1) When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If patients develop QTc prolongation >500 msec or >60 msec from baseline, withhold adagrasib until QTc interval less than 481 msec or QTc interval returns to baseline. Resume adagrasib at the next lower dose level. If patients develop torsade de pointes, polymorphic ventricular tachycardia, or signs and symptoms of serious or life-threatening arrhythmia, permanently discontinue adagrasib.(1) Monitor liver tests, including AST, ALT, total bilirubin, according to the recommendations in the Krazati package insert. Advise patients to immediately report any symptoms of hepatotoxicity. Monitor for new or worsening respiratory symptoms indicative of interstitial lung disease or pneumonitis.

DISCUSSION: Coadministration of itraconazole (strong CYP3A4 inhibitor) increased adagrasib (single dose 200 mg) maximum concentration (Cmax) and area-under-the-curve (AUC) by 2.4-fold and 4-fold. No clinically significant differences in the pharmacokinetics of adagrasib at steady state were predicted when used concomitantly with itraconazole.(1) Adagrasib has been associated with QTc interval prolongation. Adagrasib increased QTc in a concentration-dependent manner. In patients administered adagrasib 600 mg twice daily, the mean QTcF change from baseline was 18 msec. In the pooled safety population, 6% of 366 patients with at least one post-baseline ECG had an average QTc greater than 501 msec and 11% of patients had a increase from baseline QTc greater than 60 msec.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(4) Strong inhibitors of CYP3A4 linked to this monograph include: clarithromycin, telithromycin, and voriconazole.(1,3)

Cyp3a4 Inhibitors And Substrates That Prolong Qt/Encorafenib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Encorafenib is a CYP3A4 substrate and a strong CYP3A4 inducer. Strong and moderate inhibitors of CYP3A4 may inhibit the metabolism of encorafenib. Also, the metabolism of sensitive substrates of CYP3A4 may be induced by encorafenib.(1) Encorafenib may prolong the QTc interval. Concomitant use with other QT prolonging agents may result in an additive risk of QT prolongation.(1)

CLINICAL EFFECTS: Concomitant use of encorafenib with agents that are both strong or moderate CYP3A4 inhibitors and CYP3A4 substrates may result in increased levels and effects from encorafenib including QT prolongation. Concomitant use may also result in decreased levels and effectiveness of the CYP3A4 substrate.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2) Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Avoid concomitant use of encorafenib with strong or moderate CYP3A4 inhibitors that are also CYP3A4 substrates and prolong the QTc interval.(1) The US manufacturer of encorafenib states that it should be avoided with CYP3A4 substrates for which decreased plasma concentrations may result in decreased therapeutic efficacy. If coadministration cannot be avoided, refer to the CYP3A4 substrate prescribing information for recommendations.(1) In addition, concurrent use of strong or moderate CYP3A4 inhibitors or QT prolonging medications with encorafenib should be avoided.(1) The net effect of this two-way interaction is unknown and optimal doses of the drugs when used concurrently have not been determined. The manufacturer provides recommendations for dose modification when encorafenib is used with a CYP3A4 inhibitor, but the recommendations may not apply when there is a two-way interaction. Dose modifications mentioned below are informational only. If concurrent use of strong or moderate CYP3A4 inhibitors with encorafenib is unavoidable, reduce the encorafenib dose as follows: - If the current daily dose of encorafenib is 450 mg, reduce encorafenib to 150 mg with strong CYP3A4 inhibitors, and 225 mg with moderate CYP3A4 inhibitors. - If the current daily dose of encorafenib is 300 mg, reduce encorafenib to 75 mg with strong CYP3A4 inhibitors, and 150 mg with moderate CYP3A4 inhibitors. - If the current daily dose of encorafenib is 225 mg or 150 mg, reduce encorafenib to 75 mg with both strong and moderate CYP3A4 inhibitors. - After the inhibitor has been discontinued for 3 to 5 half-lives, resume encorafenib dose that was taken prior to initiating the CYP3A4 inhibitor.(1) When concurrent therapy cannot be avoided, monitor patients closely for prolongation of the QT interval. Obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. Recommended dosage modifications for encorafenib and QTc prolongation adverse reactions include: - QTcF greater than 500 ms and less than or equal to 60 ms increase from baseline: Withhold encorafenib until QTcF less than or equal to 500 ms. Resume at reduced dose. If more than one recurrence, permanently discontinue encorafenib. - QTcF greater than 500 ms and greater than 60 ms increase from baseline: Permanently discontinue encorafenib.(1) See encorafenib prescribing information for additional information regarding dose reductions.(1)

DISCUSSION: Coadministration of posaconazole (strong CYP3A4 inhibitor) or diltiazem (moderate CYP3A4 inhibitor) increased the area-under-curve (AUC) of encorafenib by 3-fold and 2-fold, respectively, and increased the maximum concentration (Cmax) by 68% and 45%, respectively, after a single dose of encorafenib 50 mg (0.1 times the recommended dose).(1) Encorafenib 450 mg daily with binimetinib 45 mg twice daily decreased the AUC and Cmax of single dose of midazolam 2 mg, a sensitive CYP3A4 substrate, by 82% and 74%, respectively, relative to midazolam 2 mg alone.(1) Encorafenib has been associated with a dose-dependent QTc interval prolongation. Following administration of encorafenib in combination with binimetinib, the largest mean (90% CI) QTcF change from baseline was 18 ms (14-22 ms), based on central tendency analysis.(1) Following administration of encorafenib in combination with cetuximab and mFOLFOX6, an increase of QTcF >500 ms was measured in 4% (9/226) of patients. Following administration of encorafenib with cetuximab and FOLFIRI, an increase of QTcF >500 ms was measured in 1.5% (1/65) of patients.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3) Agents that are both strong CYP3A4 inhibitors and CYP3A4 substrates and prolong the QTc interval linked to this monograph include: adagrasib, ceritinib, clarithromycin, and ribociclib.(4) Agents that are both moderate CYP3A4 inhibitors and CYP3A4 substrates and prolong the QTc interval linked to this monograph include: crizotinib, dronedarone, erythromycin, oral lefamulin and nilotinib.(4)

Dual Cyp2c9 And Cyp3a4 Inhibitors That Prolong Qt/Etrasimod

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Dual moderate to strong inhibitors of CYP2C9 and CYP3A4 that prolong the QTc interval may inhibit the metabolism of etrasimod. Etrasimod is metabolized by CYP2C8, CYP2C9, and CYP3A4.(1) Initiation of etrasimod has a negative chronotropic effect, which may increase the risk of developing QT prolongation.(1)

CLINICAL EFFECTS: Concurrent use of a dual moderate or strong inhibitor of CYP2C9 and CYP3A4 may result in elevated levels and increased effects of etrasimod.(1) Initiation of etrasimod may result in a transient decrease in heart rate. A mean decrease in heart rate of 7.2 (8.98) beats per minute was seen 2 to 3 hours after the first dose. The first dose has also been associated with heart block. Symptomatic bradycardia has been observed. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsades de pointes.(1)

PREDISPOSING FACTORS: Pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to etrasimod initiation, factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia), or concomitant treatment with QT prolonging agents may increase risk for cardiovascular toxicity due to etrasimod. The risk of QT prolongation or torsades de pointes may also be increased in patients with a history of torsades de pointes, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of the QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Concomitant use of etrasimod with dual moderate to strong inhibitors of CYP2C9 and CYP3A4 is not recommended.(1) If concurrent therapy is unavoidable, obtain an ECG to determine if preexisting conduction abnormalities are present prior to initiation of etrasimod.(1) Advice from a cardiologist is recommended in patients with preexisting heart and cerebrovascular conditions, prolonged QTc interval, risk factors for QT prolongation, concurrent therapy with QT prolonging drugs or drugs that slow the heart rate or AV conduction.(1) Monitor blood pressure during treatment.(1)

DISCUSSION: Initiation of etrasimod may result in a transient decrease in heart rate or transient AV conduction delays.(1) A transient decrease in heart rate was observed during the initial dosing phase of etrasimod and bradyarrhythmic events (AV blocks) were detected at a higher incidence under etrasimod treatment than placebo.(1) Concomitant use of etrasimod with steady-state fluconazole (moderate CYP2C9 and CYP3A4 inhibitor) increased etrasimod area-under-curve (AUC) by 84%.(1) Dual inhibitors of CYP2C9 and CYP3A4 include: adagrasib and fluconazole.(3)

Dual Strong Cyp3a4 & P-Gp Inhib That Prolong Qt/Pralsetinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Combined strong CYP3A4 and P-glycoprotein (P-gp) inhibitors that prolong the QTc interval may inhibit the metabolism of pralsetinib and result in additive risk of QT prolongation.(1-3)

CLINICAL EFFECTS: Concurrent administration of a combined strong CYP3A4 and P-gp inhibitor that prolongs QT may result in elevated levels of and toxicity from pralsetinib, including additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1-3) Other toxicities include hemorrhagic events, pneumonitis, hepatotoxicity, and hypertension.(1-3)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)

PATIENT MANAGEMENT: Coadministration of pralsetinib with combined strong CYP3A4 and P-gp inhibitors that prolong QT should be avoided. If coadministration with a combined strong CYP3A4 and P-gp inhibitor that prolongs QT cannot be avoided, use with caution reduce the dose of pralsetinib as follows: -If the current dose is 400 mg once daily, decrease the dose to 200 mg daily. -If the current dose is 300 mg once daily, decrease the dose to 200 mg daily. -If the current dose is 200 mg once daily, decrease the dose to 100 mg daily. After the inhibitor is discontinued for three to five half-lives, resume the dose of pralsetinib at the dose taken prior to initiation of the inhibitor.(1) When concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If the QTc interval exceeds 500 ms, interrupt pralsetinib therapy until QTc is <470 ms. Resume pralsetinib at the same dose if risk factors that cause QT prolongation an are identified and corrected. If risk factors that cause QT prolongation are not identified, resume pralsetinib at a reduced dose. Permanently discontinue pralsetinib if the patient develops life-threatening arrhythmia.(3)

DISCUSSION: Coadministration of itraconazole 200 mg once daily (a strong CYP3A4 and P-gp inhibitor) with a single pralsetinib 200 mg dose increased pralsetinib concentration maximum (Cmax) by 84% and area-under-curve (AUC) by 251%.(1) In clinical trials, QTc prolongation developed in 5.1% of patients on pralsetinib, with 2 patients (0.4%) having serious prolongation. Two patients required dose reductions or interruptions. No patients required permanent discontinuation of pralsetinib, and there was no life-threatening or fatal QT prolongation.(2) In a secondary analysis of the phase II ARROW study, ECG and plasma concentrations of 34 patients were examined. At steady state, mean change in QTc was 4.9-7.7 ms, with a greater QTc increase at higher concentrations, especially above 3,000 ng/mL. Although median minimum concentration (Cmin) is 1,150 ng/mL, there is a large interindividual variation and concentrations above 3,000 ng/mL may be expected in some patients.(2) Combined strong CYP3A4 and P-gp inhibitors linked to this monograph include: adagrasib, clarithromycin, levoketoconazole, lonafarnib, lopinavir/ritonavir, posaconazole, saquinavir, and telithromycin.(5,6)

Dual Strong Cyp3a4 Inhibitor & P-Gp Inhibitors/Riociguat

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Riociguat is primarily metabolized by CYP1A1 and to a lesser extent by CYP3A4/3A5, CYP2C8, and CYP2J2.(1) P-glycoprotein (P-gp) and BCRP (breast cancer resistance protein) transport proteins participate in the biliary/fecal elimination of riociguat.(2) Dual inhibitors of CYP3A4 and P-gp may inhibit metabolic and transporter-based elimination of riociguat.(2)

CLINICAL EFFECTS: Concurrent use with dual inhibitors of CYP3A4 and P-gp may result in elevated systemic levels and toxicity (e.g. hypotension) from riociguat.(1)

PREDISPOSING FACTORS: The risk for riociguat-associated hypotension is higher in patients with a systolic blood pressure (SBP) < or = 110 prior to treatment initiation or dose increase. Patient specific factors such as renal or hepatic impairment, or age > 65 years are associated with higher systemic exposure(1) to riociguat and may increase interaction risk or severity.

PATIENT MANAGEMENT: The manufacturer recommends a lower riociguat starting dose of 0.5 mg three times daily in patients receiving concomitant treatment with dual strong CYP and P-gp inhibitors.(1) The US manufacturer of itraconazole states that concurrent use with riociguat is not recommended during and two weeks after itraconazole treatment.(3) Patients stabilized on riociguat when a dual strong CYP and P-gp inhibitor is initiated may need to have their riociguat dose lowered for the duration of concurrent therapy. Monitor blood pressure and counsel patient to report low blood pressure, lightheadedness or chest pain. Patients stabilized on concomitant therapy may need to have their riociguat dose retitrated upward after discontinuation of the dual strong CYP and P-gp inhibitors.

DISCUSSION: In an interaction study, ketoconazole (an inhibitor of CYP1A1, CYP3A4, and P-gp) given 400 mg once daily increased the mean maximum concentration (Cmax) and area-under-curve (AUC) of riociguat by 46% and 150%, respectively.(2) The frequency or magnitude of this interaction is difficult to predict in a specific patient due to significant interpatient variability in drug kinetics. For example, between patient variability in systemic exposure(AUC)relative to dose is 90%. The amount of riociguat metabolized may be as low as 27% or as high as 72%. Cigarette smoking induces the CYP1A1 mediated metabolism of riociguat leading to about a 50% decrease in systemic exposure compared with non-smoking patients.

Myelosuppressive Cyp3a4 Inhibitors That Prolong Qt/Clozapine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: CYP3A4 inhibitors may inhibit the metabolism of clozapine.(1,2) Concurrent use of clozapine with agents that prolong the QTc interval and cause myelosuppression may result in additive effects on both the QTc interval and blood counts.(1)

CLINICAL EFFECTS: The concurrent administration of clozapine with CYP3A4 inhibitors may result in elevated levels of clozapine and an increase in clozapine related side effects such as orthostatic hypotension, syncope, QT prolongation, profound sedation and seizures.(1) The use of clozapine in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1) Moderate neutropenia, even if due to combination therapy, may require abrupt discontinuation of clozapine resulting in decompensation of the patient's psychiatric disorder (e.g. schizophrenia). The disease treated by the myelosuppressive agent may be compromised if myelosuppression requires dose reduction, delay, or discontinuation of the myelosuppressive agent. Undetected severe neutropenia or agranulocytosis may be fatal.

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3) Low white blood counts prior to initiation of the myelosuppressive agent may increase risk for clinically significant neutropenia.

PATIENT MANAGEMENT: Clozapine levels should be monitored in patients receiving concurrent therapy with strong CYP3A4 inhibitors. Patients should be monitored for signs of clozapine toxicity, including QT prolongation and myelosuppression. The dosage of clozapine may need to be adjusted, or one or both agents may need to be discontinued. Clozapine levels should also be monitored following the discontinuation of of the CYP3A4 inhibitor from concurrent therapy.(1) If a patient stabilized on clozapine therapy requires treatment with a myelosuppressive agent, the clozapine prescriber should consult with prescriber of the myelosuppressive agent (e.g. oncologist) to discuss treatment and monitoring options.(2) More frequent absolute neutrophil count (ANC) monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. The U.S. Food and Drug Administration (FDA) recommends that prescribers monitor patients' ANC according to the monitoring frequencies described in the prescribing information. Severe neutropenia remains a serious, potentially fatal risk that is greatest in the first several months of clozapine treatment. ANC monitoring can help identify neutropenia early to allow for timely intervention.(4) Australia, Canada and U.K.: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing. For most clozapine patients, clozapine treatment must be interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter. For patients with benign ethnic neutropenia (BEN), treatment must be interrupted for suspected clozapine-induced neutropenia < 500 cells/microliter.(2) If concurrent therapy is warranted in patients receiving clozapine, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study in 92 psychiatric patients maintained on clozapine, the ratio of clozapine levels/dose was found to correlate with expression of CYP3A4.(1) Clozapine is a substrate of CYP1A2, CYP2D6, and CYP3AA4.(2) Myelosuppressive CYP3A4 inhibitors that prolong QT linked to this monograph include: adagrasib, lonafarnib, and ribociclib.

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)

DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)

P-Gp And Strong Cyp3a4 Inhibitors/Apixaban

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Adagrasib, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, paritaprevir, posaconazole, telaprevir, tucatinib, and telithromycin may inhibit the metabolism of apixaban by CYP3A4 and by P-glycoprotein (P-gp).(1-4)

CLINICAL EFFECTS: Concurrent use of an agent that is both an inhibitor of P-gp and a strong inhibitor of CYP3A4 may result in elevated levels of and clinical effects of apixaban, including an increased risk of bleeding.(1-4)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The Australian(1) and Canadian(2) manufacturers of apixaban states that the concurrent use of agents that are strong inhibitors of both P-gp and CYP3A4 with apixaban is contraindicated. The UK manufacturer of apixaban states that concurrent use of these agents is not recommended.(3) The US manufacturer of apixaban states that if concurrent use cannot be avoided, the dosage of apixaban should be reduced by 50%. In patients already receiving apixaban 2.5 mg twice daily, avoid the concurrent use of strong inhibitors of both P-gp and CYP3A4.(4) The US manufacturer of itraconazole states that apixaban is not recommended during and two weeks after itraconazole treatment.(5) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Concurrent ketoconazole (400 mg daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of apixaban by 2-fold and 1.6-fold, respectively.(1) P-gp and strong CYP3A4 inhibitors linked to this monograph are: adagrasib, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, paritaprevir, posaconazole, telaprevir, tucatinib and telithromycin.

Qt Prolonging Agents/Ajmaline

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ajmaline has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of ajmaline with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1)

PREDISPOSING FACTORS: In general, the risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: If possible, avoid the use of ajmaline with other agents known to prolong the QT interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Ajmaline has been associated with case reports of QT prolongation and torsades de pointes (TdP).(1,3-8) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(9)

Qt Prolonging Agents/Dexmedetomidine Sublingual

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Dexmedetomidine sublingual has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of dexmedetomidine sublingual with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of dexmedetomidine sublingual states that concurrent use should be avoided with other agents known to prolong the QTc interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a QT study, dexmedetomidine sublingual had a concentration dependent effect on the QT interval. The mean QTc (95% confidence interval) increased from baseline by 6 (7) msec with a 120 mcg single dose, 8 (9) msec with 120 mcg followed by 2 additional doses of 60 mcg (total 3 doses), 8 (11) msec with a single 180 mcg dose, and 11 (14) msec with 180 mcg followed by 2 additional doses of 90 mcg (total 3 doses), respectively.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)

Qt Prolonging Agents/Ezogabine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The use of ezogabine in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsade de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The concurrent use of ezogabine with agents known to prolong the QT interval should be approached with caution. Patients receiving concurrent therapy with other QT prolongers, an electrocardiogram (ECG) should be performed prior to ezogabine initiation. In those patients with a corrected QT interval greater than 440 msec at baseline, a repeat ECG should be performed after reaching the maintenance dose of ezogabine.(1) Consider obtaining serum calcium, magnesium, and potassium levels at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study in healthy subjects, ezogabine titrated to 1200 mg/day increased the mean QTc interval by 6.7 msec (upper bound of 95% CI was 12.6 msec) within three hours of dosing.(1)

Qt Prolonging Agents/Firmonertinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Firmonertinib may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of firmonertinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of firmonertinib states that firmonertinib should be avoided in patients with risk factors that may increase the risk of QTc interval prolongation or arrhythmic events, such as heart failure, hypokalemia, or congenital long QT syndrome.(1) Concurrent use of QT prolonging agents should be avoided. If concurrent use cannot be avoided, obtain ECGs prior to initiating firmonertinib, during concomitant use, and as clinically indicated. More frequent ECG monitoring may be necessary. The manufacturer of firmonertinib states patients with at least two independent ECG tests indicating a QTc > 500 ms should temporarily discontinue firmonertinib until QTc < 481 ms or returns to baseline levels (e.g., baseline QTc > or = 481 ms). Patients with QTc prolongation and severe arrhythmic symptoms or signs should permanently discontinue firmonertinib.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In clinical trials, among 446 patients treated with firmonertinib at a dose of 80 mg, 57 (12.8%) experienced QT interval prolongation on an ECG, of which 6 (1.3%) were grade 3 and the rest were grade 1-2. Of these, 7 (1.6%) experienced dose interruption, 5 (1.1%) experienced dose reduction, and 1 (0.2%) experienced permanent discontinuation of treatment.(1) In another study, QTc interval prolongation was reported as an adverse event in 6% of 130 patients (in 20 mg, 40 mg, 80 mg, and 160 mg groups; n=2 each). All were classified as grade 1 or grade 2 and assessed as possibly related to treatment. Two events (grade 2 at 80 mg, grade 2 at 160 mg) led to dose interruption before resolution. QT prolongation in the remaining patients was resolved without intervention, except for one event (grade 1) reported as worsening.(3)

Qt Prolonging Agents/Gadofosveset

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: QT prolongation has been reported following gadofosveset administration. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The use of gadofosveset in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: In patients maintained on agents known to prolong the QT interval, consider a baseline ECG prior to administration of gadofosveset to asses the risk/benefit of gadofosveset. If gadofosveset is used, consider ECG monitoring for 72 hours until the majority of gadofosveset is eliminated. Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Counsel patients to report any irregular heartbeat, dizziness, or fainting episodes during this time frame.(1)

DISCUSSION: In clinical trials, 6% of patients experienced an increase in QTc of 30 msec to 60 msec 45 minutes after the administration of gadofosveset and 0.4% of patients experienced a QTc increase of greater than 60 msec at 45 minutes post-administration.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)

Qt Prolonging Agents/Givinostat

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Givinostat may prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of givinostat with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of givinostat states that the concurrent use of QT prolonging agents should be avoided. If concurrent use cannot be avoided, obtain ECGs prior to initiating givinostat, during concomitant use, and as clinically indicated.(1) If the QTc interval is greater than 500 ms or the change from baseline is greater than 60 ms, withhold givinostat therapy.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a QT study, the largest mean increase in QTc interval of 13.6 ms (upper confidence interval of 17.1 ms) occurred 5 hours after administration of givinostat 265.8 mg (approximately 5 times the recommended 53.2 mg dose in patients weighing 60 kg or more).(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)

Qt Prolonging Agents/Hydroxychloroquine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Hydroxychloroquine has been observed to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of hydroxychloroquine with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of hydroxychloroquine states that hydroxychloroquine should not be administered with other agents that prolong the QT interval.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: The manufacturer states that hydroxychloroquine has been shown to prolong the QT interval;(1) however, conditions that hydroxychloroquine treats have also been associated with QT prolongation. Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)

Qt Prolonging Agents/Hydroxyzine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of hydroxyzine with agents that prolong the QTc interval may result in additive effects on the QTc interval.(1-4)

CLINICAL EFFECTS: The concurrent use of hydroxyzine with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1-4)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(5) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(5) Doses of hydroxyzine greater than 100 mg/day may also increase the risk.(1,2)

PATIENT MANAGEMENT: Concurrent use of hydroxyzine with agents known to prolong the QT interval is contraindicated in Canada(1,2) and the UK.(3) The US manufacturer states that concurrent use should be approached with caution.(4) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In vitro data indicates that hydroxyzine blocks the hERG channel, which results in the potential risk of QT interval prolongation.(6) In a placebo controlled, non-thorough QT study, 10 patients in the placebo group (n=152) had a change in QT interval from baseline between 30 ms and 60 ms and one patient presented a change from baseline higher than 60 ms. In the hydroxyzine group (n=148), 14 subjects had a change in QT interval from baseline between 30 and 60 ms and were considered to have a potential risk factor for risk of QT interval prolongation and TdP due to relevant medical history, concomitant medication potentially associated with the induction of prolongation of QT interval, and/or polymedication.(6) Health Canada reviewed 61 cases of QT interval prolongation or torsades de pointes with hydroxyzine. In a majority of cases, patients had additional risk factors for QT prolongation. Three reports provided enough data for a more detailed review. Hydroxyzine was found to be either "possible" or "probably" contribution to QT prolongation/torsades in these reports.(1) The European Medicines Agency's Pharmacovigilance Risk Assessment Committee (PRAC) reviewed 190 case reports found in a search of "torsade de pointes/QT prolongation with hydroxyzine". Forty-two non-fatality cases were subdivided into torsades (n=16), QT prolongation (n=21), and ventricular tachycardia (n=5). All included risk factors for QT interval prolongation and TdP (cardiac disorders, hypokalemia, long QT syndrome, bradycardia, concomitant drugs which are known to prolong the QT interval). Dosages ranged from <= 100 mg/day (n=10), > 100 mg/day to <=300 mg/day (n=4), > 300 mg/day (n=8), overdosages (n=11), and premedication (n=9). Twenty-one cases involving fatalities had at least one risk factor for QT prolongation. The PRAC concluded that post-marketing cases of QT interval prolongation, TdP and ventricular tachycardia confirm the findings of the hERG studies suggesting that hydroxyzine blocks hERG channels. No difference in the risk of QT interval prolongation could be observed based on the indication, age of the subject, or dose.(6) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(7)

Qt Prolonging Agents/Inotuzumab Ozogamicin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of inotuzumab ozogamicin with agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of inotuzumab ozogamicin with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: When possible, discontinue QT prolonging agents prior to therapy with inotuzumab ozogamicin or use alternative agents during inotuzumab ozogamicin therapy.(1) When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy.(1) Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.(1)

DISCUSSION: Inotuzumab ozogamicin was shown to prolong the QT interval in clinical trials. In the INO-VATE trial, 3% (4/162) of patients experienced an increase in QTc equal to or greater than 60 msec. No patients has QTc values greater than 500 msec. Grade 2 QT prolongation was reported in 1% (2/164) patients. There were no reports of Grade 3 QT prolongation or Torsade de Pointes.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)

Qt Prolonging Agents/Lenvatinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: Concurrent use of lenvatinib in patients taking other medications that prolong the QT interval may result in additive QT prolongation. QT prolongation may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, hypoalbuminemia, bradycardia, female gender, or advanced age.(1,2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Monitor electrocardiograms during concurrent therapy with lenvatinib and agents that prolong the QT interval. In a clinical trial of patients with refractory, progressive thyroid cancer, QT prolongation was reported in 9% of lenvatinib patients. Monitor and correct electrolyte abnormalities in all patients.(1) This is particularly important in lenvatinib patients as diarrhea, nausea, vomiting, and decreased appetite are common side effects which may increase the risk for electrolyte disturbances. Monitor ECG at baseline and at regular intervals. Lenvatinib dose must be withheld if the QTc exceeds 500 msec until QTc resolves to less than 480 msec or baseline. Lenvatinib must be resumed at reduced dose when QTc prolongation resolves to less than 480 ms or to baseline. Dose adjustments below are indication specific and are for patients with normal hepatic and renal function:(1) Dose Modifications in Differentiated Thyroid Cancer(DTC): - First occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose to 20 mg once daily - Second occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose to 14 mg once daily - Third occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose 10 mg once daily Dose Modifications in Renal Cell Cancer (RCC): - First occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose to 14 mg once daily - Second occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose to 10 mg once daily - Third occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose 8 mg once daily Dose Modifications in Hepatocellular Carcinoma (HCC) for Actual weight 60 kg or greater: - First occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose to 8 mg once daily - Second occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose to 4 mg once daily - Third occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose 4 mg every other day Dose Modifications in Hepatocellular Carcinoma (HCC) for Actual weight less than 60 kg: - First occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose to 4 mg once daily - Second occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline then decrease dose to 4 mg every other day - Third occurrence of QTc > 500 msec or onset of another Grade 2 or Grade 3 Adverse Reaction or Grade 4 Laboratory Abnormality: Interrupt therapy until resolved to Grade 0-1 or baseline and discontinue lenvatinib (1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a clinical trial of patients with refractory, progressive thyroid cancer, QT prolongation was reported in 9% of lenvatinib patients and 2% of placebo patients. The incidence of Grade 3 QT prolongation of > 500 msec was reported in 2% of lenvatinib patients compared with no reports in placebo patients.(1) In contrast, a single lenvatinib dose of 32 mg (1.3 times the recommended daily dose) did not prolong the QT/QTc interval in a thorough QT study performed in healthy subjects.(1) A retrospective review of 618 cancer patients treated with 902 administrations of tyrosine kinase inhibitors were evaluated for rate and incidence of QTc prolongation. In patients who received lenvatinib, QTc prolongation was identified in 9 (42.9%) with 4 (44.4%) having Grade 1 (QTc 450-480 ms) and 3 (33.3%) having Grade 2 (QTc 480-500 ms). Grade 3 events occurred in 0 (0%) having QTc greater than or equal to 500 ms and 1 (11.1%) having QTc change greater than or equal to 60 ms. Ventricular tachycardia was seen in 1 (11.1%) patient.(3)

Qt Prolonging Agents/Levomepromazine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Levomepromazine has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of levomepromazine with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of levomepromazine states that levomepromazine is not recommended in patients receiving other drugs known to cause QT prolongation.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Case reports of QTc prolongation associated with levomepromazine have been reported.(1,3) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(4)

Qt Prolonging Agents/Lofexidine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Lofexidine has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1,2)

CLINICAL EFFECTS: Concurrent use of lofexidine and agents known to prolong the QT interval may exacerbate QT prolongation.(1,2)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age,(3) renal impairment, and/or hepatic impairment.(1,2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The UK manufacturer of lofexidine states that concurrent use of lofexidine and QT prolonging agents should be avoided.(1) The US manufacturer states that ECGs should be monitored in patients receiving concurrent therapy with lofexidine and agents that are known to prolong the QT interval.(2) Consider obtaining serum calcium, magnesium, and potassium levels at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study of healthy volunteers, lofexidine 1.44 mg to 1.8 mg had a change from baseline in QTc of 14.4 msec and 13.6 msec, respectively.(2) In a dose response study, lofexidine had a mean QTc prolongation of 7.3 msec and 9.3 msec at doses of 2.16 mg/day and 2.88 mg/day, respectively.(2) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(4)

Qt Prolonging Agents/Macimorelin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of macimorelin with agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of macimorelin with agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Avoid the concurrent use of macimorelin with medications that prolong the QT interval.(1) When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a thorough QT study in 60 healthy subjects, a supra-therapeutic dose of macimorelin (2mg/kg, 4 times the recommended dosage) produced a mean change in QTc of 9.6 msec (upper 95% CI of 11.4 msec). Similar effects were seen in a single-ascending dose study which examined dosages of 1.5 mg/kg, 1 mg/kg, and 2 mg/kg, suggesting an absence of dose-dependent changes.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)

Qt Prolonging Agents/Ondansetron

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1-3)

CLINICAL EFFECTS: The use of ondansetron in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1-3)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or in the elderly (> or = 75 years of age).(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)

PATIENT MANAGEMENT: The risk for QT prolongation due to ondansetron is dose and route related. Intravenous (IV) doses lead to higher peak concentrations and systemic exposure and so have a greater risk for QT prolongation compared with the same dose given orally. Faster rates of IV infusion are also associated with a greater risk for QT prolongation.(5) If concomitant therapy is needed, correct electrolyte abnormalities prior to starting therapy. Monitor closely, particularly in patients with predisposing risk factors for QT prolongation (e.g. cardiac disease, female, elderly). Electrocardiogram (ECG) monitoring should be performed in patients receiving concurrent therapy.(1-3) The Canadian manufacturer of Zofran injection has specific recommendations for use of IV ondansetron in oncology patients greater than or equal to 75 years of age (5): - all IV doses must be diluted in 50 - 100 mL of compatible fluid and infused over at least 15 minutes - initial and repeat IV doses must not exceed 8 mg. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a double-blind, randomized, placebo and positive controlled cross-over study, an ondansetron intravenous (IV) dose of 32 mg increased the maximum mean QTcF by 19.6 msec (upper limit of 90% CI: 21.5). A dose of 8mg increased the QTcF by a maximum mean of 5.8 (upper limit of 90% CI: 7.8). A dose of 16 mg was predicted to have a mean increase in QTcF of 9.1 msec (upper limit of 90% CI: 11.2).(1) QT prolongation and torsades de pointes have been reported in post-marketing reports in patients receiving ondansetron.(2-3) In a review of published reports of QT prolongation associated with ondansetron administration, 67% of patients were also receiving another medication known to prolong the QT interval.(6) In a prospective, observational study, administration of a single ondansetron IV dose of 4 mg in the emergency department increased the mean and median QTc interval by 16.2 msec (95% CI 4.2-28.2 msec; p=0.01) and 12 msec (IQR 5.5-18 msec; p<0.01), respectively. Three patients had extreme QTc prolongation. With exclusion of those 3 patients, the median QTc prolongation was 10 msec (IQR 5-15 msec; p<0.01).(7) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(8) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Qt Prolonging Agents/Osimertinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Osimertinib prolongs the QTc interval.(1) Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(2,3)

CLINICAL EFFECTS: The concurrent use of osimertinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(2,3)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: Osimertinib prolongs the QT interval. Premarket clinical trials excluded patients with a baseline QTc > or = 470 msec. In these trials 11 patients (2.7%) had increase in QTc greater than 60 msec.(1) Manufacturer recommendations: when feasible, avoid concurrent administrations of osimertinib with drugs known to prolong the QTc interval. Conduct baseline and periodic monitoring with ECGs in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities (e.g. serum calcium, magnesium, and potassium), or those taking medications known to prolong the QT interval.(1) Dose adjustments (1): - If QTc is greater than 500 msec on at least 2 separate ECGs, withhold osimertinib until QTc is < 481 msec or recovery to baseline (if baseline QTc was greater than or equal to 481 msec), then resume osimertinib at 40 mg per day. - For QTc prolongation with signs or symptoms of life threatening arrhythmia, permanently discontinue osimertinib. During concomitant therapy with another QT prolonging agent, monitor patients closely for prolongation of the QT interval.(1) Obtain serum calcium, magnesium, and potassium levels and monitoring ECG at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: A retrospective review of 618 cancer patients treated with 902 administrations of tyrosine kinase inhibitors were evaluated for rate and incidence of QTc prolongation. In patients who received osimertinib, QTc prolongation was identified in 4 (25%) with 1 (25%) having Grade 1 (QTc 450-480 ms) and 1 (25%) having Grade 2 (QTc 480-500 ms). Grade 3 events occurred in 1 (25%) having QTc greater than or equal to 500 ms and 1 (25%) having QTc change greater than or equal to 60 ms. No patients had ventricular tachycardia, sudden cardiac death, or TdP.(4) In clinical studies of 1813 patients treated with osimertinib monotherapy, 1.1% of patients were found to have a QTc interval greater than 500 ms and 4.3% of patients had an increase from baseline QTc > 60 ms.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)

Qt Prolonging Agents/Paliperidone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Paliperidone has been shown to cause a modest increase in the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1,2)

CLINICAL EFFECTS: The concurrent use of paliperidone with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1,2)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)

PATIENT MANAGEMENT: The US manufacturer of paliperidone states that the use of paliperidone should be avoided with other drugs that are known to prolong the QTc interval, including Class IA and Class III antiarrhythmics, antipsychotics, antibiotics such as gatifloxacin and moxifloxacin, or any other class of medications known to prolong the QTc interval.(1,2) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3)

Qt Prolonging Agents/Propafenone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Propafenone has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of propafenone with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The manufacturer of propafenone states that the use of propafenone with other agents known to prolong the QT interval should be avoided.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)

Qt Prolonging Agents/Quinine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Quinine has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of quinine with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The US manufacturer of quinine states that concurrent use with agents known to prolong the QT interval should be avoided.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.

Qt Prolonging Agents/Sorafenib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of sorafenib with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The use of sorafenib patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Patients receiving concurrent therapy with agents known to prolong the QTc interval should be monitored with electrocardiograms during treatment with sorafenib. Electrolytes (calcium, magnesium, and potassium) should also be monitored.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a non-randomized trial in 53 patients, sorafenib resulted in a mean change in QTc of 8.5 msec (upper bound of 90% CI: 13.3 msec).(1) A retrospective review of 618 cancer patients treated with 902 administrations of tyrosine kinase inhibitors were evaluated for rate and incidence of QTc prolongation. In patients who received sorafenib, QTc prolongation was identified in 13 (31.7%) with 5 (38.5%) having Grade 1 (QTc 450-480 ms) and 4 (30.7%) having Grade 2 (QTc 480-500 ms). Grade 3 events occurred in 2 (15.4%) having QTc greater than or equal to 500 ms and 2 (15.4%) having QTc change greater than or equal to 60 ms. No patients developed ventricular tachycardia, sudden cardiac death, or TdP.(3) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(4)

Qt Prolonging Agents/Telavancin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Telavancin has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of telavancin with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of telavancin recommends against the use of telavancin with other drugs known to cause QT prolongation.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a randomized, double-blind, multiple-dose, positive-controlled, placebo-controlled, parallel study in healthy subjects, the mean maximum baseline-corrected, placebo-corrected QTc prolongation was 11.6 msec and 15.1 msec for telavancin at dosages of 7.5 mg/kg and 15 mg/kg, respectively. The estimated mean maximum baseline-corrected, placebo-corrected QTc prolongation for a telavancin dosage of 10 mg/kg is 12-15 msec.(1) In studies in patients, 21% of patients receiving telavancin (214 of 1029, 10 mg/kg) and 16% of patients receiving vancomycin (164 of 1033) received concurrent QT prolonging agents. The rate of QTc prolongation greater than 60 msec was 1.5% (15 patients) in the telavancin group and 0.6% (6 patients) in the vancomycin group. Nine of the 15 telavancin subjects with QTc prolongation received concurrent QT prolongers, compared with 1 of the vancomycin patients.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)

Qt Prolonging Agents/Trazodone (>= 100 Mg)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of trazodone with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1,2)

CLINICAL EFFECTS: The use of trazodone in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1,2)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of trazodone states that concurrent use with agents known to prolong the QT interval should be avoided.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Trazodone has been reported to prolong the QT interval.(1) A thorough QT study in 20 subjects evaluated the effects of trazodone at doses of 20 mg, 60 mg and 140 mg. There was no evidence of QTc prolongation at the lowest trazodone dose of 20mg (mean effect on QTc of 4.5 ms 95% CI 3.7-5.3 ms), but at 60 mg and 140 mg, there was a significant effect that exceeds the E14 FDA Guidelines threshold of prolonging the QT/QTc interval by more than 5 ms. The study found a dose-dependent effect on QTc prolongation starting at 60 mg with a mean effect on QTc of 12.3 ms (95% CI 11-13.6 ms) and increasing with a 140 mg dose to a mean effect on QTc of 19.8 ms (95% CI 17.6-22.1).(3) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(4)

Qt Prolonging Agents/Zuclopenthixol

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Zuclopenthixol prolongs the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1) Zuclopenthixol is partially metabolized by CYP2D6. Some QT prolonging agents such as quinidine are also CYP2D6 inhibitors and may inhibit metabolism of zuclopenthixol.

CLINICAL EFFECTS: The concurrent use of zuclopenthixol with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1) CYP2D6 inhibitors such as quinidine may increase zuclopenthixol concentrations resulting in zuclopenthixol toxicity.

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The UK manufacturer of zuclopenthixol states that the concurrent administration of other drugs that are known to prolong the QTc interval should be avoided.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)

Select Moderate Cyp2d6 Inhibitors/Tamoxifen

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inhibitors of CYP2D6 may inhibit the conversion of tamoxifen to endoxifen (an active metabolite of tamoxifen).(1-2) The role of endoxifen in tamoxifen's efficacy has been debated and may involve a minimum concentration level.(3-5)

CLINICAL EFFECTS: Concurrent use of inhibitors of CYP2D6 may decrease the effectiveness of tamoxifen in preventing breast cancer recurrence.

PREDISPOSING FACTORS: Concurrent use of moderate CYP2D6 inhibitors in patients who are CYP2D6 ultrarapid, normal, or intermediate metabolizers should be avoided. Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition.

PATIENT MANAGEMENT: Although data on this interaction are conflicting, it may be prudent to use alternatives to CYP2D6 inhibitors when possible in patients taking tamoxifen. The US manufacturer of tamoxifen states that the impact on the efficacy of tamoxifen by strong CYP2D6 inhibitors is uncertain and makes no recommendation regarding coadministration with inhibitors of CYP2D6.(12) The manufacturer of paroxetine (a strong CYP2D6 inhibitor) states that alternative agents with little or no CYP2D6 inhibition should be considered.(13) The National Comprehensive Cancer Network's breast cancer guidelines advises caution when coadministering strong CYP2D6 inhibitors with tamoxifen.(14) NCCN states when prescribing a selective serotonin reuptake inhibitor (SSRI), it is reasonable to avoid SSRIs that are strong and moderate CYP2D6 inhibitors, particularly fluoxetine and paroxetine, if an appropriate alternative exists.(14) Cancer Care Ontario breast cancer guidelines state concurrent use of moderate CYP2D6 inhibitors should be approached with caution and alternative options should be considered.(15) The European Society of Medical Oncology (ESMO) clinical practice guidelines for early breast cancer states patients on tamoxifen should be advised to avoid concurrent use of strong and moderate CYP2D6 inhibitors. Consider alternatives to tamoxifen if CYP2D6 inhibitors cannot be replaced with alternative agents.(16) If concurrent therapy is warranted, the risks versus benefits should be discussed with the patient. Rolapitant, a moderate CYP2D6 inhibitor, effects on CYP2D6 are expected to last at least 28 days after administration.(17)

DISCUSSION: Some studies have suggested that administration of fluoxetine, paroxetine, and quinidine with tamoxifen or a CYP2D6 poor metabolizer phenotype may result in a decrease in the formation of endoxifen (an active metabolite of tamoxifen) and a shorter time to breast cancer recurrence.(1-2,9) A retrospective study of 630 breast cancer patients found an increasing risk of breast cancer mortality with increasing durations of coadministration of tamoxifen and paroxetine. In the adjusted analysis, absolute increases of 25%, 50%, and 75% in the proportion of time of overlapping use of tamoxifen with paroxetine was associated with 24%, 54%, and 91% increase in the risk of death from breast cancer, respectively.(18) The CYP2D6 genotype of the patient may have a role in the effects of this interaction. Patients with wild-type CYP2D6 genotype may be affected to a greater extent by this interaction. Patients with a variant CYP2D6 genotype may have lower baseline levels of endoxifen and may be affected to a lesser extent by this interaction.(6-10) In a retrospective review, 1,325 patients treated with tamoxifen for breast cancer were classified as being poor 2D6 metabolizers (lacking functional CYP2D6 enzymes), intermediate metabolizers (heterozygous alleles), or extensive metabolizers (possessing 2 functional alleles). After a mean follow-up period of 6.3 years, the recurrence rates were 14.9%, 20.9%, and 29.0%, in extensive metabolizers, intermediate metabolizers, and poor metabolizers, respectively.(11) In October of 2006, the Advisory Committee Pharmaceutical Science, Clinical Pharmacology Subcommittee of the US Food and Drug Administration recommended that the US tamoxifen labeling be updated to include information about the increased risk of breast cancer recurrence in poor CYP2D6 metabolizers (either by genotype or drug interaction).(19-20) The labeling changes were never made due to ongoing uncertainty about the effects of CYP2D6 genotypes on tamoxifen efficacy. In contrast to the above information, two studies have shown no relationship between CYP2D6 genotype and breast cancer outcome.(21-23) As well, a number of studies found no association between use of CYP2D6 inhibitors and/or antidepressants in patients on tamoxifen and breast cancer recurrence,(24-28) though the studies were limited by problematic selection of CYP2D6 inhibitors and short follow-up. A single dose of rolapitant increased dextromethorphan, a CYP2D6 substrate, about 3-fold on days 8 and day 22 following administration. Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single dose rolapitant. The inhibitory effects of rolapitant on CYP2D6 are expected to persist beyond 28 days.(17) Moderate CYP2D6 inhibitors that prolong the QT interval include adagrasib, dronedarone, levomethadone, and quinine.(29-30)

Selected Cyp3a4 Inhibitors/Meperidine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: CYP3A4 inhibitors may inhibit the metabolism of meperidine.

CLINICAL EFFECTS: The concurrent administration of a CYP3A4 inhibitor may result in elevated levels of and toxicity from meperidine, including profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If concomitant use is necessary, consider dose reduction of meperidine until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.(1) If the CYP3A4 inhibitor is discontinued, consider increasing the meperidine dose until stable drug effects are achieved. Monitor for signs of opioid withdrawal.(1) The Australian manufacturer of nirmatrelvir/ritonavir contraindicates co-administration with meperidine.(2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(3) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(4)

DISCUSSION: Plasma concentrations of the active metabolite normeperidine may be increased by ritonavir (strong CYP3A4 inhibitor).(1) Strong CYP3A4 inhibitors that would be expected to interact with meperidine include: boceprevir, clarithromycin, cobicistat, elvitegravir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, voriconazole.(5) Moderate CYP3A4 inhibitors include: erythromycin and fluconazole.(5)

Selected Cyp3a4 Inhibitors/Salmeterol Combinations

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the CYP3A4 metabolism of the portion of both the corticosteroid (budesonide or fluticasone) and salmeterol that is swallowed, resulting in significant systemic absorption.(1-18)

CLINICAL EFFECTS: Inhibitors of CYP3A4 may result in increased systemic exposure and effects of budesonide or fluticasone, including Cushing's syndrome and adrenal suppression. Systemic effects of salmeterol, including palpitations and sinus tachycardia, may also occur.(1-18)

PREDISPOSING FACTORS: The risk of Cushing's syndrome and adrenal suppression may be higher in patients with concurrent use of systemic glucocorticoids.

PATIENT MANAGEMENT: Concurrent therapy of budesonide-salmeterol or fluticasone-salmeterol with strong CYP3A4 inhibitors is not recommended.(18) Alternative corticosteroids that are less affected by CYP3A4 inhibitors should be considered, like beclomethasone. Canadian labeling contraindicates concurrent use of atazanavir/ritonavir, darunavir/cobicistat, and lopinavir/ritonavir with salmeterol.(19-22) If concurrent therapy is warranted, patients should be closely monitored for systemic effects. Advise patients receiving concurrent therapy to rinse their mouth thoroughly after administering budesonide-salmeterol or fluticasone-salmeterol to limit the amount of drug that is swallowed.

DISCUSSION: A study in 18 healthy subjects examined the effects of ritonavir (100 mg twice daily) on fluticasone nasal spray (200 mcg daily). In most subjects, fluticasone was undetectable (<10 pg/ml) when administered alone. In subjects in whom fluticasone was detectable when given alone, maximum concentration (Cmax) and area-under-curve (AUC) averaged 11.9 pg/ml and 8.43 pg x hr/ml, respectively. With concurrent ritonavir, fluticasone Cmax and AUC increased to 318 pg/ml and 3102.6 pg x hr/ml, respectively.(8,13,17) This reflects increases in Cmax and AUC by 25-fold and 350-fold, respectively. The cortisol AUC decreased by 86%.(18) There have been many case reports of Cushing's syndrome in patients treated concurrently with ritonavir and fluticasone.(23-41) In a study in 20 healthy subjects, concurrent administration of salmeterol (50 mcg twice daily) and ketoconazole (400 mg once daily, a strong inhibitor of CYP3A4) for 7 days increased the plasma AUC and Cmax of salmeterol 16-fold and 1.4-fold, respectively. Concurrent use did not result in clinically significant changes in heart rate, mean blood potassium, mean blood glucose or mean QTc; however, concurrent use was associated with more frequent increases in QTc duration. Three subjects were withdrawn from the study because of systemic salmeterol effects (2 with QTc prolongation and 1 with palpitations and sinus tachycardia).(18) An in vitro study showed that ketoconazole completely inhibited the metabolism of salmeterol to alpha-hydroxysalmeterol by CYP3A4.(42) Selected CYP3A4 inhibitors linked to this monograph include: adagrasib, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(43)

Selected Cyp3a4 Inhibitors/Selected Opioids

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: CYP3A4 inhibitors may inhibit the metabolism of alfentanil,(1,2) benzhydrocodone,(3) fentanyl,(1,2) hydrocodone,(4) oxycodone,(5) and sufentanil.(6) Benzhydrocodone is a prodrug of hydrocodone.(3)

CLINICAL EFFECTS: The concurrent administration of a CYP3A4 inhibitor may result in elevated levels of and toxicity from alfentanil,(1,2) benzhydrocodone,(3) fentanyl,(1,2) hydrocodone,(4) oxycodone,(5) and sufentanil,(6) including profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: Heat.

PATIENT MANAGEMENT: Monitor patients receiving potent or moderate CYP3A4 inhibitors for an extended period of time. Dosage adjustments should be made if warranted. The manufacturer of itraconazole states that concomitant administration of fentanyl is not recommended during and 2 weeks after itraconazole treatment.(7) Avoid exposing the fentanyl patch application site and surrounding area to direct external heat sources as there have been reports of overdose and death as a result of exposure to heat. The manufacturer of sufentanil sublingual tablets states that if concomitant use with CYP3A4 inhibitors is necessary, consider use of an alternate agent that allows dose adjustment.(6) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(8) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(9)

DISCUSSION: A nested-case control study of patients who were prescribed fentanyl patches, hydromorphone, or oxycodone and were hospitalized for opioid toxicity found that, among 70 cases and 120 control patients, CYP3A4-inhibiting macrolides (erythromycin and clarithromycin) were associated with a higher risk of opioid toxicity (aOR 3.80, 95% CI: 1.36-11.56 with fentanyl; aOR 3.38, 95% CI: 1.28-8.97 with hydromorphone; aOR 3.11, 95% CI: 1.05-9.51 with oxycodone).(10) In a randomized, placebo-controlled trial in 20 healthy subjects, clarithromycin (500 mg twice daily) increased the area-under-curve (AUC) of a single oral dose of oxycodone (10 mg) by 2-fold and 2.3-fold in young and elderly subjects, respectively.(11) In a controlled cross-over study in 6 subjects, 7 days of pretreatment with erythromycin decreased the clearance of alfentanil by 25%. Alfentanil half-life increased by 56%.(12) Erythromycin has been shown to inhibit fentanyl metabolism in vitro.(13) In a randomized, double-blind, placebo-controlled crossover study in 9 subjects, single doses of intravenous fluconazole (400 mg) and oral fluconazole (400 mg) decreased the clearance of a single dose of alfentanil (20 mcg/kg) by 58% and 55%, respectively. Alfentanil half-life almost doubled after both intravenous and oral fluconazole. Both intravenous and oral fluconazole increased subjective effects of alfentanil and increased alfentanil-induced respiratory depression.(14) In a cross-over study, pretreatment with itraconazole (200 mg daily for 4 days) had no effect on a single dose of intravenous fentanyl (3 mcg/kg).(15) In a cross-over study in 12 healthy subjects, itraconazole (200 mg daily for 5 days) increased the AUC and Cmax of a single oral dose of oxycodone (10 mg) by 144% and 45%, respectively. The AUC of noroxycodone decreased 49% and the AUC of oxymorphone increased 359% with concurrent itraconazole and oral oxycodone. Itraconazole increased the AUC of a single intravenous dose of oxycodone (0.1 mg/kg) by 51%.(16) In a randomized cross-over study in 12 healthy subjects, ketoconazole increased the AUC of oxycodone by 2-fold to 3-fold and also increased oxycodone-related nausea, drowsiness, and pruritus.(17) In a randomized cross-over study in 10 healthy subjects, ketoconazole increased the AUC of oxymorphone by 3-fold following a single dose of oxycodone (0.2 mg/kg). Increased side effects were also noted.(18,19) Ketoconazole has been shown to inhibit the metabolism of alfentanil,(20) fentanyl,(13) and oxycodone(21) in vitro. In a study of 11 subjects, ritonavir reduced the clearance of fentanyl 67% and increased the AUC 174%. Eight subjects reported nausea during the study.(22) In a randomized cross-over study in 16 healthy subjects, ritonavir (300 mg twice daily for 4 days) and lopinavir/ritonavir (400/100 mg twice daily for 4 days) increased the AUC of a single dose of oxycodone (10 mg) by 3.0-fold and 2.6-fold, respectively. Oxycodone half-life increased 55% and 58%, respectively, with concurrent ritonavir or lopinavir/ritonavir. Both regimens also increased self-reported oxycodone effects.(23) The Australian manufacturer of ritonavir states that the AUC of fentanyl may be potentially increased 3-fold with concurrent ritonavir.(24) In a randomized cross-over study in 11 healthy subjects, telithromycin (800 mg daily for 4 days) increased the AUC of a single dose of oxycodone (10 mg immediate-release) by 80%. The AUC of noroxycodone was decreased by 46%. There was a modest increase in the pharmacodynamic effects of oxycodone.(25) In a randomized cross-over study in 10 healthy subjects, troleandomycin increased the AUC of alfentanil by 135%.(26) In a randomized cross-over study in 12 healthy subjects, troleandomycin increased the AUC of a single dose of fentanyl (oral transmucosal, 10 mcg/kg) by 76%.(27) Troleandomycin has been shown to inhibit alfentanil(19) and fentanyl(28) metabolism in vitro. In a randomized, cross-over study in 12 healthy subjects, concurrent use of voriconazole and alfentanil increased the AUC of alfentanil 6-fold and decreased its clearance by 85%.(25,29) In a randomized, cross-over study in 12 healthy subjects, voriconazole (400 mg twice daily, Day 1; 200 mg twice daily, Day 2) and fluconazole (400 mg daily, Day 1; 200 mg daily, Day 2) decreased the clearance of a single dose of intravenous fentanyl (5 mcg/kg) by 23% and 16%, respectively.(30) In a randomized cross-over study in 12 healthy subjects, pretreatment with voriconazole for 4 days increased the AUC, Cmax, and half-life of a single dose of oxycodone (10 mg) by 3.6-fold, 1.7-fold, 2.0-fold, respectively.(31) There are case reports of interactions between alfentanil and erythromycin,(32) fentanyl and clarithromycin,(33) fentanyl and fluconazole,(34) fentanyl and itraconazole,(35) and oxycodone and voriconazole.(36) In the case report with fentanyl and fluconazole, the patient died of respiratory depression.(34) A study in healthy subjects shown that the application of heat over the fentanyl patch system increased mean overall fentanyl exposure by 120% and average maximum fentanyl level by 61%.(2) In a single dose study of sufentanil sublingual tablet 15 mcg with a strong CYP3A4 inhibitor, ketoconazole, resulted in 77% and 19% greater AUC and Cmax values of sufentanil, respectively, compared to its administration alone.(6) Strong CYP3A4 inhibitors that have been documented to interact with alfentanil, benzhydrocodone, fentanyl, hydrocodone, and/or oxycodone or would be expected to interact with these agents include: boceprevir, clarithromycin, cobicistat, elvitegravir, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, voriconazole.(37) Moderate CYP3A4 inhibitors that have been documented to interact with alfentanil, benzhydrocodone, fentanyl, hydrocodone, and/or oxycodone include: erythromycin and fluconazole.(37)

Selected Myelosuppressive Agents/Deferiprone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1)

CLINICAL EFFECTS: Concurrent use of deferiprone and myelosuppressive agents may result in severe neutropenia or agranulocytosis, which may be fatal.

PREDISPOSING FACTORS: Agranulocytosis may be less common in patients receiving deferiprone for thalassemia, and more common in patients treated for other systemic iron overload conditions (e.g. myelodysplastic syndromes, sickle cell disease).(2,3) Inadequate monitoring appears to increase the risk for severe outcomes. Manufacturer post market surveillance found that in all fatal cases of agranulocytosis reported between 1999 and 2005, data on weekly white blood count (WBC) monitoring was missing. In three fatal cases, deferiprone was continued for two to seven days after the detection of neutropenia or agranulocytosis.(2)

PATIENT MANAGEMENT: If possible, discontinue one of the drugs associated with risk for neutropenia or agranulocytosis. If alternative therapy is not available, documentation and adherence to the deferiprone monitoring protocol is essential. Baseline absolute neutrophil count (ANC) must be at least 1,500/uL prior to starting deferiprone. Monitor ANC weekly during therapy. If infection develops, interrupt deferiprone therapy and monitor ANC more frequently. If ANC is less than 1,500/uL but greater than 500/uL, discontinue deferiprone and any other drugs possibly associated with neutropenia. Initiate ANC and platelet counts daily until recovery (i.e. ANC at least 1,500/uL). If ANC is less than 500/uL, discontinue deferiprone, evaluate patient and hospitalize if appropriate. Do not resume deferiprone unless potential benefits outweigh potential risks.(1)

DISCUSSION: Drugs linked to this monograph have an FDA Boxed Warning for risk of neutropenia, agranulocytosis, or pancytopenia, or have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(1-25) In pooled clinical studies submitted to the FDA, 6.1% of deferiprone patients met criteria for neutropenia and 1.7% of patients developed agranulocytosis.(1) The time to onset of agranulocytosis was highly variable with a range of 65 days to 9.2 years (median, 161 days).(3)

Selected Myelosuppressive Agents/Dipyrone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of dipyrone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1-29)

CLINICAL EFFECTS: Concurrent use of dipyrone with agents that cause bone marrow depression, including myelosuppressives, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding. Undetected severe neutropenia or agranulocytosis may be fatal.(1-29)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of dipyrone and myelosuppressive agents should be avoided. The European Medicines Agency states dipyrone is contraindicated in patients with a prior medical history of dipyrone-induced agranulocytosis (or from other pyrazolones/pyrazolidines), impaired bone marrow function or diseases of the hematopoietic system.(3) International labeling for dipyrone and methotrexate state that co-administration may increase the hematotoxicity of methotrexate, especially in elderly patients, and therefore should be avoided.(1-2) The European Medicines Agency advises if agranulocytosis is suspected with dipyrone, a complete blood count (including differential blood count) should be performed immediately, and treatment must be stopped while waiting for the results. If confirmed, treatment must not be reintroduced.(1-3)

DISCUSSION: A retrospective cohort study analyzed new users of dipyrone (n=444,972), non-steroidal anti-inflammatory drugs (n=3,814,367) which served as a reference cohort, and opioids-paracetamol (n=3,129,221) which was the negative control. During continuous treatment over a median of 37-40 days, 26 cases of hospitalized agranulocytosis occurred. With the assumption that agranulocytosis onset was 7 days prior to admission, the hazard ratio of agranulocytosis associated with dipyrone was 4.40 [0.90-21.57] compared to NSAIDs and 2.45 [0.68-8.83] compared to opioid-paracetamol. HR of neutropenia from dipyrone was 2.98 [1.57-5.65] compared to NSAIDs and not statistically significant compared to opioids-paracetamol. In a sensitivity analysis assuming that the onset of agranulocytosis was the date of hospitalization, the HR of dipyrone-induced agranulocytosis was 7.20 [95% confidence interval: 1.92-26.99] compared to NSAIDs and 3.31 [1.17-9.34] compared to opioids-paracetamol. Agranulocytosis was very rare but more than 4 times more common with dipyrone than other analgesics.(4) In a review of 1,448 reports of agranulocytosis attributed to dipyrone, patients with fatal outcomes were older and more often had also received methotrexate compared to those with non-fatal outcomes (odds ratio: 5.18; 95% confidence interval: 3.06-8.78).(5) Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(2,6-26)

Selected Qt Prolonging Agents/Ziprasidone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ziprasidone has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of ziprasidone with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(1,3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The manufacturer of ziprasidone states under contraindications that ziprasidone should not be used with other drugs that prolong the QT interval such as dofetilide, sotalol, quinidine, other Class Ia and III anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol or tacrolimus.(1) It would be prudent to avoid the use of ziprasidone with medicines suspected of prolonging the QT interval. If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(2)

Selected Strong Cyp3a4 Inhibitors That Prolong Qt/Tacrolimus

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of tacrolimus CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in increased levels of tacrolimus, including QT prolongation, nephrotoxicity, neurotoxicity, cardiovascular toxicity, hypertension, anemia, and increased risk of serious infections.(1,2)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The US manufacturer of tacrolimus states that concurrent use with strong CYP3A4 inhibitors may result in a rapid and sharp rise in tacrolimus concentration despite immediate tacrolimus dose reduction. Frequent monitoring of tacrolimus levels should start within 1-3 days of initiation of concurrent therapy and continue as necessary.(2) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14% versus 30%) was observed with concomitant ketoconazole, another inhibitor of CYP3A4, administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430 L/hr/kg versus 0.148 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole coadministration, although it was highly variable between patients.(2) Tacrolimus has been associated with QT prolongation.(1) In a kidney transplant population, 98 patients received immunosuppressive management with tacrolimus, cyclosporine, everolimus, or azathioprine. All patients post-transplant had significantly prolonged QTc interval compared to pre-transplant in all groups.(4) Strong CYP3A4 inhibitors that prolong QT linked to this monograph include: adagrasib, ceritinib, levoketoconazole, and lonafarnib.

Selected Strong Cyp3a4 Inhibitors/Clopidogrel

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2 step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1,2) CYP2C19 contributes to both steps and is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite.(1) CYP3A4 is responsible for 39.8% of the second step of metabolism. Strong CYP3A4 inhibitors may inhibit the metabolism of clopidogrel to its active form by CYP3A4.(1,3)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in decreased clopidogrel effectiveness, resulting in increased risk of adverse cardiac events.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of clopidogrel does not make specific recommendations for concurrent use with strong CYP3A4 inhibitors. Patient monitoring for adequate inhibition of platelet reactivity with clopidogrel is warranted. Consider alternatives to strong CYP3A4 inhibitors in patients stabilized on clopidogrel and alternatives to clopidogrel in patients stabilized on strong CYP3A4 inhibitors. If concurrent therapy is warranted, consider appropriate testing to assure adequate inhibition of platelet reactivity.

DISCUSSION: In a randomized, cross-over study in healthy subjects, ketoconazole (400 mg daily) decreased the maximum concentration (Cmax) of the active metabolite of clopidogrel (300 mg loading dose, followed by 75 mg daily) by 61%. The area-under-curve (AUC) of the active metabolite of clopidogrel was decreased by 22% following the loading dose and by 29% during maintenance dosing. Clopidogrel-induced inhibition of platelet aggregation was decreased by 28% following the loading dose and by 33% during the maintenance dose.(4) A randomized cross over study in 12 healthy volunteers and 9 HIV-infected patients evaluated the impact of boosted antiretroviral therapy (ARV) on the pharmacokinetics and efficacy of clopidogrel. Healthy patients had 3.2-fold lower AUC (p=0.02) and Cmax of clopidogrel active metabolite (p=0.03) than HIV patients. Platelet reactivity was also 35% lower in health patients compared to HIV patients (p=0.04). All healthy patients had a platelet reactivity below the cut-off value at 4 hours after clopidogrel dose, while 44% of HIV patients were above the cut-off value of 206.(5) A cross-sectional study in 240 post acute coronary syndrome (ACS) patients compared platelet reactivity under aspirin and P2Y12 inhibitor therapy between HIV and non-HIV patients with first episode ACS on dual antiplatelet therapy. Study evaluated residual platelet aggregation (RPA), P2Y12 assay (PRU), and VASP platelet reactivity index (VASP-PRI). HIV patients were all on antiretroviral (ARV) therapy, most commonly with protease inhibitors (darunavir, lopinavir, atazanavir, and indinavir in combination with ritonavir in all but two patients). Patients on ARV containing protease inhibitors compared to other combinations had increased platelet reactivity to P2Y12 inhibitors and higher prevalence of high residual platelet reactivity (HPR) (OR 4.4 (95%CI 1.1-18.1) with RPA, P = 0.04; OR 3.1 (95%CI = 0.84-11.5) with VASP-PRI; P = 0.09, and OR 4.3 (95%CI 1.02-18.1) with PRU, P = 0.047). Patients with CD4 T cell count lower than 350/mm3 also had consistently increased platelet reactivity to P2Y12 inhibitors and higher prevalence of HPR (OR 3.41 (95%CI 0.60-19.4) with RPA, P = 0.17; OR 7.1 (95%CI 0.94-54.2) with VASP-PRI, P = 0.06; and OR 7.9 (95%CI 1.42-44.8) with PRU, P = 0.002), although this association was not significant for all three tests.(6) Selected strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, ensitrelvir, idelalisib, itraconazole, josamycin, levoketoconazole, mibefradil, nefazodone, posaconazole, relacorilant, ribociclib, telaprevir, telithromycin, tucatinib, and troleandomycin.(7)

Selected Strong Cyp3a4 Inhibitors/Salmeterol

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of the portion of salmeterol that is swallowed, resulting in significant systemic absorption.(1) An in vitro study showed that ketoconazole completely inhibited the formation of alpha-hydroxysalmeterol by CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in systemic effects of salmeterol, including palpitations and sinus tachycardia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer states that the concurrent use of salmeterol with strong inhibitors of CYP3A4 is not recommended.(1) The Canadian manufacturer of salmeterol states that concurrent use of itraconazole should be approached with caution.(2) The US manufacturer of itraconazole states that concurrent administration with salmeterol is not recommended during and two weeks after itraconazole treatment.(4) Consider the use of alternative agents.

DISCUSSION: In a study in 20 healthy subjects, concurrent administration of salmeterol (50 mcg twice daily) and ketoconazole (400 mg once daily) for 7 days increased the plasma area-under-curve (AUC) and maximum concentration (Cmax) of salmeterol 16-fold and 1.4-fold, respectively. Concurrent use did not result in clinically significant changes in heart rate, mean blood potassium, mean blood glucose or mean QTc; however, concurrent use was associated with more frequent increases in QTc duration. Three subjects were withdrawn from the study because of systemic salmeterol effects (2 with QTc prolongation and 1 with palpitations and sinus tachycardia).(1) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, ceritinib, clarithromycin, idelalisib, itraconazole, josamycin, ketoconazole, lonafarnib, mibefradil, mifepristone, nefazodone, posaconazole, relacorilant, ribociclib, telithromycin, troleandomycin, tucatinib, and voriconazole.(5,6)

Selected Strong Cyp3a4 Inhibitors/Selected Steroids

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of corticosteroids metabolized by CYP3A4.

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in increased systemic exposure to and effects from corticosteroids metabolized by CYP3A4, including Cushing's syndrome and adrenal suppression.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, avoid concurrent therapy between corticosteroids metabolized by CYP3A4 and strong CYP3A4 inhibitors. Alternative corticosteroids that are less affected by CYP3A4 inhibitors should be considered, like beclomethasone, prednisone, and prednisolone. If concurrent therapy is warranted, patients should be closely monitored for systemic effects. The corticosteroid may need to be discontinued.

DISCUSSION: In a study, boceprevir (800 mg TID for 7 days) increased the area-under-curve (AUC) of a single dose of prednisone (40 mg) by 22%. The maximum concentration (Cmax) and AUC of prednisolone increased by 16% and 37%, respectively.(3) A study of 14 healthy adults found that concurrent use of ketoconazole with ciclesonide increased the AUC of ciclesonide's active metabolite, des-ciclesonide, by approximately 3.6-fold at steady state, while levels of ciclesonide remained unchanged. However, the study concluded that no dosage adjustments were required because ciclesonide has a very low potential to cause side effects.(4) A study in 18 healthy subjects examined the effects of ritonavir (100 mg twice daily) on fluticasone nasal spray (200 mcg daily). In most subjects, fluticasone was undetectable (<10 pg/ml) when administered alone. In subjects in whom fluticasone was detectable when given alone, Cmax and area-under-curve AUC averaged 11.9 pg/ml and 8.43 pg x hr/ml, respectively. With concurrent ritonavir, fluticasone Cmax and AUC increased to 318 pg/ml and 3102.6 pg x hr/ml, respectively.(6-8) This reflects increases in Cmax and AUC by 25-fold and 350-fold, respectively.(6) The cortisol AUC decreased by 86%.(10-13) In a study in 10 healthy subjects, ritonavir (200 mg twice daily for 4 and 14 days) increased the AUC of a single dose of prednisolone by 1.41-fold and 1.30-fold, respectively, after 4 days and 14 days of ritonavir.(14) There have been several case reports of Cushing's syndrome in patients treated concurrently with ritonavir and inhaled budesonide,(15-16) dexamethasone,(17) injectable triamcinolone,(18-21) nasal fluticasone.(23-41) Hepatitis has also been reported with concurrent budesonide and ritonavir.(42) In a study in 9 healthy subjects, mibefradil (50 mg once daily for 3 days) increased the AUC, Cmax, and elimination half-life of methylprednisolone by 3.8-fold, 1.8-fold, and 2.7-fold, respectively.(43) In a study in 8 healthy subjects, following nefazodone administration the following changes were seen with methylprednisolone: mean (+/-SD) area under the concentration-time curve was significantly higher (1393 +/- 343 vs. 2966 +/- 928 ug*h/L; P < 0.005), apparent clearance was lower (28.7 +/- 7.2 vs. 14.6 +/- 7.8 L/h; P < 0.02) and the terminal elimination half-life was longer (2.28 +/- 0.49 vs. 3.32 +/- 0.95 hours; P < 0.02).(44) Selected steroids metabolized by CYP3A4 are linked to this monograph.(45) Selected CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, erythromycin, itraconazole, josamycin, ketoconazole, lonafarnib, mibefradil, nefazodone, paritaprevir, posaconazole, ribociclib, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(1-2,45)

Slt Strong 3A4 Inhibitors/Sildenafil(Pah);Tadalafil(Bph,Pah)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of sildenafil(1) and tadalafil.(2)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in increased levels, clinical effects, and side effects of sildenafil(1) and tadalafil.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sildenafil states that the concurrent use of strong CYP3A4 inhibitors with sildenafil when used for the treatment of pulmonary arterial hypertension (PAH) is not recommended.(5) The US manufacturer of tadalafil states that the concurrent use of strong CYP3A4 inhibitors with tadalafil when used for the treatment of pulmonary arterial hypertension (PAH) is not recommended.(6) The US manufacturer of itraconazole states that the concurrent use of sildenafil or tadalafil is not recommended during and for 2 weeks after treatment with itraconazole, when sildenafil or tadalafil is used for the treatment of PAH.(7) The US manufacturer of sildenafil recommends a starting dose of 25 mg of sildenafil for erectile dysfunction in patients receiving concomitant therapy with strong CYP3A4 inhibitors.(1) The US manufacturer of tadalafil states that the maximum recommended dose of as needed tadalafil for erectile dysfunction in patients taking strong inhibitors of CYP3A4 is 10 mg every 72 hours.(2) The maximum recommended dose of daily tadalafil for erectile dysfunction in patients taking strong inhibitors of CYP3A4 is 2.5 mg.(3)

DISCUSSION: Concurrent administration of a single 100 mg dose of sildenafil with erythromycin (500 mg twice daily for five days) resulted in an increase of sildenafil area-under-curve (AUC) by 182%. Therefore, the manufacturer of sildenafil recommends a starting dose of 25 mg of sildenafil in patients receiving concomitant therapy with other strong CYP3A4 inhibitors such as itraconazole or ketoconazole.(1) Concurrent administration of a single 20 mg dose of tadalafil with ketoconazole (400 mg daily) increased tadalafil AUC and maximum concentration (Cmax) by 312% and 22%, respectively. Concurrent administration of a single 10 mg dose of tadalafil with ketoconazole (200 mg daily) increased tadalafil AUC and Cmax by 107% and 15%, respectively.(2) Strong CYP3A4 inhibitors include adagrasib, ceritinib, clarithromycin, ensitrelvir, grapefruit, idelalisib, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, nefazodone, posaconazole, ribociclib, telithromycin, and voriconazole.(1-4)

Slt Strong Cyp3a4 Inhibitor & Substrate/Lumacaftor-Ivacaftor

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Adagrasib, ceritinib, clarithromycin, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, ribociclib, ritonavir, telithromycin, and tucatinib are both strong inhibitors and substrates of CYP3A4.(1,2) Strong inhibitors of CYP3A4 may inhibit the CYP3A4-mediated metabolism of ivacaftor. Lumacaftor is a strong inducer of CYP3A4. Over time, lumacaftor induction moderates the CYP3A4 inhibitor effect on ivacaftor. In addition, lumacaftor may increase the metabolism of agents that are metabolized by CYP3A4.(3)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in elevated levels of and toxicity from ivacaftor.(3) Concurrent use of lumacaftor with agents that are CYP3A4 substrates may result in decreased levels and effectiveness of the substrate.(3)

PREDISPOSING FACTORS: The interaction severity may be increased in patients with hepatic impairment.(3)

PATIENT MANAGEMENT: The US manufacturer of lumacaftor-ivacaftor states that concurrent use of sensitive CYP3A4 substrates and those with a narrow therapeutic index are not recommended. An alternative to macrolide antibiotics (e.g. clarithromycin, telithromycin) should be considered, such as ciprofloxacin, azithromycin, and levofloxacin. Azole antifungals are not recommended. Consider an alternative such as fluconazole.(3) The US manufacturer of itraconazole states that concurrent use with lumacaftor-ivacaftor is not recommended two weeks before, during, and two weeks after itraconazole treatment.(5) If concurrent use is necessary, recommended adjustments depend upon whether lumacaftor-ivacaftor or the strong CYP3A4 inhibitor was started first. - If the patient has been stabilized on lumacaftor-ivacaftor therapy when the CYP3A4 inhibitor is started, no dose adjustments are necessary. - If lumacaftor-ivacaftor tablets are started in a patient currently receiving a strong CYP3A4 inhibitor, then begin with one tablet daily for the first week of treatment. Following this period, continue with the recommended daily dose. - If lumacaftor-ivacaftor granules are started in a patient currently receiving a strong CYP3A4 inhibitor, then begin with one packet of oral granules every other day for the first week of treatment. Following this period, continue with the recommended daily dose. If lumacaftor-ivacaftor tablet therapy is stopped for more than one week while taking a strong CYP3A4 inhibitor, when re-initiated the lumacaftor-ivacaftor tablets the dose should be one tablet daily for the first week. Following this period, continue with the recommended daily dose. If lumacaftor-ivacaftor granules therapy is stopped for more than one week while taking a strong CYP3A4 inhibitor, when re-initiated the lumacaftor-ivacaftor granules the dose should be one packet of oral granules every other day for the first week. Following this period, continue with the recommended daily dose.

DISCUSSION: In an interaction study lumacaftor reduced exposure to ivacaftor, a CYP3A4 sensitive substrate, by 80%.(3) Concurrent administration with itraconazole (a strong inhibitor of CYP3A4) increased ivacaftor area-under-curve (AUC) by 4.3-fold.(3) A study in 12 subjects compared ivacaftor alone (study A), ivacaftor with ritonavir (a strong inhibitor of CYP3A4) 50 mg daily on days 1-4 (study B), and ivacaftor with ritonavir 50 mg daily for two weeks prior and on days 1-4 of ivacaftor administration (study C). In study A, B, and C, ivacaftor AUC increased from 10.94 mcg/hr to 215.6 mcg/hr and 216 mcg/hr, respectively, with the addition of ritonavir. Ivacaftor concentration maximum (Cmax) was 0.9944 mcg, 1.812 mcg, and 2.267 mcg in study A, B, and C, respectively.(4) Agents that are both strong inhibitors and substrates of CYP3A4 linked to this monograph include: adagrasib, ceritinib, clarithromycin, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, ribociclib, ritonavir, telithromycin, and tucatinib.(1-2)

Slt Strong Cyp3a4 Inhibitors That Prolong Qt/Gilteritinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong the QTc interval may inhibit the metabolism of gilteritinib and result in additive risk of QT prolongation.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors that prolong the QTc interval may increase the levels and effects of gilteritinib, including additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The use of gilteritinib with strong CYP3A4 inhibitors should be used with caution. Consider alternatives with no or minimal enzyme inhibition. If concurrent use is warranted, monitor patients more frequently for adverse reactions. Interrupt and reduce gilteritinib dose if toxicities occur.(1) If coadministration with a strong CYP3A4 inhibitor is unavoidable, monitor for prolongation of the QTc interval. When concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. Prior to initiation of therapy with gilteritinib, obtain baseline ECG and on days 8 and 15 of cycle 1, and prior to the start of the next two subsequent cycles. If QTc prolongation develops: ---Monitor and supplement electrolytes as clinically indicated ---Review and adjust concomitant QT prolonging medications For a QTc interval greater than 500 msec: ---Interrupt gilteritinib therapy ---Resume gilteritinib therapy at 80 mg when the QTc interval returns to within 30 msec of baseline or <= 480 msec. For QTc interval increased by > 30 msec on ECG on Day 8 of cycle 1: ---Confirm with ECG on Day 9 ---If confirmed, consider dose reduction to 80 mg.(1)

DISCUSSION: Itraconazole (a strong CYP3A4 inhibitor) increased maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of gilteritinib by 20% and 1200%, respectively.(1) In the gilteritinib clinical trial, 1.4% of patients developed a QTc interval greater than 500 msec and 7% of patients had an increase QTc greater than 60 msec.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(5) Strong inhibitors of CYP3A4 that prolong QT include: adagrasib, levoketoconazole, and posaconazole.(3,4)

Slt Strong Cyp3a4 Inhibitors That Prolong Qt/Iloperidone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of iloperidone and result in additive risk of QT prolongation.(1)

CLINICAL EFFECTS: Concurrent administration of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from iloperidone.(1) Elevated levels of iloperidone and concurrent use with agents that prolong the QTc interval may increase the risk of QTc prolongation.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age, and with concurrent use of inhibitors of CYP2D6, which metabolizes iloperidone.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The US manufacturer of iloperidone states that the dose of iloperidone should be reduced to one-half of its normal dose when strong CYP3A inhibitors are coadministered. If the patient is also receiving a CYP2D6 inhibitor, iloperidone should be reduced to one-half of its normal dose but no additional dose reduction is required with both a CYP2D6 inhibitor and CYP3A4 inhibitor. When the inhibitor is discontinued, the dose of iloperidone should be increased.(1) The US manufacturer of levoketoconazole states that levoketoconazole is contraindicated with other agents that prolong the QT interval.(2) Levoketoconazole is also contraindicated in patients with a prolonged QTcF interval of greater than 470 msec at baseline, history of torsades de pointes, ventricular tachycardia, ventricular fibrillation, or long QT syndrome (including first-degree family history). Use caution in patients with other risk factors for QT prolongation including congestive heart failure, bradyarrhythmias, and uncorrected electrolyte abnormalities. Consider more frequent ECG monitoring.(2) Prior to starting levoketoconazole, obtain a baseline ECG and correct hypokalemia or hypomagnesemia. If a patient develops QT prolongation with a QTc interval greater than 500 msec, temporarily discontinue levoketoconazole. After resolution of prolonged QTc interval, levoketoconazole may be resumed at a lower dose. If QTc interval prolongation recurs, permanently discontinue levoketoconazole.(1) When concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Coadministration of ketoconazole (200 mg twice daily for 4 days) increased the AUC of iloperidone (3 mg single dose) and its P88 and P95 metabolites by 57%, 55%, and 35%, respectively.(1) Coadministration of ketoconazole (200 mg twice daily) and iloperidone (12 mg twice daily) was associated with a mean QTcF increase of 19 msec from baseline, compared with an increase of 9 msec with iloperidone alone.(1) Coadministration of ketoconazole and paroxetine (a CYP2D6 inhibitor) did not increase the effects on iloperidone compared with either agent alone.(1) During phase 1 and 2 studies of levoketoconazole, which excluded patients with baseline QTcF interval greater than 470 msec, 4 (2.4%) patients experienced QTcF > 500 msec, and 23 (14.7%) patients experienced change-from-baseline QTcF > 60 msec.(1) Strong CYP3A4 inhibitors that prolong QT linked to this monograph include: adagrasib, levoketoconazole, and lonafarnib.(4)

Slt Strong Cyp3a4 Inhibitors That Prolong Qt/Midostaurin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong the QTc interval may inhibit the metabolism of midostaurin and result in additive risk of QT prolongation.(1) Levoketoconazole can also prolong the QTc interval.(2)

CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP3A4 that prolong QT may result in elevated levels of and toxicity from midostaurin, including additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The manufacturer of midostaurin states to consider alternative therapies that do not inhibit CYP3A4 whenever possible. Consider interval assessments of QT by electrocardiogram (ECG) if taken concurrently with medications that can prolong the QT interval.(1) Monitor patient for signs of midostaurin toxicity with concurrent use, especially during the first week of concurrent therapy in advanced systemic mastocytosis (SM) population and during the first week of each cycle of chemotherapy in acute myeloid leukemia (AML) population.(1) The US manufacturer of adagrasib states that adagrasib should be avoided with other agents that prolong the QT interval.(4) The US manufacturer of levoketoconazole states that levoketoconazole is contraindicated with other agents that prolong the QT interval.(2) Levoketoconazole is also contraindicated in patients with a prolonged QTcF interval of greater than 470 msec at baseline, history of torsades de pointes, ventricular tachycardia, ventricular fibrillation, or long QT syndrome (including first-degree family history). Use caution in patients with other risk factors for QT prolongation including congestive heart failure, bradyarrhythmias, and uncorrected electrolyte abnormalities. Consider more frequent ECG monitoring.(2) Prior to starting levoketoconazole, obtain a baseline ECG and correct hypokalemia or hypomagnesemia. If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Midostaurin is a substrate of CYP3A4.(1) Concurrent administration of ketoconazole (400 mg daily for 10 days, a strong CYP3A4 inhibitor) with a single 50 mg dose of midostaurin on day 6 increased the area-under-curve (AUC) of midostaurin and the active metabolite, CGP62221, 10.4-fold and 3.5-fold, respectively. The AUC over time to last measurable concentration of CGP62221 increased by 1.2-fold compared to midostaurin alone.(1) Concurrent administration of itraconazole (100 mg twice daily on days 22-28 for 13 doses, a strong CYP3A4 inhibitor) with multiple doses of midostaurin (100 mg twice daily on days 1-2 and 50 mg twice daily on days 3-28) increased day 28 minimum concentration (Cmin) of midostaurin, CGP62221 and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, compared to day 21 Cmin concentrations with midostaurin alone.(1) During phase 1 and 2 studies of levoketoconazole, which excluded patients with baseline QTcF interval greater than 470 msec, 4 (2.4%) patients experienced QTcF > 500 msec, and 23 (14.7%) patients experienced change-from-baseline QTcF > 60 msec.(2) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, lonafarnib, and levoketoconazole.(2,5-6)

Str 3A4 Inhib Prol Qt/Tolterodine (>1 Mg Ir Or >2 Mg Er)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of tolterodine by CYP3A4.(1,2) Tolterodine has been observed to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1,2)

CLINICAL EFFECTS: The concurrent administration of tolterodine with strong CYP3A4 inhibitors may result in elevated levels of tolterodine and signs of toxicity, including potentially life-threatening arrhythmias.(1,2)

PREDISPOSING FACTORS: Patients who are CYP2D6 poor metabolizers may be at increased risk.(1,2) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: The manufacturer of tolterodine recommends that a maximum tolterodine dosage of 1 mg twice daily of the non extended release dosage form(1) or 2 mg once daily of the extended release dosage form(2) be used in patients receiving concurrent therapy with strong CYP3A4 inhibitors. The manufacturer of tolterodine states concurrent use agents known to prolong the QT interval should be used with caution. Consider close observation in patients with a known history of QT prolongation or patients taking antiarrhythmic medications.(1,2) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study in eight subjects who were deficient in CYP2D6, the concurrent administration of tolterodine (2 mg) with ketoconazole (200 mg once daily for four days), another inhibitor of CYP3A4, resulted in a 60% decrease in tolterodine clearance.(6) Tolterodine AUC and Cmax increased 2.5-fold and 2-fold, respectively.(2) In a study of the effect of tolterodine immediate release tablets, the effect on the QT interval appeared greater for 8 mg/day (two times the therapeutic dose) compared to 4 mg/day. Tolterodine 2 mg BID and tolterodine 4 mg BID increased the QTcF by 5.01 msec (0.28-9.74 msec) and 11.84 msec (7.11-16.58 msec), respectively. The change in QT interval was more pronounced in CYP2D6 poor metabolizers (PM) than extensive metabolizers (EMs).(1,2) Strong inhibitors of CYP3A4 include: adagrasib, ceritinib, clarithromycin, lonafarnib, lopinavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(1,7,8)

Str 3A4 Inhibitors That Prolong Qt/Aumolertinib (<= 55 Mg)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Aumolertinib is a CYP3A4 substrate and has been shown to prolong the QTc interval. Strong inhibitors of CYP3A4 may inhibit the metabolism of aumolertinib.(1) Concurrent use of agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors that prolong QT may result in increased levels and toxicities of aumolertinib, including an additive risk of potentially life-threatening arrhythmias like torsades de pointes, cardiac failure, rhabdomyolysis, thrombosis, elevated LFTs, hyponatremia, and hematologic toxicity.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Patients with risk factors for thrombosis may be at higher risk of adverse events, including those with advanced age, obesity (BMI >30), smoking, prolonged immobilization, heart failure, hypercoagulable state, history of venous thromboembolism, malignancy, and major surgery. The risk for rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of rhabdomyolysis.

PATIENT MANAGEMENT: The manufacturer of aumolertinib states that concurrent use with strong CYP3A4 inhibitors should be avoided. If concurrent use of a strong CYP3A4 inhibitor cannot be avoided, the dose of aumolertinib should be reduced from 110 mg to 55 mg daily.(1) The manufacturer of aumolertinib states that concurrent use of other drugs that are known to prolong the QTc interval should be avoided. If a suitable alternative is not available, consider increasing the frequency of ECG and electrolyte monitoring.(1) Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If QTc prolongation occurs, follow recommended dose modifications: - Grade 2 (QTc interval >480 to 500 ms): Withhold aumolertinib for up to 2 weeks. If QTc interval has not recovered to <= 480 ms, permanently discontinue aumolertinib. If QTc interval recovers to <= 480 ms or within 30 ms of baseline, resume aumolertinib treatment at 110 mg. Monitor ECGs at least weekly for 2 weeks following return to <= 480 ms. Monitor and correct electrolytes and/or change concomitant medications. - Grade 3 (QTc interval > 500 ms or QTc interval increase of > 60 ms from baseline): Withhold aumolertinib for up to 2 weeks. If QTc interval has not recovered to <= 480 ms or within 30 ms of baseline, permanently discontinue aumolertinib. If QTc interval recovers to <= 480 ms and it is the first occurrence, resume treatment at 110 mg dose. If QTc interval recovers to <= 480 ms and it is the second occurrence or the first occurrence in patients with risk factors, resume treatment at 55 mg dose. Permanently discontinue aumolertinib if signs or symptoms recur at any time on the 55 mg dose. Monitor ECGs at least weekly for 2 weeks following return to <= 480 ms. Monitor and correct electrolytes and/or change concomitant medications. - QT interval prolongation associated with torsade de pointes, polymorphic ventricular tachycardia, or signs/symptoms of other serious arrhythmia: permanently discontinue aumolertinib.(1)

DISCUSSION: In a clinical study, itraconazole (strong CYP3A inhibitor) increased aumolertinib area-under-curve (AUC) by 3.7-fold.(1) A concentration-QT analysis predicted a QTc interval prolongation at 110 mg aumolertinib of 9.06 ms (upper confidence interval = 11.01 ms) in 49 subjects.(1) In clinical studies (n=545), QT prolongation was reported in 51 patients (9.4%) treated with aumolertinib 110 mg. Seven patients (1.3%) had symptomatic events, including cardiac arrest, syncope, and ventricular arrhythmia. One patient with cardio-respiratory arrest and one patient with sudden cardiac death died. QTcF increase >60 ms occurred in 4.2% of patients, and increase in QTcF to >500 ms occurred in 0.9% of patients.(1) Strong inhibitors of CYP3A4 that prolong QT include: adagrasib, ceritinib, ribociclib, and saquinavir.(3,4)

Strong & Moderate Cyp3a4 Inhibitors/Eliglustat

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong or moderate inhibitors of CYP3A4 may inhibit the metabolism of eliglustat. If the patient is also taking an inhibitor of CYP2D6, eliglustat metabolism can be further inhibited.(1)

CLINICAL EFFECTS: Concurrent use of an agent that is a strong or moderate inhibitor of CYP3A4 may result in elevated levels of and clinical effects of eliglustat, including prolongation of the PR, QTc, and/or QRS intervals, which may result in life-threatening cardiac arrhythmias.(1)

PREDISPOSING FACTORS: If the patient has liver disease, is also taking an inhibitor of CYP2D6 and/or is an intermediate or poor metabolizer of CYP2D6, eliglustat metabolism can be further inhibited.(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The concurrent use of eliglustat with strong or moderate inhibitors of CYP3A4 concomitantly with strong or moderate inhibitors of CYP2D6 in both extensive and intermediate metabolizers of CYP2D6 is contraindicated.(1) The concurrent use of eliglustat with strong inhibitors of CYP3A4 in intermediate and poor metabolizers of CYP2D6 is contraindicated.(1) The concurrent use of eliglustat with moderate inhibitors of CYP3A4 in intermediate and poor metabolizers of CYP2D6 should be avoided.(1) The dosage of eliglustat with strong or moderate inhibitors of CYP3A4 in extensive metabolizers of CYP2D6 should be limited to 84 mg daily.(1) The concurrent use of eliglustat with strong inhibitors of CYP3A4 concomitantly with strong or moderate inhibitors of CYP2D6 is contraindicated.(1) The concurrent use of eliglustat with moderate inhibitors of CYP3A4 concomitantly with strong or moderate inhibitors of CYP2D6 in poor metabolizers of CYP2D6 should be avoided and is contraindicated in extensive and intermediate metabolizers of CYP2D6.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Ketoconazole (400 mg daily), a strong inhibitor of CYP3A4, increased eliglustat (84 mg BID) maximum concentration (Cmax) and area-under-curve (AUC) by 4-fold and 4.4-fold, respectively, in extensive metabolizers. Physiologically-based pharmacokinetic (PKPB) models suggested ketoconazole would increase eliglustat Cmax and AUC by 4.4-fold and 5.4-fold, respectively, in intermediate metabolizers. PKPB models suggested ketoconazole may increase the Cmax and AUC of eliglustat (84 mg daily) by 4.3-fold and 6.2-fold, respectively, in poor metabolizers.(1) PKPB models suggested fluconazole, a moderate inhibitor of CYP3A4, would increase eliglustat Cmax and AUC by 2.8-fold and 3.2-fold, respectively, in extensive metabolizers and by 2.5-fold and 2.9-fold, respectively in intermediate metabolizers. PKPB models suggest that concurrent eliglustat (84 mg BID), paroxetine (a strong inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 16.7-fold and 24.2-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 7.5-fold and 9.8-fold, respectively.(1) PKPB models suggest that concurrent eliglustat (84 mg BID), terbinafine (a moderate inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 10.2-fold and 13.6-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 4.2-fold and 5-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, ensitrelvir, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tucatinib, and voriconazole.(1,3,4) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, casopitant, clofazimine, conivaptan, crizotinib, darunavir, duvelisib, erythromycin, fluconazole, fosamprenavir, fosnetupitant, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, and treosulfan.(1,3,4)

Strong & Moderate Cyp3a4 Inhibitors/Guanfacine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong or moderate inhibitors of CYP3A4 may inhibit the metabolism of guanfacine.(1)

CLINICAL EFFECTS: The concurrent administration of a strong or moderate CYP3A4 inhibitor may result in elevated levels of guanfacine, which may result in increased adverse effects such as hypotension, bradycardia, loss of consciousness, and drowsiness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients maintained on guanfacine may need dosage adjustments if strong or moderate inhibitors of CYP3A4 are initiated or discontinued. The manufacturer of extended-release guanfacine recommends a starting dose of extended-release guanfacine initiated at half the recommended level of the weight based dosing in patients receiving strong or moderate inhibitors of CYP3A4. If a patient has been maintained on extended-release guanfacine and is started on a strong or moderate CYP3A4 inhibitor, the dose of extended-release guanfacine should be decreased to half the recommended weight based dose. If a patient has been maintained on extended-release guanfacine and a strong or moderate CYP3A4 inhibitor and the strong or moderate CYP3A4 inhibitor is discontinued, the dose of extended-release guanfacine may need to be increased to the recommended weight based dose based upon patient response. Extended-release guanfacine target dose range for attention deficit hyperactivity disorder is 0.05-0.12 mg/kg/day. Doses above 4 mg/day have not been evaluated in children ages 6-12 years and doses above 7 mg/day have not been evaluated in adolescents ages 13-17 years.(1)

DISCUSSION: Ketoconazole (dosage not stated), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of guanfacine (dosage not stated) by approximately 1.75-fold and 3-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(1-3) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(1-3)

Strong 3A4 Inhibitors/Eszopiclone > 2 Mg; Zopiclone > 5 Mg

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 impair the metabolism of eszopiclone(1) and zopiclone.(2,3)

CLINICAL EFFECTS: Concurrent use of eszopiclone(1) or zopiclone(2,3) with a strong CYP3A4 inhibitor may result in an increase in hypnotic levels and clinical adverse effects such as confusion, memory loss, sleep-walking or sleep-driving behaviors, thought or behavioral changes, or excessive daytime drowsiness, as well as toxic effects such as profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: Systemic exposure may also be increased in patients with severe hepatic impairment. Elderly and debilitated patients are more likely to have impaired motor or cognitive performance when treated with hypnotics.

PATIENT MANAGEMENT: The US manufacturer of eszopiclone states the total dose should not exceed 2 mg in patients taking strong CYP3A4 inhibitors.(1) The Canadian manufacturer of zopiclone states the prescribed dose should not exceed 5 mg in patients treated with strong CYP3A4 inhibitors.(2) Patients should be counseled that concurrent use of a strong CYP3A4 inhibitor with eszopiclone or zopiclone may result in an increase in side effects such as confusion, memory loss, sleep-walking or sleep-driving behaviors, or daytime drowsiness.

DISCUSSION: Concurrent administration of ketoconazole (400 mg daily for 5 days) increased the area-under-curve (AUC) of eszopiclone by 2.2-fold. Eszopiclone maximum concentration (Cmax) and half-life were increased 1.4-fold and 1.3-fold, respectively.(1) An in vitro study in human liver microsomes found that ketoconazole inhibited the metabolism of zopiclone.(2) In a study in 10 subjects, itraconazole (200 mg daily for 4 days) increased the AUC, Cmax, and half-life of zopiclone by 73%, 29%, and 40%, respectively. However, there were no significant differences in clinical effects when compared to placebo.(4) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, elvitegravir, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(5,6)

Strong And Moderate Cyp3a4 Inhibitors/Bosentan

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Bosentan is metabolized by CYP2C9 and CYP3A4. It is also an inducer of these enzymes. With regular dosing bosentan auto-induces its own metabolism.(1) Strong and moderate CYP3A4 inhibitors may inhibit the CYP3A4 mediated metabolism of bosentan.(1,2)

CLINICAL EFFECTS: Concurrent use of bosentan with an inhibitor of CYP3A4 may result in elevated levels of and toxicity from bosentan.(1)

PREDISPOSING FACTORS: Concurrent use of bosentan, a CYP3A4 inhibitor and a CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone, sulfinpyrazone, or phenylbutazone)(3) could lead to blockade of both major metabolic pathways for bosentan, resulting in large increases in bosentan plasma concentrations.(1,3)

PATIENT MANAGEMENT: Review medication list to see if patient is also receiving a CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone, sulfinpyrazone, or phenylbutazone). Concomitant use of both a CYP2C9 and CYP3A4 inhibitor is not recommended by the manufacturer as the combination may lead to large increases in bosentan plasma concentrations.(1) For patients stabilized on bosentan when a CYP3A4 inhibitor is initiated, monitor tolerance to concomitant therapy and adjust bosentan dose if needed. In patients who have been receiving a strong CYP3A4 inhibitor for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of a strong CYP3A4 inhibitor. After at least 10 days following the initiation of a strong CYP3A4 inhibitor, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

DISCUSSION: In a study in healthy subjects, concurrent bosentan and ketoconazole (a strong CYP3A4 inhibitor) administration increased bosentan steady-state maximum concentrations (Cmax) and area-under-curve (AUC) by 2.1-fold and 2.3-fold, respectively.(2) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, itraconazole, josamycin, ketoconazole, levoketoconazole, mibefradil, mifepristone, nefazodone, posaconazole, relacorilant, ribociclib, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(3) Moderate CYP3A4 inhibitors linked to this monograph include: aprepitant, berotralstat, clofazimine, conivaptan, diltiazem, dronedarone, erythromycin, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, letermovir, netupitant, nilotinib, schisandra, stiripentol, treosulfan, and verapamil.(3)

Strong And Moderate Cyp3a4 Inhibitors/Deflazacort

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Deflazacort is a prodrug and is rapidly metabolized to the active metabolite, 21-desDFZ, by esterases. The metabolite 21-desDFZ is metabolized by CYP3A4 to inactive metabolites.(1) Inhibitors of CYP3A4 may inhibit the metabolism of the active metabolite of deflazacort metabolized by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inhibitors may result in increased systemic exposure to and effects from deflazacort.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer recommends decreasing the dose to one-third of the recommended dose of deflazacort when used concurrently with strong or moderate CYP3A4 inhibitors. For example, if the recommended dose of deflazacort is 36 mg per day, the reduced dose would be 12 mg per day when administered with strong or moderate CYP3A4 inhibitors.(1)

DISCUSSION: Deflazacort is a prodrug and is rapidly metabolized to the active metabolite, 21-desDFZ. The metabolite 21-desDFZ is metabolized by CYP3A4.(1) Coadministration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total geometric mean exposure (maximum concentration (Cmax) and area-under-curve (AUC)) to the active metabolite 21-desDFZ by 2.3- to 3.4-fold.(1)

Strong And Moderate Cyp3a4 Inhibitors/Ivacaftor

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong and moderate inhibitors of CYP3A4 may inhibit the metabolism of ivacaftor.(1)

CLINICAL EFFECTS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may result in elevated levels of and toxicity from ivacaftor.(1)

PREDISPOSING FACTORS: This interaction may be more severe in patients with hepatic impairment.(1)

PATIENT MANAGEMENT: In patients receiving concurrent strong CYP3A4 inhibitors such as boceprevir, ceritinib, clarithromycin, cobicistat, conivaptan, idelalisib, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib, or voriconazole, the dose of ivacaftor should be reduced to one 150 mg tablet or one packet (25 mg if body weight 5 kg to < 7 kg, 50 mg if body weight < 14 kg, 75 mg if weight equal or > 14 kg) two times a week.(1) In patients receiving concurrent moderate CYP3A4 inhibitors such as amprenavir, aprepitant, atazanavir, berotralstat, crizotinib, cyclosporine, darunavir/ritonavir, diltiazem, dronedarone, erythromycin, fluconazole, fosamprenavir, fosaprepitant, imatinib, isavuconazonium, ledipasvir, netupitant, schisandra or verapamil, the dose of ivacaftor should be reduced to one 150 mg tablet or one packet (25 mg if body weight 5 kg to < 7 kg, 50 mg if body weight < 14 kg, 75 mg if weight equal or > 14 kg) daily.(1) In patients who are less than 6 months of age, concurrent use of ivacaftor with strong or moderate CYP3A4 inhibitors is not recommended.(1)

DISCUSSION: Concurrent administration with ketoconazole (a strong inhibitor of CYP3A4) increased ivacaftor area-under-curve (AUC) by 8.5-fold.(1) Concurrent administration with fluconazole (a moderate inhibitor of CYP3A4) increased ivacaftor area-under-curve (AUC) by 3-fold.(1) A study in 12 subjects compared ivacaftor alone (study A), ivacaftor with ritonavir (a strong inhibitor of CYP3A4) 50 mg daily on days 1-4 (study B), and ivacaftor with ritonavir 50 mg daily for two weeks prior and on days 1-4 of ivacaftor administration (study C). In study A, B, and C, ivacaftor AUC increased from 10.94 mcg/hr to 215.6 mcg/hr and 216 mcg/hr, respectively, with the addition of ritonavir. Ivacaftor concentration maximum (Cmax) was 0.9944 mcg, 1.812 mcg, and 2.267 mcg in study A, B, and C, respectively.(2) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(3-5) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir/ritonavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, ledipasvir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan and verapamil.(3-5)

Strong And Moderate Cyp3a4 Inhibitors/Pemigatinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of pemigatinib.(1)

CLINICAL EFFECTS: Concomitant use of a strong or moderate CYP3A4 inhibitor increases pemigatinib plasma concentrations, which may increase the incidence and severity of adverse reactions.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of pemigatinib states that coadministration with strong or moderate CYP3A4 inhibitors should be avoided. If coadministration cannot be avoided, the dosage of pemigatinib should be reduced as follows: -Reduce dose from 13.5 mg to 9 mg. -Reduce dose from 9 mg to 4.5 mg. If the strong or moderate CYP3A4 inhibitor is discontinued, resume the pemigatinib dose that was taken prior to the initiation of the inhibitor after 3 half-lives of the CYP3A4 inhibitor have elapsed.(1)

DISCUSSION: Itraconazole, a strong CYP3A4 inhibitor, increased the maximum concentration (Cmax) by 17% and area-under-curve (AUC) by 88% following a single oral pemigatinib dose of 4.5 mg. Concomitant use of moderate CYP3A4 inhibitors is predicted to increase pemigatinib exposure by approximately 50-80%.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2)

Strong And Moderate Cyp3a4 Inhibitors/Selumetinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of selumetinib.(1)

CLINICAL EFFECTS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may result in increased levels of and effects from selumetinib, including vomiting, diarrhea, skin rashes, ocular toxicity (e.g., blurred vision, visual loss), cardiomyopathy, and rhabdomyolysis.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of selumetinib states that the coadministration of selumetinib with strong or moderate CYP3A4 inhibitors should be avoided. If coadministration cannot be avoided, the dosage of selumetinib should be reduced as follows: -If the current dose is 25 mg/m2 twice daily, reduce to 20 mg/m2 twice daily. -If the current dosage is 20 mg/m2 twice daily, reduce to 15 mg/m2 twice daily. If the strong or moderate CYP3A4 inhibitor is discontinued, resume the selumetinib dose that was taken prior to the initiation of the inhibitor after 3 half-lives of the CYP3A4 inhibitor have elapsed.(1)

DISCUSSION: In a study of 26 healthy subjects, itraconazole 200 mg twice daily (a strong CYP3A4 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of selumetinib 25 mg by 49% and 19%, respectively. Fluconazole 400 mg loading dose then 200 mg daily (a moderate CYP3A4 inhibitor and strong CYP2C19 inhibitor) increased AUC and Cmax of selumetinib (25 mg) by 53% and 26%.(1,2) In a pharmacokinetic model, erythromycin (a moderate CYP3A4 inhibitor) was predicted to increase selumetinib AUC and Cmax by 41% and 23%, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib and voriconazole.(3) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(3)

Strong And Moderate Cyp3a4 Inhibitors/Tezacaftor-Ivacaftor

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong and moderate inhibitors of CYP3A4 may inhibit the metabolism of tezacaftor-ivacaftor.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may result in elevated levels of and toxicity from tezacaftor-ivacaftor.(1,2)

PREDISPOSING FACTORS: This interaction may be more severe in patients with hepatic impairment.(1,2)

PATIENT MANAGEMENT: Refer to current prescribing information for tezacaftor-ivacaftor for dose adjustment recommendations with strong and moderate CYP3A4 inhibitors.(2) Dose modifications for concurrent use of strong CYP3A4 inhibitors: - In adults, patients 12 years and older, and patients 6 to 12 years old weighing at least 30 kg who are receiving concurrent strong CYP3A4 inhibitors, the morning dose of tezacaftor 100 mg/ivacaftor 150 mg should be given twice a week, approximately 3 to 4 days apart. The evening dose of ivacaftor 150 mg should not be taken. - In patients 6 to 12 years old weighing less than 30 kg who are receiving concurrent strong CYP3A4 inhibitors, the morning dose of tezacaftor 50 mg/ivacaftor 75 mg should be given twice a week, approximately 3 to 4 days apart. The evening dose of ivacaftor 75 mg should not be taken.(2) Dose modifications for concurrent use of moderate CYP3A4 inhibitors: - In adults, patients 12 years and older, and patients 6 to 12 years old weighing at least 30 kg who are receiving concurrent moderate CYP3A4 inhibitors, the morning dose of tezacaftor 100 mg/ivacaftor 150 mg should be given every other day alternating with ivacaftor 150 mg. The evening dose of ivacaftor 150 mg should not be taken. - In patients 6 to 12 years old weighing less than 30 kg who are receiving concurrent moderate CYP3A4 inhibitors, the morning dose of tezacaftor 50 mg/ivacaftor 75 mg should be given every other day alternating with ivacaftor 75 mg. The evening dose of ivacaftor 75 mg should not be taken.(2)

DISCUSSION: Concurrent administration with ketoconazole (a strong inhibitor of CYP3A4) increased ivacaftor area-under-curve (AUC) by 8.5-fold.(1) Concurrent administration with fluconazole (a moderate inhibitor of CYP3A4) increased ivacaftor AUC by 3-fold.(1) Concurrent administration with itraconazole (a strong inhibitor of CYP3A4) increased tezacaftor AUC by 4-fold and ivacaftor by 15.6-fold.(2) Concurrent administration with fluconazole (a moderate inhibitor of CYP3A4) increased tezacaftor AUC by 2-fold.(2) A study in 12 subjects compared ivacaftor alone (study A), ivacaftor with ritonavir (a strong inhibitor of CYP3A4) 50 mg daily on days 1-4 (study B), and ivacaftor with ritonavir 50 mg daily for two weeks prior and on days 1-4 of ivacaftor administration (study C). In study A, B, and C, ivacaftor AUC increased from 10.94 mcg/hr to 215.6 mcg/hr and 216 mcg/hr, respectively, with the addition of ritonavir. Ivacaftor concentration maximum (Cmax) was 0.9944 mcg, 1.812 mcg, and 2.267 mcg in study A, B, and C, respectively.(3) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(4-6) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir/ritonavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(4-6)

Strong Cyp3a4 Inhib;Moderate 3A4 & P-Gp Dual Inhib/Neratinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of neratinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors or moderate CYP3A4 and P-glycoprotein (P-gp) dual inhibitors may result in increased systemic exposure to and effects from neratinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the concurrent use of neratinib with strong CYP3A4 inhibitors or moderate CYP3A4 and P-gp dual inhibitors.(1) The Australian and Canadian manufacturer of nirmatrelvir/ritonavir state that concurrent use with neratinib is contraindicated due to the potential for hepatotoxicity and other serious reactions.(2,3) Canadian labeling contraindicates concurrent use of atazanavir/ritonavir and lopinavir/ritonavir with neratinib.(4,5) If concurrent use is warranted, monitor patients closely for increased incidence and severity of diarrhea, abdominal pain, nausea, vomiting, and dehydration.

DISCUSSION: Ketoconazole (400 mg daily for 5 days), a strong CYP3A4 inhibitor, increased maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of neratinib by 221% and 381%, respectively.(1) Pharmacokinetic models predicted that verapamil, a moderate CYP3A4 and P-gp dual inhibitor, would increase the Cmax and AUC of neratinib by 203% and 299%, respectively. Fluconazole, a moderate CYP3A4 inhibitor, is not expected to have a significant interaction with neratinib.(1) Strong CYP3A4 inhibitors include: adagrasib, boceprevir, clarithromycin, cobicistat, diltiazem, ensitrelvir, grapefruit juice, idelalisib, indinavir, itraconazole, ketoconazole, lonafarnib, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, posaconazole, ribociclib, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(1,6) Moderate CYP3A4 and P-gp dual inhibitors include: atazanavir, conivaptan, diltiazem, dronedarone, erythromycin, isavuconazole, istradefylline, josamycin, nilotinib, and verapamil.(1,6)

Strong Cyp3a4 Inhibit That Prolong Qt/Pimavanserin (<=10 Mg)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong the QTc interval may inhibit the metabolism of pimavanserin and result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors that prolong the QTc interval may increase systemic exposure and the risk for pimavanserin toxicities such as peripheral edema, confusion, or additive QTc prolongation and life-threatening cardiac arrhythmias like torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of pimavanserin recommends avoiding use with agents that prolong the QTc interval.(1) The US Department of Health and Human Services HIV guidelines state that pimavanserin should not be coadministered with saquinavir or lopinavir due to the risk of QTc prolongation.(3) If concomitant use of pimavanserin and a strong CYP3A4 inhibitor is needed, the pimavanserin dose should be reduced to 10 mg once daily.(1) During concomitant therapy with a strong CYP3A4 inhibitor, monitor patients closely for prolongation of the QT interval. Obtain serum calcium, magnesium, and potassium levels and monitor ECG at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a drug interaction study, ketoconazole increased pimavanserin maximum concentration (Cmax) 1.5-fold and area-under-curve(AUC) 3-fold. A thorough QTc study performed in 252 subjects found a mean maximum change from baseline of 13.5 msec (upper bound of the 90% confidence interval was 16.6 msec) at twice the therapeutic dose.(1) Thus, coadministration of pimavanserin and a QT prolonging agent, even at a reduced dose, may increase the risk for significant QT prolongation. Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(4)

Strong Cyp3a4 Inhibitors That Prolong Qt/Amiodarone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors that prolong the QTc interval may inhibit the metabolism of amiodarone and result in additive risk of QT prolongation. Amiodarone is a CYP3A4 substrate.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors that prolong QT may increase the levels and effects of amiodarone including additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of amiodarone states that the concurrent use of QT prolonging agents should be avoided and that the need to co-administer amiodarone with any other drug known to prolong the QTc interval must be based on a careful assessment of the potential risks and benefits of doing so for each patient. Concurrent use with CYP3A4 inhibitors should also be avoided.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: QTc prolongation has been reported during concurrent amiodarone and azole antifungals, fluoroquinolones, and macrolide antibiotics.(1) A retrospective review of patients who received concurrent amiodarone and haloperidol over a 24 month period found 49 patients who received concurrent therapy for 381 exposures. The mean increase in QTc interval was 9.8 msec; the average change in QTc interval per patient was 23.6 msec.(3) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(4) Strong inhibitors of CYP3A4 that prolong QT include: adagrasib, ceritinib, clarithromycin, lonafarnib, ribociclib, telithromycin, and voriconazole.(5,6)

Strong Cyp3a4 Inhibitors That Prolong Qt/Ceritinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong the QTc interval may inhibit the metabolism of ceritinib and result in additive risk of QT prolongation.(1)

CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP3A4 that prolong QT may result in elevated levels of and toxicity from ceritinib, including additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1) Other toxicities include bradycardia, nausea, vomiting, diarrhea, abdominal pain, transaminitis, hyperglycemia, interstitial lung disease, and pancreatitis.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Patients with severe hepatic impairment (Child-Pugh C) may be at increased risk of this interaction. Ceritinib dose reduction may be warranted in severe hepatic impairment. See prescribing information for recommendations.(1)

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors that prolong QT in patients undergoing therapy with ceritinib.(1) Consider alternatives with no or minimal enzyme inhibition and with no effect on the QTc interval. If concurrent use with ceritinib is unavoidable, reduce the dosage of ceritinib by one-third, rounding to the nearest 150 mg dosage strength. If the strong CYP3A4 inhibitor is discontinued, resume the dose that was taken prior to using the inhibitor.(1) Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and ceritinib should be monitored for prolongation of the QTc interval. When concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.(1)

DISCUSSION: In a study in 19 healthy subjects, ketoconazole (200 mg twice daily for 14 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of ceritinib (450 mg) by 22% and 2.9-fold, respectively. The steady-state AUC of ceritinib at reduced doses after concurrent ketoconazole was predicted by simulations to be similar to the steady-state AUC of ceritinib alone.(1) In a clinical trial 3% of patients experienced a QTc interval increase over baseline greater than 60 msec. Less than 1% of patients (1 of 304) treated with ceritinib was found to have a QTc greater than 500 msec. The upper limit of the 90% confidence interval for mean QTC increase was 16 msec at ceritinib 750 mg. Data suggested that ceritinib produces concentration-dependent QTc interval prolongation.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3) Strong inhibitors of CYP3A4 that prolong QT include: adagrasib, clarithromycin, lopinavir, posaconazole, telithromycin, and voriconazole.(4,5)

Strong Cyp3a4 Inhibitors That Prolong Qt/Crizotinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong the QTc interval may inhibit the metabolism of crizotinib and result in additive risk of QT prolongation.(1)

CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP3A4 that prolong QT may result in elevated levels of and toxicity from crizotinib, including additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1) Other toxicities include neutropenia, bradycardia, hepatotoxicity, interstitial lung disease, and severe visual loss.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors that prolong the QTc interval in patients undergoing therapy with crizotinib.(1) Consider alternatives with no or minimal enzyme inhibition and with no effect on the QTc interval. In Adults: If concurrent use of crizotinib for metastatic non-small cell lung cancer or inflammatory myofibroblastic tumor in adults and a strong CYP3A4 inhibitor is unavoidable, a dose reduction of crizotinib to 250 mg daily is recommended. In Pediatrics or Young Adults: If concurrent use of crizotinib for systemic anaplastic large cell lymphoma (in pediatrics), inflammatory myofibroblastic tumor (in pediatrics) or systemic anaplastic large cell lymphoma (in young adults) and a strong CYP3A4 inhibitor is unavoidable, dose reductions of crizotinib based on body surface area (BSA) are recommended for both capsule and pellet formulations. See prescribing information for dose reductions. If the strong CYP3A4 inhibitor is discontinued and not replaced with another strong CYP3A4 inhibitor, resume the dose of crizotinib that was taken prior to initiating the inhibitor.(1) Patients receiving concurrent therapy with a strong CYP3A4 inhibitor with crizotinib should be monitored for prolongation of the QTc interval.(1) When concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Ketoconazole (200 mg twice daily) increased maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of crizotinib (150 mg) by 44% and 216%, respectively. Itraconazole (200 mg twice daily) increased the Cmax and AUC of crizotinib (250 mg daily) by 33% and 57%, respectively.(1) A retrospective review of 618 cancer patients treated with 902 administrations of tyrosine kinase inhibitors were evaluated for rate and incidence of QTc prolongation. In patients who received crizotinib, QTc prolongation was identified in 1 patient (50%) with 1 patient (100%) having a Grade 1 event. No patients had a QTc change greater than or equal to 60 ms, VT, SCD, or TdP.(3) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(4) Strong inhibitors of CYP3A4 that prolong QT include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir, posaconazole, ribociclib, telithromycin, and voriconazole.(5,6)

Strong Cyp3a4 Inhibitors That Prolong Qt/Dasatinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong the QTc interval may inhibit the metabolism of dasatinib and result in additive risk of QT prolongation.(1)

CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP3A4 that prolong QT may result in elevated levels of and toxicity from dasatinib, including additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1) Other toxicities include myelosuppression, serious hemorrhages, fluid retention, pulmonary hypertension, cardiac ischemia, transient ischemic attacks, and severe dermatological reactions.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors that prolong QT in patients undergoing therapy with dasatinib.(1) Consider alternatives with no or minimal enzyme inhibition and with no effect on the QTc interval. If concurrent use with dasatinib and a strong inhibitor of CYP3A4 is warranted, consider decreasing the dose of dasatinib to 20 mg daily in patients taking dasatinib 70 mg daily, 20 mg daily in patients taking dasatinib 100 mg daily, and to 40 mg daily in patients taking dasatinib 140 mg daily. If this dose is not tolerated, either the strong CYP3A4 inhibitor must be discontinued or dasatinib should be stopped until therapy with the CYP3A4 inhibitor has been completed. When the CYP3A4 inhibitor has been discontinued, a one-week washout period should be allowed before the dosage of dasatinib is increased. For patients taking 60 mg or 40 mg daily, consider interrupting dasatinib until the inhibitor is discontinued. Allow a washout period of approximately one week after the inhibitor is stopped before reinitiating dasatinib.(1) Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and dasatinib should be monitored for prolongation of the QTc interval. When concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study in healthy subjects, concurrent ketoconazole (200 mg twice daily) with dasatinib (20 mg) increased dasatinib maximum concentration (Cmax) and area-under-curve (AUC) by 4-fold and 5-fold, respectively. Recommended dosage adjustments are expected to adjust the dasatinib AUC to ranges observed without CYP3A4 inhibitors; however, there are no clinical data available.(1) A retrospective review of 618 cancer patients treated with 902 administrations of tyrosine kinase inhibitors were evaluated for rate and incidence of QTc prolongation. In patients who received dasatinib, QTc prolongation was identified in 48 patients(41.7%) with 8 patients(16.7%) having Grade 1 and 15 patients(31.3%) having Grade 2 events. Grade 3 events occurred in 8 patients(16.7%) having QTc greater than or equal to 500 ms and 14 patients (29.2%) having QTc change greater than or equal to 60 ms. VT was seen in 2 (4.2%) patients and 1 (2.1%) patient experienced TdP.(3) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(4) Strong inhibitors of CYP3A4 that prolong QT include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir, posaconazole, ribociclib, telithromycin, and voriconazole.(5,6)

Strong Cyp3a4 Inhibitors That Prolong Qt/Dordaviprone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Dordaviprone is a CYP3A4 substrate and has been shown to prolong the QTc interval. Strong CYP3A4 inhibitors that prolong the QTc interval may inhibit the metabolism of dordaviprone and result in additive risk of QT prolongation.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors that prolong QT may increase the levels and effects of dordaviprone, including additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)

PREDISPOSING FACTORS: This interaction may be more severe in patients with renal or hepatic impairment.(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of dordaviprone states that the concurrent use of QT prolonging agents should be avoided. If current use cannot be avoided, separate administration of dordaviprone and the QT-prolonging agent. The manufacturer does not provide details about how to separate administration and states that the exposure-response relationship and time course of pharmacodynamic response is not fully characterized. Dordaviprone's time to maximum concentration (Tmax) occurs at 1.4 hours (0.5, 5.6 hours) and mean terminal half-life is 11 hours.(1) Concomitant use with strong CYP3A4 inhibitors should also be avoided.(1) If concomitant use with a strong CYP3A4 inhibitor cannot be avoided in adult and pediatric patients who weigh at least 52.5 kg, reduce the dordaviprone dosage from 625 mg to 375 mg once weekly. Recommended doses for patients weighing less than 52.5 kg receiving strong CYP3A4 inhibitors has not been established.(1) Baseline and periodic monitoring of ECG and electrolytes is recommended.(1) Increase the frequency of monitoring in patients with congenital long QT syndrome, existing QTc prolongation, history of ventricular arrhythmias, electrolyte abnormalities, heart failure, or who are taking strong CYP3A4 inhibitors.(1) If QTc interval prolongation occurs, dose modifications are warranted. If QTc is >500 msec or the change from baseline is >60 msec, interrupt dordaviprone therapy until QTc interval is <= 480 msec or returns to baseline. If the patient has Torsades de pointes, polymorphic ventricular tachycardia, or signs or symptoms of serious or life-threatening arrhythmia, permanently discontinue dordaviprone.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study, concomitant use of dordaviprone with itraconazole 200 mg daily for 8 days (a strong CYP3A4 inhibitor) increased dordaviprone maximum concentration (Cmax) and area-under-curve (AUC) by 2-fold and 4-fold, respectively.(1) Moderate CYP3A4 inhibitors (fluconazole or erythromycin) are predicted to increase dordaviprone Cmax and AUC by 1.5-fold and 2.5-fold.(1) Dordaviprone causes concentration-dependent QTc interval prolongation. In a QT study, the estimated change in QTcF was 11.8 msec (90% CI: 9.8, 13.7) with dordaviprone at 1.2 times the maximum recommended dose.(1) In a pooled safety analysis, out of 82 patients with a post-baseline ECG, 6% of patients had an increase in QTc of >60 msec from baseline and 1.2% had an increase in QTc >500 msec.(1) Strong inhibitors of CYP3A4 that prolong QT include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir-ritonavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(3,4)

Strong Cyp3a4 Inhibitors That Prolong Qt/Glasdegib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors that prolong the QTc interval may inhibit the metabolism of glasdegib and result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors that prolong the QTc interval may increase systemic exposure and the risk for glasdegib toxicities such as neutropenia. Concurrent use may also result in additive QTc prolongation, which may lead to life-threatening cardiac arrhythmias like torsade de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Avoid concurrent use of glasdegib with medications that prolong the QT interval.(1) When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If QTc prolongation develops: ---Monitor and supplement electrolytes as clinically indicated. ---Review and adjust concomitant QT prolonging medications. ---Interrupt glasdegib therapy for QTc interval greater than 500 ms. ---Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation. ---Follow labeling recommendations regarding restarting glasdegib.(1)

DISCUSSION: In a drug interaction study in healthy subjects, coadministration of ketoconazole (strong 3A4 inhibitor) with glasdegib increased glasdegib maximum concentration (Cmax) and area-under-the-curve (AUC) by 1.4 and 2.4-fold, respectively.(1) In a randomized, single-dose, double-blind, 4-way cross-over, placebo- and open-label moxifloxacin-controlled study in 36 healthy subjects, the largest placebo and baseline-adjusted QTc interval change was 8 msec (90% CI: 6-10 msec) with a single 150 mg dose of glasdegib. (The 150 mg single dose was used to achieve therapeutic plasma concentrations.) With two-fold therapeutic plasma concentrations (achieved with a 300 mg single dose), the QTc change was 13 msec (90% CI: 11-16 msec).(1) Strong CYP3A4 inhibitors that prolong QT linked to this monograph include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(3)

Strong Cyp3a4 Inhibitors That Prolong Qt/Lapatinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong the QTc interval may inhibit the metabolism of lapatinib and result in additive risk of QT prolongation.(1)

CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP3A4 that prolong QT may result in elevated levels of and toxicity from dasatinib, including additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1) Other toxicities include severe diarrhea, cardiotoxicity, hepatotoxicity, interstitial lung disease, and severe dermatological reactions.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with lapatinib.(1) Consider alternatives with no or minimal enzyme inhibition and with no effect on the QTc interval. If concurrent use with lapatinib is warranted, a dose reduction to 500 mg/day should be considered. If the 3A4 inhibitor is discontinued, at least 1 week should elapse before the lapatinib dose is adjusted upward.(1) Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and lapatinib should be monitored for prolongation of the QTc interval. When concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study in healthy subjects, ketoconazole (200 mg twice daily for 7 days) increased lapatinib area-under-curve (AUC) and half-life (T1/2) by 3.6-fold and 1.7-fold, respectively. The dosage adjustment to 500 mg/day is based on pharmacokinetic studies and is predicted to adjust lapatinib AUC to the range observed without inhibitors; however, there are no clinical data with this dosage adjustment in patients receiving strong CYP3A4 inhibitors.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3) Strong inhibitors of CYP3A4 that prolong QT include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir, posaconazole, ribociclib, telithromycin, and voriconazole.(4,5)

Strong Cyp3a4 Inhibitors That Prolong Qt/Milsaperidone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors that prolong QT may inhibit the metabolism of milsaperidone and may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: Concurrent administration of milsaperidone with strong CYP3A4 inhibitors may result in elevated milsaperidone levels and toxicities, including the risk for QTc prolongation.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age, and with concurrent use of inhibitors of CYP2D6, which metabolizes milsaperidone.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of milsaperidone states that the concurrent administration of other drugs that are known to prolong the QTc interval should be avoided.(1) If patients have a persistent QTc > 500 msec, discontinue milsaperidone.(1) If concurrent use is necessary, the US manufacturer of milsaperidone states that the maintenance dose of milsaperidone should be reduced to one-half of its normal dose when initiating a strong CYP3A4 inhibitor. If starting milsaperidone with a stable dose of a strong CYP3A4 inhibitor, follow the recommended titration schedule in the labeling.(1) Further dose reduction is not required for concurrent administration of milsaperidone with both a CYP2D6 inhibitor and CYP3A4 inhibitor. The maintenance dose of milsaperidone should be reduced to one-half of its normal dose when initiating a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor. If starting milsaperidone with a stable dose of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor, follow the recommended titration schedule in the labeling.(1) When the inhibitor is discontinued milsaperidone exposure will wane and the dose of milsaperidone should be titrated to the recommended dose in the labeling.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Milsaperidone and iloperidone rapidly interconvert in vivo. Coadministration of ketoconazole (200 mg twice daily, an inhibitor of CYP3A4) and iloperidone (12 mg twice daily) was associated with a mean QTcF increase of 19 msec from baseline, compared with an increase of 9 msec with iloperidone alone.(1) Coadministration of paroxetine (20 mg daily, an inhibitor of CYP2D6) and iloperidone (12 mg twice daily) was associated with a mean QTcF increase of 19 msec from baseline, compared with an increase of 9 msec with iloperidone alone.(1) Concomitant administration of ketoconazole (a strong CY3A4 inhibitor) (200 mg twice daily for 4 days) with a 3 mg single dose of iloperidone increased the iloperidone area-under-curve (AUC) by 57%, the milsaperidone AUC by 55%, and the P95 AUC by 35%.(1) Coadministration of ketoconazole (a CYP3A4 inhibitor) and paroxetine (strong CYP2D6 inhibitor) did not increase the effects on iloperidone compared with either agent alone.(1) Strong CYP3A4 inhibitors that prolong the QTc interval linked to this monograph include: adagrasib, levoketoconazole, lonafarnib.(2,3)

Strong Cyp3a4 Inhibitors That Prolong Qt/Nilotinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of nilotinib.(1-3)

CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP3A4 that prolong QT may result in elevated levels of and toxicity from nilotinib, including additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1-3) Other toxicities include myelosuppression, severe hemorrhage, vascular occlusive events, hepatotoxicity, pancreatitis, and fluid retention.(1-3)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors that prolong QT in patients undergoing therapy with nilotinib.(1-3) Consider alternatives with no or minimal enzyme inhibition and with no effect on the QTc interval. Consider interrupting nilotinib therapy if a strong CYP3A4 inhibitor is needed. If concurrent use is warranted with nilotinib hydrochloride, a dose reduction to 300 mg once daily in patients with resistant or intolerant Ph+CML or to 200 mg once daily in patients with newly diagnosed Ph+CML-CP should be considered.(1) If concurrent use is warranted with nilotinib tartrate, a dose reduction to 142 mg once daily in patients with resistant or intolerant Ph+CML or to 95 mg once daily in patients with newly diagnosed Ph+CML-CP should be considered.(2) If concurrent use is warranted with nilotinib orally disintegrating tablets, a dose reduction to 120 mg once daily in patients with resistant or intolerant Ph+CML or to 80 mg once daily in patients with newly diagnosed Ph+CML-CP should be considered.(3) If the 3A4 inhibitor is discontinued, a washout period should occur before the nilotinib dose is adjusted upward.(1-3) Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and nilotinib should be monitored for prolongation of the QTc interval. When concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study in healthy subjects, concurrent ketoconazole (400 mg daily) increased nilotinib area-under-curve (AUC) by 3-fold.(1-3) A retrospective review of 618 cancer patients treated with 902 administrations of tyrosine kinase inhibitors were evaluated for rate and incidence of QTc prolongation. In patients who received nilotinib, QTc prolongation was identified in 29 patients (38.7%) with 1 patient(3.5%) having Grade 1 and 2 patients(7%) having Grade 2 events. Grade 3 events occurred in 9 patients (31%) having QTc greater than or equal to 500 ms and 17 patients(58.6%) having QTc change greater than or equal to 60 ms. No patients developed VT, SCD, or TdP.(5) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(6) Strong inhibitors of CYP3A4 that prolong QT include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir, posaconazole, ribociclib, telithromycin, and voriconazole.(7,8)

Strong Cyp3a4 Inhibitors That Prolong Qt/Osilodrostat

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong the QT interval may inhibit the metabolism of osilodrostat(1,2) and result in additive effects on the QT interval.(1)

CLINICAL EFFECTS: The concurrent use of osilodrostat with strong inhibitors of CYP3A4 that prolong the QTc interval may result in elevated levels of and effects from osilodrostat, including potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of increased exposure to osilodrostat is higher if the coadministered drug also inhibits other CYP or UDP-glucuronosyltransferases (UGT) enzymes, or if the patient is taking other drugs that inhibit other CYP or UGT enzymes.(1) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of osilodrostat recommends a dose reduction by half the current dose of osilodrostat with concomitant use of agents that are strong CYP3A4 inhibitors due to a significant increase in exposure to osilodrostat.(1) Use caution when using osilodrostat concurrently with other agents that can prolong the QT interval and consider more frequent ECG monitoring. A dose-dependent QT interval prolongation was noted in clinical studies. Prior to initiating therapy with osilodrostat, obtain a baseline ECG and monitor for QTc interval changes thereafter. Consider temporary discontinuation of therapy if the QTc interval increases > 480 msec. When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.(2)

DISCUSSION: Osilodrostat is metabolized by multiple CYP and UGT enzymes. Strong CYP3A4 inhibitors are predicted to inhibit metabolism of osilodrostat.(1) QTc prolongation has been reported with osilodrostat. In a thorough QT study in 86 healthy patients, osilodrostat increased baseline QTcF by 1.73 msec at a 10 mg dose and 25.38 msec at a 150 mg dose (up to 2.5 times the maximum recommended dosage). The predicted mean placebo-corrected QTcF at the highest recommended dose in clinical practice (30 mg twice daily) was estimated as 5.3 msec.(1) In a clinical study, five patients (4%) were reported to have an event of QT prolongation, three patients (2%) had a QTcF increase of > 60 msec from baseline, and 18 patients (13%) had a new QTcF value of > 450 msec.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir/ritonavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(4,5)

Strong Cyp3a4 Inhibitors That Prolong Qt/Pazopanib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong the QTc interval may inhibit the metabolism of pazopanib and result in additive risk of QT prolongation.(1)

CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP3A4 that prolong QT may result in elevated levels of and toxicity from pazopanib, including additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1) Other toxicities include hepatotoxicity, cardiac dysfunction, serious hemorrhage, arterial and venous thrombosis, thrombotic microangiopathy, gastrointestinal perforation and fistula, hypertension, hypothyroidism, interstitial lung disease, and proteinuria.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with pazopanib.(1) Consider alternatives with no or minimal enzyme inhibition. If concurrent administration with pazopanib is warranted, the dosage of pazopanib should be reduced to 400 mg. Additional dosage reductions may be required if adverse events occur.(1) Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and pazopanib should be monitored for prolongation of the QTc interval. When concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Administration of multiple doses of oral pazopanib (400 mg) with multiple doses of oral ketoconazole (400 mg) increased the area-under-curve (AUC) and maximum concentration (Cmax) of pazopanib by 1.7-fold and 1.5-fold, respectively. Administration of a single dose of pazopanib ophthalmic drops and ketoconazole, an inhibitor of CYP3A4 and P-gp, increased the AUC and Cmax of pazopanib by 220% and 150%, respectively. Administration of lapatinib (1500 mg), a weak inhibitor of CYP3A4, P-gp, and BCRP, increased the AUC and Cmax of pazopanib (800 mg) by 50% and 60%, respectively. Decreasing the dosage of pazopanib to 400 mg in patients receiving strong CYP3A4 inhibitors is expected to adjust the AUC of pazopanib to the normal range; however, there are no clinical data available to support this.(1) A retrospective review of 618 cancer patients treated with 902 administrations of tyrosine kinase inhibitors were evaluated for rate and incidence of QTc prolongation. In patients who received pazopanib, QTc prolongation was identified in 32 patients (19.4%) with 18 patients (56.3%) having Grade 1 and 4 patients (12.5%) having Grade 2 events. Grade 3 events occurred in 3 patients (9.3%) having QTc greater than or equal to 500 ms and 4 patients (12.5%) having QTc change greater than or equal to 60 ms. VT was seen in 2 (6.3%) patients and 1 (3.1%) patient experienced SCD.(3) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(4) Strong inhibitors of CYP3A4 that prolong QT include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir, posaconazole, ribociclib, telithromycin, and voriconazole.(5,6)

Strong Cyp3a4 Inhibitors That Prolong Qt/Quetiapine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of quetiapine.(1) Quetiapine is a sensitive substrate for CYP3A4 and so an approximately 5-fold or higher increase in exposure (AUC, area-under-curve) is possible when quetiapine is given with a strong CYP3A4 inhibitor.(2) In addition, concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inhibitor that also prolongs the QT interval may result in elevated levels of and toxicity from quetiapine,(1-4) including potentially life-threatening cardiac arrhythmias, such as torsades de pointes.(1,5)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(5) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)

PATIENT MANAGEMENT: The US manufacturer of quetiapine states that concurrent use with agents known to prolong the QT interval should be avoided.(1) If addition of concomitant therapy with a strong CYP3A4 inhibitor is required, US manufacturers state the quetiapine dose should be reduced to 1/6th of the original dose. When the inhibitor is discontinued, return to the original quetiapine dose.(1) The UK manufacturer states the concurrent use of quetiapine with strong CYP3A4 inhibitors is contraindicated.(5) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, fainting, excessive drowsiness, rapid pulse/hypotension, weakness, fatigue, dizziness, or muscle stiffness/tremors (EPS). Monitor patients when strong inhibitors of CYP3A4 are co-prescribed with quetiapine as the magnitude of the interaction is highly variable between patients. Use of higher doses of either the CYP3A4 inhibitor or quetiapine are other factors which may affect the magnitude of this interaction. Decrease the quetiapine dose if needed.

DISCUSSION: In a study, concurrent use of ketoconazole (200 mg daily for 4 days, a strong inhibitor of CYP3A4) and quetiapine resulted in an increase in quetiapine Cmax and AUC by 3.35-fold and 6.2-fold, respectively. Ketoconazole also decreased the mean apparent oral clearance of quetiapine by 84%, and increased quetiapine mean elimination half-life by 2.6-fold.(1,6) Although quetiapine was not associated with QT or QTc changes in clinical trials, QT prolongation has been reported in post-marketing reports in conjunction with the use of other agents known to prolong the QT interval.(1) Strong inhibitors of CYP3A4 that also are known QT prolonging agents include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(7,8) These agents may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(8)

Strong Cyp3a4 Inhibitors That Prolong Qt/Quizartinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong the QTc interval may inhibit the metabolism of quizartinib and result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 that prolongs the QTc interval may result in elevated levels and increased effects of quizartinib such as neutropenia.(1) Concurrent use may also result in additive QTc prolongation, which may lead to life-threatening cardiac arrhythmias like torsade de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of quizartinib recommends reducing the dosage of quizartinib when used concomitantly with strong CYP3A inhibitors.(1) The manufacturer recommends the following dose reduction: -If the patient is taking 53 mg once daily, reduce the dose to 26.5 mg once daily. -If the patient is taking 35.4 mg once daily, reduce the dose to 17.7 mg once daily. -If the patient is taking 26.5 mg once daily, reduce the dose to 17.7 mg once daily. -If the patient is taking 17.7 mg once daily, interrupt treatment with quizartinib for the duration of strong CYP3A4 inhibitor use. After discontinuation of a strong CYP3A4 inhibitor for 5 half-lives, resume the quizartinib dose that was taken before initiating the strong inhibitor. Quizartinib is only available through a restricted REMS program due to the serious risk of QT prolongation, torsades de pointes (TdP), and cardiac arrest. The manufacturer recommends monitoring as follows: -Initiate quizartinib only if the QTcF is less than or equal to 450 ms. -During induction and consolidation, monitor ECGs prior to initiation and then at minimum once weekly during treatment. -During maintenance, monitor ECGs prior to initiation and then at minimum once weekly for the first month following dose initiation and escalation and clinically therafter. Dose escalation may occur only if the QTcF is less than or equal to 450 ms. The manufacturer recommends the following dose modifications for adverse reactions: -If the QTcF is 450 ms to 480 ms (Grade 1) - Continue quizartinib dose. -If the QTcF is 481 ms to 500 ms (Grade 2) - Reduce the dose of quizartinib without interruption based on prescribing information. Resume the previous dose in the next cycle if the QTcF has decreased to less than 450 ms. -If the QTcF is greater than 500 ms (Grade 3) - Interrupt quizartinib. Resume at a reduced dose based on prescribing information when the QTcF is less than 450 ms. Maintain the dose of 26.5 mg once daily during maintenance if the QTcF is greater than 500 ms during induction or consolidation. -If recurrent QTcF is greater than 500 ms (Grade 3) - Permanently discontinue quizartinib if QTcF is greater than 500 ms despite dose reduction and correction/elimination of other risk factors. -If TdP, polymorphic ventricular tachycardia, or signs/symptoms of life-threatening arrhythmia occur (Grade 4) - Permanently discontinue quizartinib. Obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: The area-under-curve (AUC) of quizartinib increased by 94% and the maximum concentration (Cmax) by 17% following coadministration of a single 26.5 mg quizartinib dose with ketoconazole (a strong CYP3A4 inhibitor). The AUC of active metabolite AC886 decreased by 15% and decreased Cmax by 60%.(1) Quizartinib has been associated with QTc interval prolongation, torsades de pointes, ventricular arrhythmias, cardiac arrest, and sudden death. Quizartinib increased QTc in a dose- and concentration-dependent manner.(1) In an exposure-response analysis, quizartinib had a predicted concentration-dependent QTc prolongation of 18 to 24 ms (upper bound of 2-sided 90% CI: 21 and 27 ms) at a median steady-state Cmax dose of 26.5 mg and 53 mg during maintenance therapy.(1) In patients administered quizartinib, 2.3% of 265 patients had a QTcF greater than 500 msec and 10% of patients had a increase from baseline QTcF greater than 60 msec.(1) In patients administered quizartinib during the induction phase, torsades de pointes occurred in approximately 0.2% of patients, cardiac arrest occurred in 0.6%, including 0.4% with a fatal outcome, and 0.1% of patients experienced ventricular fibrillation.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing torsades de pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3) Strong inhibitors of CYP3A4 include: adagrasib, ceritinib, clarithromycin, lonafarnib, lopinavir, ribociclib, saquinavir, telithromycin, and voriconazole.(4,5)

Strong Cyp3a4 Inhibitors That Prolong Qt/Revumenib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong the QTc interval may inhibit the metabolism of revumenib and result in additive risk of QT prolongation.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase the levels of and effects from revumenib including QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of revumenib states that concomitant use of other drugs that may prolong the QTc interval should be avoided. If concurrent use cannot be avoided, obtain ECGs prior to initiating revumenib, during concomitant use, and as clinically indicated.(1) If the QTc interval is greater than 480 ms, withhold revumenib therapy. Resume revumenib after the QTc interval drops to 480 msec or less.(1) If concomitant use of strong CYP3A4 inhibitors is unavoidable, dose reduction of revumenib is necessary. -For patients 1 year and older who weigh at least 40 kg, decrease the dosage of revumenib to 160 mg twice daily. -For patients 1 year and older who weigh less than 40 kg, decrease the dosage of revumenib to 95 mg/m2 twice daily. Refer to the revumenib prescribing information for total tablet dosage by body surface area. If the strong CYP3A4 inhibitor is discontinued, increase the dose of revumenib to the recommended dose without strong CYP3A4 inhibitors after at least 5 half-lives of the inhibitor.(1) If coadministration with a strong CYP3A4 inhibitor that prolongs QT is unavoidable, monitor for prolongation of the QTc interval.(1) When concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study, azole antifungals that are strong CYP3A4 inhibitors (i.e., posaconazole, itraconazole, and voriconazole) increased the area-under-curve (AUC) and maximum concentration (Cmax) of revumenib by 2-fold. Cobicistat (a strong CYP3A4 inhibitor) increased the AUC and Cmax of revumenib by 2.5-fold.(1) In clinical trials, QTc interval prolongation was reported as an adverse event in 29% of 135 patients treated with the recommended dosage of revumenib; 12% of patients had Grade 3 QTc prolongation. Revumenib increased the QTc interval in a concentration-dependent manner. At the mean steady-state Cmax using the highest approved recommended dosage of revumenib without CYP3A4 inhibitors, QTc increase was predicted to be 27 msec (upper bound of 90% confidence interval = 30 msec). At the steady-state Cmax using the highest approved recommended dosage of revumenib with CYP3A4 inhibitors, QTc increase was predicted to be 19 msec (upper bound of 90% confidence interval = 22 msec).(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3) Strong inhibitors of CYP3A4 that prolong the QT interval include: adagrasib, ceritinib, clarithromycin, lonafarnib, lopinavir, ribociclib, saquinavir.(4,5)

Strong Cyp3a4 Inhibitors That Prolong Qt/Ribociclib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong the QTc interval may inhibit the metabolism of ribociclib and result in additive risk of QT prolongation.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase systemic exposure and the risk for ribociclib toxicities such as neutropenia or QT prolongation. QT prolongation may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Avoid concomitant use of ribociclib and strong CYP3A inhibitors that prolong the QTc interval. Consider an alternative concomitant medication with less potential for CYP3A4 inhibition. The US manufacturer states the following dose modifications are needed if use of a strong CYP3A4 inhibitor cannot be avoided: -For patients with early breast cancer, decrease ribociclib to 200 mg once daily. -For patients with advanced or metastatic breast cancer, decrease ribociclib to 400 mg once daily. -If the strong CYP3A4 inhibitor is discontinued, change the ribociclib dose (after at least 5 half-lives of the strong CYP3A4 inhibitor) to the dose used prior to the initiation of the strong CYP3A4 inhibitor.(1) The Swedish manufacturer states that if patients must be given a strong CYP3A4 inhibitor concurrently with ribociclib, the ribociclib dose should be reduced to 400 mg once daily. In patients who have had their ribociclib dose reduced to 400 mg daily and in whom coadministration of a strong CYP3A4 inhibitor cannot be avoided, the ribociclib dose should be further reduced to 200 mg. In patients who have had their ribociclib dose reduced to 200 mg daily and in whom coadministration of a strong CYP3A4 inhibitor cannot be avoided, ribociclib treatment should be interrupted.(4) During concomitant therapy with a strong CYP3A4 inhibitor, monitor patients closely for prolongation of the QT interval. Obtain serum calcium, magnesium, and potassium levels and monitor ECG at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Ribociclib has been shown to prolong the QTc interval in a concentration-dependent manner. At steady state, the mean increase in QTc interval exceeded 20 msec.(1) In a drug interaction study in healthy subjects, coadministration of ritonavir (100 mg twice a day for 14 days) with a single dose of ribociclib (400 mg) increased ribociclib maximum concentration (Cmax) and area-under-the-curve (AUC) by 1.7 and 3.2-fold, respectively. Cmax and AUC for LEQ803 (ribociclib metabolite) decreased by 96% and 98%, respectively.(1) Data from a pharmacokinetic simulation suggests that erythromycin, a moderate CYP3A4 inhibitor, may increase ribociclib (600 mg)Cmax and AUC by 1.2-fold and 1.3-fold. The increase of ribociclib's Cmax and AUC was estimated to be 1.4-fold and 2.1-fold in patients on ribociclib 400 mg. The increase of ribociclib's Cmax and AUC was estimated to be 1.7-fold and 2.8-fold in patients on ribociclib 200 mg.(4) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, clarithromycin, lopinavir, posaconazole, saquinavir, telithromycin, and voriconazole.(3)

Strong Cyp3a4 Inhibitors That Prolong Qt/Romidepsin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of romidepsin.(1)

CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP3A4 may result in elevated levels of and toxicity from romidepsin, including prolongation of the QT interval which may result in life-threatening arrhythmia and death; myelosuppression including thrombocytopenia, neutropenia, lymphopenia or anemia; serious infections; or tumor lysis syndrome.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age. Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of romidepsin states that appropriate cardiovascular monitoring, such as baseline and regular monitoring of ECG and obtaining serum calcium, magnesium, and potassium levels, should be performed if concurrent therapy with agents known to prolong the ECG is warranted. Monitor for romidepsin toxicity and follow recommended dose modifications for toxicity, if necessary, when romidepsin is initially co-administered with strong CYP3A4 inhibitors. Instruct patients to report any irregular heartbeat, dizziness, or fainting episodes; unusual tiredness, shortness of breath, paleness, unusual or unexplained bleeding or bruising; signs of infection such as fever, cough, flu-like symptoms; burning on urination; muscle aches; or worsening of skin problems.(1)

DISCUSSION: In patients with advanced cancer, ketoconazole increased the Cmax and AUC of romidepsin (8mg/m2) by 10% and 25%, respectively.(1) In two clinical trials, discontinuation of romidepsin secondary to QT prolongation occurred in at least 2% of patients.(1) Strong inhibitors of CYP3A4 that prolong QT include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir/ritonavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(3)

Strong Cyp3a4 Inhibitors That Prolong Qt/Selpercatinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors that prolong the QT interval may inhibit the metabolism of selpercatinib and result in additive effects on the QT interval.(1)

CLINICAL EFFECTS: Concurrent administration of a strong CYP3A4 inhibitor that prolongs the QT interval may result in elevated levels of and toxicity from selpercatinib.(1) Elevated levels of selpercatinib may increase the risk of QTc prolongation and potentially life-threatening cardiac arrhythmias, including torsades de pointes, hepatotoxicity, hypertension, and severe or life-threatening hemorrhagic events.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of selpercatinib recommends avoiding concomitant use of strong CYP3A4 inhibitors with selpercatinib. If concomitant use cannot be avoided, monitor the QTc interval more frequently and reduce the dose of selpercatinib as follows: - If the current dose of selpercatinib is 160 mg twice daily, decrease the dose to 80 mg twice daily. - If the current dose of selpercatinib is 120 mg twice daily, decrease the dose to 40 mg twice daily. - If the current dose of selpercatinib is 80 mg twice daily, decrease the dose to 40 mg twice daily. - If the current dose of selpercatinib is 40 mg three times daily, decrease the dose to 40 mg once daily.(1) When concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.(2) If grade 3 QT interval prolongation occurs, withhold selpercatinib until recovery to baseline or Grades 0 or 1, then resume selpercatinib at a reduced dose. If grade 4 QT interval prolongation occurs, discontinue selpercatinib.(1) After the CYP3A4 inhibitor has been discontinued for 3 to 5 elimination half-lives, resume selpercatinib at the dose taken prior to initiating the CYP3A inhibitor.(1)

DISCUSSION: In a thorough QT study, selpercatinib 160 mg twice daily increased QTc by a mean of 10.6 msec (upper 90% confidence interval: 12.1 msec). An increase in QTcF interval to greater than 500 msec was measured in 6% of patients and an increase in the QTcF interval of at least 60 msec over baseline was measured in 15% of patients.(1) In a study, itraconazole (a strong CYP3A inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of selpercatinib by 133% and 30%, respectively.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(3) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir/ritonavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(4)

Strong Cyp3a4 Inhibitors That Prolong Qt/Sunitinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong the QTc interval may inhibit the metabolism of sunitinib and result in additive risk of QT prolongation.(1)

CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP3A4 that prolong QT may result in elevated levels of and toxicity from sunitinib, including additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1) Other toxicities include neutropenia, hepatotoxicity, hypertension, cardiotoxicity, hemorrhagic events, thrombotic microangiopathy, proteinuria, severe dermatological reactions, thyroid dysfunction, hypoglycemia, and osteonecrosis of the jaw.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors that prolong QT in patients undergoing therapy with sunitinib.(1) Consider alternatives with no or minimal enzyme inhibition and with no effect on the QTc interval. If concurrent therapy with sunitinib is warranted, a dosage reduction of sunitinib to a minimum of 37.5 mg daily in patients with gastrointestinal stromal tumors (GIST) or advanced renal cell carcinoma (RCC) or to a minimum of 25 mg in patients with pancreatic neuroendocrine tumors (pNET) should be considered. Monitor QT interval more frequently.(1) Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and sunitinib should be monitored for prolongation of the QTc interval. When concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study in healthy subjects, concurrent ketoconazole increased the combined (sunitinib plus primary active metabolite) maximum concentration (Cmax) and area-under-curve (AUC) by 49% and 51%, respectively, of a single dose of sunitinib.(1) A retrospective review of 618 cancer patients treated with 902 administrations of tyrosine kinase inhibitors were evaluated for rate and incidence of QTc prolongation. In patients who received sunitinib, QTc prolongation was identified in 26 patients(19.4%) with 16 patients(61.5%) having Grade 1 and 6 patients(23.1%) having Grade 2 events. Grade 3 events occurred in 1 patient(3.8%) having QTc greater than or equal to 500 ms and 1 patient(3.8%) having QTc change greater than or equal to 60 ms. VT was seen in 1 (3.8%) patient and 1 (3.8%) patient experienced SCD.(3) Strong inhibitors of CYP3A4 that prolong QT include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir, posaconazole, ribociclib, telithromycin, and voriconazole.(4,5)

Strong Cyp3a4 Inhibitors That Prolong Qt/Toremifene

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong the QTc interval may inhibit the metabolism of toremifene and result in additive risk of QT prolongation.(1)

CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP3A4 that prolong QT may result in elevated levels of and toxicity from toremifene, including additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1) Other toxicities include hepatotoxicity and hypercalcemia.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors that prolong QT in patients undergoing therapy with toremifene.(1) Consider alternatives with no or minimal enzyme inhibition and with no effect on the QTc interval. If treatment with a strong CYP3A4 inhibitor is required, toremifene therapy should be interrupted. If it is not possible to interrupt toremifene therapy, electrocardiograms (ECGs) should be obtained and patients should be closely monitored for QT prolongation.(1) Consider obtaining serum calcium, magnesium, and potassium levels at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study in 18 subjects, ketoconazole (200 mg daily) increased the maximum concentration (Cmax) and area-under-curve (AUC) of toremifene (80 mg daily) by 1.4-fold and 2.9-fold, respectively. N-demethyltoremifene Cmax and AUC decreased by 56% and 20%, respectively.(1) Strong inhibitors of CYP3A4 that prolong QT include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir, posaconazole, ribociclib, telithromycin, and voriconazole.(3,4)

Strong Cyp3a4 Inhibitors That Prolong Qt/Vemurafenib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Vemurafenib is a substrate of CYP3A4. Strong inhibitors of CYP3A4 may inhibit the metabolism of vemurafenib.(1) Use of CYP3A4 inhibitors that prolong the QTc interval may result in additive effects on the QTc interval.

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 that prolongs the QTc interval may result in increased levels and toxicity from vemurafenib, including additive QT prolongation and life-threatening cardiac arrhythmias like torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of vemurafenib states to avoid concurrent administration with strong CYP3A4 inhibitors and replace these drugs with alternative drugs whenever possible.(1) If concurrent therapy is warranted, monitor the patient for signs of vemurafenib toxicity. Consider dose reduction of vemurafenib if clinically indicated. Consider obtaining serum calcium, magnesium, and potassium levels. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. Vemurafenib should not be initiated in patients taking medications known to prolong the QT interval, patients having a baseline QTc greater than 500 msec, uncorrectable electrolyte abnormalities, or known long QT syndrome.(1) All patients receiving vemurafenib should undergo ECG testing at baseline, after 15 days of treatment, monthly during the first 3 months of treatment, and then every 3 months. If a patient's QTc exceeds 500 msec during treatment, vemurafenib should be discontinued and cardiac risk factors for QT prolongation should be controlled. Consider discontinuing other medications known to prolong the QT interval at this time. If the patient's QTc decreases below 500 msec, vemurafenib may be introduced at a lower dosage according to the current labeling recommendations. If the patient's QTc remains greater than 500 msec and increased >60 msec from pre-treatment values after controlling cardiac risk factors for prolongation, permanently discontinue vemurafenib.(1)

DISCUSSION: A study of vemurafenib 960 mg twice daily with itraconazole 200 mg daily increased vemurafenib area-under-curve (AUC) by 40% with a similar increase in concentration maximum (Cmax).(1) Vemurafenib is associated with concentration-dependent QTc interval prolongation. In the first month of treatment, the largest mean QTc change was 12.8 msec (upper boundary of 90% CI: 14.9 msec). In the first 6 months of treatment, the largest mean QTc change was 15.1 msec (upper boundary of 90% CI: 17.7 msec).(1) Strong CYP3A4 inhibitors that prolong QT linked to this monograph include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(3,4)

Strong Cyp3a4 Inhibitors That Prolong Qt/Vepdegestrant

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors that prolong the QTc interval may inhibit the metabolism of vepdegestrant and cause an additive risk of QTc prolongation.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors that prolong QT may result in elevated vepdegestrant levels and toxicities, including neutropenia, hepatotoxicity, and additive QT prolongation, which may lead to potentially life-threatening cardiac arrhythmias like torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, and advanced age.(1,2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of vepdegestrant states that concurrent use of strong CYP3A4 inhibitors should be avoided.(1) The manufacturer of vepdegestrant also states that concurrent use of other drugs that are known to prolong the QTc interval should be avoided.(1) In patients taking 200 mg daily of vepdegestrant, if concurrent use cannot be avoided, lower the dosage of vepdegestrant to 100 mg daily. After the CYP3A4 inhibitor is discontinued for 3 to 5 elimination half-lives, resume vepdegestrant 200 mg daily. Patients on vepdegestrant 100 mg daily should avoid coadministration of strong CYP3A4 inhibitors.(1) For levoketoconazole, the manufacturer states that levoketoconazole is contraindicated with other agents that prolong the QT interval.(3) If concurrent use is warranted, monitor ECG when initiating vepdegestrant, during concurrent use, and as clinically indicated. Consider increasing the frequency of ECG monitoring. Do not initiate vepdegestrant in patients with a baseline QTc >470 ms. Withhold vepdegestrant if the QTc is >480 ms or the change from baseline is >60 ms.(1) Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Vepdegestrant is a CYP3A4 substrate. In a study, itraconazole 200 mg daily (a strong CYP3A4 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of vepdegestrant by 1.7-fold and 1.5-fold, respectively.(1) Vepdegestrant 200 mg daily increased QTc by 12 ms (upper confidence interval = 15 ms) in patients with ESR1 mutation-positive breast cancer.(1) In VERITAC-2, QTc prolongation occurred in 10% of patients, with 1.6% of patients having Grade 3 events. QTc was >500 ms in 1.6% of patients and QTc increase from baseline of >60 ms occurred in 2.6% of patients.(1) Strong CYP3A4 inhibitors that prolong the QTc interval linked to this monograph include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir, posaconazole, ribociclib, saquinavir, telithromycin and voriconazole.(4,5)

Strong Cyp3a4 Inhibitors That Prolong Qt/Ziftomenib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ziftomenib is a CYP3A4 substrate and has been shown to prolong the QTc interval. Strong CYP3A4 inhibitors that prolong the QTc interval may inhibit the metabolism of ziftomenib and result in additive risk of QT prolongation.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase the levels and effects of ziftomenib, including differentiation syndrome, neutropenia, and additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of ziftomenib states that concomitant use with strong CYP3A4 inhibitors should be monitored more closely for adverse reactions.(1) The manufacturer of ziftomenib states that the concurrent use of QT prolonging agents should be avoided. If concurrent use cannot be avoided, obtain ECGs prior to initiating ziftomenib, during concomitant use, and as clinically indicated. More frequent ECG monitoring may be necessary. Do not initiate ziftomenib if baseline QTcF > 480 ms.(1) Perform ECG at least once weekly for the first 4 weeks on treatment, then at least monthly thereafter. If the QTc interval is greater than 500 ms or the change from baseline is greater than 60 ms, withhold ziftomenib therapy.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Concomitant use of ziftomenib with itraconazole, voriconazole, and posaconazole (strong CYP3A4 inhibitors) is predicted to increase ziftomenib area-under-curve (AUC) and maximum concentration (Cmax) by 3-fold and 2-fold, respectively.(1) Moderate CYP3A4 inhibitors (fluconazole, erythromycin, and isavuconazole) are predicted to increase ziftomenib AUC and Cmax by 2-fold and 2-fold, respectively.(1) Weak CYP3A4 inhibitors (cimetidine) are predicted to increase ziftomenib AUC and Cmax by 1.4-fold and 1.4-fold, respectively.(1) In clinical trials, QTc interval prolongation was reported as an adverse event in 12% of 112 patients treated with the recommended dosage of ziftomenib. QTc was >500 ms in 9% of patients and the increase from baseline QTcF was >60 ms in 12% of patients. Ziftomenib increased the QTc interval in a concentration-dependent manner. At a dose of 600 mg daily, the largest mean increase in QTc was 7.7 ms (upper bound of confidence interval = 12.6 ms).(1) Strong inhibitors of CYP3A4 include: adagrasib, clarithromycin, levoketoconazole, and lonafarnib.(3,4)

Strong Cyp3a4 Inhibitors/Aripiprazole Lauroxil Submicronized

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of aripiprazole.(1)

CLINICAL EFFECTS: Concurrent administration of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from aripiprazole.(1)

PREDISPOSING FACTORS: With aripiprazole(1), this interaction is expected to be more severe in patients who are CYP2D6 poor metabolizers, or who receive concomitant treatment with a strong CYP2D6 inhibitor (e.g. bupropion, fluoxetine, paroxetine, quinidine) in addition to treatment with a strong CYP3A4 inhibitor.

PATIENT MANAGEMENT: The US manufacturer of the extended release injectable aripiprazole lauroxil, submicronized (Aristada Initio) recommends avoiding use of strong 3A4 inhibitors with Aristada Initio. Aristada Initio is only available as a single strength as a single-dose prefilled syringe.(1)

DISCUSSION: Drug interaction studies have not been conducted with Aristada Initio. Aristada Initio has a long half-life (15-18 days).(1) The coadministration of ketoconazole (200 mg daily for 14 days) with a single dose of aripiprazole (15 mg) resulted in increases in the area-under-curve (AUC) of aripiprazole and its active metabolite by 63% and 77%, respectively. Itraconazole is expected to interact similarly.(1) CYP3A4 inhibitors linked to this monograph include: adagrasib, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2)

Strong Cyp3a4 Inhibitors/Avacopan

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of avacopan.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from avacopan, including serious infections, elevated liver enzymes, or hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Reduce the dose of avacopan to 30 mg once daily when coadministered with strong CYP3A4 inhibitors.(1) Australian and UK manufacturers of avacopan state coadministration with strong CYP3A4 inhibitors should be used with caution. Patients must be monitored for potential increase of side effects due to the increased exposure of avacopan.(2,3) Monitor liver tests, including AST, ALT, alkaline phosphatase, and total bilirubin. Advise patients to report any symptoms of hepatotoxicity.

DISCUSSION: In a study, administration of itraconazole 200 mg once daily for 4 days increased the maximum concentration (Cmax) and area-under-curve (AUC) of avacopan by 1.87-fold and 2.19-fold.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(4,5)

Strong Cyp3a4 Inhibitors/Avapritinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of avapritinib.(1)

CLINICAL EFFECTS: Concurrent use of avapritinib with a strong CYP3A4 inhibitor increases avapritinib plasma concentrations, which may increase the incidence and severity of adverse reactions of avapritinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant use of avapritinib with strong CYP3A4 inhibitors.(1)

DISCUSSION: Coadministration of avapritinib 300 mg once daily with itraconazole 200 mg daily, a strong CYP3A4 inhibitor, is predicted to increase avapritinib AUC by 600% at steady state.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Axitinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of axitinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from axitinib, including hypertension, thromboembolic events, or hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with axitinib.(1) Consider alternatives with no or minimal enzyme inhibition. If concurrent use with axitinib is warranted, consider decreasing the dose of axitinib by one-half (e.g. start with an initial dose of 2 mg twice daily). Subsequent doses may be increased or decreased based on patient response. When the CYP3A4 inhibitor has been discontinued, allow a washout period equal to 3-5 half-lives of the inhibitor before increasing the dose of axitinib.(1) The manufacturer of itraconazole states avoid concomitant use during and 2 weeks after itraconazole treatment.(2,3)

DISCUSSION: Ketoconazole (400 mg twice daily, a strong inhibitor of CYP3A4) increased the maximum concentration (Cmax) and area-under-curve (AUC) of axitinib (5 mg) by approximately 1.5-fold and 2-fold, respectively. Recommended dosage adjustments are expected to produce AUC levels comparable to axitinib administered without a strong CYP3A4 inhibitor; however, no data is available.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(4,5)

Strong Cyp3a4 Inhibitors/Brigatinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Brigatinib is a substrate of CYP3A4. Strong inhibitors of CYP3A4 may inhibit the metabolism of brigatinib.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels and toxicity from brigatinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of brigatinib states to avoid concurrent administration with strong CYP3A4 inhibitors. If concurrent therapy cannot be avoided, reduce the once daily dose of brigatinib by approximately 50% (i.e. from 180 mg to 90 mg). Upon discontinuation of a strong CYP3A4 inhibitor, resume the brigatinib dose that was tolerated prior to initiating the strong CYP3A4 inhibitor.(1) Monitor patient for signs of brigatinib toxicity with concurrent use.

DISCUSSION: Brigatinib is a substrate of CYP3A4.(1) Concurrent administration of itraconazole (200 mg twice daily, a strong CYP3A4 inhibitor) with a single 90 mg dose of brigatinib increased the brigatinib maximum concentration (Cmax) by 21% and area-under-curve (AUC) by 101% compared to brigatinib alone.(1) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Cabazitaxel

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of cabazitaxel.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from cabazitaxel, including bone marrow suppression, renal failure, cystitis, or pulmonary dysfunction.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with cabazitaxel.(1) Consider alternatives with no or minimal enzyme inhibition. If concurrent use is required, consider a 25% cabazitaxel dose reduction.(1) The manufacturer of itraconazole states avoid concomitant use during and 2 weeks after itraconazole treatment.(2,3)

DISCUSSION: In a study in 23 advanced cancer patients, ketoconazole (400 mg daily) increased the exposure of cabazitaxel (5 mg/m2) by 25%.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(4,5)

Strong Cyp3a4 Inhibitors/Cabozantinib Lauryl Sulfate

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of cabozantinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from cabozantinib, including hemorrhage, thrombotic events, hypertension and hypertensive crisis, diarrhea, proteinuria, or osteonecrosis of the jaw.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with cabozantinib.(1) Consider alternatives with no or minimal enzyme inhibition. Dosage adjustments are specific to the formulation of cabozantinib prescribed. If concurrent use of cabozantinib CAPsules are warranted, the dose of cabozantinib CAPsules should be reduced by 11.5 mg (e.g. from 34.5 mg to 23 mg daily, or from 23 mg to 11.5 mg daily, or from 11.5 mg to 11.5 mg every other day).(1) When the CYP3A4 inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the dose of cabozantinib that was used prior to initiating the inhibitor.(1) The manufacturer of itraconazole states avoid concomitant use during and 2 weeks after itraconazole treatment.(2,3)

DISCUSSION: In a study in healthy subjects, ketoconazole (400 mg daily for 27 days) increased the area-under-curve (AUC) of a single dose of cabozantinib by 38%.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(4,5)

Strong Cyp3a4 Inhibitors/Cabozantinib S-Malate Capsules

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of cabozantinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from cabozantinib, including hemorrhage, thrombotic events, hypertension and hypertensive crisis, diarrhea, proteinuria, or osteonecrosis of the jaw.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with cabozantinib.(1) Consider alternatives with no or minimal enzyme inhibition. Dosage adjustments are specific to the formulation of cabozantinib prescribed. If concurrent use of cabozantinib CAPsules are warranted, the dose of cabozantinib CAPsules should be reduced by 40 mg (e.g. from 140 mg to 100 mg daily or from 100 mg to 60 mg daily).(1) When the CYP3A4 inhibitor has been discontinued, resume the dose of cabozantinib that was used previously 2-3 days after discontinuation of the inhibitor.(1) The manufacturer of itraconazole states avoid concomitant use during and 2 weeks after itraconazole treatment.(2,3)

DISCUSSION: In a study in healthy subjects, ketoconazole (400 mg daily for 27 days) increased the area-under-curve (AUC) of a single dose of cabozantinib by 38%.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(4,5)

Strong Cyp3a4 Inhibitors/Cabozantinib S-Malate Tablets

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of cabozantinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from cabozantinib, including hemorrhage, thrombotic events, hypertension and hypertensive crisis, diarrhea, proteinuria, or osteonecrosis of the jaw.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with cabozantinib.(1) Consider alternatives with no or minimal enzyme inhibition. Dosage adjustments are specific to the formulation of cabozantinib prescribed. If concurrent use of cabozantinib TABlets are warranted, reduce the daily dose of cabozantinib TABlets by 20 mg (e.g. from 60 mg to 40 mg daily, or from 40 mg to 20 mg daily, or from 20 mg daily to 20 mg every other day in pediatric patients 12 years of age and older with bodyweight less than 40kg).(1) When the CYP3A4 inhibitor has been discontinued, resume the dose of cabozantinib that was used previously 2-3 days after discontinuation of the inhibitor.(1) The manufacturer of itraconazole states avoid concomitant use during and 2 weeks after itraconazole treatment.(2,3)

DISCUSSION: In a study in healthy subjects, ketoconazole (400 mg daily for 27 days) increased the area-under-curve (AUC) of a single dose of cabozantinib by 38%.(3,4) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(4,5)

Strong Cyp3a4 Inhibitors/Capivasertib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the CYP3A4 metabolism of capivasertib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in increased systemic exposure to and effects from capivasertib, hyperglycemia, severe diarrhea, and cutaneous adverse reactions.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant use with strong CYP3A4 inhibitors. If concomitant use cannot be avoided, reduce the capivasertib dose to 320 mg twice daily for 4 days followed by 3 days off.(1) After discontinuation of the strong CYP3A4 inhibitor for 3 to 5 half-lives of the inhibitor, resume the capivasertib dosage that was taken prior to initiating the strong CYP3A4 inhibitor.(1)

DISCUSSION: Itraconazole (strong CYP3A4 inhibitor) is predicted to increase capivasertib area-under-curve (AUC) by up to 1.7-fold and maximum concentration (Cmax) by up to 1.4-fold.(1) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Colchicine (For Gout & Fmf)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of colchicine.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from colchicine. Symptoms of colchicine toxicity include muscle weakness or pain; numbness or tingling in the fingers or toes; myelosuppression; abdominal pain; nausea; severe diarrhea or vomiting; feeling weak or tired; increased infections; and pale or gray color of the lips, tongue, or palms of hands.(1,2)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with renal and/or hepatic impairment(1,2) and in patients who receive concurrent therapy.

PATIENT MANAGEMENT: The concurrent use of a strong CYP3A4 inhibitor with colchicine is contraindicated in patients with renal or hepatic impairment.(1-3) Avoid concurrent use in other patients, if possible.(3) In patients without renal or hepatic impairment who are currently taking or have taken strong CYP3A4 inhibitors in the previous 14 days, the dosage of colchicine should be reduced. For gout flares, the recommended colchicine dosage is 0.6 mg (1 tablet) for one dose, then 0.3 mg (half tablet) 1 hour later. This dose should be repeated no earlier than in 3 days.(1,2) For gout prophylaxis, if the original colchicine dosage was 0.6 mg twice daily, use 0.3 mg daily. If the original dosage was 0.6 mg daily, use 0.3 mg every other day.(3-11) For Familial Mediterranean fever (FMF), the recommended maximum daily dose of colchicine is 0.6 mg (may be given as 0.3 mg twice a day).(1,2) Patients should be instructed to immediately report any signs of colchicine toxicity, such as muscle weakness/pain, numbness/tingling in fingers/toes, unusual bleeding or bruising, infections, weakness/tiredness, pale/gray color of the lips/tongue/palms of hands, and/or severe diarrhea/vomiting.

DISCUSSION: In a study in 21 subjects, pretreatment with azithromycin (500 mg Day 1, then 250 mg daily Days 2-5) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by 21.6% (range -41.7% to 222%) and by 57.1% (range -24.3% to 241.1%), respectively.(1) There are several reports of colchicine toxicity(4-6) and death(7,8) following the addition of clarithromycin to therapy. In a retrospective review of 116 patients who received clarithromycin and colchicine during the same hospitalization, 10.2% (9/88) of patients who received simultaneous therapy died, compared to 3.6% (1/28) of patients who received sequential therapy.(9) An FDA review of 117 colchicine-related deaths that were not attributable to overdose found that 60 deaths (51%) involved concurrent use of clarithromycin.(2) In a study in 23 subjects, pretreatment with clarithromycin (250 mg twice daily for 7 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by 227.2% (range 65.7% to 591.1%) and by 281.5% (range 88.7% to 851.6%), respectively.(1) In a study in 24 subjects, pretreatment with ketoconazole (200 mg twice daily for 5 days) increased the Cmax and AUC of a single dose of colchicine (0.6 mg) by 101.7% (range 19.6% to 219%) and by 212.2% (range 76.7% to 419.6%), respectively.(1) In a study in 18 subjects, pretreatment with ritonavir (100 mg twice daily for 5 days) increased the Cmax and AUC of a single dose of colchicine (0.6 mg) by 184.4% (range 79.2% to 447.4%) and by 296% (range 53.8% to 924.4%), respectively.(1) Colchicine toxicity has been reported with concurrent use of CYP3A4 and P-gp inhibitors such as clarithromycin, cyclosporine, diltiazem, erythromycin, and verapamil.(1,2) Strong inhibitors of CYP3A4 include: adagrasib, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(1,10)

Strong Cyp3a4 Inhibitors/Copanlisib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Copanlisib is a substrate of CYP3A4. Strong inhibitors of CYP3A4 may inhibit the metabolism of copanlisib.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels and toxicity from copanlisib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of copanlisib states to avoid concurrent administration with strong CYP3A4 inhibitors. If concurrent therapy cannot be avoided, reduce the dose of copanlisib to 45 mg.(1) Monitor patient for signs and symptoms of copanlisib toxicity with concurrent use.

DISCUSSION: Copanlisib is a substrate of CYP3A4.(1) Concurrent administration of itraconazole (200 mg once daily for 10 days, a strong CYP3A4 inhibitor) with a single 60 mg dose of copanlisib increased the copanlisib area-under-curve (AUC) by 53% with no effect on maximum concentration (Cmax) compared to copanlisib alone.(1) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, lonafarnib, ketoconazole, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Culmerciclib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of culmerciclib.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in elevated levels and increased effects of culmerciclib, such as hepatotoxicity, immunosuppression, neutropenia, or gastrointestinal adverse reactions.(1,2) Symptoms can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of culmerciclib states that culmerciclib coadministration with strong inhibitors of CYP3A4 should be avoided. If concurrent use is medically necessary, reduce the dose of culmerciclib to 120 mg once daily.(1) If the concurrent strong CYP3A4 inhibitor is discontinued, increase the culmerciclib dose after 3-5 half-lives of the inhibitor to the dose that was used prior to starting the strong inhibitor.(1) Monitor liver tests, including AST, ALT, before treatment initiation, every 2 weeks for the first 2 months of treatment, monthly for the following two months, and upon clinical indication. Advise patients to immediately report any symptoms of hepatotoxicity. Monitor complete blood counts before treatment initiation, at the start of each cycle, on day 15 of the first two cycles, and upon clinical indication.

DISCUSSION: Coadministration of itraconazole (200 mg, a strong CYP3A4 inhibitor) increased culmerciclib (single dose 60 mg) maximum concentration (Cmax) and area-under-the-curve (AUC) by 30.1% and 72.3%.(1) Strong inhibitors of CYP3A4 linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir-ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(1,3)

Strong Cyp3a4 Inhibitors/Daclatasvir

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of daclatasvir.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 is expected to increase levels of and side effects from daclatasvir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The dose of daclatasvir should be reduced to 30 mg in patients taking strong inhibitors of CYP3A4.(1) Concurrent therapy with the following regimens warrants a dose reduction of daclatasvir to 30 mg daily: atazanavir/cobicistat, atazanavir/ritonavir, indinavir/ritonavir, nelfinavir, and saquinavir/ritonavir.(1,2) No dosage adjustment for daclatasvir is necessary with unboosted atazanavir, darunavir/cobicistat, darunavir/ritonavir, unboosted indinavir, or lopinavir/ritonavir.(1,2)

DISCUSSION: Atazanavir/ritonavir (300/100 mg daily) increased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of daclatasvir by 1.35-fold, 2.10-fold, and 3.65-fold, respectively.(1) Ketoconazole (400 mg daily) increased the Cmax and AUC of daclatasvir by 1.57-fold and 3.00-fold, respectively.(1) Telaprevir (500 mg q12h) increased the Cmax and AUC of daclatasvir by 1.46-fold and 2.32-fold, respectively. There were no significant changes in telaprevir concentrations.(1) Telaprevir (750 mg q8h) increased the Cmax and AUC of daclatasvir by 1.22-fold and 2.15-fold, respectively. There were no significant changes in telaprevir concentrations.(1) In a study, concomitant administration of daclatasvir (30 mg once daily) with lopinavir/ritonavir (400 mg/100 mg twice daily) did not result in any clinically relevant changes of exposure. Strong inhibitors of CYP3A4 include: adagrasib, atazanavir (when coadministered with ritonavir or cobicistat), boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, indinavir (when coadministered with ritonavir), itraconazole, josamycin, ketoconazole, lonafarnib, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir/ritonavir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(1-4)

Strong Cyp3a4 Inhibitors/Docetaxel

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of docetaxel.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from docetaxel, including cutaneous reactions, neurologic reactions, eye disorders, or asthenia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with docetaxel.(1) Consider alternatives with no or minimal enzyme inhibition. If concurrent therapy with docetaxel is required, consider a 50% reduction in the dose of docetaxel. Monitor patients receiving concurrent therapy closely for signs of toxicity.(1) The manufacturer of itraconazole states avoid concomitant use during and 2 weeks after itraconazole treatment.(3,4)

DISCUSSION: In a randomized, cross-over study in 7 cancer patients, patients received docetaxel (100 mg/m2 intravenous) alone and docetaxel (10 mg/m2 intravenous) with ketoconazole (200 mg daily for 3 days). The mean dose-normalized area-under-curve (AUC) of docetaxel increased 2.2-fold and docetaxel clearance decreased 49% when administered with ketoconazole.(1) In a randomized, cross-over study in 7 subjects, subjects received docetaxel (100 mg/m2) alone and docetaxel (15 mg/m2) with ketoconazole (400 mg 3 times daily). Ketoconazole decreased docetaxel clearance by 50%. There was large inter-patient variability.(2) In a study in 15 subjects, ketoconazole increased fecal docetaxel excretion by 2-fold but did not affect urinary parent drug excretion.(5) In a study in 41 patients, concurrent ketoconazole allowed a dose of 70 mg docetaxel with similar docetaxel AUC and toxicity compared to the administration of docetaxel (75 mg/m2) alone.(6) A study in 42 patients examined escalating doses of ketoconazole on docetaxel pharmacokinetics. Ketoconazole at doses of 1200 mg daily, 800 mg daily, and 600 mg daily increased docetaxel exposure 2.6-fold, 1.6-fold, and 1.3 to 1.5-fold, respectively.(7) A parallel study in 82 subjects compared docetaxel (75 mg/m2) alone with docetaxel (70 mg) with ketoconazole. Concurrent ketoconazole decreased docetaxel clearance by 40%. Similar docetaxel AUC and tumor efficacy were noted, with decreased toxicity during concurrent ketoconazole and reduced-dose docetaxel therapy.(8) In a study in 12 patients, the administration of ritonavir (100 mg) simultaneously or 60 minutes before docetaxel (100 mg orally) increased the bioavailability of docetaxel by 131% and 161%, respectively.(9) Data from two clinical trials involving patients taking docetaxel concurrently with ritonavir and patients taking docetaxel oral or I.V. alone were analyzed in order to determine the impact of ritonavir's strong inhibition of CYP3A4 on the pharmacokinetics of docetaxel. Patients from the first trial were randomly assigned to receive either ritonavir 100 mg followed by oral docetaxel 10 mg 60 minutes later on day 1, ritonavir 100 mg and docetaxel 10 mg simultaneously on day 8, and I.V. docetaxel 100 mg on day 22 or an identical regimen with the only difference being that days 1 and 8 were reversed. The second trial was utilized solely for the data on patients being administered oral docetaxel 75 mg/m2 alone or I.V. docetaxel 100 mg/m2. The results of the study showed an increase in the gut bioavailability of docetaxel from 19 to 39% with co-administration of ritonavir as well as a reduction in the clearance of docetaxel by approximately 90%.(10) There are several case reports of docetaxel toxicity in patients treated with concurrent ritonavir.(11,12) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(13,14)

Strong Cyp3a4 Inhibitors/Duvelisib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of duvelisib.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in elevated levels and increased effects of duvelisib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of duvelisib states that use of strong inhibitors of CYP3A4 should be avoided. When strong CYP3A4 inhibitors are required, reduce the dose of duvelisib to 15 mg twice daily.(1)

DISCUSSION: Coadministration of ketoconazole (200 mg twice daily for 5 days) with a single oral 10 mg dose of duvelisib increased the area-under-curve (AUC) and maximum concentration (Cmax) of duvelisib approximately 4-fold and 1.7-fold, respectively. Based on physiologically-based pharmacokinetic (PKPB) modeling, the increase in exposure to duvelisib is estimated to be approximately 2-fold at steady state with concurrent use of strong CYP3A4 inhibitors. PKPB modeling showed no effect on duvelisib exposure with concurrent use of mild or moderate CYP3A4 inhibitors.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Elagolix

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Agents which inhibit the CYP3A4 enzyme may inhibit the metabolism of elagolix.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase systemic exposure and the risk for elagolix toxicities including an increased risk of ALT elevations.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concomitant use of elagolix 200 mg twice daily and strong CYP3A4 inhibitors for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and strong CYP3A4 inhibitors to 6 months.

DISCUSSION: In a drug interaction study in 11 healthy subjects, coadministration of ketoconazole (400 mg once daily) with a single dose of elagolix (150 mg) increased elagolix maximum concentration (Cmax) and area-under-the-curve (AUC) by 1.77-fold and 2.2-fold, respectively.(1) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, indinavir, itraconazole, josamycin, ketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Elexacaftor-Tezacaftor-Ivacaftor

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of elexacaftor-tezacaftor-ivacaftor.(1)

CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from elexacaftor-tezacaftor-ivacaftor.(1)

PREDISPOSING FACTORS: This interaction may be more severe in patients with hepatic impairment.(1)

PATIENT MANAGEMENT: The dosage of elexacaftor-tezacaftor-ivacaftor should be reduced when co-administered with strong CYP3A4 inhibitors. -The evening dose of ivacaftor should not be taken. -For individuals 12 years and older or children 6 to less than 12 years old weighing more than 30 kg, the morning dose of therapy should be modified as follows: Day 1 - two tablets of elexacaftor-tezacaftor-ivacaftor; Day 2 - no dose; Day 3 - no dose; Day 4 - two tablets of elexacaftor-tezacaftor-ivacaftor. Thereafter, continue two elexacaftor-tezacaftor-ivacaftor tablets twice a week, approximately 3 to 4 days apart. -For children 2 to less than 6 years old weighing less than 14 kg, the morning dose of therapy should be modified as follows: Day 1 - one packet of elexacaftor-tezacaftor-ivacaftor (elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg); Day 2 - no dose; Day 3 - no dose; Day 4 - one packet of elexacaftor-tezacaftor-ivacaftor. Thereafter, continue two elexacaftor-tezacaftor-ivacaftor tablets twice a week, approximately 3 to 4 days apart. -For children 2 to less than 6 years old weighing 14 kg or more, the morning dose of therapy should be modified as follows: Day 1 - one packet of elexacaftor-tezacaftor-ivacaftor (elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg); Day 2 - no dose; Day 3 - no dose; Day 4 - one packet of elexacaftor-tezacaftor-ivacaftor. Thereafter, continue two elexacaftor-tezacaftor-ivacaftor tablets twice a week, approximately 3 to 4 days apart. -For children 6 to less than 12 years old weighing less than 30 kg, the morning dose of therapy should be modified as follows: Day 1 - two tablets of elexacaftor-tezacaftor-ivacaftor (elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg); Day 2 - no dose; Day 3 - no dose; Day 4 - two tablets of elexacaftor-tezacaftor-ivacaftor. Thereafter, continue two elexacaftor-tezacaftor-ivacaftor tablets twice a week, approximately 3 to 4 days apart.(1)

DISCUSSION: Co-administration with itraconazole, a strong CYP3A4 inhibitor, increased elexacaftor area-under-curve (AUC) by 2.8-fold and tezacaftor AUC by 4 to 4.5-fold. When co-administered with itraconazole and ketoconazole, ivacaftor AUC increased by 15.6-fold and 8.5-fold, respectively.(1) A study in 12 subjects compared ivacaftor alone (study A), ivacaftor with ritonavir (a strong inhibitor of CYP3A4) 50 mg daily on days 1-4 (study B), and ivacaftor with ritonavir 50 mg daily for two weeks prior and on days 1-4 of ivacaftor administration (study C). In study A, B, and C, ivacaftor AUC increased from 10.94 mcg/hr to 215.6 mcg/hr and 216 mcg/hr, respectively, with the addition of ritonavir. Ivacaftor concentration maximum (Cmax) was 0.9944 mcg, 1.812 mcg, and 2.267 mcg in study A, B, and C, respectively.(2) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3-5)

Strong Cyp3a4 Inhibitors/Elinzanetant

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Elinzanetant is metabolized via CYP3A4. Strong inhibitors of CYP3A4 may inhibit the metabolism of elinzanetant.(1,2)

CLINICAL EFFECTS: Concurrent use of elinzanetant with strong CYP3A4 inhibitors may result in a significant increase in exposure of elinzanetant.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Canadian manufacturer of elinzanetant states coadministration with strong CYP3A4 inhibitors is contraindicated.(1) The US manufacturer of elinzanetant states concurrent use with strong CYP3A4 inhibitors should be avoided.(2)

DISCUSSION: Coadministration of elinzanetant with itraconazole 200 mg daily, a strong CYP3A4 inhibitor, resulted in a 4.6-fold to 6.3-fold increase in area-under-curve (AUC) and a 3.3-fold increase in maximum concentration (Cmax).(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3,4)

Strong Cyp3a4 Inhibitors/Erlotinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of erlotinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from erlotinib, including interstitial lung disease, renal failure, hepatotoxicity, gastrointestinal perforation, skin disorders, ocular disorders, or cerebrovascular events.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with erlotinib.(1) Consider alternatives with no or minimal enzyme inhibition. If concurrent therapy with erlotinib is required, decrease the dose of erlotinib by 50 mg decrements.(1) The AU manufacturer of erlotinib cautions administering erlotinib with potent CYP3A4 inhibitors and states the dose of erlotinib should be reduced if toxicity is observed.(2)

DISCUSSION: Co-administration of erlotinib with a strong CYP3A4 inhibitor, ketoconazole, increased erlotinib area-under-curve (AUC) by 67%.(1) In a study, 24 healthy subjects received a single erlotinib 100 mg dose alone or after ketoconazole 200 mg twice daily for 5 days. Mean AUC and concentration maximum (Cmax) increased by approximately 2-fold.(3) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(4,5)

Strong Cyp3a4 Inhibitors/Fedratinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of fedratinib.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in elevated levels and increased effects of fedratinib, such as neutropenia, thrombocytopenia, hepatotoxicity, or gastrointestinal toxicity.(1) Symptoms of hepatotoxicity can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Consider alternative therapies that do not strongly inhibit CYP3A4 when taking fedratinib.(1) Reduce the fedratinib dose to 200 mg once daily when administered concurrently with a strong CYP3A4 inhibitor.(1) If the strong CYP3A4 inhibitor is discontinued, the fedratinib dose should be increased to 300 mg once daily during the first two weeks after discontinuation of the CYP3A4 inhibitor, and then to 400 mg once daily thereafter as tolerated.(1) Monitor liver tests, including AST, ALT, and bilirubin. Advise patients to immediately report any symptoms of hepatotoxicity.

DISCUSSION: In a pharmacokinetic study in healthy subjects, coadministration of ketoconazole 200 mg twice daily (strong CYP3A4 inhibitor) with a single 300 mg fedratinib dose increased fedratinib area-under-the-curve (AUC) by 3.06-fold and maximum concentration (Cmax) by 1.93-fold. The exposure to fedratinib was determined to be similar to the exposure from a single 500 mg dose of fedratinib alone.(1,2) Based on modeling and simulation, coadministration of a strong CYP3A4 inhibitor, such as ketoconazole 400 mg once daily, with fedratinib 400 mg once daily is predicted to increased fedratinib AUC by 2-fold.(1) Based on modeling and simulation, coadministration of a moderate CYP3A4 inhibitor, such as erythromycin 500 mg three times daily or diltiazem 120 mg twice daily, with fedratinib 400 mg once daily is predicted to increased fedratinib AUC by 1.2-fold and 1.1-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, and tucatinib.(1,3,4)

Strong Cyp3a4 Inhibitors/Iberdomide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Iberdomide is primarily metabolized by CYP3A4. Strong inhibitors of CYP3A4 may inhibit the metabolism of iberdomide.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase the levels and effects of iberdomide, including thromboembolic events and hematologic abnormalities (neutropenia, thrombocytopenia).(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of iberdomide states that concomitant use of strong CYP3A4 inhibitors should be avoided. If concomitant use with strong CYP3A4 inhibitors cannot be avoided, reduce iberdomide dose to 1 mg every other day on Days 1 to 21 of a 28-day cycle.(1)

DISCUSSION: In a clinical study of healthy subjects, itraconazole (a strong CYP3A inhibitor) increased iberdomide area-under-curve (AUC) to 2.4-fold.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Ibrutinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of ibrutinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from ibrutinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with ibrutinib.(1) The concurrent chronic use of strong CYP3A4 inhibitors with ibrutinib is not recommended. For short-term use of strong CYP3A4 inhibitors, such as 7 days or less of antibiotics/antifungals, consider interruption of ibrutinib therapy.(1) The Australian and UK manufacturers of ibrutinib state that use of strong CYP3A4 inhibitors should be avoided. If the benefit outweighs the risk and a strong CYP3A4 inhibitor must be used, reduce the ibrutinib dose to 140 mg for the duration of the inhibitor use or withhold ibrutinib temporarily (for 7 days or less). Monitor patient closely for toxicity and follow dose modification guidance as needed.(2,3)

DISCUSSION: In a study in 18 healthy subjects, ketoconazole (400 mg daily for 7 days) increased the Cmax and AUC of ibrutinib (single 40 mg dose) by 24-fold and 29-fold, respectively.(1) The coadministration of multiple doses of voriconazole increased ibrutinib's Cmax and AUC by 6.7-fold and 5.7-fold.(1) Simulations under fed conditions suggest that posaconazole may increase ibrutinib's AUC by 7-fold to 10-fold.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, troleandomycin and tucatinib.(4,5)

Strong Cyp3a4 Inhibitors/Idelalisib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of idelalisib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from idelalisib, including hepatotoxicity, diarrhea, colitis, pneumonitis, neutropenia or intestinal perforation.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with idelalisib.(1) Consider alternatives with no or minimal enzyme inhibition. If concurrent use with idelalisib is warranted, monitor patients for toxicity and follow toxicity dose modification guidelines.(1) The Australian manufacturer of idelalisib states that while no initial dose adjustment of idelalisib is considered necessary when coadministered with a CYP3A4 inhibitor, intensified monitoring of side effects is recommended.(2)

DISCUSSION: In a study in healthy subjects, ketoconazole (400 mg daily for 4 days) increased the area-under-curve (AUC) of idelalisib (400 mg single dose) by 1.8-fold.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, clarithromycin, cobicistat, ensitrelvir, indinavir, itraconazole, josamycin, ketoconazole, lopinavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(3,4)

Strong Cyp3a4 Inhibitors/Imlunestrant

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of imlunestrant.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from imlunestrant, including hepatotoxicity, myelosuppression, interstitial lung disease, and gastrointestinal adverse effects.(1)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with hepatic impairment.(1) The recommended dosage of imlunestrant for patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment is 200 mg once daily. See prescribing information for recommendations.(1)

PATIENT MANAGEMENT: Avoid concomitant use of imlunestrant with strong CYP3A4 inhibitors. If concomitant use cannot be avoided, reduce the dose of imlunestrant to 200 mg once daily.(1)

DISCUSSION: In a clinical study, imlunestrant area-under-curve (AUC) increased 2.1-fold and maximum concentration (Cmax) increased by 1.9-fold following concomitant use of itraconazole (strong CYP3A inhibitor) for multiple days.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit (Citrus paradisi), idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Istradefylline

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of istradefylline.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in elevated levels and increased effects of istradefylline, such as dyskinesias, impulse control disorder, hallucinations and psychosis.(1)

PREDISPOSING FACTORS: Patients with hepatic impairment may be exposed to higher concentrations of istradefylline and may be more susceptible to the effects of strong CYP3A4 inhibitors.(1)

PATIENT MANAGEMENT: The manufacturer of istradefylline states that the maximum dose of istradefylline in patients on concomitant strong CYP3A4 inhibitors is 20 mg daily.(1)

DISCUSSION: Coadministration of ketoconazole (a strong CYP3A4 inhibitor) 200 mg twice daily for 4 days with a single 40 mg dose of istradefylline increased the area-under-the-curve (AUC) of istradefylline by 2.5-fold, but did not affect the maximum concentration (Cmax).(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, tucatinib, and voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Ixabepilone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of ixabepilone.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from ixabepilone, including hepatotoxicity, peripheral neuropathy, myelosuppression, or neutropenia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with ixabepilone.(1) Consider alternatives with no or minimal enzyme inhibition. If concurrent use with ixabepilone is warranted, a dose reduction to 20 mg/m2 of ixabepilone should be considered. Patients receiving concurrent therapy should be closely monitored for acute toxicities (e.g. frequent monitoring of peripheral blood counts). If the inhibitor is discontinued, allow a 1 week washout period before adjusting the dose of ixabepilone to recommended amounts.(1)

DISCUSSION: In vitro studies indicate that CYP3A4 is the main route of metabolism for ixabepilone.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Larotrectinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Agents which inhibit the CYP3A4 enzyme may inhibit the metabolism of larotrectinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase systemic exposure and the risk for larotrectinib toxicities such as neurotoxicity or hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant use of larotrectinib and strong CYP3A inhibitors. Consider an alternative concomitant medication with less potential for CYP3A4 inhibition.(1) The US manufacturer of larotrectinib states when concomitant use of larotrectinib and a strong CYP3A4 inhibitor is needed, the larotrectinib dose should be reduced by 50%.(1) If the strong CYP3A4 inhibitor is discontinued, change the larotrectinib dose to the dose used prior to the initiation of the strong CYP3A4 inhibitor after 3 to 5 elimination half-lives.(1)

DISCUSSION: In a drug interaction study in healthy subjects, coadministration of itraconazole (strong 3A4 inhibitor) with a single dose of larotrectinib (100 mg) increased larotrectinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 2.8 and 4.3-fold, respectively. (1) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3)

Strong Cyp3a4 Inhibitors/Lirafugratinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Lirafugratinib is primarily metabolized by CYP3A4. Strong CYP3A4 inhibitors may inhibit the metabolism of lirafugratinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase the levels and toxicities of lirafugratinib, including ocular toxicities (retinal pigment epithelial detachment, blurred vision, corneal keratitis) and hyperphosphatemia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant use of strong CYP3A4 inhibitors with lirafugratinib. If concomitant use cannot be avoided, reduce the dosage of lirafugratinib to 40 mg once daily. If the CYP3A4 inhibitor is discontinued, resume the prior dosage of lirafugratinib after 3 elimination half-lives of the inhibitor.(1)

DISCUSSION: In a clinical study, itraconazole 200 mg daily for 8 days increased lirafugratinib area-under-curve (AUC) by 2-fold and maximum concentration (Cmax) by 1.3-fold.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2-3)

Strong Cyp3a4 Inhibitors/Lorlatinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of lorlatinib.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in elevated levels and increased effects of lorlatinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of lorlatinib states that use of strong inhibitors of CYP3A4 should be avoided. When strong CYP3A4 inhibitors are required, reduce the dose of lorlatinib to 75 mg once daily. In patients who have had a dose reduction to 75 mg once daily due to adverse reactions and who initiate a strong CYP3A4 inhibitor, reduce the lorlatinib dose to 50 mg once daily.(1) If concurrent use of a strong CYP3A4 inhibitor is discontinued, increase the lorlatinib dose after 3 plasma half-lives of the strong CYP3A4 inhibitor to the dose that was used before starting the strong inhibitor.(1)

DISCUSSION: Coadministration of itraconazole with a single oral 100 mg dose of lorlatinib increased the area-under-curve (AUC) and maximum concentration (Cmax) of lorlatinib approximately 42% and 24%, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, clarithromycin, cobicistat, ensitrelvir, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Lurbinectedin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of lurbinectedin.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors with lurbinectedin may increase systemic exposure and the risk for toxicities such as myelosuppression, hepatotoxicity, neuropathy, fatigue, nausea, and musculoskeletal pain.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of lurbinectedin states that the concurrent use of lurbinectedin with strong CYP3A4 inhibitors should be avoided. If the use of a strong CYP3A4 inhibitor cannot be avoided, reduce the dose of lurbinectedin by 50%. After discontinuation of the strong CYP3A4 inhibitor for 5 half-lives of the inhibitor, resume the lurbinectedin dose used before starting the inhibitor.(1)

DISCUSSION: Itraconazole (a strong CYP3A4 inhibitor) increased the area-under-curve (AUC) of total lurbinectedin by 2.7-fold and unbound lurbinectedin by 2.4-fold.(1) In a study including data from 443 patients with solid and hematologic malignancies treated in six phase I and three phase II trials with lurbinectedin as a single agent or combined with other agents, lurbinectedin clearance decreased by 30%, area-under-curve (AUC) increased by 42%, and concentration maximum (Cmax) increased by 7% when coadministered with a CYP3A inhibitor.(2) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3,4)

Strong Cyp3a4 Inhibitors/Maraviroc

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of maraviroc.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 without a dosage adjustment of maraviroc may result in elevated levels of and toxicity from maraviroc. (1)

PREDISPOSING FACTORS: This interaction may be more severe in patients with renal and/or hepatic impairment.(1)

PATIENT MANAGEMENT: The US manufacturer of maraviroc states that adult patients receiving concurrent therapy with strong inhibitors of CYP3A4 should receive a dose of 150 mg maraviroc twice daily. This is the recommended dose in patients receiving strong CYP3A4 inhibitors regardless of whether or not the patient is also receiving a strong inducer of CYP3A4.(1) In adults, maraviroc should not be used with a strong CYP3A4 inhibitor in patients with a creatinine clearance less than 30 ml/min or end-stage renal disease.(1) Adult patients with hepatic impairment should be closely monitored for maraviroc-related side effects.(1) In pediatric patients aged 2 years and older weighing at least 10 kg, patients receiving concurrent therapy with strong inhibitors of CYP3A4 should receive the following maraviroc dose based on tablet or oral solution (20 mg/ml): - 10 - <20 kg: 50 mg twice daily or 50 mg (2.5ml) twice daily - 20 - <30 kg: 75 mg twice daily or 80 mg (4 ml) twice daily - 30 - <40 kg: 100 mg twice daily or 100 mg (5 ml) twice daily - >= 40 kg: 150 mg twice daily or 150 mg (7.5 ml) twice daily In pediatric patients aged 2 years and older weighing at least 10 kg, no dose recommendations are available with mild to moderate renal impairment. Maraviroc is contraindicated in pediatric patients with severe renal impairment or end-stage renal disease who are on concurrent therapy with strong CYP3A4 inhibitors.(1) NIH guidelines recommend a dose reduction of 150 mg maraviroc twice daily with itraconazole and posaconazole. Dose reduction should also be considered with concurrent isavuconazole and voriconazole.(2)

DISCUSSION: In a study in 12 subjects, concurrent atazanavir (400 mg daily) increased the Cmin, AUC, and Cmax of maraviroc (300 mg twice daily) by 4.19-fold, 3.57-fold, and 2.09-fold, respectively.(1) In a study in 12 subjects, concurrent atazanavir/ritonavir (300/100 mg twice daily) increased the Cmin, AUC, and Cmax of maraviroc (300 mg twice daily) by 6.67-fold, 4.88-fold, and 2.67-fold, respectively.(1) In a study in 12 subjects, concurrent darunavir/ritonavir (600/100 mg twice daily) increased the Cmin, AUC, and Cmax of maraviroc (150 mg twice daily) by 8.00-fold, 4.05-fold, and 2.29-fold, respectively.(1) In a study in 10 subjects, concurrent darunavir/ritonavir (600/100 mg twice daily) and etravirine (200 mg twice daily) increased the Cmin, AUC, and Cmax of maraviroc (150 mg twice daily) by 5.27-fold, 3.10-fold, 1.77-fold, respectively.(1) In a study in 12 subjects, concurrent ketoconazole (400 mg daily) increased the Cmin, AUC, and Cmax of maraviroc (100 mg twice daily) by 3.75-fold, 5.00-fold, and 3.38-fold, respectively.(1) In a study in 11 subjects, concurrent lopinavir/ritonavir (400/100 mg twice daily) increased the Cmin, AUC, and Cmax of maraviroc (300 mg twice daily) by 9.24-fold, 3.95-fold, and 1.97-fold, respectively.(1) In a study in 11 subjects, concurrent lopinavir/ritonavir (400/100 mg twice daily) and efavirenz (600 mg daily) increased the Cmin, AUC, and Cmax of maraviroc (300 mg twice daily) by 6.29-fold, 2.53-fold, 1.25-fold, respectively.(1) In a study in 8 subjects, concurrent ritonavir (100 mg twice daily) increased the Cmin, AUC, and Cmax of maraviroc (100 mg twice daily) by 4.55-fold, 2.61-fold, and 1.28-fold, respectively.(1) In a study in 11 subjects, concurrent saquinavir/ritonavir (1000/100 mg twice daily) increased the Cmin, AUC, and Cmax of maraviroc (100 mg twice daily) by 11.3-fold, 9.77-fold, 4.78-fold, respectively.(1) In a study in 11 subjects, concurrent saquinavir/ritonavir (1000/100 mg twice daily) and efavirenz (600 mg daily) increased the Cmin, AUC, and Cmax, of maraviroc (100 mg twice daily) by 8.42-fold, 5.00-fold, and 2.26-fold, respectively.(1) In a study in 12 subjects, concurrent tipranavir/ritonavir (500/200 mg twice daily) increased the Cmin and AUC of maraviroc (150 mg twice daily) by 80% and 2%, respectively. The Cmax of maraviroc decreased by 14%.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, delavirdine, idelalisib, isavuconazonium, itraconazole, josamycin, ketoconazole, lonafarnib, mibefradil, mifepristone, nefazodone, relacorilant, ribociclib, posaconazole, telaprevir, telithromycin, tucatinib, and voriconazole.(2)

Strong Cyp3a4 Inhibitors/Mavacamten

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of mavacamten.(1-3)

CLINICAL EFFECTS: Concurrent use of an inhibitor of CYP3A4 increases plasma exposure of mavacamten which may increase the incidence and severity of adverse reactions of mavacamten.(1-3)

PREDISPOSING FACTORS: CYP2C19 poor metabolizers may experience an increased incidence or severity of adverse effects.(1-3)

PATIENT MANAGEMENT: The US manufacturer of mavacamten recommends initiating mavacamten at one dose below the recommended starting dose in patients who are on stable therapy with a strong CYP3A4 inhibitor. Reduce dose by one level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients who are on mavacamten treatment and intend to initiate a strong CYP3A4 inhibitor. Schedule clinical and echocardiographic assessment 4 weeks after inhibitor initiation, and do not up-titrate mavacamten until 12 weeks after inhibitor initiation.(1) Avoid initiation of concomitant strong CYP3A4 inhibitors in patients who are on stable treatment with the lowest recommended dose of mavacamten because a lower dose is not available.(1) For short-term use (e.g. 1 week), interrupt mavacamten therapy for the duration of the strong CYP3A4 inhibitor. After therapy with the strong CYP3A4 inhibitor is discontinued, mavacamten may be reinitiated at the previous dose immediately upon discontinuation.(1) The Canadian manufacturers of mavacamten state concomitant use with strong CYP3A4 inhibitors is contraindicated.(2) The UK manufacturer of mavacamten states concomitant use with strong CYP3A4 inhibitors is dependent on CYP2C19 phenotype. In patients who are CYP2C19 poor metabolizers, concurrent use of strong CYP3A4 inhibitors is contraindicated. In patient who are CYP2C19 intermediate, normal, rapid, or ultrarapid metabolizers, strong CYP3A4 inhibitors may be used concurrently without dose adjustment of mavacamten. Monitor left ventricular ejection fraction (LVEF) in 4 weeks then resume usual monitoring schedule.(3)

DISCUSSION: Concomitant use of mavacamten (15 mg) with ketoconazole 400 mg, a strong CYP3A4 inhibitor, once daily is predicted to increase mavacamten area-under-curve (AUC) and maximum concentration (Cmax) up to 130% and 90%, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, and tucatinib.(4,5)

Strong Cyp3a4 Inhibitors/Naldemedine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of naldemedine.(1)

CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP3A4 may result in increased levels and potential risk of adverse reactions of naldemedine.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The UK manufacturer states concurrent use of a strong inhibitor of CYP3A4 should be avoided.(1) The US manufacturer recommends monitoring for potential naldemedine-related adverse reactions.(2) If concurrent use is unavoidable, monitor patients for signs of naldemedine adverse reactions, such as abdominal pain and opioid withdrawal.

DISCUSSION: Itraconazole, a strong inhibitor of CYP3A, increased exposure to naldemedine area-under-curve (AUC) by 2.9-fold which may result in an increased risk of adverse reactions.(1) Strong inhibitors of CYP3A include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(1-4)

Strong Cyp3a4 Inhibitors/Omaveloxolone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of omaveloxolone.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels of and effects from omaveloxolone including hepatotoxicity and hyperlipidemia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of strong CYP3A4 inhibitors with omaveloxolone should be avoided. If concurrent use cannot be avoided, reduce the omaveloxolone dosage to 50 mg daily and monitor closely. If adverse reactions emerge, coadministration with strong CYP3A4 inhibitors should be discontinued.(1)

DISCUSSION: Coadministration of omaveloxolone with itraconazole (a strong CYP3A4 inhibitor) increased the concentration maximum (Cmax) and area-under-curve (AUC) of omaveloxolone by 3-fold and 4-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2)

Strong Cyp3a4 Inhibitors/Paclitaxel

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of paclitaxel.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from paclitaxel, including myelosuppression, neutropenia, sensory neuropathy, pneumonitis, anemia, or thrombocytopenia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with paclitaxel.(1) Consider alternatives with no or minimal enzyme inhibition.

DISCUSSION: In vitro studies indicate CYP3A4 may be the secondary pathway for two minor metabolites of paclitaxel.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Palbociclib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of palbociclib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from palbociclib, including neutropenia, interstitial lung disease, or pneumonitis.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with palbociclib.(1) Consider alternatives with no or minimal enzyme inhibition. If concurrent use with palbociclib cannot be avoided, reduce the dose of palbociclib to 75 mg daily. If the 3A4 inhibitor is discontinued, a washout period of 3-5 half-lives of the inhibitor should occur before the palbociclib dose is adjusted upward.(1)

DISCUSSION: In a study in 12 healthy subjects, itraconazole (200 mg daily) increased the concentration maximum (Cmax) and area-under-curve (AUC) of a single dose of palbociclib by 34% and 87%, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Pexidartinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of pexidartinib.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in elevated levels and increased effects of pexidartinib, such as hepatotoxicity.(1,2) Symptoms can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of pexidartinib states that pexidartinib coadministration with strong inhibitors of CYP3A4 should be avoided.(1) If coadministration with a strong CYP3A4 inhibitor cannot be avoided, reduce the pexidartinib dose according to the following recommendations. If the planned total daily dose is currently 500 mg, modify the total daily dose to 250 mg by administering 125 mg twice daily. If the planned total daily dose is currently 375 mg, modify the total daily dose to 250 mg by administering 125 mg twice daily. If the planned total daily dose is currently 250 mg, modify the total daily dose to 125 mg by administering 125 mg once daily. If concomitant use of a strong CYP3A4 inhibitor is discontinued, increase the pexidartinib dose to the dose that was used before starting the inhibitor after three plasma half-lives of the strong CYP3A4 inhibitor. Monitor liver tests, including AST, ALT, total bilirubin, direct bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the recommendations in the Turalio package insert. Advise patients to immediately report any symptoms of hepatotoxicity.

DISCUSSION: Coadministration of itraconazole (strong CYP3A4 inhibitor) increased pexidartinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 48% and 70%.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, indinavir, itraconazole, josamycin, ketoconazole, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, tucatinib, and voriconazole.(1,3)

Strong Cyp3a4 Inhibitors/Pexidartinib (200 Mg)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of pexidartinib.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in elevated levels and increased effects of pexidartinib, such as hepatotoxicity.(1,2) Symptoms can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of pexidartinib states that pexidartinib coadministration with strong inhibitors of CYP3A4 should be avoided.(1) If coadministration with a strong CYP3A4 inhibitor cannot be avoided, reduce the pexidartinib dose according to the following recommendations. If the planned total daily dose is currently 800 mg, modify the total daily dose to 400 mg by administering 200 mg twice daily. If the planned total daily dose is currently 600 mg, modify the total daily dose to 400 mg by administering 200 mg twice daily. If the planned total daily dose is currently 400 mg, modify the total daily dose to 200 mg by administering 200 mg once daily. If concomitant use of a strong CYP3A4 inhibitor is discontinued, increase the pexidartinib dose to the dose that was used before starting the inhibitor after three plasma half-lives of the strong CYP3A4 inhibitor. Monitor liver tests, including AST, ALT, total bilirubin, direct bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the recommendations in the Turalio package insert. Advise patients to immediately report any symptoms of hepatotoxicity.

DISCUSSION: Coadministration of itraconazole (strong CYP3A4 inhibitor) increased pexidartinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 48% and 70%.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, indinavir, itraconazole, josamycin, ketoconazole, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, tucatinib, and voriconazole.(1,3)

Strong Cyp3a4 Inhibitors/Pirtobrutinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of pirtobrutinib.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels of and effects from pirtobrutinib including hemorrhage and cytopenias such as neutropenia, anemia, and thrombocytopenia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of strong CYP3A4 inhibitors with pirtobrutinib should be avoided. If concurrent use cannot be avoided, reduce the dose of pirtobrutinib by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of strong CYP3A4 inhibitor use.(1) After discontinuation of a strong CYP3A4 inhibitor for 5 half-lives, resume the previous pirtobrutinib dose.(1)

DISCUSSION: Co-administration of a single 200 mg dose of pirtobrutinib with itraconazole (a strong CYP3A4 inhibitor) increased area-under-curve (AUC) of pirtobrutinib by 49%.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2)

Strong Cyp3a4 Inhibitors/Ponatinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of ponatinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from ponatinib, including thromboembolic events, hepatotoxicity, heart failure, hypertension, pancreatitis, neuropathy, ocular toxicity, hemorrhage, myelosuppression, or tumor lysis syndrome.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with ponatinib.(1) Consider alternatives with no or minimal enzyme inhibition. If concurrent administration with ponatinib is warranted, the recommended ponatinib dose should be reduced based on current daily dose during concomitant treatment:(1) -If current daily dose is 45 mg, reduce to 30 mg daily. -If current daily dose is 30 mg, reduce to 15 mg daily. -If current daily dose is 15 mg, reduce to 10 mg daily. -If current daily dose is 10 mg, avoid concurrent use with strong CYP3A4 inhibitors. Even with the dose reduction, patients receiving concomitant therapy may be at increased risk for adverse reactions. Assure recommended monitoring (e.g. complete blood counts, liver function, lipase, blood pressure measurement) is scheduled and patient is aware of signs of thrombosis (e.g. symptoms of myocardial infarction or stroke). If the ponatinib dose has been reduced due to coadministration of a CYP3A4 inhibitor, and the inhibitor is subsequently discontinued, reevaluate ponatinib efficacy and safety to determine if a dose increase is appropriate.(1)

DISCUSSION: In 22 healthy volunteers, ketoconazole (400 mg once daily) increased the concentration maximum (Cmax) and area-under-curve (AUC) of a single 15 mg dose of ponatinib by 47% and 78%, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Reboxetine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Reboxetine is primarily metabolized by CYP3A4. Strong inhibitors of CYP3A4 may inhibit the metabolism of reboxetine.(1,2)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase the levels and effects of reboxetine, including hypertension, tachycardia, orthostasis, and urinary retention.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The UK prescribing information states that reboxetine should not be given with drugs known to inhibit CYP3A4.(1)

DISCUSSION: In healthy volunteers, ketoconazole 200 mg daily with single dose reboxetine 4 mg increased R,R(-)-reboxetine and S,S(+)-reboxetine area-under-curve (AUC) by 58% and 43%, respectively. Half life increased significantly but maximum concentration (Cmax) did not change, which the authors postulated was the reason for lack of increased side effects. The authors recommended caution and considering reboxetine dose reduction.(3) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(4,5)

Strong Cyp3a4 Inhibitors/Regorafenib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Regorafenib and active M2 and M5 metabolites contribute to anticancer activity. Although interpatient variability is high, with repeated dosing the systemic exposure to each component (regorafenib, M2 and M5) is similar. CYP3A4 converts regorafenib to the active M2 metabolite. M2 is subsequently converted, via an unknown pathway, to the active M5 metabolite.(1) Thus, inhibition of CYP3A4 leads to increased serum levels of regorafenib, but decreased levels of both M2 and M5.(1,2)

CLINICAL EFFECTS: In an interaction study of regorafenib with a strong CYP3A4 inhibitor, a 33% increase in exposure to regorafenib did not compensate for a 93% decrease in exposure to M2 and M5. Overall, mean exposure to the combination of regorafenib, M2 and M5 decreased by approximately 50 per cent.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of regorafenib states concomitant use with strong inhibitors of CYP3A4 should be avoided. Whenever possible, to assure maximal efficacy of regorafenib it would be prudent to use an alternative agent in place of the strong CYP3A4 inhibitor.(2) The US manufacturer of itraconazole states that concurrent use of regorafenib is not recommended during and two weeks after itraconazole treatment.(4)

DISCUSSION: Regorafenib was approved for use prior to completion of an exposure-response analysis or a population pharmacokinetic study.(1) The outcomes of these studies will increase understanding and improve prediction of regorafenib interaction risks. Strong CYP3A4 inhibitors linked to this monograph are: adagrasib, boceprevir, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, tucatinib, and voriconazole.(3)

Strong Cyp3a4 Inhibitors/Rivoceranib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of rivoceranib.(1)

CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from rivoceranib, including increased risk of hypertension, proteinuria, leukopenia, thrombocytopenia, neutropenia, hyperbilirubinemia, anemia, and hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with rivoceranib. Consider alternatives with minimal or little enzyme inhibition. If concurrent use is necessary, closely monitor for adverse effects.(1)

DISCUSSION: In vitro data shows that rivoceranib is metabolized by CYP3A4.(1) A study with rivoceranib showed that itraconazole reduced the clearance of rivoceranib by 40% and increased the area-under-curve (AUC) by 75%.(1) In an animal study, rivoceranib levels were significantly increased when coadministered with ketoconazole and voriconazole.(2) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3-5)

Strong Cyp3a4 Inhibitors/Rupatadine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of rupatadine.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from rupatadine, including increased risk of somnolence, headache, tiredness, asthenia, or dry mouth.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Canadian prescribing information states concurrent use of rupatadine with strong CYP3A4 inhibitors is not recommended.(1) The UK prescribing information states concurrent use of rupatadine with strong CYP3A4 inhibitors should be avoided.(2)

DISCUSSION: Concurrent use of rupatadine 20 mg and ketoconazole increased the systemic exposure of rupatadine 10-fold.(1,2) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3-4)

Strong Cyp3a4 Inhibitors/Sevabertinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sevabertinib is metabolized via CYP3A4. Strong inhibitors of CYP3A4 may inhibit the metabolism of sevabertinib.(1)

CLINICAL EFFECTS: Concurrent use of sevabertinib with strong CYP3A4 inhibitors may result in a significant increase in exposure of sevabertinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sevabertinib states coadministration with strong CYP3A4 inhibitors should be avoided.(1) If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce sevabertinib dosage as follows: - If current dosage is 20 mg twice daily; reduce to 10 mg twice daily - If current dosage is 10 mg twice daily; reduce to 10 mg once daily - If current dosage is 10 mg once daily; withhold sevabertinib until the strong CYP3A4 inhibitor is discontinued.(1) After the strong CYP3A4 inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the sevabertinib dosage that was used prior to initiating the strong inhibitor.(1)

DISCUSSION: Coadministration of sevabertinib with itraconazole 200 mg daily, a strong CYP3A4 inhibitor, resulted in a 2.3-fold increase in area-under-curve (AUC) and a 1.6-fold increase in maximum concentration (Cmax).(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Sonrotoclax

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors inhibit the metabolism of sonrotoclax.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in elevated levels of sonrotoclax, increasing the risk for tumor lysis syndrome and other toxicities.(1)

PREDISPOSING FACTORS: Risk factors for tumor lysis syndrome include higher tumor burden such as bulky lymphadenopathy or lymphocytosis and reduced renal function.(1)

PATIENT MANAGEMENT: Recommendations vary depending the stage of therapy. During the initiation and ramp-up phase of sonrotoclax therapy, strong CYP3A4 inhibitors are contraindicated due to the increased risk for tumor lysis syndrome. In patients taking the target daily dose of sonrotoclax after the ramp-up phase who start a strong CYP3A4 inhibitor, decrease sonrotoclax daily dose to 20 mg. Monitor for tumor lysis syndrome, hematologic and non-hematologic toxicity and adjust dosage as directed in prescribing information. If the strong CYP3A4 inhibitor is discontinued, resume the prior (i.e., pre-inhibitor) sonrotoclax dose at least 5 days after discontinuation of the inhibitor.(1)

DISCUSSION: In a study, itraconazole (a strong CYP3A inhibitor and P-gp inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of sonrotoclax by 11-fold and 4-fold, respectively. Posaconazole (a strong CYP3A inhibitor) increased sonrotoclax AUC and Cmax by 13-fold and 7-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3-4)

Strong Cyp3a4 Inhibitors/Sunvozertinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of sunvozertinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from sunvozertinib, including interstitial lung disease, gastrointestinal adverse reactions, dermatologic adverse reactions, or ocular toxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with sunvozertinib.(1) Consider alternatives with no or minimal enzyme inhibition. If concurrent therapy with sunvozertinib is required, decrease the dose of sunvozertinib from 200 mg to 150 mg.(1) After discontinuing the CYP3A4 inhibitor, the prior sunvozertinib dose can be resumed after 3 to 5 half-lives of the CYP3A4 inhibitor.(1)

DISCUSSION: Co-administration of sunvozertinib with a strong CYP3A4 inhibitor, itraconazole, increased sunvozertinib area-under-curve (AUC) and maximum concentration (Cmax) by 1.5-fold and 1.3-fold.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Surufatinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of surufatinib.(1)

CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from surufatinib, including increased risk of bleeding, hepatotoxicity, hypertension, and proteinuria.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with surufatinib. Consider alternatives with minimal or little enzyme inhibition. If concurrent use is necessary, closely monitor for adverse effects.(1) If concurrent therapy is warranted, monitor patients for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In vitro data shows that surufatinib is metabolized by CYP3A4. The manufacturer of surufatinib states that concomitant use with strong CYP3A4 inhibitors should be avoided.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2-4)

Strong Cyp3a4 Inhibitors/Tavapadon

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Tavapadon is primarily metabolized by CYP3A4. Strong CYP3A4 inhibitors may inhibit the metabolism of tavapadon.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase the levels and toxicities of tavapadon, including hypotension, altered impulse control, hallucinations, and dyskinesias.(1)

PREDISPOSING FACTORS: The risk of hallucinations appears to be increased in patients 65 years of age and older.

PATIENT MANAGEMENT: During tavapadon titration, concomitant use with strong CYP3A4 inhibitors should be avoided. During tavapadon maintenance, if strong CYP3A4 inhibitors are initiated, decrease the dosing frequency from once daily to every 7 days: - If the current dose of tavapadon is 5 mg daily, lower dosage to 5 mg every 7 days. - If the current dose of tavapadon is 10 mg daily, lower dosage to 10 mg every 7 days. - If the current dose of tavapadon is 15 mg daily, lower dosage to 15 mg every 7 days. If the CYP3A4 inhibitor is discontinued, resume the prior maintenance dosage of tavapadon and monitor patients for clinical response and tolerability.(1)

DISCUSSION: In a clinical study, itraconazole 200 mg daily for 14 days increased tavapadon area-under-curve (AUC) by 5-fold and maximum concentration (Cmax) by 4-fold. When itraconazole is given with tavapadon once weekly, steady-state AUC and Cmax are predicted to fluctuate between +84% to -23% and +50% to -41%, respectively, across the 7-day dosing interval compared to tavapadon once daily alone.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2-3)

Strong Cyp3a4 Inhibitors/Tazemetostat

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of tazemetostat.(1)

CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from tazemetostat.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of tazemetostat says to avoid coadministration of strong CYP3A4 inhibitors with tazemetostat.(1) If coadministration of strong CYP3A4 inhibitors cannot be avoided, reduce the tazemetostat dose as follows: If the current tazemetostat dose is 800 mg twice daily, reduce the dose to 400 mg twice daily. If the current tazemetostat dose is 600 mg twice daily, reduce the dose to 400 mg for the first dose and 200 mg for the second dose. If the current tazemetostat dose is 400 mg twice daily, reduce the dose to 200 mg twice daily.(1) After discontinuation of the strong CYP3A4 inhibitor for 3 elimination half-lives, resume the prior tazemetostat dose.(1)

DISCUSSION: Coadministration of fluconazole, a moderate CYP3A4 inhibitor, with tazemetostat 400 mg twice daily in patients increased tazemetostat steady-state area-under-curve (AUC) by 3.1-fold and maximum concentration (Cmax) by 2.3-fold.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2-4)

Strong Cyp3a4 Inhibitors/Tretinoin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of tretinoin.(1)

CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inhibitor may result in increased levels of and effects from tretinoin including hepatotoxicity and hyperlipidemia.(1) Retinoids, including tretinoin, have been associated with intracranial hypertension, especially in pediatric patients. Early signs and symptoms include papilledema, headache, nausea, vomiting, and visual disturbances.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of strong CYP3A4 inhibitors with tretinoin should be avoided. If concurrent use cannot be avoided, monitor patients more frequently for adverse reactions.(1) Evaluate patients with symptoms for intracranial hypertension (such as papilledema, headache, nausea, vomiting, and visual disturbances), and, if present, institute care in concert with neurological assessment. Consider interruption, dose reduction, or discontinuation of tretinoin as appropriate.(1) The Australian manufacturer of tretinoin states that serum concentration levels should be monitored and, if needed, appropriate dose adjustments of tretinoin should be considered during treatment with antifungal agents such as posaconazole, voriconazole, ketoconazole, and itraconazole, and during the following days after treatment.(2)

DISCUSSION: In 13 patients on tretinoin for 4 weeks, single-dose ketoconazole (400 to 1200 mg) increased tretinoin area-under-curve (AUC) by 72%.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3)

Strong Cyp3a4 Inhibitors/Upadacitinib (>=30 Mg)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of upadacitinib.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from upadacitinib, including neutropenia, serious infections, thrombosis, myocardial infarction, stroke, GI perforation, and transaminitis.(1,2) Concurrent use of upadacitinib with immunosuppressives or immunomodulators, including idelalisib, lonafarnib, and ribociclib, may result in an increased risk of serious infections.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of upadacitinib states that upadacitinib requires a dose adjustment with concurrent strong CYP3A4 inhibitors.(1) If upadacitinib is being used for atopic dermatitis concurrently with strong CYP3A4 inhibitors, limit the upadacitinib dose to 15 mg once daily. Coadministration of upadacitinib 30 mg once daily with strong CYP3A4 inhibitors is not recommended.(1) If upadacitinib is being used for ulcerative colitis concurrently with strong CYP3A4 inhibitors, limit the upadacitinib dose to 30 mg once daily for 8 weeks during the induction phase and then 15 mg once daily in the maintenance phase.(1) If upadacitinib is being used for Crohn's disease concurrently with strong CYP3A4 inhibitors, limit the upadacitinib dose to 30 mg once daily for 12 weeks during the induction phase and then 15 mg once daily in the maintenance phase.(1) If upadacitinib is being used for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, polyarticular juvenile idiopathic arthritis, or giant cell arteritis, no dose adjustment is needed with strong CYP3A4 inhibitors. Monitor closely for adverse reactions.(1) Concurrent use of upadacitinib 15 mg with strong CYP3A4 inhibitors should be approached with caution. Patients should be closely monitored for adverse reactions.(1,2) For concurrent treatment with nirmatrelvir-ritonavir, dose adjustments should be considered throughout the nirmatrelvir-ritonavir treatment and for 3 days following the last dose of nirmatrelvir-ritonavir.(3)

DISCUSSION: In a study of 11 subjects, ketoconazole (400 mg daily for 6 days, a strong CYP3A4 inhibitor) increased the maximum concentration (Cmax) and area-under-curve (AUC) of single-dose upadacitinib 3 mg by 1.7-fold and 1.75-fold, respectively.(1,2) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(4,5)

Strong Cyp3a4 Inhibitors/Venetoclax

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors inhibit the metabolism of venetoclax.(1)

CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP3A4 may result in elevated levels of venetoclax, increasing the risk for tumor lysis syndrome and other toxicities.(1)

PREDISPOSING FACTORS: Risk factors for tumor lysis syndrome include (1): - the ramp-up phase of venetoclax therapy when tumor burden is highest - initial magnitude of tumor burden - renal impairment The risk of venetoclax toxicities may be increased in patients with severe hepatic impairment.(1)

PATIENT MANAGEMENT: Recommendations vary depending on diagnosis, stage of therapy, and strong CYP3A4 inhibitor. During the initiation/ramp-up phase of venetoclax therapy in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), strong CYP3A4 inhibitors are contraindicated due to the increased risk for tumor lysis syndrome. During the initiation/ramp-up phase of venetoclax therapy in patients with acute myeloid leukemia (AML) who are taking strong CYP3A4 inhibitors, decrease venetoclax dose as follows: - With posaconazole, decrease venetoclax dose on day 1 to 10 mg, on day 2 to 20 mg, on day 3 to 50 mg, and on day 4 to 70 mg. - With other strong CYP3A4 inhibitors, decrease venetoclax dose on day 1 to 10 mg, on day 2 to 20 mg, on day 3 to 50 mg, and on day 4 to 100 mg. In patients taking a steady daily dosage for CLL, SLL, or AML (after completion of the ramp-up phase), avoid use of a strong CYP3A4 inhibitor if possible. If a strong CYP3A4 inhibitor must be used, decrease venetoclax daily dose as follows: - When used concomitantly with posaconazole, decrease venetoclax to 70 mg daily. - When used concomitantly with other strong CYP3A4 inhibitors, decrease venetoclax to 100 mg daily. Monitor for tumor lysis syndrome, hematologic and non-hematologic toxicity and adjust dosage as directed in prescribing information. If the strong CYP3A4 inhibitor is discontinued, the manufacturer of venetoclax recommends resuming the prior (i.e. pre-inhibitor) venetoclax dose 2 to 3 days after discontinuation of the strong CYP3A4 inhibitor.(1)

DISCUSSION: In 11 previously treated NHL subjects, ketoconazole (a strong CYP3A4 inhibitor which also inhibits P-gp and BCRP) 400 mg daily for 7 days increased the maximum concentration (Cmax) and area-under-curve (AUC) of venetoclax by 130 % and 540 %, respectively.(1) In 12 patients with NHL, venetoclax 50 mg single dose was administered on day 1 and day 8 with ketoconazole 400 mg once daily administered on days 5-11 to evaluate pharmacokinetic parameters of concurrent administration. Coadministration increased venetoclax Cmax and AUC with a mean increase of 2.3-fold and 6.4-fold, respectively, with a range in AUC change of 2-12-fold. One patient excluded from statistical analysis due to receiving a dose of ketoconazole of 200 mg once daily had an increase in venetoclax Cmax and AUC of 2.3-fold and 3.5-fold, respectively.(2) In a study in 6 healthy subjects, coadministration of venetoclax and ritonavir (50 mg once daily) for 14 days increased venetoclax's Cmax and AUC by 140 % and 690 %, respectively.(1) Coadministration of posaconazole (a strong CYP3A4 and P-gp inhibitor) 300 mg daily and venetoclax 50 mg daily for 7 days led to a 61 % and 86 % increase in venetoclax Cmax, respectively, compared to venetoclax 400 mg daily administered alone. Venetoclax AUC increased by 90 % and 144 %, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3-4)

Strong Cyp3a4 Inhibitors/Vinblastine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of vinblastine.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from vinblastine, including leukopenia, alopecia, hypertension, or constipation.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with vinblastine.(1) Consider alternatives with no or minimal enzyme inhibition. The manufacturer of vinblastine states that caution should be used if coadministered with strong CYP3A4 inhibitors.(1) The manufacturer of lopinavir/ritonavir states that patients who develop significant hematological or gastrointestinal toxicity on concomitant vinblastine should temporarily hold lopinavir/ritonavir, or use alternative medications that do not inhibit CYP3A4 or P-gp.(2)

DISCUSSION: There have been 2 case reports of vinblastine hematologic toxicity during concurrent lopinavir-ritonavir therapy. In both cases, vinblastine was administered without toxicity when lopinavir-ritonavir therapy was suspended.(3,4) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(5,6)

Strong Cyp3a4 Inhibitors; Amprenavir;Atazanavir/Mifepristone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of mifepristone.

CLINICAL EFFECTS: Concurrent use of mifepristone with a strong inhibitor of CYP3A4 may result in a 5-fold increase in area-under-curve (AUC) or 80 per cent decrease in mifepristone clearance, leading to toxicity such as adrenal insufficiency and hypokalemia.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of mifepristone for use in patients with endogenous Cushing's syndrome states the benefit of the CYP3A4 inhibitor must be carefully weighed against the potential risks and concurrent use should only occur when necessary.(1) If starting mifepristone in a patient already taking a strong CYP3A4 inhibitor, initiate mifepristone at 300 mg and titrate if clinically indicated to a maximum dose of 900 mg.(1) If a strong CYP3A4 inhibitor is started in a patient already taking mifepristone, the following dose adjustments are recommended: - If current mifepristone dose is 300 mg, no dose change warranted; - If current mifepristone dose is 600 mg, reduce dose to 300 mg and titrate if clinically indicated to a maximum dose of 600 mg; - If current mifepristone dose is 900 mg, reduce dose to 600 mg and titrate if clinically indicated to a maximum dose of 900 mg; and - If current mifepristone dose if 1200 mg, reduce dose to 900 mg.(1)

DISCUSSION: A drug interaction study examined mifepristone 600 mg daily with concurrent ketoconazole 200 mg twice daily on days 13-17. Concurrent administration increased mifepristone area-under-curve (AUC) and maximum concentration (Cmax) by 1.38-fold and 1.28-fold, respectively.(1) A drug interaction study of 33 healthy subjects on itraconazole 200 mg daily coadministered with mifepristone 900 mg daily for 14 days found that itraconazole increased the Cmax and AUC of mifepristone by 1.1-fold and 1.2-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, amprenavir, atazanavir, boceprevir, clarithromycin, cobicistat, ensitrelvir, fosamprenavir, indinavir, itraconazole, josamycin, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, saquinavir, relacorilant, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(1,2)

Strong Cyp3a4 Inhibitors; Darunavir/Everolimus

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of everolimus.(1,2)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in elevated levels of and toxicity from everolimus.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of everolimus states that concurrent use of strong inhibitors of CYP3A4 should be avoided.(1,2) The Department of Health and Human Services HIV guidelines state that darunavir should not be coadministered with everolimus, and therapeutic drug monitoring is recommended when everolimus is used with other protease inhibitors.(3) The American Society of Transplantation (AST) guidelines state that clarithromycin, ketoconazole, voriconazole, and HIV protease inhibitors are contraindicated with everolimus.(4) If the combination of clarithromycin and everolimus must be used, AST guidelines recommend lowering the dose of everolimus by up to 50% upon initiation of the antibiotic and monitoring levels daily.(4) The US manufacturer of itraconazole states that concurrent use of everolimus is not recommended during and two weeks after itraconazole treatment.(5) If everolimus is used with itraconazole or ketoconazole, AST guidelines recommend lowering the dose of everolimus by at least 50% and monitoring everolimus levels closely.(4) Case reports have described the use of voriconazole with everolimus.(6)

DISCUSSION: In a study in healthy subjects, concurrent use of ketoconazole, a strong CYP3A4 inhibitor and a Pg-p inhibitor, increased everolimus area-under-curve (AUC) and maximum concentration (Cmax) by 3.9-fold and 15.0-fold, respectively.(1) In a case report, a renal transplant patient on everolimus and started on voriconazole experienced an increase in everolimus trough concentration (Cmin) of 7.5-fold, which was normalized with a lowering of everolimus dose from 1.5 mg twice daily to 0.25 mg twice daily. Voriconazole was discontinued after one month, and another month later, posaconazole was started. Cmin increased by 3.8-fold, which led to an adjustment of everolimus dose from 1 mg twice daily to 0.5 mg twice daily.(6) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, ketoconazole, lonafarnib, lopinavir, nefazodone, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(1,7,8) Moderate inhibitors of CYP3A4 have been shown to have less of an effect on everolimus pharmacokinetics. In a study in healthy subjects, concurrent use of erythromycin, a moderate CYP3A4 inhibitor and a P-gp inhibitor, increased everolimus AUC and Cmax by 2.0-fold and 4.4-fold, respectively.(1) In a study in healthy subjects, concurrent use of verapamil, a moderate CYP3A4 inhibitor and a P-gp inhibitor, increased everolimus AUC and Cmax by 2.3-fold and 3.5-fold, respectively.(1)

Strong Cyp3a4 Inhibitors; Protease Inhibitors/Cariprazine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Cariprazine and its major active metabolite DDCAR are metabolized by CYP3A4.

CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inhibitor or protease inhibitor may result in elevated levels of and toxicity from cariprazine.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When possible, avoid the use of strong CYP3A4 inhibitors and protease inhibitors with cariprazine. The US manufacturer of cariprazine states that concurrent use of strong CYP3A4 inhibitors requires a dose adjustment. If a strong CYP3A4 inhibitor is initiated in a patient on a stable dose of cariprazine, the following dose adjustments are recommended: -If current cariprazine dose is 1.5 or 3 mg daily - Decrease cariprazine dose to 0.5 mg daily. -If current cariprazine dose is 4.5 or 6 mg daily - Decrease cariprazine dose to 0.75 mg daily. In adult patients taking a strong CYP3A4 inhibitor when cariprazine is started, the following dose adjustments are recommended: -For schizophrenia or bipolar mania: Start cariprazine dose at 0.5 mg daily; increase to 0.75 mg daily, if needed. -For bipolar depression or adjunctive therapy for treatment of Major Depressive Disorder (MDD): Start cariprazine dose at 0.5 mg daily.(1) -Initiating cariprazine is not recommended in pediatric patients while taking a strong CYP3A4 inhibitor.(1) Cariprazine has two active metabolites, DCAR and DDCAR which have similar in vitro activity and potency. However, DDCAR has a longer half-life (1-3 weeks) than cariprazine (2-4 days), resulting in systemic DDCAR concentrations that are about 4-fold higher than cariprazine. Thus although interaction onset may begin within a few days, the full effect of inhibition may not be seen for 4 or more weeks. When the inhibitor is discontinued, cariprazine, DCAR and DDCAR will begin to fall and the dosage may need be increased. Monitor for decreased effectiveness for 4 or more weeks. The Australian, Canadian, and UK manufacturers of cariprazine state that concurrent use of strong CYP3A4 inhibitors is contraindicated.(2-4) The Canadian manufacturer of cariprazine states that concurrent use of strong CYP3A4 inhibitors is also contraindicated for at least 2 weeks after cariprazine discontinuation.(3)

DISCUSSION: In an interaction study, coadministration of ketoconazole 400 mg/day with cariprazine 0.5 mg/day increased cariprazine exposure (AUC, area-under-curve) 4-fold and increased DDCAR AUC about 1.5-fold.(1) In a PKPB model, coadministration of ketoconazole 400 mg/day with cariprazine 0.5 mg/day is predicted to increase cariprazine concentration maximum (Cmax) and AUC by 5.5-fold and 6-fold, respectively. Coadministration of fluconazole 200 mg/day with cariprazine 0.5 mg/day is predicted to increased cariprazine Cmax and AUC by up to 3-fold.(1) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir-ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(6,7)

Strong Cyp3a4 Or Strong & Moderate Cyp2c9 Inhib/Erdafitinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Erdafitinib is metabolized by CYP3A4 and CYP2C9. Strong inhibitors of CYP3A4 or moderate inhibitors of CYP2C9 may inhibit the metabolism of erdafitinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 or moderate CYP2C9 inhibitors may increase the levels and effects of erdafitinib, including retinopathy and hyperphosphatemia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US prescribing information states that concurrent use of erdafitinib with strong CYP3A4 inhibitors or moderate CYPC9 inhibitors should be avoided. If concurrent use cannot be avoided, monitor closely for adverse reactions and consider a dose modification based on prescribing information. If the strong CYP3A4 or moderate CYP2C9 inhibitor is discontinued, consider increasing the erdafitinib dose if patient does not have any drug-related toxicity.(1) If concurrent use with nitisinone cannot be avoided, the manufacturer of nitisinone recommends reducing the dosage of a CYP2C9 substrate like erdafitinib by one-half.(2)

DISCUSSION: In PKPB models, concurrent use of fluconazole (a moderate CYP2C9 and CYP3A4 inhibitor) resulted in erdafitinib mean ratios for concentration maximum (Cmax) and area-under-curve (AUC) of 121% and 148% , respectively, compared to erdafitinib alone.(1) In PKPB models, concurrent use of itraconazole (a strong CYP3A4 inhibitor and P-gp inhibitor) resulted in erdafitinib mean ratios for Cmax and AUC of 105% and 134%, respectively, compared to erdafitinib alone.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3,4) Strong CYP2C9 inhibitors include: camizestrant.(3,4) Moderate inhibitors of CYP2C9 include: adagrasib, amiodarone, apazone, asciminib, benzbromarone, fluconazole, miconazole, mifepristone, milk thistle, nitisinone, oxandrolone, phenylbutazone, and sulfaphenazole.(3,4)

Strong Or Moderate Cyp3a4 Inhibitors/Simeprevir

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong or moderate inhibitors of CYP3A4 may slow down the metabolism of simeprevir.(1) Simeprevir may inhibit the metabolism of darunavir, diltiazem, erythromycin, and verapamil.(1)

CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inhibitors may result in elevated levels of and toxicity from simeprevir.(1) Simeprevir may increase levels and toxicity of darunavir, diltiazem, erythromycin, and verapamil.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of simeprevir states that concurrent administration of strong or moderate inhibitors of CYP3A4 is not recommended due to risk of toxicity.(1) The American Society of Transplantation guidelines state that the combination of cyclosporine and simeprevir is contraindicated.(7) The US manufacturer of itraconazole states that concurrent administration with simeprevir is not recommended during and two weeks after itraconazole treatment (6).

DISCUSSION: In a study in 24 subjects, erythromycin (500 mg TID for 7 days) increased the maximum concentration (Cmax), area-under-curve (AUC) and Cmin of simeprevir (150 mg daily for 7 days) by 4.53-fold, 7.47-fold, and 12.74-fold, respectively. The Cmax and AUC of erythromycin increased by 1.59-fold and 1.39-fold, respectively.(1) In a study in 9 subjects, an individualized dose of cyclosporine increased the Cmax and AUC of simeprevir (150 mg daily for 14 days) by 4.74 fold and 5.81-fold.(1) In a study in 25 subjects, simeprevir (50 mg once daily) increased the Cmax, AUC, and Cmin of darunavir (800 mg once daily) by 4%, 18%, and 31%.(4) In a study in 25 subjects, darunavir-ritonavir (800 mg-100 mg once daily) increased the Cmax, AUC, and Cmin of simeprevir (50 mg once daily) by 1.79-fold, 2.59-fold, and 4.58-fold.(4) In a study in 12 subjects, ritonavir (100 mg twice daily, 15 days) increased the AUC, Cmax, and Cmin of simeprevir (200 mg daily, 7 days) by 618% (463-815%), 370% (284-476%), and 1335% (929-1901%).(5) Strong and moderate inhibitors of CYP3A4 linked to this monograph include adagrasib, amprenavir, aprepitant, atazanavir, avacopan, berotralstat, boceprevir, ceritinib, clarithromycin, clofazimine, cobicistat, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, ensitrelvir, erythromycin, fedratinib, fosamprenavir, fluconazole, fluvoxamine, fosnetupitant, idelalisib, imatinib, indinavir, isavuconazonium, itraconazole, josamycin, ketoconazole, lefamulin, lenacapavir, lonafarnib, lopinavir, mibefradil, mifepristone, milk thistle, nefazodone, nelfinavir, netupitant, nilotinib, nirmatrelvir/ritonavir, nirogacestat, posaconazole, relacorilant, ribociclib, rilzabrutinib, ritonavir, saquinavir, schisandra, silibinin, stiripentol, telaprevir, telithromycin, tipranavir, treosulfan, troleandomycin, tucatinib, verapamil, and voriconazole.(1-3)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Adagrasib/Possible Qt Prolonging Agents

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Adagrasib has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1-3)

CLINICAL EFFECTS: The concurrent use of adagrasib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1-3)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of adagrasib states that the concurrent use of QT prolonging agents should be avoided.(1) When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If patients develop QTc prolongation >500 msec or >60 msec from baseline, withhold adagrasib until QTc interval less than 481 msec or QTc interval returns to baseline. Resume adagrasib at the next lower dose level. If patients develop torsade de pointes, polymorphic ventricular tachycardia, or signs and symptoms of serious or life-threatening arrhythmia, permanently discontinue adagrasib.(1)

DISCUSSION: Adagrasib has been associated with QTc interval prolongation. Adagrasib increased QTc in a concentration-dependent manner. In patients administered adagrasib 600 mg twice daily, the mean QTcF change from baseline was 18 msec. In the pooled safety population, 6% of 366 patients with at least one post-baseline ECG had an average QTc greater than 501 msec and 11% of patients had a increase from baseline QTc greater than 60 msec.(1) Agents that are linked to this monograph may have been associated with Torsade de Pointes and/or QT prolongation but at this time lack substantial evidence for causing Torsade de Pointes.(3)

Dual Cyp3a4 & P-Gp Inhibitors/Nintedanib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Nintedanib is a substrate for the P-glycoprotein (P-gp) transporter and is metabolized to a minor extent by CYP3A4.

CLINICAL EFFECTS: Concurrent use of an agent that is both an inhibitor of P-gp and CYP3A4 may result in elevated levels of and clinical effects of nintedanib.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of nintedanib recommends close monitoring for nintedanib patients receiving drugs which are both P-gp and CYP3A4 inhibitors. In an interaction study ketoconazole increased exposure to nintedanib by 60%. Nintedanib therapy may need to be interrupted or the dose may need to be reduced.(1)

DISCUSSION: In an interaction study coadministration with ketoconazole, a P-gp and CYP3A4 inhibitor, increased nintedanib exposure (area-under-curve, AUC) and maximum concentration (Cmax) by 1.61-fold and 1.83 fold respectively.(1) Strong CYP3A4 & P-gp inhibitors include: adagrasib, boceprevir, clarithromycin, cobicistat, grapefruit, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, and tucatinib. Moderate CYP3A4 & P-gp inhibitors include: conivaptan, diltiazem, dronedarone, erythromycin, fluvoxamine, isavuconazonium, schisandra, and verapamil. Weak CYP3A4 & P-gp inhibitors include: amiodarone, azithromycin, cimetidine, cyclosporine, daclatasvir, daridorexant, diosmin, flibanserin, fluvoxamine, fostamatinib, glecaprevir/pibrentasvir, ivacaftor, lapatinib, mavorixafor, ranolazine, and vepdegestrant.(2)

Dual P-Gp And Strong Cyp3a4 Inhibitors/Darolutamide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Combined inhibitors of P-glycoprotein (P-gp) and CYP3A4 may increase the absorption and inhibit the metabolism of darolutamide.(1-3)

CLINICAL EFFECTS: Concurrent use of an agent that is both an inhibitor of P-gp and a strong inhibitor of CYP3A4 may result in elevated levels of and clinical effects of darolutamide.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of darolutamide recommends increased monitoring if agents that are combined P-gp and strong CYP3A4 inhibitors are used in patients receiving darolutamide.(1) Darolutamide dosage may need to be adjusted. Monitor absolute neutrophil count (ANC). If patient experiences a greater than or equal to Grade 3 toxicity, dose may need to be withheld or reduced until symptoms improve.(1)

DISCUSSION: Concurrent itraconazole increased the area-under-curve (AUC) and maximum concentration (Cmax) of darolutamide by 1.7-fold and 1.4-fold, respectively.(1) P-gp and strong CYP3A4 inhibitors linked to this monograph are: adagrasib, cobicistat, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir, mifepristone, nirmatrelvir/ritonavir, posaconazole, ritonavir, saquinavir, telaprevir, tucatinib and telithromycin.

Qt Prolonging Agents/Bedaquiline

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of bedaquiline with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The use of bedaquiline patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Bedaquiline should be used with caution in patients receiving therapy with agents that prolong the QT interval. Patients should receive a baseline electrocardiogram (ECG) before initiation, 2 weeks after initiation, during treatment as clinically indicated, and at the expected time of maximum increase of the QT interval when receiving concurrent agents that prolong the QT interval. Bedaquiline and other QT prolonging agents should be discontinued if the patient develops a clinically significant ventricular arrhythmia or a QTcF of greater than 500 msec confirmed by repeat ECGs. If a patient develops syncope, perform an ECG.(1) Also consider obtaining serum calcium, magnesium, and potassium levels at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a clinical trial, mean increases in QTc were greater in patients treated with bedaquiline than with placebo. At Week 1, bedaquiline increased QTc by an average of 9.9 msec, compared with 2.5 msec for placebo. At Week 24, bedaquiline increased QTc by an average of 15.7 msec, compared with 6.2 msec for placebo. In another clinical trial in which patients received bedaquiline with other QT prolonging agents, QT prolongation was additive and proportional to the number of QT prolonging drugs used. Patients receiving bedaquiline alone averaged a QTc increase of 23.7 msec over baseline, while patients receiving bedaquiline with at least one other QT prolonging agent averaged a QTc increase of 30.7 msec.(1) In a study, bedaquiline was coadministered with QTc prolonging agents clofazimine and levofloxacin. In the study, 5% of patients had a QTc >= 500 ms and 43% of patients had an increase in QTc >= 60 ms from baseline.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)

Qt Prolonging Agents/Catequentinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Catequentinib has been shown to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1)

CLINICAL EFFECTS: The concurrent use of catequentinib with other agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1)

PREDISPOSING FACTORS: In general, the risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The concurrent use of catequentinib with other agents known to prolong the QTc interval should be monitored closely. Monitor ECG and electrolytes regularly (every 3-6 weeks) if catequentinib is administered with concurrent QTc prolonging drugs.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Catequentinib causes QTc prolongation. In clinical studies, QTc prolongation was reported as a very common adverse effect.(1) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(3)

Qt Prolonging Agents/Trazodone (< 100 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of trazodone with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1,2)

CLINICAL EFFECTS: The use of trazodone in patients maintained on agents that prolong the QTc interval may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1,2)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of trazodone states that concurrent use with agents known to prolong the QT interval should be avoided.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Trazodone has been reported to prolong the QT interval.(1) A thorough QT study in 20 subjects evaluated the effects of trazodone at doses of 20 mg, 60 mg and 140 mg. There was no evidence of QTc prolongation at the lowest trazodone dose of 20mg (mean effect on QTc of 4.5 ms 95% CI 3.7-5.3 ms), but at 60 mg and 140 mg, there was a significant effect that exceeds the E14 FDA Guidelines threshold of prolonging the QT/QTc interval by more than 5 ms. The study found a dose-dependent effect on QTc prolongation starting at 60 mg with a mean effect on QTc of 12.3 ms (95% CI 11-13.6 ms) and increasing with a 140 mg dose to a mean effect on QTc of 19.8 ms (95% CI 17.6-22.1).(3) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(4)

Selected Cyp3a4 Inhibitors/Felodipine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of felodipine by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent administration of strong CYP3A4 inhibitors may result in elevated levels of felodipine leading to adverse effects, including severe hypotension and peripheral edema.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of felodipine with strong CYP3A4 inhibitors should be approached with caution.(1) When these agents are used concurrently, the dose of felodipine may need to be decreased and patients should be observed for increased effects.(1) If the strong CYP3A4 inhibitor is discontinued, the dose of felodipine may need to be increased and patients should be observed for decreased effects.(1)

DISCUSSION: Concurrent use of an extended release formulation of felodipine with itraconazole resulted in approximately 8-fold increase in the AUC, more than 6-fold increase in the Cmax, and 2-fold prolongation in the half-life of felodipine.(1) A double-blind, randomized, two-phase crossover study in nine subjects examined the effects of itraconazole, a strong CYP3A4 inhibitor, on felodipine. The half-life of felodipine increased by 71% during concurrent itraconazole. In seven of the nine subjects, the maximum concentration (Cmax) of felodipine when administered with placebo was lower than the 32-hour concentration of felodipine when administered with itraconazole. Concurrent use also resulted in significantly greater effects on both blood pressure and heart rate.(1,2) There are two case reports of patients developing edema following the addition of itraconazole to felodipine therapy.(5) In the second report, the patient was rechallenged with concurrent itraconazole and again developed edema.(3) Voriconazole has been shown to inhibit the metabolism of felodipine in vitro.(4) Selected strong CYP3A4 inhibitors linked to this monograph are: adagrasib, cobicistat, conivaptan, ensitrelvir, grapefruit, idelalisib, indinavir, lopinavir, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, relacorilant, ribociclib, ritonavir, saquinavir, troleandomycin, and tucatinib.(5)

Selected Strong Cyp3a4 Inhibitors/Orforglipron (<=9 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Orforglipron is metabolized via CYP3A4. Strong inhibitors of CYP3A4 may inhibit the metabolism of orforglipron.(1)

CLINICAL EFFECTS: Concurrent use of orforglipron with strong CYP3A4 inhibitors may increase the levels and toxicities of orforglipron, including severe gastrointestinal adverse effects.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of orforglipron states that when used concomitantly with strong CYP3A4 inhibitors, the orforglipron maximum dosage is 9 mg once daily.(1)

DISCUSSION: In a clinical study, coadministration of orforglipron with clarithromycin 500 mg twice daily, a strong CYP3A4 inhibitor, resulted in a 3.5-fold increase in orforglipron area-under-curve (AUC) and a 1.9-fold increase in maximum concentration (Cmax).(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, mibefradil, mifepristone, nefazodone, nelfinavir, posaconazole, relacorilant, ribociclib, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(2,3)

Selected Strong Cyp3a4 Inhibitors;Protease Inhib/Mefloquine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of mefloquine.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors or protease inhibitors with mefloquine may result in elevated levels of mefloquine and toxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of mefloquine states that concurrent use with strong CYP3A4 inhibitors should be approached with caution.(1) The US Department of Health and Human Services HIV guidelines recommend considering alternative therapies to protease inhibitors or monitoring for adverse events and virologic response.(2)

DISCUSSION: In a study in 8 healthy subjects, administration of ketoconazole (400 mg daily) for 10 days followed by a single 500 mg dose of mefloquine resulted in an increase in the AUC of mefloquine by 79%. The elimination half-life was increased from 322 hours to 448 hours.(1) Strong CYP3A4 inhibitors and protease inhibitors linked to this monograph include: adagrasib, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, ensitrelvir, fosamprenavir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3,4)

Slt Strong Cyp3a4 Inhibit/Amlodipine; Levamlodipine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the first-pass and elimination metabolism of calcium channel blockers by CYP3A4.

CLINICAL EFFECTS: The concurrent use of strong CYP3A4 inhibitors with calcium channel blockers metabolized by CYP3A4 may result in elevated levels of the calcium channel blocker and risk of adverse effects, including hypotension and bradycardia.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of strong CYP3A4 inhibitors with calcium channel blockers should be approached with caution. When these agents are used concurrently, the dose of the calcium channel blocker may need to be adjusted or an alternative agent considered. Monitor patients for increased calcium channel blocker effects. If the strong CYP3A4 inhibitor is discontinued, the dose of the calcium channel blocker may need to be increased and patients should be observed for decreased effects.

DISCUSSION: Coadministration of a 180 mg dose of diltiazem (moderate CYP3A4 inhibitor) with 5 mg amlodipine resulted in a 60% increase in amlodipine systemic exposure. Strong inhibitor of CYP3A4 may increase plasma concentrations of amlodipine to a greater extent.(1) In a study in 19 healthy subjects, telaprevir (750 mg every 8 hours for 7 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of amlodipine (5mg) by 1.27-fold and 2.79-fold, respectively.(3) Strong CYP3A4 inhibitors include: adagrasib, ceritinib, clarithromycin, cobicistat, ensitrelvir, fluconazole, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, posaconazole, relacorilant, ribociclib, saquinavir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(4,5)

Slt Strong Cyp3a4 Inhibit/Selected Calcium Channel Blockers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the first-pass and elimination metabolism of calcium channel blockers by CYP3A4.

CLINICAL EFFECTS: The concurrent use of strong CYP3A4 inhibitors with calcium channel blockers metabolized by CYP3A4 may result in elevated levels of the calcium channel blocker and risk of adverse effects, including hypotension and bradycardia.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of strong CYP3A4 inhibitors with calcium channel blockers should be approached with caution. When these agents are used concurrently, the dose of the calcium channel blocker may need to be adjusted or an alternative agent considered. Monitor patients for increased calcium channel blocker effects. If the strong CYP3A4 inhibitor is discontinued, the dose of the calcium channel blocker may need to be increased and patients should be observed for decreased effects.

DISCUSSION: A double-blind, randomized, two-phase crossover study in nine subjects examined the effects of itraconazole on felodipine. The half-life of felodipine increased by 71% during concurrent itraconazole. In seven of the nine subjects, the maximum concentration (Cmax) of felodipine when administered with placebo was lower than the 32-hour concentration of felodipine when administered with itraconazole. Concurrent use also resulted in significantly greater effects on both blood pressure and heart rate.(10,11) A randomized cross-over trial in seven subjects examined the effects of ketoconazole (200 mg daily for 4 days) on nisoldipine (5 mg daily). The concurrent use of ketoconazole increased the nisoldipine area-under-curve (AUC) and Cmax by 24-fold and 11-fold, respectively. Increases in the M9 nisoldipine metabolite were similar.(7) PKPB modeling of nifedipine and ritonavir noted a decreased systolic blood pressure > 40 mmHg.(8) There are several case reports of patients developing increased levels of calcium channel blockers and adverse effects with concurrent strong CYP3A4 inhibitors.(9-16) Strong CYP3A4 inhibitors include: adagrasib, ceritinib, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, posaconazole, relacorilant, ribociclib, saquinavir, tipranavir, troleandomycin, tucatinib, and voriconazole.(17,18)

Slt Strong Cyp3a4 Inhibitors/Sildenafil (Ed); Tadalafil (Ed)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of sildenafil(1) and tadalafil.(2)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in increased levels, clinical effects, and side effects of sildenafil(1) and tadalafil.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sildenafil states the recommended dose of sildenafil when used for erectile dysfunction in patients receiving concomitant therapy with strong CYP3A4 inhibitors is 25 mg in a 48 hour period.(1) The US manufacturer of tadalafil states that the maximum recommended dose of as needed tadalafil for erectile dysfunction in patients taking strong inhibitors of CYP3A4 is 10 mg every 72 hours.(2) The maximum recommended dose of daily tadalafil for erectile dysfunction in patients taking strong inhibitors of CYP3A4 is 2.5 mg.(3) The US manufacturer of tadalafil chewable tablets (Chewtadzy) states the maximum recommended dose of as needed tadalafil for erectile dysfunction in patients taking strong CYP3A4 inhibitors is 10 mg every 72 hours. The use of tadalafil chewable tablets (Chewtazdy) for once daily use for erectile dysfunction or benign prostatic hyperplasia (BPH) is not recommended in patients taking strong CYP3A4 inhibitors due to the lack of a 2.5 mg tablet strength.(3)

DISCUSSION: Concurrent administration of a single 100 mg dose of sildenafil with erythromycin (500 mg twice daily for five days) resulted in an increase of sildenafil area-under-curve (AUC) by 182%. Therefore, the manufacturer of sildenafil recommends a starting dose of 25 mg of sildenafil in patients receiving concomitant therapy with other strong CYP3A4 inhibitors such as itraconazole or ketoconazole.(1) Concurrent administration of a single 20 mg dose of tadalafil with ketoconazole (400 mg daily) increased tadalafil AUC and maximum concentration (Cmax) by 312% and 22%, respectively. Concurrent administration of a single 10 mg dose of tadalafil with ketoconazole (200 mg daily) increased tadalafil AUC and Cmax by 107% and 15%, respectively.(2) Strong CYP3A4 inhibitors include adagrasib, ceritinib, clarithromycin, ensitrelvir, grapefruit, idelalisib, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, nefazodone, posaconazole, relacorilant, ribociclib, telithromycin, tucatinib, and voriconazole.(4,5)

Str 3A4 Inhib That Prol Qt/Tolterodine (<=1 Mg Or <=2 Mg Er)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of tolterodine by CYP3A4.(1,2) Tolterodine has been observed to prolong the QTc interval. Concurrent use with other agents that prolong the QTc interval may result in additive effects on the QTc interval.(1,2)

CLINICAL EFFECTS: The concurrent administration of tolterodine with strong CYP3A4 inhibitors may result in elevated levels of tolterodine and signs of toxicity, including potentially life-threatening cardiac arrhythmias.(1,2)

PREDISPOSING FACTORS: Patients who are CYP2D6 poor metabolizers may be at increased risk.(1,2) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: The manufacturer of tolterodine recommends that a maximum tolterodine dosage of 1 mg twice daily of the non extended release dosage form(1) or 2 mg once daily of the extended release dosage form(2) be used in patients receiving concurrent therapy with strong CYP3A4 inhibitors. The manufacturer of tolterodine states concurrent use agents known to prolong the QT interval should be used with caution. Consider close observation in patients with a known history of QT prolongation or patients taking antiarrhythmic medications.(1,2) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study in eight subjects who were deficient in CYP2D6, the concurrent administration of tolterodine (2 mg) with ketoconazole (200 mg once daily for four days), another inhibitor of CYP3A4, resulted in a 60% decrease in tolterodine clearance.(6) Tolterodine AUC and Cmax increased 2.5-fold and 2-fold, respectively.(2) In a study of the effect of tolterodine immediate release tablets, the effect on the QT interval appeared greater for 8 mg/day (two times the therapeutic dose) compared to 4 mg/day. Tolterodine 2 mg BID and tolterodine 4 mg BID increased the QTcF by 5.01 msec (0.28-9.74 msec) and 11.84 msec (7.11-16.58 msec), respectively. The change in QT interval was more pronounced in CYP2D6 poor metabolizers (PM) than extensive metabolizers (EMs).(1,2) Strong inhibitors of CYP3A4 include: adagrasib, ceritinib, clarithromycin, lonafarnib, lopinavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(1,7,8)

Str 3A4 Inhibitors That Prolong Qt/Panobinostat (<= 10 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of panobinostat.(1)

CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP3A4 may result in elevated levels of and toxicity from panobinostat, including increased risk of bleeding and prolongation of the QT interval which may result in life-threatening arrhythmia and death.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Reduce the dose of panobinostat to 10 mg when coadministered with strong CYP3A4 inhibitors. Limit the starting dose of panobinostat to 10 mg in patients taking strong CYP3A4 inhibitors.(1) If concurrent therapy is warranted, continue standard monitoring of complete blood counts, ECG, and serum electrolytes. Instruct patients to report any irregular heartbeat, dizziness, or fainting; nausea, vomiting, or diarrhea; unusual tiredness, shortness of breath, paleness; unusual or unexplained bleeding or bruising; signs of infection such as fever, cough, or flu-like symptoms. If panobinostat toxicity occurs, panobinostat or the CYP3A4 inhibitor may need to be discontinued.(1) Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In 14 patients with advanced cancer, ketoconazole (a strong CYP3A4 inhibitor, 200 mg twice daily for 14 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of panobinostat by 62% and 73%, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, ceritinib, lopinavir/ritonavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(3,4)

Str Cyp3a4 Inhib;Atazan;Darun/Aripiprazole Im Every 2 Months

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of aripiprazole.(1)

CLINICAL EFFECTS: Concurrent administration of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from aripiprazole.(1)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients who are CYP2D6 poor metabolizers, or who receive concomitant treatment with a strong CYP2D6 inhibitor (e.g. bupropion, fluoxetine, paroxetine, quinidine) in addition to treatment with a strong CYP3A4 inhibitor.(1)

PATIENT MANAGEMENT: The US manufacturer of aripiprazole IM every 2 months injection (Abilify Asimtufii) makes the following recommendations for patients who receive a strong CYP3A4 inhibitor for greater than 14 days:(1) - if the aripiprazole dose is 960 mg every 2 months and a strong CYP3A4 inhibitor is started, reduce the aripiprazole dose to 720 mg once every 2 months. - if the patient is taking both a strong CYP3A4 inhibitor AND a strong CYP2D6 inhibitor, avoid use of Abilify Asimtufii. - if the patient is a poor CYP2D6 metabolizer and receives treatment with a strong CYP3A4 inhibitor, avoid use of Abilify Asimtufii.

DISCUSSION: There have been no specific drug-drug interaction studies with aripiprazole long-acting injections. The coadministration of ketoconazole (200 mg daily for 14 days) with a single oral dose of aripiprazole (15 mg) resulted in increases in the area-under-curve (AUC) of aripiprazole and its active metabolite by 63% and 77%, respectively. In simulations, the combination of strong CYP2D6 and CYP3A4 inhibitors is predicted to increase aripiprazole Cmax and AUC by 4.5-fold. The concurrent use of strong CYP3A4 inhibitors in poor CYP2D6 metabolizers is predicted to increase aripiprazole Cmax and AUC by 3-fold.(1) CYP3A4 inhibitors linked to this monograph include: adagrasib, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2)

Str Cyp3a4 Inhib;Atazanavir;Darunav/Aripiprazole Im Monthly

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of aripiprazole.(1)

CLINICAL EFFECTS: Concurrent administration of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from aripiprazole.(1)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients who are CYP2D6 poor metabolizers, or who receive concomitant treatment with a strong CYP2D6 inhibitor (e.g. bupropion, fluoxetine, paroxetine, quinidine) in addition to treatment with a strong CYP3A4 inhibitor.(1-2)

PATIENT MANAGEMENT: The US manufacturer of aripiprazole IM monthly injection (Abilify Maintena) recommends the following dose adjustments for patients who receive a strong CYP3A4 inhibitor for longer than 14 days:(1) - if the aripiprazole dose is 400 mg per month and a strong CYP3A4 inhibitor is started, then decrease aripiprazole dose to 300 mg per month. - if the aripiprazole dose is 400 mg per month and patient receives concomitant treatment with a strong CYP3A4 inhibitor AND a strong CYP2D6 inhibitor, then decrease dose to 200 mg per month. - if the aripiprazole dose is 300 mg per month and a strong CYP3A4 inhibitor is started, then decrease aripiprazole dose to 200 mg per month. Patients who are CYP2D6 poor metabolizers and receive treatment with a strong CYP3A inhibitor should also receive 200 mg per month. - if the aripiprazole dose is 300 mg per month and patient receives concomitant treatment with a strong CYP3A4 inhibitor AND a strong CYP2D6 inhibitor, then decrease dose to 160 mg per month. The monthly aripiprazole dose may need to be increased if long-term CYP3A4 inhibitor treatment is discontinued.(1)

DISCUSSION: There have been no specific drug-drug interaction studies with aripiprazole long-acting injections. The coadministration of ketoconazole (200 mg daily for 14 days) with a single oral dose of aripiprazole (15 mg) resulted in increases in the area-under-curve (AUC) of aripiprazole and its active metabolite by 63% and 77%, respectively. In simulations, the combination of strong CYP2D6 and CYP3A4 inhibitors is predicted to increase aripiprazole Cmax and AUC by 4.5-fold. The concurrent use of strong CYP3A4 inhibitors in poor CYP2D6 metabolizers is predicted to increase aripiprazole Cmax and AUC by 3-fold.(1) CYP3A4 inhibitors linked to this monograph include: adagrasib, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2)

Strong 3A4 Inhibitors That Prolong Qt/Delamanid

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors that prolong the QTc interval may inhibit the metabolism of delamanid and result in additive risk of QT prolongation.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors that prolong the QTc interval may result in increased levels of and toxicity from delamanid, including QT prolongation. QT prolongation may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: Concurrent use of delamanid and strong CYP3A4 inhibitors that prolong the QTc interval should be approached with caution. If concurrent use is necessary, frequently monitor ECGs (more frequently than the standard recommended monthly ECG during delamanid therapy) throughout the full delamanid treatment period. Discontinue delamanid if a QTcF greater than 500 msec is observed. Discontinue delamanid if albumin falls below 2.8 g/DL.(1) If concurrent therapy with either delamanid and a strong CYP3A4 inhibitor that prolongs the QTc interval is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study in healthy subjects, lopinavir/ritonavir (400/100 mg daily) administered with delamanid (100 mg twice daily) increased exposure to delamanid exposed by 30%. There was no effect on delamanid levels.(1) QT prolongation has been observed with delamanid and increases over the first 6-10 weeks of therapy. In a placebo controlled study in healthy subjects, the mean increase in QTcF from baseline during delamanid therapy was 7/6 msec at 1 month and 12.1 msec at 2 months. Three percent of patients experienced an increase of 60 msec or greater at some point during therapy. One patient had a QTcF greater than 500 msec. All patients with a QTcF greater than 60 msec were also taking a fluoroquinolone.(1) Strong inhibitors of CYP3A4 that prolong the QTc interval include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lonafarnib, lopinavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(3,4)

Strong Cyp3a4 Inhib; Atazanavir; Darunavir/Aripiprazole Ir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of aripiprazole.(1-2)

CLINICAL EFFECTS: Concurrent administration of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from aripiprazole.(1-2)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients who are CYP2D6 poor metabolizers, or who receive concomitant treatment with a strong CYP2D6 inhibitor (e.g. bupropion, fluoxetine, paroxetine, quinidine) in addition to treatment with a strong CYP3A4 inhibitor.(1-2)

PATIENT MANAGEMENT: The US manufacturer of aripiprazole states that the dose of immediate release oral or injectable aripiprazole should be reduced to one-half of its normal dose when strong CYP3A4 inhibitors are coadministered, unless aripiprazole is being administered as adjunctive therapy for Major Depressive Disorder. If the patient is also receiving a strong CYP2D6 inhibitor or is a known CYP2D6 poor metabolizer, the dose of aripiprazole should be reduced to one-fourth its normal dose. When the inhibitors are discontinued, the dose of aripiprazole should be increased.(1) The US Department of Health and Human Services HIV guidelines state that patients on ritonavir- or cobicistat-boosted protease inhibitors should have their dose of aripiprazole decreased to one-fourth of the usual dose. Patients on unboosted atazanavir should have their aripiprazole decreased to one-half of the usual dose.(2)

DISCUSSION: The coadministration of ketoconazole (200 mg daily for 14 days) with a single oral dose of aripiprazole (15 mg) resulted in increases in the area-under-curve (AUC) of aripiprazole and its active metabolite by 63% and 77%, respectively. In simulations, the combination of strong CYP2D6 and CYP3A4 inhibitors is predicted to increase aripiprazole Cmax and AUC by 4.5-fold. The concurrent use of strong CYP3A4 inhibitors in poor CYP2D6 metabolizers is predicted to increase aripiprazole Cmax and AUC by 3-fold.(1) CYP3A4 inhibitors linked to this monograph include: adagrasib, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3)

Strong Cyp3a4 Inhib; Protease Inhib/Lumateperone (<=10.5 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 and protease inhibitors may inhibit the metabolism of lumateperone.(1,2)

CLINICAL EFFECTS: Concurrent use of lumateperone with strong CYP3A4 inhibitors or protease inhibitors increases lumateperone exposure, which may increase the risk of adverse reactions.(1,2)

PREDISPOSING FACTORS: Patients with moderate or severe hepatic impairment (Child-Pugh class B or C) may be at higher risk of increased lumateperone exposure.(1)

PATIENT MANAGEMENT: The manufacturer of lumateperone recommends decreasing the dosage of lumateperone to 10.5 mg once daily in patients receiving strong CYP3A4 inhibitors.(1) The US Department of Health and Human Services HIV guidelines state that protease inhibitors should not be coadministered with lumateperone.(2)

DISCUSSION: Coadministration of lumateperone with itraconazole, a strong CYP3A4 inhibitor, resulted in a 4-fold and 3.5-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively.(1) Coadministration of lumateperone with diltiazem, a moderate CYP3A4 inhibitor, resulted in a 2.5-fold and 2-fold increase AUC and Cmax, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, amprenavir, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, ensitrelvir, fosamprenavir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2-4)

Strong Cyp3a4 Inhib;Atazanav;Darunavir/Saxagliptin(<=2.5 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of saxagliptin.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in elevated levels and increased effects of saxagliptin.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of saxagliptin states that the dose of saxagliptin should be limited to 2.5 mg daily in patients taking strong inhibitors of CYP3A4.(1)

DISCUSSION: Pretreatment with ketoconazole (200 mg every 12 hours for 9 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of saxagliptin (100 mg) by 62% and 2.5-fold, respectively. The Cmax and AUC of the active metabolite of saxagliptin decreased 95% and 91%, respectively. The Cmax and AUC of ketoconazole decreased 16% and 13%, respectively.(1,2) Pretreatment with ketoconazole (200 mg every 12 hours for 7 days) increased the Cmax and AUC of a single dose of saxagliptin (100 mg) by 2.4-fold and 3.7-fold, respectively. The Cmax and AUC of the active metabolite of saxagliptin decreased 96% and 90%, respectively.(1) Inhibitors of CYP3A4 linked to this monograph include: adagrasib, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(1,3,4)

Strong Cyp3a4 Inhib;Atazanavir;Darunav/Aripiprazole Lauroxil

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of aripiprazole.(1)

CLINICAL EFFECTS: Concurrent administration of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from aripiprazole.(1)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients who are CYP2D6 poor metabolizers, or who receive concomitant treatment with a strong CYP2D6 inhibitor (e.g. bupropion, fluoxetine, paroxetine, quinidine) in addition to treatment with a strong CYP3A4 inhibitor.(1)

PATIENT MANAGEMENT: The US manufacturer of aripiprazole lauroxil extended-release injection (Aristada) recommends the following dose adjustments for patients who receive a strong CYP3A4 inhibitor for greater than 14 days:(1) - in patients already receiving aripiprazole lauroxil, reduce dose to the next lower strength. For patients receiving 441 mg, no further dose reduction is necessary, if tolerated. - for patients who are known to be poor CYP2D6 metabolizers and are taking a strong CYP3A4 inhibitor for greater than 14 days, reduce dose to 441 mg per month. For patients receiving 441 mg, no further dose reduction is necessary, if tolerated. - for patients taking both a strong CYP2D6 and CYP3A4 inhibitor for greater than 14 days, avoid 662 mg, 882 mg, and 1,064 mg doses. No dose adjustment is necessary in patients taking the 441 mg dose, if tolerated.

DISCUSSION: The coadministration of ketoconazole (200 mg daily for 14 days) with a single oral dose of aripiprazole (15 mg) resulted in increases in the area-under-curve (AUC) of aripiprazole and its active metabolite by 63% and 77%, respectively. In simulations, the combination of strong CYP2D6 and CYP3A4 inhibitors is predicted to increase aripiprazole Cmax and AUC by 4.5-fold. The concurrent use of strong CYP3A4 inhibitors in poor CYP2D6 metabolizers is predicted to increase aripiprazole Cmax and AUC by 3-fold.(1) CYP3A4 inhibitors linked to this monograph include: adagrasib, atazanavir, boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2)

Strong Cyp3a4 Inhibitors That Prolong Qt/Mavorixafor

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors that prolong the QTc interval may inhibit the metabolism of mavorixafor and result in additive risk of QT prolongation.(1) Mavorixafor is also a substrate of P-glycoprotein (P-gp). P-gp inhibitors may increase mavorixafor exposure.(1) Many CYP3A4 inhibitors also inhibit P-glycoprotein (P-gp), including adagrasib, clarithromycin, lopinavir/ritonavir, saquinavir, and telithromycin.(2)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors that prolong QT may increase the levels and effects of mavorixafor including additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: Reduce the dose of mavorixafor to 200 mg once daily when used concomitantly with strong CYP3A4 inhibitors.(1) If concurrent use is warranted, monitor ECG prior to initiation, during concurrent therapy, and as clinically indicated.(1) When concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If QT prolongation occurs, a dose reduction or discontinuation of mavorixafor may be required.(1)

DISCUSSION: In a study with healthy subjects, itraconazole 200 mg daily (a strong CYP3A4 and P-gp inhibitor) increased the exposure to single-dose mavorixafor 200 mg similar to that from single-dose mavorixafor 400 mg alone. This suggests that itraconazole increased mavorixafor exposure by about 2-fold.(1) A study in healthy volunteers found that ritonavir 100 mg twice daily (a strong CYP3A4 inhibitor and P-gp inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose mavorixafor 200 mg by 60% and 39%, respectively.(4) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(5) Strong inhibitors of CYP3A4 that prolong QT include: adagrasib, ceritinib, clarithromycin, lonafarnib, lopinavir/ritonavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(2,6)

Strong Cyp3a4 Inhibitors/Alitretinoin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of alitretinoin.(1)

CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inhibitor may result in increased levels of and effects from tretinoin including hepatotoxicity and hyperlipidemia.(1) Retinoids, including alitretinoin, have been associated with intracranial hypertension, especially in pediatric patients. Early signs and symptoms include papilledema, headache, nausea, vomiting, and visual disturbances.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of alitretinoin recommends a reduction in alitretinoin dose to 10 mg once daily when coadministered with strong CYP3A4 inhibitors.(1) Evaluate patients with symptoms for intracranial hypertension (such as papilledema, headache, nausea, vomiting, and visual disturbances), and, if present, institute care in concert with neurological assessment. Consider interruption, dose reduction, or discontinuation of alitretinoin as appropriate.(1)

DISCUSSION: In a clinical study, ketoconazole (strong CYP3A4 inhibitor) increased the concentration max (Cmax) of alitretinoin by around 50% and 4-oxo-alitretinoin (active metabolite) by around 13%. Similar increases were seen with the area-under-curve (AUC) of alitretinoin.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2)

Strong Cyp3a4 Inhibitors/Atogepant

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of atogepant.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from atogepant, including nausea, constipation, and fatigue.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of atogepant recommends that patients on concomitant strong CYP3A4 inhibitors receive atogepant 10 mg once daily for prevention of episodic migraines and for prevention of chronic migraines.(1)

DISCUSSION: In a study of healthy subjects, itraconazole, a strong CYP3A4 inhibitor, increased the atogepant area-under-curve (AUC) by 5.5-fold and maximum concentration (Cmax) by 2.15-fold.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Bortezomib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of bortezomib.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels of and effects from bortezomib including peripheral neuropathy, thrombocytopenia, and neutropenia.(1)

PREDISPOSING FACTORS: Patients with moderate to severe hepatic impairment have increased exposure to bortezomib.

PATIENT MANAGEMENT: The concurrent use of strong CYP3A4 inhibitors with bortezomib should be approached with caution. If concurrent use is necessary, monitor patients for signs of bortezomib toxicity and consider a dose reduction of bortezomib.(1)

DISCUSSION: In a 2-way crossover study, 12 patients were randomized to receive concomitant ketoconazole (a strong CYP3A4 inhibitor) during one of either 2 cycles of bortezomib. Ketoconazole 400 mg daily for 4 days increased the AUC of bortezomib by 35% and increased blood proteasome inhibitory effect by 24-46%. However, the frequency and grade of adverse events were not increased by ketoconazole.(2) In a retrospective review, 6 patients with relapsed multiple myeloma received bortezomib; 2 patients were also on itraconazole (a strong CYP3A4 inhibitor), 1 patient was on lansoprazole (a CYP2C19 inhibitor), and 1 patient was on itraconazole and lansoprazole. New or worsening peripheral neuropathy and grade 4 thrombocytopenia occurred in all 3 patients on itraconazole, and grade 3 neutropenia occurred in 2 of the patients, compared to none of the patients not on itraconazole.(3) In a case report, two patient with refractory multiple myeloma started on bortezomib with itraconazole or voriconazole and developed paralytic ileus 12 and 15 days later. The authors suggest that these were cases of autonomic neuropathy caused by concomitant use of itraconazole or voriconazole with bortezomib.(4) In a retrospective study of 48 patients with relapsed or refractory multiple myeloma on bortezomib, concomitant use of itraconazole was a risk factor for developing early-onset peripheral neuropathy [OR 19.0 (1.89-190.96, p=0.01)] on multivariate logistic regression analysis.(5) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(6)

Strong Cyp3a4 Inhibitors/Buspirone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of buspirone.(1-4)

CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inhibitor may result in elevated levels of and increased effects from buspirone, including lightheadedness, asthenia, dizziness, and somnolence.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Australian,(2) UK,(3) and US(4) manufacturers of buspirone recommend a lower dose of 2.5 mg twice daily of buspirone in patients receiving strong CYP3A4 inhibitors.

DISCUSSION: In a study in 8 healthy subjects, pretreatment with 4 days of erythromycin (1.5 g/day) increased the area-under curve (AUC) and maximum concentration (Cmax) of a single dose of buspirone (10 mg) by 6-fold and 5-fold, respectively. The relative increase in buspirone AUC varied by 15-fold. There was a significant difference in scores on the Digit Symbol Substitution test when buspirone was administered with erythromycin.(1) In a study in 8 healthy subjects, pretreatment with itraconazole (200 mg daily for 4 days) increased the Cmax and AUC of buspirone by 13-fold and 19-fold, respectively.(1,2) However, only the Critical Flicker Fusion test showed statistically significant differences when compared to the administration of buspirone alone.(1) In a study in 6 subjects, pretreatment with itraconazole (200 mg daily for 4 days) increased the Cmax and AUC of buspirone by 10.5-fold and 14.5-fold, respectively. The Cmax and AUC of the piperazine metabolite of buspirone increased by 57% and 50%, respectively.(3) In a study in healthy subjects, concurrent use of buspirone (2.5 mg or 5 mg twice daily) with nefazodone (250 mg twice daily) resulted in increases in the Cmax and AUC of buspirone, up to 20-fold and up to 50-fold, respectively. The concentration of 1-pyrimidinylpiperazine (a buspirone metabolite) decreased 50%.(4)

Strong Cyp3a4 Inhibitors/Cannabidiol-Tetrahydrocannabinol

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of cannabidiol (CBD) and tetrahydrocannabinol (THC).(1,2)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels of and effects from CBD and THC, including transaminitis, euphoria, somnolence, sedation, and dizziness.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Canadian and Australian manufacturers of CBD-THC spray state that a new dosage may be required if concomitant therapy with strong CYP3A4 inhibitors is started or stopped.(1,2)

DISCUSSION: In a study of 12 healthy volunteers who were given CBD-THC buccal spray, ketoconazole 400 mg increased the maximum concentration (Cmax) and area-under curve (AUC) of CBD by 2-fold and 1.9-fold, respectively, of THC by 1.25-fold and 1.8-fold, respectively, and of 11-hydroxy-THC (a primary THC metabolite) by 3.1-fold and 3.6-fold, respectively.(3) In a study of 32 healthy volunteers, steady state itraconazole (strong inhibitor) did not affect the Cmax or AUC of oral CBD solution, but increased the Cmax and AUC of 7-hydroxy-CBD by 6% and 17% and increased the AUC of 7-carboxy-CBD by 12%. Steady state fluconazole (moderate CYP3A4 inhibitor and CYP2C19 inhibitor) increased the Cmax and AUC of CBD by 24% and 21% and decreased the Cmax and AUC of 7-hydroxy-CBD by 41% and 29% and of 7-carboxy-CBD by 48% and 34%.(3) The manufacturer of oral CBD solution states that these changes are not clinically meaningful.(5) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(6)

Strong Cyp3a4 Inhibitors/Cinacalcet

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of cinacalcet by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in elevated levels of and toxicity from cinacalcet.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: PTH and serum calcium concentrations should be closely monitored if a strong CYP3A4 inhibitor is initiated or discontinued in patients receiving cinacalcet therapy. The dosage of cinacalcet may need to be adjusted.(1)

DISCUSSION: In a study, administration of cinacalcet on day 5 of a seven day course of ketoconazole (200 mg twice daily) increased cinacalcet area-under-curve (AUC) and maximum concentration (Cmax) by 2.3-fold and by 2.2-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib and voriconazole.(2)

Strong Cyp3a4 Inhibitors/Clonazepam

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of clonazepam by CYP3A4.(1,2)

CLINICAL EFFECTS: The concurrent administration of strong CYP3A4 inhibitors with clonazepam may result in elevated levels of and increased clinical effects from clonazepam. Toxic effects of increased levels of benzodiazepines include profound sedation, respiratory depression, coma, and/or death.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with strong CYP3A4 inhibitors should be monitored for increased clonazepam effects. The dosage of clonazepam may need to be decreased or discontinued.(1,2) If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: In a study in 98 patients with schizophrenia or bipolar disorder, the expression of CYP3A4 was found to be the major determinant of clonazepam plasma concentrations normalized by the dose and bodyweight (1263 +/- 482.9 and 558.5 +/- 202.4 ng/mL per mg/kg bodyweight in low and normal expressers, respectively, p<0.0001).(2) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone, nefazodone, paritaprevir, posaconazole, relacorilant, ribociclib, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(3,4)

Strong Cyp3a4 Inhibitors/Daraxonrasib (<=150 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Daraxonrasib is a substrate of CYP3A4. Strong CYP3A4 inhibitors may inhibit the metabolism of daraxonrasib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase the levels and toxicities of daraxonrasib, including dermatologic toxicity, stomatitis, GI perforation, and interstitial lung disease/pneumonitis.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: For patients taking agents that are strong CYP3A4 inhibitors, reduce the dose of daraxonrasib to 150 mg once daily. If the inhibitor is discontinued, resume the previous dose of daraxonrasib after 5 days or 3 to 5 half-lives of the inhibitor, whichever is longer.(1)

DISCUSSION: In a pharmacokinetic model, voriconazole 200 mg twice daily (a strong CYP3A inhibitor) increased the area under curve (AUC) of daraxonrasib by 2-fold.(1) Strong CYP3A4 inhibitors include: adagrasib, boceprevir, ceritinib, ensitrelvir, idelalisib, mibefradil, nefazodone, nelfinavir, relacorilant, ribociclib, troleandomycin, and voriconazole.(2-3)

Strong Cyp3a4 Inhibitors/Eszopiclone; Zopiclone; Zolpidem

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 impair the metabolism of eszopiclone, zopiclone, and zolpidem.(1-5,8)

CLINICAL EFFECTS: Concurrent use of eszopiclone, zopiclone, or zolpidem with a strong CYP3A4 inhibitor may result in an increase in hypnotic levels and clinical effects, as well as toxic effects such as profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: Systemic exposure may also be increased in patients with severe hepatic impairment. Elderly and debilitated patients are more likely to have impaired motor or cognitive performance when treated with hypnotics.

PATIENT MANAGEMENT: The US manufacturer of eszopiclone states the total dose should not exceed 2 mg in patients taking strong CYP3A4 inhibitors.(1) The Canadian manufacturer of zopiclone states the prescribed dose should not exceed 5 mg in patients treated with strong CYP3A4 inhibitors.(8) Patients should be counseled that concurrent use of a strong CYP3A4 inhibitor with eszopiclone, zopiclone, or zolpidem may result in an increase in side effects such as confusion, memory loss, sleep-walking or sleep-driving behaviors, or daytime drowsiness.

DISCUSSION: Concurrent administration of ketoconazole (400 mg daily for 5 days) increased the area-under-curve (AUC) of eszopiclone by 2.2-fold. Eszopiclone maximum concentration (Cmax) and half-life were increased 1.4-fold and 1.3-fold, respectively.(1) An in vitro study in human liver microsomes found that ketoconazole inhibited the metabolism of zopiclone.(2) In a study in 10 subjects, itraconazole (200 mg daily for 4 days) increased the AUC, Cmax, and half-life of zopiclone by 73%, 29%, and 40%, respectively. However, there were no significant differences in clinical effects when compared to placebo.(6) In a randomized, double-blind, cross-over study in 12 healthy subjects, concurrent use of ketoconazole (200 mg twice daily) and zolpidem (5 mg) decreased zolpidem clearance by 64% and increased its AUC 1.83-fold. In the same study, concurrent use of itraconazole and fluconazole with zolpidem had no clinically significant effects on zolpidem pharmacokinetics.(3,5) In a randomized, cross-over study in 10 healthy subjects, concurrent use of itraconazole (200 mg daily for 4 days) with a single dose of zolpidem (10 mg on day 4) increased the AUC of zolpidem by 34% when compared to placebo. However, there were no significant differences in clinical effects when compared to placebo.(5,7) Strong CYP3A4 inhibitors linked to this monograph are: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, lonafarnib, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, ritonavir, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.

Strong Cyp3a4 Inhibitors/Fostamatinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of R406, the active metabolite of fostamatinib.(1)

CLINICAL EFFECTS: Concurrent administration of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from R406, the major metabolite of fostamatinib.(1) Elevated levels of fostamatinib may increase the risk of hepatotoxicity, hypertension, diarrhea, and neutropenia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Recommendations for concurrent use of fostamatinib with strong CYP3A4 inhibitors differ in different regions. The US manufacturer of fostamatinib advises monitoring for fostamatinib toxicities that may require a dose reduction.(1) The UK manufacturer of fostamatinib states that a 50% dose reduction of fostamatinib may be warranted for short-term use of a strong CYP3A4 inhibitor (e.g., antifungals, antibacterials). After discontinuation of the CYP3A4 inhibitor for 2-3 days, the original dose of fostamatinib that was used prior to the start of the inhibitor should be resumed. Monitor the patient for fostamatinib toxicities that may require dose reduction.(2)

DISCUSSION: In a study of 8 healthy males, ketoconazole (200 mg twice daily), a strong CYP3A4 inhibitor, increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose fostamatinib 80 mg by 102% and 37%, respectively.(3) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3)

Strong Cyp3a4 Inhibitors/Ibrexafungerp

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of ibrexafungerp.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from ibrexafungerp.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The prescribing information for ibrexafungerp advises that patients on concomitant strong CYP3A4 inhibitors should receive a reduced ibrexafungerp dose of 150 mg approximately 12 hours apart, in the morning and in the evening, for one day.(1)

DISCUSSION: In a study of healthy subjects, ketoconazole (400 mg once daily for 15 days, a strong CYP3A4 inhibitor), increased the ibrexafungerp area-under-curve (AUC) by 5.8-fold and maximum concentration (Cmax) by 2.5-fold.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Levomilnacipran (<= 80 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of levomilnacipran.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in elevated levels and increased effects of levomilnacipran.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The dose of levomilnacipran should not exceed 80 mg daily in patients taking strong inhibitors of CYP3A4.(1)

DISCUSSION: Pretreatment with ketoconazole, a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of levomilnacipran between 1.25 and 1.50-fold and between 1.50 and 1.75-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib and voriconazole.(1-3)

Strong Cyp3a4 Inhibitors/Nerandomilast

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Agents that are strong CYP3A4 inhibitors may inhibit the metabolism of nerandomilast.(1)

CLINICAL EFFECTS: The coadministration of nerandomilast with strong CYP3A4 inhibitors may increase nerandomilast systemic exposure and may result in increased adverse reactions.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of nerandomilast states the dose of nerandomilast should be reduced to 9 mg twice daily with concurrent use of strong CYP3A4 inhibitors.(1)

DISCUSSION: In healthy subjects, concurrent use of nerandomilast with itraconazole, a strong CYP3A4 inhibitor, (200 mg once daily for 4 days) increased the area-under-curve (AUC) and concentration maximum (Cmax) of nerandomilast by 2.2-fold and 1.3-fold, respectively.(1) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Oliceridine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Oliceridine is metabolized equally by CYP2D6 and CYP3A4. Oliceridine metabolism may be inhibited by inhibitors of CYP2D6 or CYP3A4.(1)

CLINICAL EFFECTS: The concurrent administration of a strong or moderate CYP2D6 or strong or moderate CYP3A4 inhibitor may result in elevated levels of and toxicity from oliceridine including profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Patients with CYP2D6 poor metabolizer phenotype may be affected to a greater extent by CYP3A4 inhibitors. Inhibition of both CYP2D6 and CYP3A4 pathways may result in a greater increase in the levels of and toxcity of oliceridine.(1)

PATIENT MANAGEMENT: Caution should be used when administering oliceridine to patients taking strong or moderate inhibitors of CYP2D6 or CYP3A4. Dosage adjustments should be made if warranted. Closely monitor these patients for respiratory depression and sedation at frequent intervals and evaluate subsequent doses based on response. If concomitant use of a strong or moderate CYP2D6 or CYP3A4 inhibitor is necessary, less frequent dosing of oliceridine may be required. If a strong or moderate CYP2D6 or CYP3A4 inhibitor is discontinued, increase of the oliceridine dosage may be necessary. Monitor for signs of opioid withdrawal. Patients receiving concurrent therapy with both a strong or moderate CYP3A4 inhibitor and CYP2D6 inhibitors may be at greater risk of adverse effects. Patient who are CYP2D6 normal metabolizers taking a CYP2D6 inhibitor and a strong CYP3A4 inhibitor may require less frequent dosing of oliceridine.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(2) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(3)

DISCUSSION: In a study of four healthy subjects who are CYP2D6 poor metabolizers, itraconazole (200 mg daily for 5 days) increased the area-under-curve (AUC) of single-dose oliceridine (0.25 mg) by 80%.(1) In a study of subjects who were not CYP2D6 poor metabolizers, ketoconazole (200 mg for 2 doses 10 hours apart) did not affect the pharmacokinetics of oliceridine.(1) Strong CYP3A4 inhibitors include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(4)

Strong Cyp3a4 Inhibitors/Repaglinide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of repaglinide by CYP3A4.(1-3)

CLINICAL EFFECTS: Concurrent use of repaglinide and strong CYP3A4 inhibitors may result in elevated levels of and effects from repaglinide, including hypoglycemia.

PREDISPOSING FACTORS: Concurrent administration with a CYP2C8 inhibitor.

PATIENT MANAGEMENT: Patients maintained on repaglinide should be closely monitored if a strong CYP3A4 inhibitor is added to or withdrawn from concurrent therapy. A dosage adjustment of the antidiabetic agent may be required during therapy with a strong CYP3A4 inhibitor.

DISCUSSION: In a study, concurrent administration of itraconazole (100 mg twice daily for 3 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of repaglinide (0.25 mg) by 1.4 fold and 1.5 fold, respectively. Concurrent administration of itraconazole (100 mg twice daily for 3 days) and gemfibrozil (600 mg twice daily for 3 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of repaglinide (0.25 mg) by 19 fold and 2.8 fold, respectively.(1,5) In a randomized, double-blind, crossover study in nine healthy subjects, clarithromycin (250 mg daily for 5 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of repaglinide (0.25 mg) by 40% and 67%, respectively. The AUC and Cmax of insulin increased by 51% and 61%, respectively.(2) In a randomized, cross-over study of 12 healthy volunteers, telithromycin (800 mg for 3 days) raised the mean Cmax and AUC of repaglinide (0.25 mg single dose on day 3) to 138% and 177% respectively. Telithromycin did not effect the elimination half-life of repaglinide. Telithromycin increased the urinary excretion of unchanged repaglinide to 229%. The renal clearance of repaglinide was increased by telithromycin to 138%. Telithromycin also lowered the Cmax of blood glucose by 10% and mean concentration of blood glucose by as much as 12% after repaglinide intake.(3) Severe hypoglycemia has been reported in patients following the addition of clarithromycin to repaglinide therapy.(4)

Strong Cyp3a4 Inhibitors/Ruxolitinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of ruxolitinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from ruxolitinib, including thrombocytopenia, risk of infection, non-melanoma skin cancer, lipid elevations.(1)

PREDISPOSING FACTORS: In patients taking ruxolitinib, this interaction may be more severe in patients with a low platelet count.(1)

PATIENT MANAGEMENT: Reduce the dosage of ruxolitinib when coadministered with strong CYP3A4 inhibitors. Dose modifications of ruxolitinib in patients on concomitant strong CYP3A4 inhibitors depend on the indication. For myelofibrosis, starting doses of ruxolitinib therapy in patients concurrently taking strong CYP3A4 inhibitors is based on platelet count: -In patients with a platelet count greater than or equal to 100 X 10x9/L who are receiving a strong inhibitor of CYP3A4, the recommended starting dose of ruxolitinib is 10 mg twice daily or ruxolitinib XR 22 mg once daily. -In patients with a platelet count greater than 50 X 10x9/L to less than 100 X 10x9/L who are receiving a strong inhibitor of CYP3A4, the recommended starting dose of ruxolitinib is 5 mg once daily. Do not use ruxolitinib XR. For polycythemia vera, the starting dose of ruxolitinib in patients concurrently taking a strong CYP3A4 inhibitor is 5 mg twice daily or ruxolitinib XR 11 mg once daily. In patients with a diagnosis of myelofibrosis or polycythemia vera who are stabilized on ruxolitinib doses of 10 mg twice daily or more or on ruxolitinib XR doses of 22 mg once daily or more, and in whom a strong CYP3A4 inhibitor is initiated, reduce the dose of ruxolitinib by 50% (rounded up to the closest available tablet strength). In patients with a diagnosis of myelofibrosis or polycythemia vera who are stabilized on ruxolitinib doses of 5 mg twice daily in whom a strong CYP3A4 inhibitor is initiated, reduce the dose of ruxolitinib to 5 mg once daily. Do not use ruxolitinib XR. In patients with a diagnosis of myelofibrosis or polycythemia vera stabilized on ruxolitinib doses of 5 mg once daily or ruxolitinib XR doses of 11 mg once daily, avoid the use of strong CYP3A4 inhibitors or interrupt ruxolitinib therapy for the duration of the CYP3A4 inhibitor treatment. In patients with a diagnosis of acute or chronic graft-versus-host disease, no dose adjustment is recommended for concurrent use of strong CYP3A4 inhibitors in patients on ruxolitinib. It is recommended to increase the frequency of blood count monitoring when ruxolitinib is used with strong CYP3A4 inhibitors for acute or chronic graft-versus-host disease. The dose should be adjusted based on monitoring of safety and efficacy.(1)

DISCUSSION: In healthy subjects, ketoconazole (200 mg twice daily for 4 days) increased the concentration maximum (Cmax), area-under-curve (AUC), and half-life of a single dose of ruxolitinib (10 mg) by 33%, 91%, and 62%, respectively. There was also a corresponding increase in pSTAT3 inhibition, a pharmacodynamic marker for ruxolitinib.(1) In healthy subjects, erythromycin (a moderate inhibitor of CYP3A4, 500 mg twice daily for 4 days) increased the Cmax and AUC of a single dose of ruxolitinib (10 mg) by 8% and 27%, respectively. Therefore, no dosage adjustment is recommended with moderate or mild inhibitors of CYP3A4.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(2,3)

Strong Cyp3a4 Inhibitors/Slt Low Strength Antimuscarinics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of darifenacin(1) and fesoterodine.(2)

CLINICAL EFFECTS: The concurrent administration of a strong inhibitor of CYP3A4 may result in elevated levels of and signs of toxicity from darifenacin(1) and fesoterodine.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of darifenacin states that the daily dose of darifenacin should not exceed 7.5 mg in patients receiving potent CYP3A4 inhibitors.(1) The US manufacturer of fesoterodine states that the daily dose of fesoterodine should not exceed 4 mg in adult patients receiving potent CYP3A4 inhibitors. In pediatric patients, the daily dose of fesoterodine taking strong CYP3A4 inhibitors should be reduced to 4 mg in patients weighing greater than 35 kilograms. Use of fesoterodine in pediatric patients weighing greater than 25 kilograms and up to 35 kilograms is not recommended.(2)

DISCUSSION: In a study in 10 extensive CYP2D6 metabolizers and 1 poor CYP2D6 metabolizer, concurrent administration of ketoconazole (400 mg) increased the area-under-curve (AUC) and maximum concentration (Cmax) of darifenacin (7.5 mg daily) by 3.9-fold and 4.6-fold, respectively, in extensive metabolizers and by 12.9-fold and 12-fold, respectively, in the poor metabolizer, compared to historical controls. The concurrent administration of ketoconazole (400 mg) and darifenacin (15 mg daily) increased darifenacin AUC and Cmax by 11.5-fold and 10.73-fold, respectively, in extensive metabolizers and by 4.9-fold and 4.9-fold, respectively, in the poor metabolizer, compared to historical controls.(1) Concurrent administration of darifenacin (30 mg daily) and erythromycin, a moderate CYP3A4 inhibitor, increased darifenacin AUC and Cmax by 128% and 95%, respectively. Administration of darifenacin (30 mg daily) and fluconazole, another moderate CYP3A4 inhibitor, increased darifenacin AUC and Cmax by 84% and 88%, respectively. No dosage adjustment is recommended during concurrent therapy with moderate inhibitors of CYP3A4.(1) In a study, co-administration of ketoconazole (200 mg twice a day) increased the Cmax and AUC of the active metabolite of fesoterodine 2.0 and 2.3-fold in CYP2D6 extensive metabolizers and 2.1 and 2.5-fold in CYP2D6 poor metabolizers, respectively. Fesoterodine Cmax and AUC were 4.5-fold and 5.7-fold higher in subjects who were CYP2D6 poor metabolizers and taking ketoconazole when compared to extensive CYP2D6 metabolizers not taking ketoconazole.(2) In another study, ketoconazole (200 mg daily) increased the Cmax and AUC of the active metabolite of fesoterodine 2.2-fold in CYP2D6 extensive metabolizers and 1.5-fold and 1.9-fold in CYP2D6 poor metabolizers, respectively.(1,2) Fesoterodine Cmax and AUC were 3.4-fold and 4.2-fold higher in subjects who were CYP2D6 poor metabolizers and taking ketoconazole when compared to extensive CYP2D6 metabolizers not taking ketoconazole.(2) Based on a controlled randomized study in 28 healthy adults, oral fluconazole (200 mg daily) taken with oral fesoterodine (8 mg daily) was generally well tolerated in patients. A slightly non-clinically significant rise in plasma fesoterodine levels did occur. No clinically significant side effects were reported. The most common side effects reported by patients include: dizziness, blurred vision and abdominal distension when fluconazole was taken with fesoterodine.(3) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(4)

Strong Cyp3a4 Inhibitors/Solifenacin (<= 5 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of solifenacin.(1-3)

CLINICAL EFFECTS: The concurrent administration of a strong inhibitor of CYP3A4 may result in elevated levels of and signs of toxicity from solifenacin.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US and Swedish manufacturers of solifenacin state the daily dose should be limited to 5 mg in adults and should not exceed the starting dose in children and adolescents when administered with strong CYP3A4 inhibitors. The starting dose of solifenacin is 2 mg for patients weighing up to 15 kg, 3 mg for patients over 15 kg to 45 kg, 4 mg for patients over 45 kg to 60 kg, and 5 mg for patients over 60 kg.(1,2) The Swedish manufacturer of the combination product of tamsulosin-solifenacin states that the daily dose of solifenacin should not exceed 6 mg in patients receiving potent CYP3A4 inhibitors.(3)

DISCUSSION: Concurrent use of ketoconazole (400 mg daily for 21 days) increased the Cmax and AUC of solifenacin (10 mg) by 1.5-fold and 2.7-fold,respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(4)

Strong Cyp3a4 Inhibitors/Tofacitinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of tofacitinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from tofacitinib, including serious infections, thrombosis, gastrointestinal perforation, neutropenia, anemia, elevated liver enzymes, or lipid elevations.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: In patients taking a strong CYP3A4 inhibitor, the starting dose of tofacitinib should be reduced as follows: - Xeljanz for rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: reduce to 5 mg once daily. - Xeljanz XR for rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: switch to Xeljanz 5 mg once daily. - Xeljanz for ulcerative colitis: - Induction: 5 mg twice daily for 8 weeks. If needed continue for maximum of 16 weeks. - Maintenance: 5 mg once daily. May consider 5 mg twice daily if loss of response. - Xeljanz XR for ulcerative colitis: - Induction: 11 mg once daily for 8 weeks. If needed continue for maximum of 16 weeks. - Maintenance: Not recommended. Switch to Xeljanz and follow strong CYP3A4 inhibitor recommendation. - Xeljanz oral solution for polyarticular course juvenile idiopathic arthritis (pcJIA) or psoriatic arthritis (patients 2 years or older): - >= 10 kg to <20 kg: 3.2 mg once daily - >= 20 kg to <40 kg: 4 mg once daily - >= 40 kg: 5 mg once daily (1)(1) For concurrent treatment with nirmatrelvir-ritonavir, dose adjustments should be considered throughout the nirmatrelvir-ritonavir treatment and for 3 days following the last dose of nirmatrelvir-ritonavir.(2)

DISCUSSION: In a study, administration of ketoconazole, increased the area-under-curve (AUC) of tofacitinib by more than 2-fold.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, indinavir, itraconazole, josamycin, ketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or voriconazole.(3,4)

Strong Cyp3a4 Inhibitors/Upadacitinib (<30 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of upadacitinib.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from upadacitinib, including neutropenia, serious infections, thrombosis, myocardial infarction, stroke, GI perforation, and transaminitis.(1,2) Concurrent use of upadacitinib with immunosuppressives or immunomodulators, including idelalisib, lonafarnib, and ribociclib, may result in an increased risk of serious infections.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of upadacitinib states that upadacitinib requires a dose adjustment with concurrent strong CYP3A4 inhibitors.(1) If upadacitinib is being used for atopic dermatitis concurrently with strong CYP3A4 inhibitors, limit the upadacitinib dose to 15 mg once daily. Coadministration of upadacitinib 30 mg once daily with strong CYP3A4 inhibitors is not recommended.(1) If upadacitinib is being used for ulcerative colitis concurrently with strong CYP3A4 inhibitors, limit the upadacitinib dose to 30 mg once daily for 8 weeks during the induction phase and then 15 mg once daily in the maintenance phase.(1) If upadacitinib is being used for Crohn's disease concurrently with strong CYP3A4 inhibitors, limit the upadacitinib dose to 30 mg once daily for 12 weeks during the induction phase and then 15 mg once daily in the maintenance phase.(1) If upadacitinib is being used for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, polyarticular juvenile idiopathic arthritis, or giant cell arteritis, no dose adjustment is needed with strong CYP3A4 inhibitors. Monitor closely for adverse reactions.(1) Concurrent use of upadacitinib 15 mg with strong CYP3A4 inhibitors should be approached with caution. Patients should be closely monitored for adverse reactions.(1,2) For concurrent treatment with nirmatrelvir-ritonavir, dose adjustments should be considered throughout the nirmatrelvir-ritonavir treatment and for 3 days following the last dose of nirmatrelvir-ritonavir.(3)

DISCUSSION: In a study of 11 subjects, ketoconazole (400 mg daily for 6 days, a strong CYP3A4 inhibitor) increased the maximum concentration (Cmax) and area-under-curve (AUC) of single-dose upadacitinib 3 mg by 1.7-fold and 1.75-fold, respectively.(1,2) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(4,5)

Strong Cyp3a4 Inhibitors/Valbenazine (<= 40 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Agents which inhibit the CYP3A4 enzyme may inhibit the metabolism of valbenazine.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase systemic exposure and the risk for valbenazine toxicities such as QT prolongation.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Concurrent use of strong CYP2D6 inhibitors may further increase levels of valbenazine.(1)

PATIENT MANAGEMENT: Reduce the valbenazine dose to 40 mg once daily when valbenazine is coadministered with a strong CYP3A4 inhibitor.(1) During concomitant therapy with a strong CYP3A4 inhibitor, monitor patients closely for prolongation of the QT interval. Obtain serum calcium, magnesium, and potassium levels and monitor ECG at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a drug interaction study in healthy subjects, coadministration of ketoconazole with valbenazine increased valbenazine maximum concentration (Cmax) and area-under-the-curve (AUC) by 2 and 1.5-fold, respectively. Cmax and AUC for the active metabolite of valbenazine (alpha-HTBZ) increased by approximately 2 and 1.6-fold, respectively. Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3)

Strong Cyp3a4 Inhibitors/Vamorolone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of vamorolone which is metabolized by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in increased systemic exposure to and effects from vamorolone, including Cushing's syndrome and adrenal suppression.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If vamorolone is used concurrently with a strong CYP3A4 inhibitor, reduce the dose of vamorolone to 4 mg/kg once daily. No dose adjustment is needed with moderate or weak CYP3A4 inhibitors.(1)

DISCUSSION: In a study, multiple doses of itraconazole (a strong CYP3A4 inhibitor) increased vamorolone concentration maximum (Cmax) and area-under-curve (AUC) by 8% and 44%, respectively.(1) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2)

Strong Cyp3a4 Inhibitors/Vanzacaftor-Tezacaftor-Deutivacafto

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of vanzacaftor-tezacaftor-deutivacaftor. Vanzacaftor, tezacaftor, and deutivacaftor are CYP3A4 substrates.(1)

CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from vanzacaftor-tezacaftor-deutivacaftor, such as hepatotoxicity.(1)

PREDISPOSING FACTORS: This interaction may be more severe in patients with hepatic impairment.(1)

PATIENT MANAGEMENT: The US manufacturer of vanzacaftor-tezacaftor-deutivacaftor states that concurrent use with strong CYP3A4 inhibitors requires a dose adjustment. If concurrent use is warranted, the following dose adjustments are recommended: -For individuals 12 years and older AND any weight OR children 6 to less than 12 years old AND weight greater than or equal to 40 kg - one tablet of vanzacaftor 10mg/tezacaftor 50 mg/deutivacaftor 125 mg once a week; -For children 6 to less than 12 years old AND weighing less than 40 kg - two tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg once a week.(1)

DISCUSSION: Concurrent administration with itraconazole (200 mg every 12 hours on Day 1, followed by 200 mg daily, a strong inhibitor of CYP3A4) with tezacaftor (25 mg daily)-ivacaftor (50 mg daily) increased tezacaftor area-under-curve (AUC) and concentration maximum (Cmax) by 4-fold and 2.83-fold, respectively.(1) Concurrent administration with itraconazole (200 mg daily, a strong inhibitor of CYP3A4) with single-dose elexacaftor 20 mg-tezacaftor 50 mg-deutivacaftor 50 mg increased tezacaftor AUC and Cmax by 4.51-fold and 1.48-fold and deutivacaftor AUC and Cmax by 11.1-fold and 1.96-fold.(1) Concurrent administration with itraconazole (200 mg daily, a strong inhibitor of CYP3A4) with vanzacaftor (5 mg single dose) increased vanzacaftor AUC and Cmax by 6.37-fold and 1.55-fold, respectively.(1) Concurrent administration with fluconazole (200 mg daily, a moderate inhibitor of CYP3A4) with vanzacaftor (20 mg daily)-tezacaftor (100 mg daily)-deutivacaftor (250 mg daily) is predicted to increase vanzacaftor AUC and Cmax by 2.55-fold and 2.48-fold and deutivacaftor by 3.13-fold and 2.27-fold, respectively.(1) Concurrent administration with erythromycin (500 mg four times daily, a moderate inhibitor of CYP3A4) with vanzacaftor (20 mg daily)-tezacaftor (100 mg daily)-deutivacaftor (250 mg daily) is predicted to increase vanzacaftor AUC and Cmax by 3.29-fold and 3.19-fold and deutivacaftor by 4.13-fold and 2.89-fold, respectively.(1) Concurrent administration with verapamil (80 mg three times daily, a moderate inhibitor of CYP3A4) with vanzacaftor (20 mg daily)-tezacaftor (100 mg daily)-deutivacaftor (250 mg daily) is predicted to increase vanzacaftor AUC and Cmax by 3.93-fold and 3.8-fold and deutivacaftor by 5.11-fold and 3.43-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2-4)

Strong Cyp3a4 Inhibitors/Vardenafil (<=2.5 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of vardenafil.(1-3)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in increased levels, clinical effects, and side effects of vardenafil, including hypotension, visual changes, and sustained erections.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of vardenafil states that a maximum dose of 2.5 mg of vardenafil every 24 hours should not be exceeded in patients taking strong CYP3A4 inhibitors.(1) Note that other countries have different warnings. The Canadian(3) and UK(3) manufacturer of vardenafil state that vardenafil should not exceed 5 mg in patients taking clarithromycin. The UK manufacturer of vardenafil states that the concurrent use of vardenafil with strong CYP3A4 inhibitors should be avoided.(3) The US manufacturer of cobicistat states that a maximum dose of 2.5 mg of vardenafil every 72 hours should not be exceeded in patients taking cobicistat.(4)

DISCUSSION: Concurrent use of ketoconazole (200 mg, a strong inhibitor of CYP3A4) with vardenafil (5 mg) increased the vardenafil area-under-curve (AUC) and maximum concentration (Cmax) by 10-fold and 4-fold, respectively.(1-3) Concurrent administration of erythromycin (500 mg three times daily, a moderate inhibitor of CYP3A4) with vardenafil (5 mg) increased the AUC and Cmax of vardenafil by 4-fold and 3-fold, respectively.(1-3)

Strong Cyp3a4 Inhibitors/Vilazodone (<= 20 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of vilazodone.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in elevated levels and increased effects of vilazodone.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The dose of vilazodone should be reduced to 20 mg daily when coadministered with strong inhibitors of CYP3A4.(1)

DISCUSSION: Ketoconazole increased vilazodone concentrations by 50%.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(1-3)

Strong Cyp3a4 Inhibitors/Zanubrutinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of zanubrutinib.(1)

CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from zanubrutinib.(1)

PREDISPOSING FACTORS: Patients with severe hepatic impairment (Child-Pugh class C) have elevated zanubrutinib plasma concentrations and may be more susceptible to the effects of this interaction.(1)

PATIENT MANAGEMENT: The dosage of zanubrutinib should be reduced when coadministered with strong CYP3A4 inhibitors. Interrupt the dose as recommended by prescribing information for adverse reactions.(1) The US manufacturer of zanubrutinib states that when it is coadministered with: -Clarithromycin 250 mg twice daily, limit the dose of zanubrutinib to 80 mg twice daily. -Clarithromycin 500 mg twice daily, limit the dose of zanubrutinib to 80 mg once daily. -Posaconazole suspension 100 mg once daily, limit the dose of zanubrutinib to 80 mg twice daily. -Posaconazole suspension at a dosage higher than 100 mg once daily, or posaconazole delayed-release tablets 300 mg once daily, or posaconazole intravenous 300 mg once daily, limit the dose of zanubrutinib to 80 mg once daily. -Other CYP3A4 inhibitors, limit the dose of zanubrutinib to 80 mg once daily.(1) The Canadian manufacturer of zanubrutinib states that the dosage of zanubrutinib should be reduced to 80 mg once daily when coadministered with all strong CYP3A4 inhibitors.(2)

DISCUSSION: Co-administration with itraconazole 200 mg once daily, a strong CYP3A4 inhibitor, increased zanubrutinib concentration maximum (Cmax) and area-under-curve (AUC) by 157% and 278%, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(3-5)

Strong Cyp3a4 Inhibitors/Zilurgisertib (<=50 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Zilurgisertib is primarily metabolized by CYP3A4. Strong CYP3A4 inhibitors may inhibit the metabolism of zilurgisertib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase the levels and toxicities of zilurgisertib including headaches, arthralgias, and upper respiratory infections.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When used concomitantly with a strong CYP3A4 inhibitor, reduce zilurgisertib dose to 50 mg once daily.(1)

DISCUSSION: In a clinical study, itraconazole increased zilurgisertib area-under-curve (AUC) by 2.13-fold and maximum concentration (Cmax) by 1.28-fold.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2-3)

Strong Cyp3a4 Inhibitors/Zuranolone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of zuranolone.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase the levels and effects of zuranolone, including somnolence and CNS depression.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US prescribing information recommends dose adjustment if zuranolone is to be given with a strong CYP3A4 inhibitor. Reduce the zuranolone dose to 30 mg orally once daily in the evening for 14 days when used concurrently with strong CYP3A4 inhibitors.(1)

DISCUSSION: Coadministration of zuranolone with itraconazole (a strong CYP3A4 inhibitor) increased the maximum concentration (Cmax) by 25% and area-under-curve (AUC) by 62%.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2,3)

Strong Cyp3a4 Inhibitors; Protease Inhibitors/Brexpiprazole

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of brexpiprazole.(1)

CLINICAL EFFECTS: Concurrent administration of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from brexpiprazole.(1)

PREDISPOSING FACTORS: With brexpiprazole(1) this interaction is expected to be more severe in patients who are CYP2D6 poor metabolizers, or who receive concomitant treatment with a strong CYP2D6 inhibitor (e.g. bupropion, fluoxetine, paroxetine, quinidine) in addition to treatment with a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are expected to increase brexpiprazole levels 4.8-fold in poor CYP2D6 metabolizers. Concurrent use of strong CYP2D6 and CYP3A4 inhibitors is expected to increase brexpiprazole levels 5.1-fold in extensive metabolizers of CYP2D6. With brexpiprazole, the interaction may also be more severe in patients taking moderate CYP2D6 inhibitors.(1)

PATIENT MANAGEMENT: The US manufacturer of brexpiprazole recommends the following dose adjustments for patients who are receiving a strong CYP3A4 inhibitor: - in patients taking a strong CYP3A4 inhibitor without a strong or moderate CYP2D6 inhibitor, administer half the usual dosage of brexpiprazole. - in patients taking a strong CYP3A4 inhibitor who are poor CYP2D6 metabolizers or are receiving a strong or moderate inhibitor of CYP2D6, decrease the dose to one-fourth the usual dose.(1) The dose of brexpiprazole should be adjusted to its original level if the CYP3A4 inhibitor is discontinued.(1) The US Department of Health and Human Services HIV guidelines recommend that patients taking any ritonavir- or cobicistat-boosted protease inhibitor have their dose of brexpiprazole decreased to 25% of the usual dose. Patients on unboosted atazanavir should have their dose of brexpiprazole decreased to 50% of the usual dose.(2)

DISCUSSION: Coadministration of ketoconazole increased the AUC of brexpiprazole approximately 2-fold.(1) CYP3A4 inhibitors linked to this monograph include: adagrasib, amprenavir, atazanavir, boceprevir, clarithromycin, cobicistat, darunavir, ensitrelvir, fosamprenavir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(3)

Strong Or Mod 3A4 Inh; Dual 3A4 And 1A2 Inhibit/Roflumilast

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Agents that are either strong or moderate CYP3A4 inhibitors or dual inhibitors of CYP1A2 and CYP3A4 may inhibit the metabolism of roflumilast.(1)

CLINICAL EFFECTS: The coadministration of roflumilast with strong or moderate CYP3A4 inhibitors or dual inhibitors of CY3A4 and CYP1A2 may increase roflumilast systemic exposure and may result in increased adverse reactions.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of roflumilast states concurrent use with CYP3A4 inhibitors or dual inhibitors of CYP3A4 and CYP1A2 should be approached with caution and the risk should be weighed carefully against the benefit. Consider alternatives with no or minimal enzyme inhibition.(1)

DISCUSSION: In healthy subjects, concurrent use of roflumilast (500 mcg single dose) with erythromycin, a moderate CYP3A4 inhibitor, (500 mg three times daily for 15 days) increased the area-under-curve (AUC) and concentration maximum (Cmax) of roflumilast by 70% and 40%, respectively, and decreased the AUC and Cmax of roflumilast N-oxide by 4% and 34%, respectively.(1,2) In healthy subjects, concurrent use of roflumilast (500 mcg single dose) with ketoconazole, a strong CYP3A4 inhibitor, (200 mg twice daily for 13 days) increased the AUC and Cmax of roflumilast by 99% and 23%, respectively, and decreased the AUC and Cmax of roflumilast N-oxide by 3% and 38%, respectively.(1) In healthy subjects, concurrent use of roflumilast (500 mcg single dose) with fluvoxamine, a dual CYP3A4 and CYP1A2 inhibitor, (50 mg daily for 14 days) increased the AUC and Cmax of roflumilast by 156% and 12%, respectively, and decreased the AUC and Cmax of roflumilast N-oxide by 52% and 210%, respectively.(1) In healthy subjects, concurrent use of roflumilast (500 mcg single dose) with cimetidine, a dual CYP3A4 and CYP1A2 inhibitor, (400 mg twice daily for 14 days) increased the AUC and Cmax of roflumilast by 85% and 46%, respectively, and increased the AUC and decreased Cmax of roflumilast N-oxide by 27% and 4%, respectively.(1) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, saquinavir, telaprevir, tipranavir, tucatinib, and voriconazole.(3,4) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, lefamulin (oral), lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, schisandra, stiripentol, tofisopam, treosulfan, and voxelotor.(3,4) Dual CYP3A4 and CYP1A2 inhibitors linked to this monograph include: belumosudil, cannabidiol, cimetidine, ciprofloxacin, fluvoxamine, glecaprevir/pibrentasvir, grapefruit, osilodrostat, piperine, ribociclib, rucaparib, simeprevir, telithromycin, troleandomycin, verapamil, and viloxazine.(3,4)

Strong&Mod 3A4 Inhib That Prolong Qt/Cilostazol (<=50Mg Bid)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong and moderate inhibitors of CYP3A4 may inhibit the metabolism of cilostazol at CYP3A4.(1) Both agents have been shown to prolong the QT interval.(1,2)

CLINICAL EFFECTS: The concurrent use of cilostazol and strong and moderate inhibitors of CYP3A4 may result in elevated levels of cilostazol, which may produce increased effects of cilostazol and adverse effects.(1) Concurrent use may also result in potentially life-threatening cardiac arrhythmias, including torsades de pointes(TdP).(2)

PREDISPOSING FACTORS: In general, the risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(1) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(1) This interaction may also be more severe in patients taking inhibitors of CYP2C19.(1)

PATIENT MANAGEMENT: The dose of cilostazol should be limited to 50 mg twice daily in patients receiving concurrent therapy with strong and moderate inhibitors of CYP3A4.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study in 16 healthy males, the administration of a single dose of cilostazol (10 mg) with erythromycin (500 mg every eight hours) increased the maximum concentration (Cmax) and area-under-curve (AUC) of cilostazol by 47% and 73%, respectively. The Cmax and AUC of 4'-trans-hydroxy-cilostazol were increased by 29% and 141%, respectively.(3) Analysis of population pharmacokinetics indicated that the concurrent administration of diltiazem with cilostazol increased cilostazol concentrations by 53%.(1) Concurrent administration of diltiazem and cilostazol decreased cilostazol clearance by 30%, increased the Cmax by 30%, and increased AUC by 40%. In a study, the administration of a single dose of cilostazol (10 mg) with erythromycin (500 mg every eight hours) increased the Cmax and AUC of cilostazol by 47% and 73%, respectively. The AUC of 4'-trans-hydroxy-cilostazol was increased by 141%.(1) In an vitro study in human liver microsomes, ketoconazole inhibited the metabolism of cilostazol.(4) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

*None.

• Congenital long QT syndrome
• Lactation
• Torsades de pointes

• Interstitial lung disease
• Pregnancy
• Prolonged QT interval

• Bradycardia
• Chronic heart failure
• Hypocalcemia
• Hypokalemia
• Hypomagnesemia

The most common adverse reactions (>=25%) in clinical trials of patients with NSCLC receiving adagrasib as a single agent include nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, renal impairment, edema, dyspnea, and decreased appetite.

The most common grade 3 or 4 laboratory abnormalities (>=2%) include decreased lymphocytes, decreased hemoglobin, increased ALT, increased AST, hypokalemia, hyponatremia, increased lipase, decreased leukocytes, decreased neutrophils, and increased alkaline phosphatase.

The most common adverse reactions (>=25%) in clinical trials of patients with colorectal cancer receiving adagrasib in combination with cetuximab include rash, nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, headache, dry skin, abdominal pain, decreased appetite, edema, anemia, and cough.

The most common grade 3 or 4 laboratory abnormalities (>=2%) include decreased lymphocytes, decreased potassium, decreased magnesium, decreased hemoglobin, increased AST, increased lipase, decreased albumin, and increased ALT.

More Frequent

• Anemia
• Drug-induced hepatitis
• Elevated serum lipase
• Hypokalemia
• Hypomagnesemia
• Hyponatremia
• Increased alkaline phosphatase
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Leukopenia
• Lymphopenia
• Neutropenic disorder

Less Frequent

• Acute respiratory failure
• Gastrointestinal hemorrhage
• Gastrointestinal obstruction
• Heart failure
• Hypoxia
• Interstitial lung disease
• Interstitial pneumonitis
• Pleural effusions
• Pneumonia
• Prolonged QT interval
• Sepsis

Rare or Very Rare

• Cerebrovascular accident
• Colitis
• Ileus
• Intestinal stenosis
• Pulmonary hemorrhage
• Pulmonary thromboembolism

More Frequent

• Abnormal hepatic function tests
• Acute abdominal pain
• Anorexia
• Diarrhea
• Dry skin
• Dyspnea
• Edema
• Fatigue
• Headache disorder
• Hypoalbuminemia
• Musculoskeletal pain
• Nausea
• Skin rash
• Vomiting

Less Frequent

• Altered mental status
• Constipation
• Cough
• Dehydration
• Dizziness
• Elevated serum amylase
• Fever
• Hypocalcemia
• Hypotension
• Muscle weakness
• Peripheral neuropathy

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Safety and efficacy of adagrasib have not been established in pediatric patients.

There are no available human data on the use of adagrasib during pregnancy. In animal reproduction studies, oral administration of adagrasib to pregnant rats and rabbits during organogenesis did not result in adverse developmental effects or embryofetal lethality at exposures below the human exposure at the recommended dosage of 600 mg twice daily.

It is unknown whether adagrasib (or its metabolites) is distributed into human milk or if the drug has any effect on milk production or the nursing infant.

Because of the potential for serious adverse reactions in nursing infants, advise women not to breast-feed during treatment with adagrasib and for 1 week after the last dose.

The manufacturer makes no specific dosage recommendations for geriatric patients.

In the KRYSTAL-1 study evaluating adagrasib in patients with locally advanced or metastatic KRAS G12C-mutated non-small cell lung cancer (NSCLC), 49% of patients who received adagrasib 600 mg orally twice daily were >=65 years of age and 13% were >=75 years of age. There were no overall differences in adagrasib efficacy or safety between geriatric and younger patients.

In patients with metastatic colorectal cancer who received adagrasib 600 mg orally twice daily in combination with cetuximab, 33% were >=65 years of age and 2.1% were >=75 years of age. There were no overall differences in efficacy or safety between geriatric and younger patients with combination therapy.