Tavneos (avacopan)
Complement Inhibitors Oral Capsule
Last reviewed · Source: First Databank (FDB) drug data
Overview
Avacopan is a complement 5a receptor (C5aR) antagonist that blocks C5a-mediated neutrophil activation and migration.
Avacopan is a selective C5aR antagonist. The pathogenesis of ANCA-associated vasculitis is not fully understood, but animal models suggest that neutrophils and the alternative complement system have a central role. The alternative complement pathway generates complement 5a (C5a), which amplifies the inflammatory response by recruiting and priming more neutrophils, creating an amplification loop for neutrophil activation.
This neutrophil amplification loop leads to the chronic inflammation, vasculitis, and organ damage of ANCA-associated vasculitis. Avacopan blocks the binding of C5a with C5aR, which inhibits neutrophil recruitment and activation. The exact mechanism that exerts the therapeutic effect in patients with ANCA-associated vasculitis is not well understood.
When avacopan is administered with a high-fat, high-calorie meal, the AUC and maximum plasma concentrations of avacopan increase by about 72 and 8%, respectively; the time to peak plasma concentrations is delayed to 6 hours (from 2 hours). Avacopan doses should be administered with food. Steady state is reached by 13 weeks; accumulation is about fourfold.
Avacopan is highly plasma protein bound (>99.9%). Avacopan is primarily metabolized by CYP3A4, which also forms the major circulating active metabolite, M1. The M1 metabolite exhibits approximately the same activity as the parent drug on C5aR.
Approximately 12% of the total drug-related materials present in plasma is the M1 metabolite. The estimated total apparent body clearance of avacopan is 16.3 L/hour. The mean elimination half-life is 97.6 hours and 55.6 hours for avacopan and the M1 metabolite, respectively, when administered with food.
Avacopan is primarily cleared via biliary excretion of its metabolites into the feces with 77 and 10% of the avacopan dose recovered in the feces and urine, respectively, mostly as metabolites of avacopan. Race (Asian, Black, white), sex, age (18 to 83 years of age), body weight (40.3 to 174 kg), or renal function (estimated glomerular filtration rate 14 to 170 mL/minute per 1.73 m2) do not alter the pharmacokinetics of avacopan or the M1 metabolite to a clinically relevant extent. Neither mild (Child-Pugh class A) nor moderate (Child-Pugh class B) hepatic impairment have a clinically relevant effect on the pharmacokinetics of avacopan or the M1 metabolite.
The manufacturer has no pharmacokinetic data for avacopan in patients with severe hepatic impairment (Child-Pugh class C).
USES: This medication is used to treat a certain type of blood vessel disease: anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis. It works by blocking the immune system from damaging the blood vessels.
Generic name: avacopan
Pronunciation: (A-va-KOE-pan)
Drug class: Complement Inhibitors
Therapeutic class: Analgesic, Anti-inflammatory or Antipyretic
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
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Indications
The following indications are listed for Tavneos:
- Granulomatosis With Polyangiitis
- Microscopic Polyangiitis
Also known as: Necrotizing Respiratory Granulomatosis, Pathergic Granulomatosis, Wegener Granulomatosis.
Dosing
If avacopan is used concomitantly with strong CYP3A4 inhibitors, the dosage of avacopan should be decreased to 30 mg once daily.
No dosing information is available for this tab.
| Drug label | Dosing type | Instructions |
|---|---|---|
| Tavneos 10 Mg Capsule | Maintenance | Take 3 capsules (30 mg) by oral route 2 times per day. |
No dosing information is available for this tab.
Drug interactions
Avacopan is primarily metabolized by and inhibits cytochrome P-450 (CYP) isoenzyme 3A4. Avacopan does not appear to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. The M1 metabolite may inhibit CYP2C9 and CYP3A4, may have a low potential to induce CYP3A4, CYP1A2, and CYP2B6, and does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C19, or CYP2D6. Avacopan does not appear to be a substrate of breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), organic anion transporting polypeptide 1B1 (OATP1B1), or OATP1B3; the M1 metabolite is a P-gp substrate, but is not a substrate of BCRP, OATP1B1, or OATP1B3. Neither avacopan nor the M1 metabolite meaningfully inhibit P-gp, BCRP, OATP1B1, OATP1B3, organic cation transporter 2 (OCT2), organic anion transporter 1 (OAT1), OAT3, multidrug and toxin extrusion transporter 1 (MATE1), or MATE2K.
Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
Avacopan/Simvastatin (>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: Avacopan is a moderate CYP3A4 inhibitor and may decrease the metabolism of simvastatin.(1)
CLINICAL EFFECTS: Concurrent avacopan may result in elevated levels of simvastatin, which may result in myopathy and rhabdomyolysis.(1)
PREDISPOSING FACTORS: The risk for myopathy or 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 myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.
PATIENT MANAGEMENT: When used concurrently with simvastatin, limit the dose of simvastatin to 10 mg daily (or 20 mg daily for patients who have previously tolerated simvastatin 80 mg daily for at least one year.)(1) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine.
DISCUSSION: In a study, avacopan 60 mg twice daily with food was administered for 7 days with simvastatin. Since it takes 13 weeks to reach steady state, this high dose of avacopan was used to achieve systemic levels similar to those achieved at steady state with a dose of 30 mg twice daily with food. Avacopan increased the area-under-curve (AUC) and maximum concentration (Cmax) of simvastatin by 3.53-fold and 3.20-fold, respectively.(1)
Avacopan/Strong Or Moderate 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: Avacopan is a substrate of CYP3A4. Strong or moderate inducers of CYP3A4 may induce the metabolism of avacopan.(1)
CLINICAL EFFECTS: The concurrent administration of strong or moderate CYP3A4 inducers may result in decreased levels and effectiveness of avacopan.(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 avacopan states that concurrent use with strong or moderate CYP3A4 inducers should be avoided.(1) The Australian manufacturer of avacopan states that patients anticipated to require long-term administration of a CYP3A4 inducer should not be treated with avacopan. If short term co-administration cannot be avoided in a patient already on avacopan, closely monitor for reoccurrence of disease activity.(4)
DISCUSSION: Co-administration of rifampin 600 mg once daily for 11 days, a strong CYP3A4 inducer, decreased the avacopan concentration maximum (Cmax) by 79% and area-under-curve (AUC) by 93%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate inducers of CYP3A4 include: belzutifan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, lesinurad, lorlatinib, modafinil, nafcillin, rifabutin, sotorasib, telotristat ethyl, thioridazine and tovorafenib.(2-3)
Moderate Cyp3a4 Inhibitors/Aumolertinib
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 metabolized via CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of aumolertinib.(1)
CLINICAL EFFECTS: Concurrent use of aumolertinib with moderate CYP3A4 inhibitors may increase the levels and toxicities of aumolertinib, including cardiac failure, rhabdomyolysis, thrombosis, elevated LFTs, hyponatremia hematologic toxicity, and QT prolongation, which may lead to potentially life-threatening arrhythmias like torsades the 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) 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 moderate CYP3A4 inhibitors should be avoided.(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: The impact of moderate CYP3A4 inhibitors on the pharmacokinetics of aumolertinib has not been investigated in clinical studies. In a clinical study, itraconazole (strong CYP3A inhibitor) increased aumolertinib area-under-curve (AUC) by 3.7-fold.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, darunavir, duvelisib, fedratinib, fosamprenavir, fosnetupitant, imatinib, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and voxelotor.(2,3)
Moderate Cyp3a4 Inhibitors/Avanafil (> 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: Moderate inhibitors of CYP3A4 may inhibit the metabolism of avanafil.(1)
CLINICAL EFFECTS: The concurrent administration of a moderate CYP3A4 inhibitor may result in elevated levels of avanafil, which may result in increased adverse effects such as hypotension, visual changes, and priapism.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of avanafil states that in patients receiving moderate inhibitors of CYP3A4, the dose of avanafil should be limited to 50 mg in 24 hours.(1)
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 2C19, increased the Cmax and AUC of a single dose of avanafil (50 mg) by 2-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) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, grapefruit juice, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(1-3)
Moderate 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 both 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 moderate 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 moderate CYP3A4 inhibitors should be avoided.(1)
DISCUSSION: The impact of moderate CYP3A4 inhibitors on the pharmacokinetics of defactinib has not been investigated in clinical studies. 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) 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, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2-3)
Moderate Cyp3a4 Inhibitors/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: Agents that inhibit CYP3A4 may inhibit the metabolism of bosutinib.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase levels of and effects from bosutinib.(1) Elevated levels of bosutinib may result in QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP). Other toxicities include nausea, vomiting, diarrhea, abdominal pain, myelosuppression, transaminitis, renal toxicity, and cardiac failure.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid the use of moderate CYP3A4 inhibitors in patients undergoing therapy with bosutinib.(1)
DISCUSSION: In a study in 24 healthy subjects, ketoconazole (400 mg daily for 5 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of bosutinib (100 mg) by 5.2-fold and 8.6-fold, respectively.(1) In a cross-over study in 18 healthy subjects, aprepitant (125 mg) increased the Cmax and AUC of bosutinib (single dose 500 mg) by 1.5-fold and 2.0-fold, respectively.(1) A study using PKPB modeling found concurrent use of bosutinib and schisandra would result in an increase in bosutinib exposure with an increased AUC by 3.0-fold.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, boceprevir, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(3-4)
Moderate Cyp3a4 Inhibitors/Dapoxetine (>30 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: Moderate CYP3A4 inhibitors may inhibit the metabolism of dapoxetine.(1-3)
CLINICAL EFFECTS: Concurrent use of a moderate 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: The manufacturers of dapoxetine state that the dose of dapoxetine should not exceed 30 mg daily if coadministered with moderate CYP3A4 inhibitors.(1-3)
DISCUSSION: The impact of moderate CYP3A4 inhibitors on the pharmacokinetics of dapoxetine has not been investigated in clinical studies.(1-3) 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) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(4,5)
Moderate Cyp3a4 Inhibitors/Daraxonrasib (> 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: Daraxonrasib is a substrate of CYP3A4. Moderate 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 moderate CYP3A4 inhibitors, reduce the dose of daraxonrasib to 200 mg once daily. If the inhibitor is discontinued, resume the previous dose of daraxonrasib after 3 to 5 half-lives of the inhibitor.(1)
DISCUSSION: In a pharmacokinetic model, fluconazole 200 mg twice daily (a moderate CYP3A inhibitor) increased the area under curve (AUC) of daraxonrasib by 1.5-fold.(1) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, crizotinib, darunavir, duvelisib, fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, stiripentol, tofisopam, treosulfan, and voxelotor.(2-3)
Moderate Cyp3a4 Inhibitors/Daridorexant (>25 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: Moderate inhibitors of CYP3A4 may inhibit the metabolism of daridorexant.(1)
CLINICAL EFFECTS: Concurrent use of a moderate 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 dose of daridorexant should be limited to 25 mg daily when used with a moderate CYP3A4 inhibitor.(1)
DISCUSSION: Daridorexant is a CYP3A4 substrate. In a PKPB model, concurrent use of daridorexant with diltiazem, a moderate CYP3A4 inhibitor, increased daridorexant area-under-curve (AUC) and maximum concentration (Cmax) by 2.4-fold and 1.4-fold, respectively.(1) 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, treosulfan and verapamil.(2)
Moderate Cyp3a4 Inhibitors/Dordaviprone
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: Moderate CYP3A4 inhibitors may inhibit the metabolism of dordaviprone.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase the levels and effects of dordaviprone, including 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 concomitant use with moderate CYP3A4 inhibitors should be avoided.(1). If concomitant use with a moderate 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 500 mg once weekly. Recommended doses for patients weighing less than 52.5 kg receiving moderate CYP3A4 inhibitors has not been established.(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) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)
Moderate Cyp3a4 Inhibitors/Lumateperone (>21 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: Moderate inhibitors of CYP3A4 may inhibit the metabolism of lumateperone.(1)
CLINICAL EFFECTS: Concurrent use of lumateperone with moderate CYP3A4 inhibitors increases lumateperone exposure, which may increase the risk of adverse reactions.(1)
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 21 mg once daily in patients receiving moderate CYP3A4 inhibitors.(1)
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) Moderate inhibitors of CYP3A4 include: aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, verapamil, treosulfan, and voxelotor.(2,3)
Moderate Cyp3a4 Inhibitors/Naloxegol (> 12.5 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: Inhibitors of CYP3A4 may inhibit the metabolism of naloxegol.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 without a dosage adjustment of naloxegol 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 daily dose of naloxegol should be limited to 12.5 mg daily in patients taking moderate inhibitors of CYP3A4.(1) 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) According to Physiologically-based-Pharmacokinetic (PBPK) models, erythromycin, a moderate inhibitor of CYP3A4, at a dose of 250 mg QID is expected to increase the Cmax and AUC of naloxegol by 2.77-fold and 3.47-fold, respectively.(2) According to PBPK models, erythromycin at a dose of 400 mg QID is expected to increase the Cmax and AUC of naloxegol by 3.42-fold and 4.63-fold, respectively.(2) According to PBPK models, fluconazole, a moderate inhibitor of CYP3A4, at a dose of 200 mg daily is expected to increase the Cmax and AUC of naloxegol by 2.4-fold and 2.81-fold, respectively.(2) According to PBPK models, verapamil moderate inhibitor of CYP3A4, at a dose of 120 mg daily is expected to increase the Cmax and AUC of naloxegol by 1.97-fold and 2.21-fold, respectively.(2) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(1,3,4)
Moderate 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. Moderate inhibitors of CYP3A4 may inhibit the metabolism of olverembatinib.(1)
CLINICAL EFFECTS: Concurrent use of olverembatinib with moderate 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 moderate 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) In a PBPK model, the moderate CYP3A4 inhibitors verapamil 80 mg three times daily, fluconazole 200 mg daily, and erythromycin 500 mg every 6 hours increased the AUC of olverembatinib 40 mg by 2.25-, 1.8-, and 2.39-fold, respectively. Olverembatinib Cmax was increased by 1.55-, 1.42-, and 1.6-fold, respectively.(3) Moderate inhibitors of CYP3A4 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, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(4-5)
Moderate Cyp3a4 Inhibitors/Oveporexton (>0.5 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: Oveporexton is metabolized by CYP3A4. Moderate CYP3A4 inhibitors may inhibit the metabolism of oveporexton.(1)
CLINICAL EFFECTS: Concurrent use of moderate 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: In patients on concomitant moderate CYP3A4 inhibitors with oveporexton, reduce the dosage of oveporexton to 0.5 mg after awakening and then 0.5 mg three to five hours later (maximum recommended dosage is 1 mg per day).(1)
DISCUSSION: In a study, fluconazole (a moderate CYP3A inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of oveporexton by 2.9-fold and 1.5-fold, respectively. Oveporexton half-life was increased by about 2-fold.(1) Moderate inhibitors of CYP3A4 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.(2-3)
Moderate Cyp3a4 Inhibitors/Pyrotinib (> 80 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: Pyrotinib is metabolized via CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of pyrotinib.(1)
CLINICAL EFFECTS: Concurrent use of pyrotinib with moderate 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 moderate CYP3A4 inhibitors requires a dose adjustment. Reduce the dose of pyrotinib to 80 mg daily with moderate CYP3A4 inhibitors.(1)
DISCUSSION: In a clinical study of healthy subjects, coadministration of pyrotinib with fluconazole, a moderate CYP3A4 inhibitor, resulted in a 3.6-fold increase in area-under-curve (AUC) and a 2.16-fold increase in maximum concentration (Cmax).(1) Moderate inhibitors of CYP3A4 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, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)
Moderate Cyp3a4 Inhibitors/Ranolazine (> 500 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: Moderate inhibitors of CYP3A4 may inhibit the metabolism of ranolazine. Verapamil may also increase the absorption of ranolazine by inhibiting P-glycoprotein.(1)
CLINICAL EFFECTS: Concurrent use of moderate inhibitors of CYP3A4 may result in elevated levels of and clinical effects from ranolazine. Elevated ranolazine levels may result in QTc prolongation, which may result in life-threatening cardiac arrhythmia, 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 ranolazine states that the dosage of ranolazine should be limited to 500 mg twice daily in patients receiving moderate inhibitors of CYP3A4.(1) If 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.
DISCUSSION: Concurrent use of diltiazem, a moderate inhibitor of CYP3A4, at daily doses of 180 mg to 360 mg increased plasma levels of ranolazine (1000 mg twice daily) by 50% and 130%, respectively.(1,4) In healthy subjects, concurrent ranolazine (1000 mg twice daily) had no effects on the pharmacokinetics of diltiazem (60 mg three times daily).(1) Concurrent use of verapamil (120 mg three times daily) increased plasma levels of ranolazine (750 mg twice daily) by 100%.(1) In a study in 12 healthy males, ranolazine immediate release (IR, 240 mg three times daily) had no effect on diltiazem (60 mg three times daily) pharmacokinetics. However, at ranolazine IR steady state, diltiazem increased ranolazine IR area under the curve (AUC) by 85%, on average, and increased maximum concentration (Cmax) by 1.9-fold and minimum concentration (Cmin) by 2.1-fold.(4) In a study in 12 subjects, ranolazine sustained release (SR, 500 mg twice daily) had no effect on diltiazem (60 mg three times daily) pharmacokinetics. However, at ranolazine steady state, diltiazem increased ranolazine SR Cmax, concentration minimum (Cmin), AUC by 80%, 216%, and 90%, on average, respectively.(4) In a study in 8 healthy males, diltiazem modified release (MR, 180 mg, or 240 mg, or 360 mg, once daily) increased ranolazine sustained release (SR, 1000 mg twice daily) AUC by 52%, 93%, and 139%, respectively. Ranolazine half-lives did not show any consistent trend of changes with increasing doses of diltiazem.(4) In a study of patients with severe chronic angina, the addition of ranolazine 750 mg twice daily or 1,000 mg twice daily along with their standard dose of diltiazem (180 mg once daily) provided additional antianginal relief, without evident adverse, long-term survival consequences over 1 to 2 years of therapy.(5) Ranolazine-induced QTc prolongation is dose and concentration-related.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, treosulfan and verapamil.(1,3,6,7)
Moderate 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. Moderate inhibitors of CYP3A4 may inhibit the metabolism of remibrutinib.(1)
CLINICAL EFFECTS: Concurrent use of moderate 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 moderate CYP3A4 inhibitors in patients taking remibrutinib.(1)
DISCUSSION: Remibrutinib maximum concentration (Cmax) is predicted to increase by approximately 1.9-fold and area-under-curve (AUC) is predicted to increase by approximately 2.3-fold following concomitant administration with erythromycin (a moderate CYP3A4 inhibitor) 500 mg four times a day for 7 days. Moderate inhibitors of CYP3A4 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, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2-3)
Moderate 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. Moderate inhibitors of CYP3A4 may inhibit the metabolism of rilzabrutinib.(1)
CLINICAL EFFECTS: Concurrent use of moderate 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 moderate 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: Concurrent use of rilzabrutinib with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, verapamil) is predicted to increase rilzabrutinib Cmax and AUC by 3-fold at steady state.(1) Moderate inhibitors of CYP3A4 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, lenacapavir, letermovir, netupitant, nilotinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2-3)
Moderate Cyp3a4 Inhibitors/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: Taletrectinib is a substrate of CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of taletrectinib.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in increased levels and toxicity from taletrectinib including hepatotoxicity, myalgia, 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) Taletrectinib should be taken on an empty stomach. Administration with food may increase the risk of QT prolongation or torsade de pointes.
PATIENT MANAGEMENT: The manufacturer of taletrectinib recommends avoiding concurrent administration with moderate CYP3A4 inhibitors.(1) 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: Concomitant administration with moderate inhibitors of CYP3A4 (fluconazole, erythromycin, or verapamil) is predicted to increase taletrectinib area under the curve (AUC) up to 2.6-fold and maximum concentration (Cmax) up to 1.5-fold.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, schisandra, tofisopam, treosulfan, verapamil, and voxelotor.(3)
Moderate 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: Moderate inhibitors of CYP3A4 may inhibit the metabolism of tolvaptan.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in elevated levels of and toxicity from 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: The US manufacturer of Samsca for the treatment of clinically significant hypervolemic and euvolemic hyponatremia states that concurrent administration with moderate CYP3A4 inhibitors should be avoided.(1) The US manufacturer of Jynarque for the management to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease states concurrent administration with moderate CYP3A4 inhibitors warrants a dose reduction of Jynarque as follows: - Standard morning and evening dose: 90 mg and 30 mg should be dose adjusted to 45 mg and 15 mg, respectively - Standard morning and evening dose: 60 mg and 30 mg should be dose adjusted to 30 mg and 15 mg, respectively - Standard morning and evening dose: 45 mg and 15 mg should be dose adjusted to 15 mg and 15 mg, respectively Interrupt Jynarque temporarily for short term therapy with moderate CYP3A4 inhibitors if the recommended reduced doses are not available.(2)
DISCUSSION: Fluconazole 400 mg (moderate inhibitor of CYP3A4) given one day prior and 200 mg given concomitantly produced an 80% and 200% increase in tolvaptan maximum concentration (Cmax) and area-under-curve (AUC), respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, crizotinib, darunavir, diltiazem, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(1-4)
Moderate Cyp3a4 Inhibitors/Ubrogepant (> 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: Moderate inhibitors of CYP3A4 may inhibit the metabolism of ubrogepant.(1)
CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor may result in elevated levels of ubrogepant.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when used concomitantly with moderate CYP3A4 inhibitors. Initial dose of ubrogepant should not exceed 50 mg. A second dose should be avoided within 24 hours of the first dose when used concurrently with moderate CYP3A4 inhibitors.(1)
DISCUSSION: Co-administration with verapamil, a moderate CYP3A4 inhibitor, resulted in a 3.5-fold and 2.8-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively.(1) Moderate inhibitors of CYP3A4 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.(2-4)
Moderate Cyp3a4 Inhibitors/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: Moderate CYP3A4 inhibitors may inhibit the metabolism of zidesamtinib.(1)
CLINICAL EFFECTS: Concurrent use of zidesamtinib with moderate CYP3A4 inhibitors may result in elevated zidesamtinib levels and toxicities, including interstitial lung disease, pneumonitis, pancreatitis, myalgias, and 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 moderate CYP3A4 inhibitors should be avoided.(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) 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) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)
Selected Cyp3a4 Inhibitors/Vardenafil (> 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: CYP3A4 inhibitors may inhibit the metabolism of vardenafil by CYP3A4.(1-4)
CLINICAL EFFECTS: Concurrent use of CYP3A4 inhibitors may result in increased levels of and adverse effects from vardenafil, including hypotension, visual changes, and sustained erections.(1-4)
PREDISPOSING FACTORS: The interaction may be more severe in men older than 75 years.(4)
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 400 mg of itraconazole or ketoconazole and that a maximum dose of 5 mg of vardenafil every 24 hours should not be exceeded in patients taking 200 mg of itraconazole or ketoconazole.(1) For moderate CYP3A4 inhibitors, do not exceed a maximum dose of 5 mg of vardenafil every 24 hours.(1) Note that other countries have stricter warnings. The Australian manufacturer of vardenafil states that vardenafil must not be taken with dosages of itraconazole or ketoconazole greater than 200 mg. A maximum dose of 5 mg of vardenafil should not be exceeded if used with lower dosages of itraconazole and ketoconazole.(2) The Canadian manufacturer of vardenafil states that the concurrent use of vardenafil with itraconazole or ketoconazole is contraindicated and that the dosage should not exceed 5 mg in patients taking erythromycin.(3) The UK manufacturer of vardenafil states that the concurrent use of vardenafil with either oral itraconazole or oral ketoconazole is contraindicated in men older than 75 years and should be avoided in all patients. The dosage of vardenafil should not exceed 5 mg in patients taking erythromycin.(4)
DISCUSSION: Concurrent use of ketoconazole (200 mg) with vardenafil (5 mg) increased the vardenafil area-under-curve (AUC) and maximum concentration (Cmax) by 10-fold and 4-fold, respectively.(1-4) Concurrent administration of erythromycin (500 mg three times daily) with vardenafil (5 mg) increased the AUC and Cmax of vardenafil by 4-fold and 3-fold, respectively.(1-4)
Selected Moderate 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 moderate CYP3A4 inhibitors.(1)
CLINICAL EFFECTS: The concurrent administration of a moderate 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 moderate CYP3A4 inhibitors should be avoided.(1)
DISCUSSION: Ensartinib is predominately metabolized by CYP3A4.(1) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, crizotinib, darunavir, duvelisib, fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, stiripentol, tofisopam, treosulfan, and voxelotor.(2,3)
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)
Slt Strong & Moderate 3A4 Inhibitors/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.(1)
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)
PREDISPOSING FACTORS: None determined.
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)
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.(2) Analysis of population pharmacokinetics indicated that the concurrent administration of diltiazem with cilostazol increased cilostazol concentrations by 53%. Concurrent administration of diltiazem and cilostazol decreased cilostazol clearance by 30%, increased the Cmax by 30%, and increased AUC by 40%.(1) 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.(3)
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 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)
Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
Avacopan/Mitapivat
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Avacopan and mitapivat are both substrates of CYP3A4. Avacopan, a moderate CYP3A4 inhibitor, may inhibit the metabolism of mitapivat. Mitapivat, a moderate CYP3A4 inducer, may induce the metabolism of avacopan.(1,2)
CLINICAL EFFECTS: The concurrent use of avacopan with moderate CYP3A4 inducers may result in decreased levels and effectiveness of avacopan.(1) Concurrent use of mitapivat with moderate inhibitors 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.(2)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Avoid the concurrent use of avacopan and mitapivat.(1,2) The effect of the two-way inhibition and induction of avacopan and mitapivat metabolism is unknown. The optimal doses of avacopan and mitapivat when used concurrently have not been determined. Dose modifications mentioned below are informational only. When mitapivat is used for the treatment of hemolytic anemia in patients with pyruvate kinase deficiency, the US manufacturer of mitapivat states that mitapivat dose should not exceed 20 mg twice daily with concurrent moderate CYP3A4 inhibitors.(2) When mitapivat is used for the treatment of anemia in patients with alpha- or beta-thalassemia, the US manufacturer of mitapivat states that concurrent moderate CYP3A4 inhibitors should be avoided.(3) The Middle Eastern manufacturer of mitapivat states that alternative agents that do not inhibit CYP3A4 should be considered. If concomitant use of a moderate CYP3A4 inhibitor is unavoidable, the dose of mitapivat should not exceed 100 mg once daily.(4)
DISCUSSION: Co-administration of rifampin 600 mg once daily for 11 days, a strong CYP3A4 inducer, decreased the avacopan concentration maximum (Cmax) by 79% and area-under-curve (AUC) by 93%.(1) In a pharmacokinetic study with mitapivat 5, 20, or 50 mg twice daily dosing, fluconazole increased mitapivat AUC and Cmax by 2.6-fold and 1.6-fold, respectively.(2) In a pharmacokinetic study, midazolam (a CYP3A4 substrate) area-under-curve (AUC) and maximum concentration (Cmax) decreased by 65% and 59%, respectively, with mitapivat 100 mg twice daily.(3)
Avacopan/Strong Cyp3a4 Inhib And Substrates That Prolong Qt
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Avacopan is a moderate inhibitor and substrate of CYP3A4. Strong inhibitors of CYP3A4 may inhibit the metabolism of avacopan. Avacopan may inhibit the metabolism of CYP3A4 substrates.(1) Some CYP3A4 substrates have the potential to prolong the QTc interval.(2-3)
CLINICAL EFFECTS: Concurrent use may increase the levels of and effects from avacopan.(1) Concurrent use of avacopan with QT-prolonging CYP3A4 substrates may also increase the risk of adverse reactions from the CYP3A4 substrate including QT prolongation and potentially life-threatening cardiac arrhythmias such as torsades de pointes.(2-3)
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: Reduce the dose of avacopan to 30 mg once daily when coadministered with strong CYP3A4 inhibitors.(1) Monitor liver tests, including AST, ALT, alkaline phosphatase, and total bilirubin. Advise patients to report any symptoms of hepatotoxicity. If the patient is on lonafarnib, approach concurrent use with caution. No dose adjustment of lonafarnib is recommended when moderate CYP3A4 inhibitors are added to steady-state lonafarnib. When initiating lonafarnib therapy in a patient already taking a moderate CYP3A4 inhibitor, monitor the patient closely for the first 7 days of therapy. If the patient does not tolerate lonafarnib, consider an alternative that is not a moderate CYP3A4 inhibitor.(2) 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.(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. 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.(5-6)
DISCUSSION: In a study, administration of itraconazole 200 mg once daily for 4 days (a strong CYP3A4 inhibitor) increased the maximum concentration (Cmax) and area-under-curve (AUC) of avacopan by 1.87-fold and 2.19-fold.(1) Avacopan 60 mg twice daily for 7 days under fed conditions increased the Cmax and AUC of simvastatin (a sensitive CYP3A4 substrate) by 3.2-fold and 3.53-fold, respectively. This regimen of avacopan provided systemic levels similar to exposure from avacopan 30 mg twice daily under fed conditions at steady state.(1) Strong CYP3A4 inhibitors and substrates that prolong QT linked to this monograph include: lonafarnib.(7-8)
Avacopan/Strong Cyp3a4 Inhibitors
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)
Avacopan/Strong Or Moderate Cyp3a4 Inducer And Substrates
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Avacopan is moderate inhibitor and substrate of CYP3A4. Strong or moderate inducers of CYP3A4 may induce the metabolism of avacopan.(1) Avacopan may inhibit the metabolism of CYP3A4 substrates.(1)
CLINICAL EFFECTS: The concurrent administration of strong or moderate CYP3A4 inducers may result in decreased levels and effectiveness of avacopan.(1) Concurrent administration of avacopan with CYP3A4 substrates may result in increased levels and side effects of the CYP3A4 substrate.(1) If the patient is on fexinidazole, concurrent administration of avacopan with fexinidazole may result in decreased levels of fexinidazole's active metabolite, resulting in decreased efficacy.(2)
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 avacopan states that concurrent use with strong or moderate CYP3A4 inducers should be avoided.(1) Consider dose reduction of CYP3A4 substrates when coadministering avacopan with CYP3A4 substrates. Consult the concomitant CYP3A4 substrate product information when considering administration with avacopan.(1) The manufacturer of fexinidazole states that concurrent use with moderate CYP3A4 inhibitors should be avoided.(2)
DISCUSSION: Co-administration of rifampin 600 mg once daily for 11 days, a strong CYP3A4 inducer, decreased the avacopan maximum concentration (Cmax) by 79% and area-under-curve (AUC) by 93%.(1) In a study, avacopan 60 mg twice daily with food was administered for 7 days with simvastatin. Since it takes 13 weeks to reach steady state, this high dose of avacopan was used to achieve systemic levels similar to those achieved at steady state with a dose of 30 mg twice daily with food. Avacopan increased the AUC and Cmax of simvastatin by 3.53-fold and 3.20-fold, respectively.(1) Moderate inducers and substrates of CYP3A4 include: bosentan, encorafenib, fexinidazole, ivosidenib, mavacamten, pacritinib, pexidartinib, and repotrectinib.(3-4)
Moderate 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. Moderate inhibitors of CYP3A4 may inhibit the metabolism of brigatinib.(1)
CLINICAL EFFECTS: Concurrent use of a moderate 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 moderate CYP3A4 inhibitors. If concurrent therapy cannot be avoided, reduce the once daily dose of brigatinib by approximately 40% (i.e. from 180 mg to 120 mg, 120 mg to 90 mg). Upon discontinuation of a moderate CYP3A4 inhibitor, resume the brigatinib dose that was tolerated prior to initiating the moderate 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. Moderate CYP3A4 inhibitors are expected to increase the AUC of brigatinib by approximately 40%.(1) 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, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2,3)
Moderate Cyp3a4 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.(1-4)
CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 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 moderate CYP3A4 inhibitors with cariprazine. The US manufacturer of cariprazine states that concurrent use of moderate CYP3A4 inhibitors requires a dose adjustment. If a moderate 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 0.75 mg daily. -If current cariprazine dose is 4.5 or 6 mg daily: Decrease cariprazine dose to 1.5 mg daily. In adult patients taking a moderate CYP3A4 inhibitor when cariprazine is started, the following dose adjustments are recommended: -For schizophrenia or bipolar mania: Start cariprazine dose at 0.75 mg daily; increase to 1.5 mg daily, if needed. -For bipolar depression or adjunctive therapy for treatment of Major Depressive Disorder (MDD): Start cariprazine dose at 0.75 mg daily.(1) -Initiating cariprazine is not recommended in pediatric patients while taking a moderate 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, and Canadian manufacturers of cariprazine state that concurrent use of moderate CYP3A4 inhibitors is contraindicated.(2,3) The UK manufacturer of cariprazine states that concurrent use of moderate CYP3A4 inhibitors may require a dose adjustment.(4) The Canadian manufacturer of cariprazine states that concurrent use of moderate 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) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(5,6)
Moderate Cyp3a4 Inhibitors/Cobimetinib; Olaparib; Sonidegib
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 cobimetinib, olaparib, and sonidegib.(1-4)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase systemic exposure and the risk for adverse effects from cobimetinib, olaparib, or sonidegib.(1-4)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: When possible, avoid the use of moderate CYP3A4 inhibitors in patients receiving cobimetinib, olaparib, or sonidegib.(1-4) For patients taking cobimetinib 60 mg daily, if concurrent short term use (14 days or less) of a moderate CYP3A4 inhibitor cannot be avoided, reduce cobimetinib dose to 20 mg daily. After discontinuation of the moderate CYP3A4 inhibitor resume the previous 60 mg dose. Patients who are taking cobimetinib 40 mg or 20 mg daily should not receive a moderate or strong CYP3A4 inhibitor.(1) If concomitant use with olaparib cannot be avoided, reduce the olaparib dose. Dosage adjustments are specific to the formulation of olaparib.(2,3) Reduce the dosage of the CAPsule formulation to 200 mg (four 50 mg CAPsules) taken twice daily.(2) Reduce the dosage of the TABlet formulation to 150 mg (one 150 mg TABlet) twice daily). 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.(3) If sonidegib and a moderate CYP3A4 inhibitor must be used, administer the moderate CYP3A4 inhibitor for less than 14 days and monitor closely for adverse effects, particularly musculoskeletal adverse reactions.(4)
DISCUSSION: In an interaction study, itraconazole (a strong CYP3A4 inhibitor) given 200 mg once daily for 14 days followed by a single dose of cobimetinib 10 mg increased mean cobimetinib AUC 6.7-fold (90% CI 5.6, 8.0). Subsequent simulations showed that predicted steady-state concentrations of cobimetinib at a reduced daily dose of 20 mg given with short term use of a moderate CYP3A4 inhibitor were similar to observed steady-state concentrations at the 60 mg dose without an inhibitor.(1) In simulations using physiologically-based pharmacokinetic (PBPK) models, concurrent use of fluconazole, a moderate CYP3A4 inhibitor, may increase the area-under-curve (AUC) of olaparib by 2.2-fold.(2,3) Based upon PBPK simulations, sonidegib mean steady-state AUC would increase 1.8-fold if administered with a moderate CYP3A4 inhibitor for 14 days and would further increase to 2.8-fold if the moderate CYP3A4 inhibitor is coadministered with sonidegib for 4 months.(4) Moderate CYP3A4 inhibitors linked to this monograph include: aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, schisandra, rilzabrutinib, stiripentol, tofisopam, treosulfan, and verapamil.(5)
Moderate Cyp3a4 Inhibitors/Colchicine (For Cardioprotection)
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of colchicine.(1,2)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors 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)
PATIENT MANAGEMENT: Monitor patients receiving moderate CYP3A4 inhibitors for signs of colchicine toxicity. Avoid concurrent use in patients with existing renal or hepatic impairment.(1) 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: There is one case report of colchicine toxicity with concurrent erythromycin.(4) In a study in 20 subjects, pretreatment with diltiazem (240 mg daily for 7 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by 44.2% (range -46.6% to 318.3%) and by 93.4% (range -30.2% to 338.6%), 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) In a study in 24 subjects, pretreatment with verapamil (240 mg twice daily for 7 days) increased the Cmax and AUC of a single dose of colchicine (0.6 mg) by 40.1% (range -47.1% to 149.5%) and by 103.3% (range -9.8% to 217.2%), respectively.(1) Colchicine toxicity has been reported with concurrent use of CYP3A4 inhibitors such as clarithromycin, cyclosporine, diltiazem, erythromycin, and verapamil.(1,2) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, avacopan, clofazimine, conivaptan, crizotinib, duvelisib, fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, stiripentol, and treosulfan.(1,5,6)
Moderate 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: Moderate CYP3A4 inhibitors may inhibit the metabolism of colchicine(1-3)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors 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.(1-3)
PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with renal and/or hepatic impairment.(1-3)
PATIENT MANAGEMENT: Avoid use of colchicine concurrently with or within 14 days of taking moderate CYP3A4 inhibitors (without ritonavir). If concurrent use is unavoidable, the dosage of colchicine should be reduced.(1-3) For gout flares, the recommended dosage is 1.2 mg (2 tablets) for one dose. This dose should be repeated no earlier than in 3 days.(1-4) For gout prophylaxis, if the original dosage was 0.6 mg twice daily, use 0.3 mg twice daily or 0.6 mg daily. If the original dosage was 0.6 mg daily, use 0.3 mg daily.(1-4) For Familial Mediterranean fever (FMF), the recommended maximum daily dose is 1.2 mg (may be given as 0.6 mg twice a day).(1-4) 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: Fluconazole (400 mg loading dose followed by 200 mg daily for 4 days) increased the area-under-curve (AUC) of colchicine by 40%.(2) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, avacopan, clofazimine, conivaptan, crizotinib, duvelisib, fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, stiripentol, and treosulfan.(1,5,6)
Moderate Cyp3a4 Inhibitors/Elexacaftor-Tezacaftor-Ivacaftor
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the CYP3A4-mediated metabolism of elexacaftor, tezacaftor, and ivacaftor.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in elevated levels of and toxicity from elexacaftor, tezacaftor, and 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 moderate CYP3A4 inhibitors as follows: - In 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 evening dose of ivacaftor should not be taken. The morning dose of therapy should be modified to the following alternate daily dosing schedule: Day 1 - two tablets of elexacaftor 100 mg-tezacaftor 50 mg-ivacaftor 75 mg (total dose of elexacaftor 200 mg-tezacaftor 100 mg-ivacaftor 150 mg); Day 2 - one tablet of ivacaftor 150 mg. - In patients 6 to 12 years old weighing less than 30 kg who are receiving concurrent moderate CYP3A4 inhibitors, the evening dose of ivacaftor should not be taken. The morning dose of therapy should be modified to the following alternate daily dosing schedule: Day 1 - two tablets of elexacaftor 50 mg-tezacaftor 25 mg-ivacaftor 37.5 mg (total daily dose of elexacaftor 100 mg-tezacaftor 50 mg-ivacaftor 75 mg); Day 2 - one tablet of ivacaftor 75 mg. - In patients 2 to less than 6 years old weighing at least 14 kg who are receiving concurrent moderate CYP3A4 inhibitors, the evening dose of ivacaftor should not be taken. The morning dose of therapy should be modified to the following alternate daily dosing schedule: Day 1 - one packet of oral granules containing elexacaftor 100 mg-tezacaftor 50 mg-ivacaftor 75 mg; Day 2 - one packet of oral granules containing ivacaftor 75 mg.(1) - In patients 2 to less than 6 years old weighing less than 14 kg who are receiving concurrent moderate CYP3A4 inhibitors, the evening dose of ivacaftor should not be taken. The morning dose of therapy should be modified to the following alternate daily dosing schedule: Day 1 - one packet of oral granules containing elexacaftor 80 mg-tezacaftor 40 mg-ivacaftor 60 mg; Day 2 - one packet of oral granules containing ivacaftor 59.5 mg.(1)
DISCUSSION: In a study, fluconazole (400 mg on day 1 then 200 mg daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of ivacaftor (150 mg every 12 hours) by 2.95-fold and 2.45-fold, respectively.(1) Simulations suggest that moderate CYP3A inhibitors may increase the AUC of elexacaftor and tezacaftor by approximately 1.9 to 2.3-fold and 2.1-fold, respectively.(1) Moderate inhibitors of CYP3A4 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.(2-4)
Moderate Cyp3a4 Inhibitors/Entrectinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of entrectinib.(1,2)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in elevated levels and increased effects of entrectinib, such as QT prolongation, hepatotoxicity, CNS effects, hyperuricemia, anemia, or neutropenia.(1,2) Symptoms of hepatotoxicity can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue.
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).(3)
PATIENT MANAGEMENT: The US manufacturer of entrectinib states that entrectinib coadministration with moderate inhibitors of CYP3A4 should be avoided.(1) If concurrent therapy cannot be avoided, reduce the entrectinib dose as follows for adult and pediatric patients 2 years and older: -If the starting dose is 600 mg, reduce the entrectinib dose to 200 mg daily. -If the starting dose is 400 mg, reduce the entrectinib dose to 200 mg daily. -If the starting dose is 300 mg, reduce the entrectinib dose to 100 mg daily. -If the starting dose is 200 mg, reduce the entrectinib dose to 50 mg daily.(1) For pediatric patients less than 2 years old, avoid coadministration with moderate CYP3A4 inhibitors.(1) If concomitant use of a moderate CYP3A4 inhibitor 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 moderate CYP3A4 inhibitor. Monitor liver tests, including AST and ALT. Advise patients to immediately report any symptoms of hepatotoxicity. During concomitant therapy with a moderate 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. The Australian manufacturer of entrectinib states that entrectinib coadministration with moderate inhibitors of CYP3A4 should be avoided. If concurrent therapy with a moderate CYP3A4 inhibitor cannot be avoided, reduce the dose of entrectinib to 200 mg once daily.(4) If concomitant use of a moderate CYP3A4 inhibitor 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 moderate CYP3A4 inhibitor.(4)
DISCUSSION: 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.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, ciprofloxacin, conivaptan, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(1,5)
Moderate Cyp3a4 Inhibitors/Ergot Alkaloids
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of ergot alkaloids.
CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor may result in increased levels of the ergot alkaloid, which may result in clinical signs of ergotism, including vasospasm, dysesthesia, renal ischemia, and peripheral ischemia.
PREDISPOSING FACTORS: Patients receiving the maximum recommended (or higher than recommended) dosages of ergot alkaloids may be at a higher risk of adverse effects from this combination.
PATIENT MANAGEMENT: When possible, avoid the concurrent use of moderate CYP3A4 inhibitors in patients taking ergot alkaloids. If concurrent use is warranted, consider reducing the dose of the ergot alkaloid during concurrent therapy. Patients receiving concurrent therapy should be monitored for and instructed to report any signs of ergotism.
DISCUSSION: Coadministration of dihydroergotamine and ergotamine with potent inhibitors of CYP3A4 such as clarithromycin, erythromycin, indinavir, nelfinavir, ritonavir, and troleandomycin has resulted in ergotism, characterized by vasospasm and ischemia of the extremities. Inhibition of ergot alkaloid metabolism by moderate inhibitors would also be expected, but to a lesser degree. Moderate CYP3A4 inhibitors linked to this monograph are aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lenacapavir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, tofisopam, treosulfan and verapamil.
Moderate Cyp3a4 Inhibitors/Gepotidacin
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Gepotidacin is a substrate of CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of gepotidacin.(1)
CLINICAL EFFECTS: Concurrent use of moderate 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.
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 that concomitant use of moderate CYP3A4 inhibitors in patients being treated for uncomplicated urogenital gonorrhea should be avoided.(1) For patients being treated for uncomplicated UTI, no dosage adjustment is needed when taken with moderate CYP3A4 inhibitors.(1)
DISCUSSION: Gepotidacin is primarily metabolized by CYP3A4.(1) Concomitant administration of fluconazole (moderate CYP3A4 inhibitor) and single 1,500 mg dose of gepotidacin is predicted to increase gepotidacin maximum concentration (Cmax) by 1.3-fold and area-under-curve (AUC) by 1.5-fold.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)
Moderate 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. Moderate inhibitors of CYP3A4 may inhibit the metabolism of iberdomide.(1)
CLINICAL EFFECTS: Concurrent use of moderate 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 moderate CYP3A4 inhibitors should be avoided. If concomitant use with moderate CYP3A4 inhibitors cannot be avoided, reduce iberdomide dose to 0.75 mg once daily on Days 1 to 21 of a 28-day cycle.(1)
DISCUSSION: In a PBPK model in patients with cancer, iberdomide area-under-curve (AUC) was predicted to be increased by 1.7-fold and maximum concentration (Cmax) by 1.5-fold following concomitant use with fluconazole or diltiazem (moderate CYP3A4 inhibitors).(1) Moderate inhibitors of CYP3A4 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.(2,3)
Moderate Cyp3a4 Inhibitors/Ivabradine
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of ivabradine. Increased levels of ivabradine may cause ivabradine-induced reduction in heart rate which can contribute to increased QT prolongation risk.(1-3)
CLINICAL EFFECTS: Concurrent use of moderate inhibitors may result in elevated levels of and toxicity from ivabradine including a reduction in heart rate which can contribute to QT prolongation or 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.(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 ivabradine states that concurrent use of moderate inhibitors of CYP3A4, including diltiazem and verapamil, should be avoided.(1) The Australian and UK manufacturers of ivabradine state that concurrent use of diltiazem or verapamil is contraindicated but that other moderate inhibitors of CYP3A4 may be considered with monitoring of heart rate and with a starting dose of 2.5 mg ivabradine twice daily if resting heart rate is above 70 bpm.(2-3) 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. Concurrent use of moderate CYP3A4 inhibitors diltiazem and verapamil increased ivabradine area-under-curve (AUC) by 2- to 3-fold and reduced heart rate by an additional 5 bpm.(2) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, avacopan, berotralstat, conivaptan, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(5)
Moderate 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. Moderate CYP3A4 inhibitors may inhibit the metabolism of lirafugratinib.(1)
CLINICAL EFFECTS: Concurrent use of moderate 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 moderate CYP3A4 inhibitors with lirafugratinib. If concomitant use cannot be avoided, reduce the dosage of lirafugratinib to 50 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 pharmacokinetic model, erythromycin 500 mg four times daily for 15 days was predicted to increase the area-under-curve (AUC) and maximum concentration (Cmax) of lirafugratinib by 1.7-fold and 1.1-fold, respectively.(1) Moderate inhibitors of CYP3A4 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.(2-3)
Moderate Cyp3a4 Inhibitors/Lurbinectedin
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of lurbinectedin.(1)
CLINICAL EFFECTS: Concurrent use of moderate 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 moderate CYP3A4 inhibitors should be avoided. If the use of a moderate CYP3A4 inhibitor cannot be avoided, reduce the dose of lurbinectedin by 50%. After discontinuation of the moderate 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) 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, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)
Moderate Cyp3a4 Inhibitors/Mobocertinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of mobocertinib.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase levels of and effects from mobocertinib.(1) Elevated levels of mobocertinib may result in 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: Avoid the use of moderate CYP3A4 inhibitors in patients undergoing therapy with mobocertinib.(1) If concurrent therapy with a moderate CYP3A4 inhibitor is warranted, reduce the dose of mobocertinib by approximately 50% (ie, 160 to 80 mg, 120 to 40 mg, or 80 to 40 mg) and monitor the QTc interval more frequently. After the moderate CYP3A4 inhibitor has been discontinued for 3 to 5 elimination half-lives, resume mobocertinib at the dose taken prior to initiating the moderate CYP3A4 inhibitor. 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 a moderate CYP3A inhibitor is predicted to increase the steady-state combined molar area-under curve (AUC) of mobocertinib and its active metabolites by approximately 100 to 200%.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)
Moderate Cyp3a4 Inhibitors/Naloxegol (<= 12.5 Mg)
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 naloxegol.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 without a dosage adjustment of naloxegol 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: Avoid the use of moderate inhibitors of CYP3A4 in patients who require therapy with naloxegol. If concurrent use cannot be avoided, the daily dose of naloxegol should be limited to 12.5 mg daily in patients taking moderate inhibitors of CYP3A4.(1) 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) According to Physiologically-based-Pharmacokinetic (PBPK) models, erythromycin, a moderate inhibitor of CYP3A4, at a dose of 250 mg QID is expected to increase the Cmax and AUC of naloxegol by 2.77-fold and 3.47-fold, respectively.(2) According to PBPK models, erythromycin at a dose of 400 mg QID is expected to increase the Cmax and AUC of naloxegol by 3.42-fold and 4.63-fold, respectively.(2) According to PBPK models, fluconazole, a moderate inhibitor of CYP3A4, at a dose of 200 mg daily is expected to increase the Cmax and AUC of naloxegol by 2.4-fold and 2.81-fold, respectively.(2) According to PBPK models, verapamil moderate inhibitor of CYP3A4, at a dose of 120 mg daily is expected to increase the Cmax and AUC of naloxegol by 1.97-fold and 2.21-fold, respectively.(2) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(1,3,4)
Moderate Cyp3a4 Inhibitors/Omaveloxolone
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 omaveloxolone.(1)
CLINICAL EFFECTS: Concurrent use of a moderate 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 moderate CYP3A4 inhibitors with omaveloxolone should be avoided. If concurrent use cannot be avoided, reduce the omaveloxolone dosage to 100 mg daily and monitor closely. If adverse reactions emerge, reduce the dose to 50 mg once daily.(1)
DISCUSSION: Coadministration of omaveloxolone with verapamil (a moderate CYP3A4 inhibitor) increased both the concentration maximum (Cmax) and area-under-curve (AUC) of omaveloxolone by 1.25-fold.(1) Moderate inhibitors of CYP3A4 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, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)
Moderate Cyp3a4 Inhibitors/Selpercatinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of selpercatinib.(1) Cimetidine increases gastric pH and may decrease pH-dependent solubility and absorption of selpercatinib.(1)
CLINICAL EFFECTS: Concurrent administration of a moderate CYP3A4 inhibitor 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 arrhythmias, including torsades de pointes, hepatotoxicity, hypertension, and severe or life-threatening hemorrhagic events.(1) Conversely, concurrent use of cimetidine may result in decreased levels and effectiveness of selpercatinib. The overall effect of cimetidine on selpercatinib pharmacokinetics is unknown.(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 moderate CYP3A4 inhibitors with selpercatinib. If concomitant use cannot be avoided, reduce the dose of selpercatinib as follows: - If the current dose of selpercatinib is 160 mg twice daily, decrease the dose to 120 mg twice daily. - If the current dose of selpercatinib is 120 mg twice daily, decrease the dose to 80 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. If concomitant use of cimetidine is unavoidable, take selpercatinib at least 2 hours before or 10 hours after cimetidine. 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. 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 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: Coadministration of diltiazem, fluconazole, or verapamil (moderate CYP3A inhibitors) is predicted to increase the area-under-curve (AUC) and maximum concentration (Cmax) of selpercatinib by 60-99% and 46-76%, respectively.(1) 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) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3)
Moderate Cyp3a4 Inhibitors/Sonrotoclax
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors inhibit the metabolism of sonrotoclax.(1)
CLINICAL EFFECTS: Concurrent use of moderate 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 sonrotoclax initiation and at the 1 mg and 2 mg dose of sonrotoclax ramp-up therapy, avoid moderate CYP3A4 inhibitors. Reduce all other ramp-up doses of sonrotoclax by at least 4-fold as follows: - If original sonrotoclax dose is 5 mg, reduce sonrotoclax dose to 1 mg. - If original sonrotoclax dose is 10 mg, reduce sonrotoclax dose to 2 mg. - If original sonrotoclax dose is 20 mg, reduce sonrotoclax dose to 5 mg. - If original sonrotoclax dose is 40 mg, reduce sonrotoclax dose to 10 mg. - If original sonrotoclax dose is 80 mg, reduce sonrotoclax dose to 20 mg. - If original sonrotoclax dose is 160 mg, reduce sonrotoclax dose to 40 mg. - If original sonrotoclax dose is 320 mg, reduce sonrotoclax dose to 80 mg. In patients taking the target daily dose of sonrotoclax after the ramp-up phase who start a moderate CYP3A4 inhibitor, decrease sonrotoclax daily dose to 80 mg. Monitor for tumor lysis syndrome, hematologic and non-hematologic toxicity and adjust dosage as directed in prescribing information. If the moderate 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) Moderate inhibitors of CYP3A4 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.(3-4)
Moderate Cyp3a4 Inhibitors/Suvorexant (> 10 Mg)
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate and strong inhibitors of CYP3A4 may inhibit the metabolism of suvorexant.(1)
CLINICAL EFFECTS: Concurrent use of an agent that is a moderate or strong inhibitor of CYP3A4 may result in elevated levels of and clinical effects of suvorexant.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of suvorexant recommends a starting dose of 5 mg daily and a maximum dose of 10 mg daily in patients receiving concomitant therapy with a moderate inhibitor of CYP3A4.(1) Concurrent use with strong inhibitors of CYP3A4 is not recommended.(1)
DISCUSSION: Diltiazem, a moderate inhibitor of CYP3A4, increased suvorexant AUC and Cmax by approximately 2-fold and 1.25-fold, respectively.(1) Ketoconazole, a strong inhibitor of CYP3A4, increased suvorexant area-under-curve (AUC) and maximum concentration (Cmax) by approximately 2.75-fold and 1.25-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(1-3)
Moderate 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. Moderate CYP3A4 inhibitors may inhibit the metabolism of tavapadon.(1)
CLINICAL EFFECTS: Concurrent use of moderate 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 moderate CYP3A4 inhibitors should be avoided. During tavapadon maintenance, if moderate CYP3A4 inhibitors are initiated, decrease the dosing frequency from once daily to every 3 days: - If the current dose of tavapadon is 5 mg daily, lower dosage to 5 mg every 3 days. - If the current dose of tavapadon is 10 mg daily, lower dosage to 10 mg every 3 days. - If the current dose of tavapadon is 15 mg daily, lower dosage to 15 mg every 3 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, fluconazole 200 mg daily was predicted to increase the area-under-curve (AUC) and maximum concentration (Cmax) of tavapadon 15 mg by approximately 2.6-fold and 2.3-fold, respectively. When fluconazole is given with tavapadon once every 3 days, steady-state AUC and Cmax are predicted to fluctuate between +14% to -40% and +1 to -43%, respectively from Day 1 to Day 3 of the dosing interval, compared to tavapadon once daily alone.(1) Moderate inhibitors of CYP3A4 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.(2-3)
Moderate Cyp3a4 Inhibitors/Tazemetostat
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of tazemetostat.(1)
CLINICAL EFFECTS: Coadministration of tazemetostat with a moderate CYP3A4 inhibitor may increase tazemetostat plasma concentrations and increase the frequency or severity of adverse reactions.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of tazemetostat states to avoid coadministration of moderate CYP3A4 inhibitors with tazemetostat.(1) If coadministration of moderate 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 moderate 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 area-under-curve (AUC) by 3.1-fold and maximum concentration (Cmax) by 2.3-fold.(1) Moderate inhibitors of CYP3A4 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.(2-4)
Moderate Cyp3a4 Inhibitors/Venetoclax
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors inhibit the metabolism of venetoclax.(1)
CLINICAL EFFECTS: Concurrent use of moderate 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: Avoid moderate CYP3A4 inhibitors and consider alternative treatments when possible. If a moderate CYP3A4 inhibitor must be used, reduce venetoclax dose by at least 50%. Monitor more closely for signs of toxicity such as tumor lysis syndrome, hematologic and non-hematologic toxicities.(1) Canadian labeling for atazanavir contraindicates concurrent use of atazanavir/ritonavir with venetoclax at venetoclax dose initiation and during the ramp-up phase.(2) If the moderate CYP3A4 inhibitor is discontinued, the manufacturer of venetoclax recommends resuming the prior (i.e. pre-inhibitor) dose of venetoclax 2 to 3 days after discontinuation of the moderate CYP3A4 inhibitor.
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 2.3-fold and 6.4-fold respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(3-4)
Moderate Cyp3a4 Inhibitors/Voclosporin
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 voclosporin.(1)
CLINICAL EFFECTS: Concurrent use of moderate 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 moderate CYP3A4 inhibitors in patients undergoing therapy with voclosporin requires a dose adjustment. Voclosporin dose should be reduced to 15.8 mg in the morning and 7.9 mg in the evening.(1) Consider alternatives with no or minimal enzyme inhibition.
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) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)
Selected Moderate Cyp3a4 Inhibitors/Alprazolam
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of alprazolam.(1)
CLINICAL EFFECTS: Concurrent use may result in increased pharmacologic or toxic effects of alprazolam. Toxic effects include profound sedation, respiratory depression, coma, and/or death.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid concomitant use with moderate CYP3A4 inhibitors. Consider reducing the dose of alprazolam when coadministered with a moderate CYP3A4 inhibitor. If fluvoxamine is concurrently administered with alprazolam, the manufacturer of fluvoxamine recommends that the initial dose of alprazolam be reduced by 50%, followed by titration to the lowest effective dose.(2) If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.
DISCUSSION: Coadministration of cimetidine, a moderate CYP3A4 inhibitor, increased the maximum concentration (Cmax) of alprazolam by 82%.(1) Coadministration with erythromycin, a moderate CYP3A4 inhibitor, increased the area-under-curve (AUC) of alprazolam by 1.61-fold.(1) Coadministration of fluvoxamine 100 mg daily and alprazolam 1 mg given 4 times per day resulted in a 2-fold increase of AUC, Cmax, and half-life of alprazolam.(2) Selected moderate CYP3A4 inhibitors linked to this monograph include: aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(3,4)
Selected Moderate Cyp3a4 Inhibitors/Domperidone
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors impair the CYP3A4 mediated metabolism of domperidone.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in elevated levels of and toxicity from domperidone, including life-threatening cardiac arrhythmias such as torsades de pointes.(1)
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 moderate CYP3A4 inhibitors with domperidone is not recommended. Use alternative antiemetics, or an alternative to the 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.
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.(3) Moderate CYP3A4 inhibitors linked to this monograph include: aprepitant, avacopan, berotralstat, conivaptan, crizotinib, diltiazem, duvelisib, fedratinib, fluvoxamine, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(4-5)
Selected Moderate Cyp3a4 Inhibitors/Eplerenone
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of eplerenone.(1)
CLINICAL EFFECTS: Concurrent use of moderate inhibitors of CYP3A4 may result in a 2-fold increase in eplerenone concentration and toxicity (e.g. hyperkalemia, hypotension).(1)
PREDISPOSING FACTORS: Severe renal disease increases the risk for hyperkalemia.
PATIENT MANAGEMENT: The starting dose of eplerenone for hypertension should be reduced to 25 mg in patients receiving moderate CYP3A4 inhibitors. For inadequate blood pressure response, dosing may be increased to a maximum of 25 mg twice daily. Do not exceed 25 mg once daily in post-MI CHF patients receiving a moderate CYP3A4 inhibitor.(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) Moderate inhibitors of CYP3A4 include: aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(1-3)
Selected Moderate Cyp3a4 Inhibitors/Pimozide
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of pimozide.(1)
CLINICAL EFFECTS: Concurrent administration of a moderate inhibitor of CYP3A4 may result in elevated levels of pimozide, which may result in prolongation of the QTc interval and potentially life-threatening ventricular arrhythmias.(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: Avoid concurrent use, 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, e.g. correct electrolyte disturbances, use the lowest effective dose of pimozide, and discontinue other concurrent QT prolonging agents or CYP3A4 inhibitors if possible. Consider ECG to evaluate baseline and/or concurrent QT prolongation risk. Monitor patients on the combination and counsel patients accordingly.
DISCUSSION: Pimozide is metabolized at CYP3A.(1,4) Elevated levels of pimozide may prolong the QTc interval resulting in life-threatening ventricular arrhythmias.(1) Moderate inhibitors of CYP3A4 include: avacopan, berotralstat, conivaptan, diltiazem, duvelisib, fedratinib, fosnetupitant, imatinib, isavuconazonium, lenacapavir, netupitant, rilzabrutinib, schisandra, tofisopam, treosulfan and verapamil.(5,6)
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 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/Pralsetinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Strong and moderate CYP3A4 inhibitors (including combined moderate CYP3A4 and P-glycoprotein (P-gp) inhibitors) may inhibit the metabolism of pralsetinib.(1)
CLINICAL EFFECTS: Concurrent administration of a strong or moderate CYP3A4 inhibitor (including combined moderate CYP3A4 and P-gp inhibitors) may result in elevated levels of and toxicity from pralsetinib, including QTc prolongation which may lead to potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP). 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 strong or moderate CYP3A4 inhibitors (including combined moderate CYP3A4 and P-gp inhibitors) should be avoided.(1) If coadministration with a strong or moderate CYP3A4 inhibitor cannot be avoided, use with caution and reduce the dose of pralsetinib as follows: -If the current dose is 400 mg once daily, decrease the dose to 300 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 voriconazole 400 mg twice daily for 1 day then 200 mg twice daily (a strong CYP3A inhibitor) resulted in 122% and 20% increase in pralsetinib area-under-curve (AUC) and maximum concentration (Cmax), respectively.(1) Fluconazole 400 mg daily (a moderate CYP3A4 inhibitor) increased pralsetinib AUC and Cmax by 71% and 15%, respectively.(1) Verapamil 80 mg three times daily (a moderate CYP3A4 and P-glycoprotein inhibitor) increased pralsetinib AUC and Cmax by 108% and 60%, respectively.(1) Strong CYP3A4 inhibitors linked to this monograph include: boceprevir, ensitrelvir, idelalisib, nelfinavir, relacorilant, and troleandomycin.(5,6) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, clofazimine, conivaptan, darunavir, duvelisib, fedratinib, fosamprenavir, fosnetupitant, imatinib, letermovir, netupitant, nilotinib, rilzabrutinib, stiripentol, tofisopam, treosulfan, and voxelotor.(5,6) Dual moderate CYP3A4 and P-gp inhibitors include: berotralstat, diltiazem, fluvoxamine, isavuconazonium, lenacapavir, schisandra, and verapamil.(5,6)
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 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.
Avacopan/Simvastatin (<=20 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Avacopan is a moderate CYP3A4 inhibitor and may decrease the metabolism of simvastatin.(1)
CLINICAL EFFECTS: Concurrent avacopan may result in elevated levels of simvastatin, which may result in myopathy and rhabdomyolysis.(1)
PREDISPOSING FACTORS: The risk for myopathy or 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 myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.
PATIENT MANAGEMENT: When used concurrently with simvastatin, limit the dose of simvastatin to 10 mg daily (or 20 mg daily for patients who have previously tolerated simvastatin 80 mg daily for at least one year.)(1) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine.
DISCUSSION: In a study, avacopan 60 mg twice daily with food was administered for 7 days with simvastatin. Since it takes 13 weeks to reach steady state, this high dose of avacopan was used to achieve systemic levels similar to those achieved at steady state with a dose of 30 mg twice daily with food. Avacopan increased the area-under-curve (AUC) and maximum concentration (Cmax) of simvastatin by 3.53-fold and 3.20-fold, respectively.(1)
Moderat Cyp3a4 Inhibitor/Vanzacaftor-Tezacaftor-Deutivacafto
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of vanzacaftor-tezacaftor-deutivacaftor. Vanzacaftor, tezacaftor, and deutivacaftor are CYP3A substrates.(1)
CLINICAL EFFECTS: Concurrent use of a moderate 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 moderate CYP3A4 inhibitors requires a dose adjustment. If concurrent use is warranted, the following dose adjustments are recommended: -For age 6 to less than 12 years old AND less than 40 kg - Two tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg every other day; -For age 6 to less than 12 years old AND greater than or equal to 40 kg - One tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every other day; -For age 12 years and older AND any weight - One tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every other day.(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) Moderate inhibitors of CYP3A4 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, verapamil, and voxelotor.(2-4)
Moderate And Weak Cyp3a4 Inhibitors/Tacrolimus
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate and weak inhibitors of CYP3A4 may inhibit the metabolism of tacrolimus.(1)
CLINICAL EFFECTS: Concurrent use of a CYP3A4 inhibitor may result in elevated levels of and toxicity from tacrolimus, including nephrotoxicity, neurotoxicity, and prolongation of the QTc interval and 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 US manufacturer of tacrolimus recommends monitoring tacrolimus whole blood trough concentrations and reducing tacrolimus dose if needed.(1) 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 26 renal transplant recipients, conjugated estrogens 3.75 mg daily increased the tacrolimus dose-corrected concentration of tacrolimus by 85.6%. Discontinuation of the conjugated estrogens led to a decrease in tacrolimus concentration of 46.6%.(3) A case report describes a 65-year-old kidney transplant recipient who was stable on tacrolimus 9 mg per day with trough levels of 5 to 7.5 ng/mL. Ten days after starting on estradiol gel 0.5 mg per day, her tacrolimus level rose to 18.3 ng/mL and serum creatinine (Scr) rose from 1.1 mg/dL at baseline to 2 mg/dL. Tacrolimus dose was reduced by 60%, and trough levels and Scr normalized after two weeks.(4) A study of 16 healthy volunteers found that elbasvir 50 mg/grazoprevir 200 mg daily increased the area-under-curve (AUC) of tacrolimus by 43%, while the maximum concentration (Cmax) of tacrolimus was decreased by 40%.(5) An analysis of FAERS data from 2004-2017, found a significant association between transplant rejection and concurrent use of tacrolimus and clotrimazole (reporting odds ratio 1.92, 95% CI). A retrospective study of 7 heart transplant patients on concurrent tacrolimus and clotrimazole troche showed a significant correlation between tacrolimus trough concentration and AUC after clotrimazole discontinuation. Tacrolimus clearance and bioavailability after clotrimazole discontinuation was 2.2-fold greater (0.27 vs. 0.59 L/h/kg) and the trough concentration decreased from 6.5 ng/mL at 1 day to 5.3 ng/mL at 2 days after clotrimazole discontinuation.(7) A retrospective study of 26 heart transplant patients found that discontinuation of concurrent clotrimazole with tacrolimus in the CYP3A5 expresser group had a 3.3-fold increase in apparent oral clearance and AUC of tacrolimus (0.27 vs. 0.89 L/h/kg) compared to the CYP3A5 non expresser group with a 2.2-fold mean increase (0.18 vs. 0.39 L/h/kg).(8) A study of 6 adult kidney transplant recipients found that clotrimazole (5-day course) increased the tacrolimus AUC 250% and the blood trough concentrations doubled (27.7 ng/ml versus 27.4 ng/ml). Tacrolimus clearance decreased 60% with coadministration of clotrimazole.(9) A case report describes a 23-year-old kidney transplant recipient who was stable on tacrolimus 5 mg twice daily, mycophenolate mofetil 30 mg daily, prednisone (30 mg daily tapered over time to 5 mg), and clotrimazole troche 10 mg four times daily. Discontinuation of clotrimazole resulted in a decrease in tacrolimus trough levels from 13.7 ng/ml to 5.4 ng/ml over a period of 6 days. Clotrimazole was restarted with tacrolimus 6 mg resulting in an increased tacrolimus level of 19.2 ng/ml.(10) A retrospective study in 95 heart transplant recipients on concurrent clotrimazole and tacrolimus found a median tacrolimus dose increase of 66.7% was required after clotrimazole discontinuation. Tacrolimus trough concentration was found to have decreased 42.5% after clotrimazole discontinuation.(11) A retrospective study in 65 pancreas transplant patients on concurrent tacrolimus, clotrimazole, cyclosporine, and prednisone found that clotrimazole discontinuation at 3 months after transplantation may cause significant tacrolimus trough level reductions.(12) A case report describes a 6-year-old kidney transplant recipient who was on a regimen of tacrolimus and mycophenolate mofetil. The patient was started letermovir 240 mg via G-tube 2 months post kidney transplant. One week after starting letermovir, the routine tacrolimus level showed a supratherapeutic concentration of 22.9 ng/L. A 36% dose reduction of tacrolimus was required. Upon discontinuation of letermovir, the tacrolimus level decreased by 42%.(13) Moderate CYP3A4 inhibitors linked to this monograph include: berotralstat, conivaptan, fluvoxamine, lenacapavir, letermovir, netupitant, nirogacestat, sevabertinib, stiripentol, and tofisopam.(6) Weak CYP3A4 inhibitors linked to this monograph include: avacopan, baikal skullcap, berberine, bicalutamide, blueberry, brodalumab, camizestrant, chlorzoxazone, cimetidine, cranberry juice, daclatasvir, daridorexant, delavirdine, diosmin, elinzanetant, estrogens, flibanserin, fostamatinib, ginkgo biloba, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lazertinib, linagliptin, lomitapide, lumateperone, lurasidone, peppermint oil, piperine, propiverine, ranitidine, resveratrol, rimegepant, simeprevir, sitaxsentan, skullcap, ticagrelor, tolvaptan, trofinetide, viloxazine, and vonoprazan-amoxicillin.(6)
Moderate Cyp3a4 Inhibitors/Abemaciclib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Abemaciclib is a substrate of CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of abemaciclib.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels and toxicity from abemaciclib.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of abemaciclib recommends monitoring for adverse reactions and consider a dose reduction of abemaciclib dose in 50 mg decrements as detailed in prescribing information (based on starting dose, previous dose reductions, and combination or monotherapy use) with concurrent use of moderate CYP3A4 inhibitors.(1) Monitor patient for signs and symptoms of abemaciclib toxicity with concurrent use.
DISCUSSION: Abemaciclib is a substrate of CYP3A4.(1) Concurrent administration of verapamil and diltiazem (moderate CYP3A4 inhibitors) are predicted to increase the relative adjusted unbound area-under-curve (AUC) of abemaciclib and its active metabolites (M2, M18, and M20) by approximately 1.6-fold and 2.4-fold, respectively.(1) Concurrent administration of ketoconazole (a strong CYP3A4 inhibitor) is predicted to increase the 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 2.5-fold.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, avacopan, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2,3)
Moderate Cyp3a4 Inhibitors/Avanafil (<= 50 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of avanafil.(1)
CLINICAL EFFECTS: The concurrent administration of a moderate CYP3A4 inhibitor may result in elevated levels of avanafil, which may result in increased adverse effects such as hypotension, visual changes, and priapism.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of avanafil states that in patients receiving moderate inhibitors of CYP3A4, the dose of avanafil should be limited to 50 mg in 24 hours.(1)
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 2C19, increased the Cmax and AUC of a single dose of avanafil (50 mg) by 2-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) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, grapefruit juice, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(1-3)
Moderate Cyp3a4 Inhibitors/Avapritinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of avapritinib.(1)
CLINICAL EFFECTS: Concurrent use of avapritinib with a moderate 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 or moderate CYP3A4 inhibitors. If coadministration of avapritinib with a moderate CYP3A4 inhibitor cannot be avoided, reduce the dose of avapritinib to 100 mg once daily for treatment of gastrointestinal stromal tumors or 50 mg once daily for treatment of advanced systemic mastocytosis.(1)
DISCUSSION: Coadministration of avapritinib 300 mg once daily with fluconazole 200 mg once daily, a moderate CYP3A4 inhibitor, is predicted to increase avapritinib AUC by 210% at steady state.(1) Moderate inhibitors of CYP3A4 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.(2,3)
Moderate Cyp3a4 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: This interaction is expected to be more severe in patients who are CYP2D6 poor metabolizers, or who receive concomitant treatment with a strong or moderate CYP2D6 inhibitor (e.g. bupropion, fluoxetine, paroxetine, quinidine) in addition to treatment with a moderate CYP3A4 inhibitor.
PATIENT MANAGEMENT: The US manufacturer of brexpiprazole recommends the following dose adjustments for patients who are receiving a moderate CYP3A4 inhibitor: - in patients taking a moderate 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. The dose of brexpiprazole should be adjusted to its original level if the CYP3A4 inhibitor is discontinued.(1) No empiric dosage adjustment is recommended in other patients.
DISCUSSION: Coadministration of ketoconazole, a strong inhibitor of CYP3A4, increased the area-under-curve (AUC) of brexpiprazole approximately 2-fold.(1) Moderate CYP3A4 inhibitors linked to this monograph include aprepitant, avacopan, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.
Moderate Cyp3a4 Inhibitors/Bromocriptine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of bromocriptine.
CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor may result in increased levels of bromocriptine, which may result in increased side effects of these agents.
PREDISPOSING FACTORS: Patients receiving the maximum recommended (or higher than recommended) dosages of ergotamine derivatives may be at a higher risk of adverse effects from this combination.
PATIENT MANAGEMENT: Use caution with concurrent therapy with bromocriptine with azole antifungals. The US manufacturer of bromocriptine states use caution when co-administering drugs that are inhibitors of CYP3A4. Bromocriptine dose should not exceed 1.6 mg per day when used with a moderate CYP3A4 inhibitor. Concomitant use of strong CYP3A4 inhibitors should be avoided. Ensure adequate washout of strong CYP3A4 inhibitor drug before initiating bromocriptine.(1)
DISCUSSION: A study in five healthy subjects found that concurrent administration of erythromycin and bromocriptine resulted in a 268% increase in area-under-curve (AUC) for bromocriptine and a 4.6-fold increase in bromocriptine maximum concentration (Cmax).(2) Inhibition of ergotamine derivative metabolism by moderate inhibitors would also be expected, but to a lesser degree. Moderate CYP3A4 inhibitors linked to this monograph are aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(3,4)
Moderate Cyp3a4 Inhibitors/Cabergoline
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of cabergoline.
CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor may result in increased levels of cabergoline, which may result in increased side effects of cabergoline.
PREDISPOSING FACTORS: Patients receiving the maximum recommended (or higher than recommended) dosages of cabergoline may be at a higher risk of adverse effects from this combination.
PATIENT MANAGEMENT: Use caution with concurrent therapy with cabergoline and moderate CYP3A4 inhibitors.
DISCUSSION: Cabergoline metabolism has been shown to be inhibited by strong CYP3A4 inhibitors, including macrolides and itraconazole.(1,2) Inhibition of cabergoline metabolism by moderate inhibitors would also be expected, but to a lesser degree. Moderate CYP3A4 inhibitors linked to this monograph are aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(3,4)
Moderate Cyp3a4 Inhibitors/Capivasertib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the CYP3A4 metabolism of capivasertib.(1)
CLINICAL EFFECTS: Concurrent use of moderate 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: Concomitant use of capivasertib with moderate CYP3A4 inhibitors requires a dose reduction of capivasertib. 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) Moderate inhibitors of CYP3A4 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, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)
Moderate Cyp3a4 Inhibitors/Dapoxetine (<= 30 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of dapoxetine.(1-3)
CLINICAL EFFECTS: Concurrent use of a moderate 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: The manufacturers of dapoxetine state that the dose of dapoxetine should not exceed 30 mg daily if coadministered with moderate CYP3A4 inhibitors.(1-3)
DISCUSSION: The impact of moderate CYP3A4 inhibitors on the pharmacokinetics of dapoxetine has not been investigated in clinical studies.(1-3) 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) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(4,5)
Moderate Cyp3a4 Inhibitors/Daraxonrasib (<=200 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. Moderate CYP3A4 inhibitors may inhibit the metabolism of daraxonrasib.(1)
CLINICAL EFFECTS: Concurrent use of moderate 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 moderate CYP3A4 inhibitors, reduce the dose of daraxonrasib to 200 mg once daily. If the inhibitor is discontinued, resume the previous dose of daraxonrasib after 3 to 5 half-lives of the inhibitor.(1)
DISCUSSION: In a pharmacokinetic model, fluconazole 200 mg twice daily (a moderate CYP3A inhibitor) increased the area under curve (AUC) of daraxonrasib by 1.5-fold.(1) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, crizotinib, darunavir, duvelisib, fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, stiripentol, tofisopam, treosulfan, and voxelotor.(2-3)
Moderate Cyp3a4 Inhibitors/Daridorexant (<=25 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of daridorexant.(1)
CLINICAL EFFECTS: Concurrent use of a moderate 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 dose of daridorexant should be limited to 25 mg daily when used with a moderate CYP3A4 inhibitor.(1)
DISCUSSION: Daridorexant is a CYP3A4 substrate. In a PKPB model, concurrent use of daridorexant with diltiazem, a moderate CYP3A4 inhibitor, increased daridorexant area-under-curve (AUC) and maximum concentration (Cmax) by 2.4-fold and 1.4-fold, respectively.(1) 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, treosulfan, and verapamil.(2)
Moderate Cyp3a4 Inhibitors/Elinzanetant
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Elinzanetant is metabolized via CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of elinzanetant.(1,2)
CLINICAL EFFECTS: Concurrent use of elinzanetant with moderate CYP3A4 inhibitors may result in an increase in exposure of elinzanetant.(1,2)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The Canadian(1) and US(2) manufacturers of elinzanetant recommends reducing the dose of elinzanetant to 60 mg once daily at bedtime when coadministered with moderate CYP3A4 inhibitors. After discontinuation of the moderate inhibitor (after 3 to 5 half lives of the inhibitor), elinzanetant should be used at the usual dose of 120 mg once daily.(1,2)
DISCUSSION: Concomitant use of erythromycin (moderate CYP3A4 inhibitor) increased elinzanetant 120 mg area-under-curve (AUC) and maximum concentration (Cmax) by 3-fold and 2-fold, respectively. Concomitant use of erythromycin with elinzanetant 60 mg increased elinzanetant AUC by 1.4-fold.(1) 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, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)
Moderate Cyp3a4 Inhibitors/Finerenone
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of finerenone.(1)
CLINICAL EFFECTS: Concurrent use of finerenone with a moderate inhibitor of CYP3A4 increases finerenone concentrations and may increase the risk of toxicity (e.g., hyperkalemia, hypotension).(1)
PREDISPOSING FACTORS: Severe renal disease and concurrent use of potassium supplements increase the risk for hyperkalemia.
PATIENT MANAGEMENT: The manufacturer of finerenone states that use with moderate CYP3A4 inhibitors should be closely monitored. Check serum potassium during drug initiation or dosage adjustment of either finerenone or the moderate CYP3A4 inhibitor. Dose adjustment of finerenone may be necessary.(1)
DISCUSSION: Concurrent use of finerenone with erythromycin, a moderate CYP3A4 inhibitor, increased finerenone area-under-curve (AUC) by 248% and maximum concentration (Cmax) by 88%.(1) Concurrent use of finerenone with verapamil, a moderate CYP3A4 inhibitor, increased finerenone AUC by 170% and Cmax by 122%.(1) 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, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)
Moderate Cyp3a4 Inhibitors/Gepirone
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 gepirone.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase the levels of and effects from gepirone, including QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP). 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: If gepirone is used concurrently with a moderate CYP3A4 inhibitor, reduce the dose of gepirone by 50%.(1) 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 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, verapamil (80 mg 3 times daily), a moderate CYP3A4 inhibitor, increased both the maximum concentration (Cmax) and area-under-curve (AUC) of gepirone 18.2 mg by about 2.75-fold.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)
Moderate Cyp3a4 Inhibitors/Ibrutinib
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 ibrutinib.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase levels of and effects from ibrutinib.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Concurrent use of moderate CYP3A4 inhibitors in patients undergoing therapy with ibrutinib requires a dose adjustment.(1) If a moderate CYP3A4 inhibitor is required for B-cell malignancies treatment, reduce the dose of ibrutinib to 280 mg daily.(1) If a moderate CYP3A4 inhibitor is required for chronic graft versus host disease treatment, reduce the dose of ibrutinib in patients 12 years and older to 420 mg once daily, and in patients 1 year to 12 years old to 240 mg/m2 once daily.(1) After discontinuation of a CYP3A4 inhibitor, resume previous dose of ibrutinib.(1)
DISCUSSION: The coadministration of multiple doses of erythromycin (moderate CYP3A inhibitor) increased ibrutinib's concentration maximum (Cmax) and area-under-curve (AUC) by 3.4-fold and 3-fold.(1) In a case report, concomitant administration of ibrutinib and verapamil/trandolapril resulted in ibrutinib toxicity consisting of nausea, dizziness, malaise, and severe diarrhea.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, casopitant, clofazimine, clotrimazole, conivaptan, crizotinib, darunavir, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, grapefruit juice, imatinib, isavuconazonium, ledipasvir, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(1,3,4)
Moderate Cyp3a4 Inhibitors/Larotrectinib
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 larotrectinib.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase systemic exposure and the risk for larotrectinib toxicities such as neurotoxicity or hepatotoxicity.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Patients receiving a moderate CYP3A4 inhibitor concurrently with larotrectinib should be monitored for adverse effects more frequently. A dose reduction may be needed based on the severity of adverse effects. Refer to prescribing information for dosage modifications.
DISCUSSION: In a drug interaction study in healthy subjects, coadministration of itraconazole (a strong CYP3A4 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) Fluconazole (a moderate CYP3A4 inhibitor) is predicted to increase the AUC and Cmax of larotrectinib by 2.7-fold and 1.9-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)
Moderate Cyp3a4 Inhibitors/Lumateperone (<=21 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of lumateperone.(1)
CLINICAL EFFECTS: Concurrent use of lumateperone with moderate CYP3A4 inhibitors increases lumateperone exposure, which may increase the risk of adverse reactions.(1)
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 21 mg once daily in patients receiving moderate CYP3A4 inhibitors.(1)
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) Moderate inhibitors of CYP3A4 include: aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)
Moderate Cyp3a4 Inhibitors/Macitentan
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Macitentan is primarily metabolized by CYP3A4, with minor contributions from CYP2C8, CYP2C9, and CYP2C19. Moderate inhibitors of CYP3A4 may inhibit the metabolism of macitentan.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in elevated levels and increased effects of macitentan, including hepatotoxicity and fluid retention.(1)
PREDISPOSING FACTORS: Concomitant use of a moderate CYP2C9 inhibitor increases the magnitude of this interaction and the risk of adverse events.
PATIENT MANAGEMENT: The US manufacturer of macitentan states that concurrent use of both a moderate CYP2C9 inhibitor and a moderate CYP3A4 inhibitor should be avoided.(1) The Australian and Canadian manufacturers of macitentan state caution should be exercised when macitentan is administered concomitantly with a moderate CYP3A4 inhibitor.(2,3) While the manufacturer does not provide recommendations for concurrent use of a moderate CYP3A4 inhibitor alone, it would be prudent to use caution and monitor for adverse effects.
DISCUSSION: Based on pharmacokinetic (PBPK) modeling, dual moderate inhibitors of CYP2C9 and CYP3A4 such as fluconazole are predicted to increase macitentan exposure by 4-fold.(1) Pretreatment with ketoconazole increased the area-under-curve (AUC) and maximum concentration (Cmax) of macitentan by approximately 2.3 and 1.3-fold, respectively.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(4)
Moderate Cyp3a4 Inhibitors/Mavorixafor
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of mavorixafor.(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 cimetidine, diltiazem, fluvoxamine, isavuconazonium, schisandra, and verapamil.(2)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase the levels and effects of mavorixafor, including thrombocytopenia and 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: When used concomitantly with moderate CYP3A4 inhibitors, monitor more frequently for mavorixafor adverse effects and reduce the dose in 100 mg increments, if necessary, but not to a dose less than 200 mg.(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: There are no clinical studies for the combination of mavorixafor and moderate CYP3A4 inhibitors. 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) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, cimetidine, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil and voxelotor.(2,5)
Moderate 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) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(4)
Moderate Cyp3a4 Inhibitors/Oral Lefamulin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of oral lefamulin.(1,2)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in elevated levels and increased effects of lefamulin, such as QT prolongation.
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).(4)
PATIENT MANAGEMENT: The US manufacturer of lefamulin states that oral lefamulin coadministration with moderate inhibitors of CYP3A4 should be monitored for adverse effects.(1) During concomitant therapy with a moderate 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: Coadministration of ketoconazole (strong CYP3A4 inhibitor) with lefamulin tablets increased lefamulin area-under-the-curve (AUC) and maximum concentration (Cmax) by 165% and 58%.(1) Moderate inhibitors of CYP3A4 include: amprenavir, avacopan, conivaptan, duvelisib, fedratinib, fosamprenavir, fosnetupitant, imatinib, lenacapavir, letermovir, netupitant, schisandra, stiripentol, tofisopam, and treosulfan.(1,3)
Moderate Cyp3a4 Inhibitors/Oveporexton (<=0.5 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Oveporexton is metabolized by CYP3A4. Moderate CYP3A4 inhibitors may inhibit the metabolism of oveporexton.(1)
CLINICAL EFFECTS: Concurrent use of moderate 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: In patients on concomitant moderate CYP3A4 inhibitors with oveporexton, reduce the dosage of oveporexton to 0.5 mg after awakening and then 0.5 mg three to five hours later (maximum recommended dosage is 1 mg per day).(1)
DISCUSSION: In a study, fluconazole (a moderate CYP3A inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of oveporexton by 2.9-fold and 1.5-fold, respectively. Oveporexton half-life was increased by about 2-fold.(1) Moderate inhibitors of CYP3A4 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.(2-3)
Moderate Cyp3a4 Inhibitors/Palovarotene
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of palovarotene.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in elevated levels of and toxicity 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 moderate CYP3A4 inhibitors with palovarotene should be avoided. If concurrent use cannot be avoided, reduce the dose of palovarotene by half, according to the US prescribing information.(1)
DISCUSSION: In a clinical trial, erythromycin, a moderate CYP3A4 inhibitor, increased the maximum concentration (Cmax) and area-under-curve (AUC) of palovarotene by 1.6- and 2.5-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)
Moderate Cyp3a4 Inhibitors/Pyrotinib (<= 80 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Pyrotinib is metabolized via CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of pyrotinib.(1)
CLINICAL EFFECTS: Concurrent use of pyrotinib with moderate 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 moderate CYP3A4 inhibitors requires a dose adjustment. Reduce the dose of pyrotinib to 80 mg daily with moderate CYP3A4 inhibitors.(1)
DISCUSSION: In a clinical study of healthy subjects, coadministration of pyrotinib with fluconazole, a moderate CYP3A4 inhibitor, resulted in a 3.6-fold increase in area-under-curve (AUC) and a 2.16-fold increase in maximum concentration (Cmax).(1) Moderate inhibitors of CYP3A4 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, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)
Moderate Cyp3a4 Inhibitors/Quetiapine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of quetiapine. Quetiapine is a sensitive substrate for CYP3A4 and so an approximately 2-fold or higher increase in exposure (AUC, area-under-curve) is possible when quetiapine is given with a moderate CYP3A4 inhibitor.(1-4)
CLINICAL EFFECTS: Concurrent use of a strong or moderate CYP3A4 inhibitor may result in elevated levels of and toxicity from quetiapine, including potentially life-threatening cardiac arrhythmias such as torsades de pointes.(2,3)
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: Monitor patients when moderate inhibitors of CYP3A4 are co-prescribed with quetiapine as the magnitude of the interaction is highly variable between patients.(6) 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. 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).
DISCUSSION: In a study in 19 Chinese patients with schizophrenia, patients received quetiapine (200 mg twice daily) alone and with erythromycin (500 mg 3 times daily, a moderate inhibitor of CYP3A4). Erythromycin increased the quetiapine maximum concentration (Cmax)by 68%(range approximately 20-130%), area-under-curve (AUC) 129% (range approximately 20-300%), and half-life by 92% (range approximately 0-250%). Quetiapine clearance decreased 52% (range approximately -15 to -80%).(6) Moderate inhibitors of CYP3A4 include: aprepitant, avacopan, berotralstat, conivaptan, diltiazem, duvelisib, fedratinib, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(4)
Moderate Cyp3a4 Inhibitors/Ranolazine (<=500 Mg Bid)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of ranolazine. Verapamil may also increase the absorption of ranolazine by inhibiting P-glycoprotein.(1)
CLINICAL EFFECTS: Concurrent use of moderate inhibitors of CYP3A4 may result in elevated levels of and clinical effects from ranolazine. Elevated ranolazine levels may result in QTc prolongation, which may result in life-threatening cardiac arrhythmia, 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.(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).(2)
PATIENT MANAGEMENT: The US manufacturer of ranolazine states that the dosage of ranolazine should be limited to 500 mg twice daily in patients receiving moderate inhibitors of CYP3A4.(1) 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 diltiazem, a moderate inhibitor of CYP3A4, at daily doses of 180 mg to 360 mg increased plasma levels of ranolazine (1000 mg twice daily) by 50% and 130%, respectively.(1,3) In healthy subjects, concurrent ranolazine (1000 mg twice daily) had no effects on the pharmacokinetics of diltiazem (60 mg three times daily).(1) Concurrent use of verapamil (120 mg three times daily) increased plasma levels of ranolazine (750 mg twice daily) by 100%.(1) In a study in 12 healthy males, ranolazine immediate release (IR, 240 mg three times daily) had no effect on diltiazem (60 mg three times daily) pharmacokinetics. However, at ranolazine IR steady state, diltiazem increased ranolazine IR area under the curve (AUC) by 85%, on average, and increased maximum concentration (Cmax) by 1.9-fold and minimum concentration (Cmin) by 2.1-fold.(4) In a study in 12 subjects, ranolazine sustained release (SR, 500 mg twice daily) had no effect on diltiazem (60 mg three times daily) pharmacokinetics. However, at ranolazine steady state, diltiazem increased ranolazine SR Cmax, concentration minimum (Cmin), AUC by 80%, 216%, and 90%, on average, respectively.(4) In a study in 8 healthy males, diltiazem modified release (MR, 180 mg, or 240 mg, or 360 mg, once daily) increased ranolazine sustained release (SR, 1000 mg twice daily) AUC by 52%, 93%, and 139%, respectively. Ranolazine half-lives did not show any consistent trend of changes with increasing doses of diltiazem.(4) In a study of patients with severe chronic angina, the addition of ranolazine 750 mg twice daily or 1,000 mg twice daily along with their standard dose of diltiazem (180 mg once daily) provided additional antianginal relief, without evident adverse, long-term survival consequences over 1 to 2 years of therapy.(5) Ranolazine-induced QTc prolongation is dose and concentration-related.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, erythromycin, dronedarone, duvelisib, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, treosulfan and verapamil.(1,3,6,7)
Moderate Cyp3a4 Inhibitors/Rimegepant
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Rimegepant is primarily metabolized by CYP3A4. Moderate inhibitors of CYP3A4 may decrease the metabolism of rimegepant.(1)
CLINICAL EFFECTS: Concurrent use of moderate 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 a second dose of rimegepant within 48 hours of a first dose when used concomitantly with moderate CYP3A4 inhibitors.(1)
DISCUSSION: In a drug interaction study (n=23), fluconazole, a moderate CYP3A4 inhibitor, increased rimegepant mean area-under-curve from time 0 to infinity (AUC 0-inf) by 1.8-fold (90% confidence interval 1.68-1.93), with no impact on the maximum concentration (Cmax) (1.04-fold; 90% CI 0.94-1.15). (2) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, and treosulfan.(3-4)
Moderate Cyp3a4 Inhibitors/Sebetralstat
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of sebetralstat.(1)
CLINICAL EFFECTS: Concurrent use of CYP3A4 inhibitors may increase the levels and effects of sebetralstat including 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 when used concomitantly with moderate CYP3A4 inhibitors, reduce the dose of sebetralstat to one dose of 300 mg (one tablet) orally at the earliest recognition of a hereditary angioedema attack. A second dose of 300 mg (one tablet) may be taken at least 3 hours after the first dose if response is inadequate, or if symptoms worsen or recur.(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 verapamil (240 mg once daily for 6 days), a moderate CYP3A4 inhibitor, increased sebetralstat maximum concentration (Cmax) and area-under-curve (AUC) by 1.8-fold and 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) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, rilzabrutinib, schisandra, tofisopam, treosulfan, verapamil, voxelotor.(3-4)
Moderate Cyp3a4 Inhibitors/Suvorexant (<= 10 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of suvorexant.(1)
CLINICAL EFFECTS: Concurrent use of an agent that is a moderate inhibitor of CYP3A4 may result in elevated levels of and clinical effects of suvorexant.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of suvorexant recommends a starting dose of 5 mg daily and a maximum dose of 10 mg daily in patients receiving concurrent therapy with a moderate CYP3A4 inhibitor.(1)
DISCUSSION: Diltiazem, a moderate inhibitor of CYP3A4, increased suvorexant AUC and Cmax by approximately 2-fold and 1.25-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, erythromycin, duvelisib, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(1-3)
Moderate Cyp3a4 Inhibitors/Suzetrigine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Suzetrigine and M6-SUZ (active metabolite of suzetrigine) are CYP3A4 substrates. Moderate CYP3A4 inhibitors increase suzetrigine and M6-SUZ exposures, which may cause suzetrigine adverse reactions.(1)
CLINICAL EFFECTS: The concurrent administration of a moderate 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: When possible, avoid the use of moderate CYP3A4 inhibitors with suzetrigine. The US manufacturer of suzetrigine states when suzetrigine is administered to patients taking moderate CYP3A4 inhibitors reduce the suzetrigine dose as follows: -Dose 1: The recommended starting dose of suzetrigine is 100 mg orally. -Dose 2, 3, and 4: Starting 12 hours after the initial dose, take 50 mg of suzetrigine orally every 12 hours. -Dose 5 and Subsequent Doses: Starting 12 hours after Dose 4, take 50 mg of suzetrigine orally every 24 hours.(1)
DISCUSSION: In a PKPB model, concomitant administration of fluconazole (a moderate CYP3A4 inhibitor) with suzetrigine with the recommended dosage modification is predicted to increase the area-under-curve (AUC) of suzetrigine and active metabolite M6-SUZ by 1.5-fold and 1.2-fold, respectively, while the maximum concentration (Cmax) of suzetrigine and M6-SUZ by 1.4-fold and 1.1-fold, respectively, when compared to the regular recommended dosage in the absence of fluconazole.(1) 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, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2-3)
Moderate 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 moderate 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: Patients who are also on a drug that is a strong inhibitor of CYP2C19 are at higher risk of increased tofacitinib levels and effects.
PATIENT MANAGEMENT: In patients taking a moderate CYP3A4 inhibitor but not also a strong CYP2C19 inhibitor, no dosage modification of tofacitinib is recommended. Concurrent therapy with tofacitinib should be approached with caution as an interaction is likely.(1) In patients taking a strong CYP2C19 inhibitor in addition to a moderate CYP3A4 inhibitor, the 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. Use the lowest effective dosage for the shortest possible duration needed to maintain 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 recommendations with Xeljanz. - 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)
DISCUSSION: In a study, administration of ketoconazole (a strong CYP3A4 inhibitor), increased the area-under-curve (AUC) of tofacitinib by more than 2-fold. Fluconazole (a moderate CYP3A4 and strong CYP2C19 inhibitor) increased tofacitinib AUC by about 1.75-fold.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, erythromycin, fluvoxamine, fosamprenavir, fosnetupitant, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nirogacestat, schisandra, stiripentol, tofisopam, verapamil, and voxelotor.(3-4)
Moderate Cyp3a4 Inhibitors/Tretinoin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of tretinoin.(1)
CLINICAL EFFECTS: Concurrent use of a moderate 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 manufacturer of tretinoin recommends monitoring patients taking a moderate CYP3A4 inhibitor in combination with tretinoin 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)
DISCUSSION: In 13 patients on tretinoin for 4 weeks, single-dose ketoconazole (400 to 1200 mg) (strong CYP3A4 inhibitor) increased tretinoin area-under-curve (AUC) by 72%.(1) There are no clinical pharmacokinetic studies on the combination of tretinoin with a moderate CYP3A4 inhibitor. The US manufacturer of tretinoin states increased tretinoin toxicity following concomitant use of tretinoin with certain antimycotics that are moderate CYP3A4 inhibitors has been reported post-marketing.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, and treosulfan.(2-3)
Moderate Cyp3a4 Inhibitors/Ubrogepant (<= 50 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of ubrogepant.(1)
CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor may result in elevated levels of ubrogepant.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when used concomitantly with moderate CYP3A4 inhibitors. Initial dose of ubrogepant should not exceed 50 mg. A second dose should be avoided within 24 hours of the first dose when used concurrently with moderate CYP3A4 inhibitors.(1)
DISCUSSION: Co-administration with verapamil, a moderate CYP3A4 inhibitor, resulted in a 3.5-fold and 2.8-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively.(1) Moderate inhibitors of CYP3A4 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.(2-4)
Moderate Cyp3a4 Inhibitors/Zanubrutinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of zanubrutinib.(1)
CLINICAL EFFECTS: Concurrent use of a moderate 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 to 80 mg twice daily when co-administered with moderate CYP3A4 inhibitors. Modify the dose as recommended by prescribing information for adverse reactions.(1)
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. It is predicted co-administration with fluconazole 200 mg daily, a moderate CYP3A4 inhibitor, would increase zanubrutinib Cmax and AUC by 179% and 177%, respectively.(1) Moderate inhibitors of CYP3A4 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.(2-4)
Moderate Cyp3a4 Inhibitors/Ziftomenib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of ziftomenib.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase the levels and effects of ziftomenib, including differentiation syndrome, neutropenia, and 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 moderate CYP3A4 inhibitors should be monitored more closely for adverse reactions.(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) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, Schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)
Selected Cyp3a4 Inhibitors/Vardenafil (<= 5 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: CYP3A4 inhibitors may inhibit the metabolism of vardenafil by CYP3A4.(1-4)
CLINICAL EFFECTS: Concurrent use of CYP3A4 inhibitors may result in increased levels of and adverse effects from vardenafil, including hypotension, visual changes, and sustained erections.(1-4)
PREDISPOSING FACTORS: The interaction may be more severe in men older than 75 years.(4)
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 400 mg of itraconazole or ketoconazole and that a maximum dose of 5 mg of vardenafil every 24 hours should not be exceeded in patients taking 200 mg of itraconazole or ketoconazole.(1) For moderate CYP3A4 inhibitors, do not exceed a maximum dose of 5 mg of vardenafil every 24 hours.(1) Patients receiving concurrent therapy should be monitored for increased vardenafil effects. Note that other countries have stricter warnings. The Australian manufacturer of vardenafil states that vardenafil must not be taken with dosages of itraconazole or ketoconazole greater than 200 mg. A maximum dose of 5 mg of vardenafil should not be exceeded if used with lower dosages of itraconazole and ketoconazole.(2) The Canadian manufacturer of vardenafil states that the concurrent use of vardenafil with itraconazole or ketoconazole is contraindicated and that the dosage should not exceed 5 mg in patients taking erythromycin.(3) The UK manufacturer of vardenafil states that the concurrent use of vardenafil with either oral itraconazole or oral ketoconazole is contraindicated in men older than 75 years and should be avoided in all patients. The dosage of vardenafil should not exceed 5 mg in patients taking erythromycin.(4))
DISCUSSION: Concurrent use of ketoconazole (200 mg) with vardenafil (5 mg) increased the vardenafil area-under-curve (AUC) and maximum concentration (Cmax) by 10-fold and 4-fold, respectively.(1-4) Concurrent administration of erythromycin (500 mg three times daily) with vardenafil (5 mg) increased the AUC and Cmax of vardenafil by 4-fold and 3-fold, respectively.(1-4)
Selected Moderate Cyp3a4 Inhibitors/Acalabrutinib
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 acalabrutinib.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase levels of and effects from acalabrutinib.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Recommendations for management of this interaction vary in different regions. The US and Australian manufacturers of acalabrutinib state that the concurrent chronic use of moderate CYP3A4 inhibitors should be approached with caution. If a moderate CYP3A4 inhibitor is required, reduce the dose of acalabrutinib to 100 mg once daily.(1,2) The UK manufacturer of acalabrutinib states no dose adjustment is needed for concurrent use of acalabrutinib with moderate CYP3A4 inhibitors. Patients should be monitored closely for adverse effects.(3)
DISCUSSION: In a study with healthy volunteers, single-dose fluconazole 400 mg and isavuconazole 200 mg daily for 5 days (both moderate CYP3A4 inhibitors) increased the maximum concentration (Cmax) and area-under-curve (AUC) of acalabrutinib by 1.4- to 2-fold. The Cmax and AUC of the active metabolite ACP-5862 was decreased by 0.65- to 0.88-fold.(2) A physiologically based pharmacokinetic simulation with acalabrutinib and moderate CYP3A inhibitors (erythromycin, fluconazole, diltiazem) predicted that coadministration increases acalabrutinib Cmax and AUC by 2- to almost 3-fold.(1) In a study in healthy subjects, itraconazole (200mg once daily for 5 days, a strong inhibitor) increased the Cmax and AUC of acalabrutinib by 3.9-fold and 5.1-fold, respectively.(1) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, grapefruit juice, imatinib, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(4,5)
Selected Moderate Cyp3a4 Inhibitors/Cyclosporine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of cyclosporine.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in elevated levels of and toxicity from cyclosporine, including serious infections, nephrotoxicity, and hepatotoxicity.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: If cyclosporine is used with a moderate CYP3A4 inhibitor, dose adjustment of cyclosporine may be necessary to achieve the desired cyclosporine concentration.(1)
DISCUSSION: In a study, renal and cardiac patients required a cyclosporine dose reduction of 15% to 48% when diltiazem was co-administered to maintain a cyclosporine trough similar to cyclosporine alone.(2) In a study, cyclosporine required a 25% dose reduction when co-administered with fluconazole to maintain a goal serum concentration similar to cyclosporine alone.(3) Moderate inhibitors of CYP3A4 include: avacopan, berotralstat, clofazimine, duvelisib, fedratinib, fluvoxamine, oral lefamulin, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, and treosulfan.(4,5)
Selected Moderate Cyp3a4 Inhibitors/Selected Opioids
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 alfentanil, benzhydrocodone, fentanyl,(1) hydrocodone, meperidine,(2) oxycodone,(3) and sufentanil.(4)
CLINICAL EFFECTS: The concurrent administration of a CYP3A4 inhibitor may result in elevated levels of and toxicity from alfentanil, benzhydrocodone, fentanyl,(1,5) hydrocodone, meperidine,(2) oxycodone(3) and sufentanil(4), including somnolence and potentially fatal respiratory depression.
PREDISPOSING FACTORS: Heat.
PATIENT MANAGEMENT: Monitor patients receiving moderate CYP3A4 inhibitors for an extended period of time. Dosage adjustments should be made if warranted. 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.(4) 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.(6) 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).(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.(1)
DISCUSSION: Fentanyl(1) and oxycodone(3) are metabolized by the CYP3A4 isoenzyme. Moderate and strong inhibitors of this isoenzyme are expected to increase fentanyl(1) and oxycodone(3) levels. 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.(4) In a randomized study in 30 patients, continuous diltiazem (1 mcg/kg/min) infusion had no effect on epidural fentanyl consumption when compared to placebo. There were no significant differences in Visual Analogue Scores (VAS), Verbal Rating Scores (VRS), or incidence of side effects, although there was a trend towards increased nausea with concurrent diltiazem.(5) In a randomized study of coronary artery bypass patients, concurrent diltiazem (60 mg orally 2 hours before induction of anesthesia then 0.1 mg/kg/hr infusion) increased the area-under-curve (AUC) and half-life of alfentanil by 40% and 50%, respectively, when compared to placebo. Patients who received diltiazem were extubated an average of 2.5 hours later than in patients who received placebo.(8) In a study in 13 patients, administration of a single dose of verapamil (75mcg/kg to 150mcg/kg) had no significant effects on the pharmacodynamic effects of a single dose of fentanyl; however, individual patients had modest decreases in blood pressure.(9) In a case report, concurrent diltiazem and fentanyl produced delirium.(10) 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%.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, duvelisib, fedratinib, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(11,12)
Slt Moderate And Weak Cyp3a4 Inhibit/Sirolimus Protein-Bound
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate and weak CYP3A4 inhibitors may inhibit the metabolism of sirolimus by CYP3A4.(1)
CLINICAL EFFECTS: Concurrent use of moderate or weak CYP3A4 inhibitors may result in elevated levels of and side effects from sirolimus.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(1)
DISCUSSION: In an open, randomized, cross-over trial in 18 healthy subjects, concurrent single doses of diltiazem (120 mg) and sirolimus (10 mg) increased sirolimus area-under-curve (AUC) and maximum concentration (Cmax) by 60% and by 43%, respectively. Sirolimus apparent oral clearance and volume of distribution decreased by 38% and 45%, respectively. There were no effects on diltiazem pharmacokinetics or pharmacodynamics.(2) In a study in 26 healthy subjects, concurrent sirolimus (2 mg daily) with verapamil (180 mg twice daily) increased sirolimus AUC and Cmax by 2.2-fold and 2.3-fold, respectively. The AUC and Cmax of the active S-enantiomer of verapamil each increased by 1.5-fold. Verapamil time to Cmax (Tmax) was increased by 1.2 hours.(2) Moderate and weak CYP3A4 inhibitors linked to this monograph include: amlodipine, anamorelin, aprepitant, avacopan, azithromycin, berberine, berotralstat, bicalutamide, blueberry, brodalumab, camizestrant, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clofazimine, conivaptan, crizotinib, daclatasvir, daridorexant, delavirdine, diltiazem, diosmin, elinzanetant, estrogen, flibanserin, fluvoxamine, fosaprepitant, fosnetupitant, fostamatinib, ginkgo, givinostat, glecaprevir/pibrentasvir, gepotidacin, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lazertinib, oral lefamulin, lenacapavir, levamlodipine, linagliptin, lomitapide, lumateperone, lurasidone, mavorixafor, netupitant, nicardipine, omeprazole, osilodrostat, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, rimegepant, roxithromycin, scutellarin, sevabertinib, simeprevir, sitaxsentan, stiripentol, ticagrelor, tofisopam, tolvaptan, trofinetide, vonoprazan, and voxelotor.(3,4)
Slt Strong & Moderate 3A4 Inhibitors/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.(1)
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)
PREDISPOSING FACTORS: None determined.
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)
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.(2) Analysis of population pharmacokinetics indicated that the concurrent administration of diltiazem with cilostazol increased cilostazol concentrations by 53%. Concurrent administration of diltiazem and cilostazol decreased cilostazol clearance by 30%, increased the Cmax by 30%, and increased AUC by 40%.(1) 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.(3)
Strong And Moderate Cyp3a4 Inhibitors/Apixaban
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Apixaban is a substrate of CYP3A4 and P-glycoprotein (P-gp). It is about 20% metabolized, mainly by CYP3A4.(1-4) Strong and moderate CYP3A4 inhibitors may inhibit the metabolism of apixaban by CYP3A4.
CLINICAL EFFECTS: Concurrent use of a CYP3A4 inhibitor may result in elevated levels of and clinical effects of apixaban, including an increased risk of bleeding, especially in the setting of concurrent therapy with an agent that inhibits P-gp.(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 P-gp inhibitors and concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism or have an inherent risk for bleeding (e.g. NSAIDs).
PATIENT MANAGEMENT: The US manufacturer of apixaban provides recommendations regarding concurrent use with strong inhibitors of both CYP3A4 and P-gp, but does not provide guidance for concurrent use with agents that inhibit CYP3A4 alone.(1) The Australian, Canadian, and UK labels for apixaban state that no dose adjustment for apixaban is required when co-administered with agents that are not strong inhibitors of both CYP3A4 and P-gp.(2-4) Expert opinion on the clinical significance of this interaction is varied and depends on the inhibitor. Some experts state that specific agents (i.e., voriconazole, imatinib, and crizotinib) should be contraindicated.(5) Others state that concurrent use is acceptable if there are no other pharmacokinetic interactions; otherwise, a 50% dose reduction of apixaban is suggested.(6) In patients who are also on concurrent P-gp inhibitors, consider the manufacturer recommendations for use with dual CYP3A4 and P-gp inhibitors. The US manufacturer of apixaban states that if concurrent use of strong CYP3A4 and P-gp inhibitors 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.(1) The Australian(2) and Canadian(3) 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.(4) Concurrent use of agents that are dual P-gp and moderate CYP3A4 inhibitors are expected to increase apixaban levels to a lesser extent than agents that are P-gp and strong CYP3A4 inhibitors. No dose adjustment of apixaban is necessary. Use caution when administering apixaban with moderate inhibitors of CYP3A4. 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: The US manufacturer of apixaban states that apixaban dose reduction is recommended when apixaban exposure increases by more than 50%, while efficacy is maintained when exposure is 25% lower. Therefore, no dose adjustment of apixaban is recommended for drug interactions that affect apixaban exposure by 75% to 150%.(7) In a microdose cocktail study using apixaban 25 mcg, voriconazole 400 mg every 12 hours for 2 doses then 200 mg every 12 hours (strong CYP3A4 inhibitor) had "only a minor interaction," increasing the AUC of apixaban by 1.33-fold (95% CI 1.01-1.75) while the Cmax and half-life remained unchanged.(8) Another microdose cocktail study with apixaban 25 mcg and voriconazole 400 mg twice daily found that apixaban AUC increased by 1.24-fold with a non-significant change in Cmax.(9) A retrospective cohort study of 50 oncology patients on apixaban identified 14 patients on concurrent voriconazole, with 3 of those patients receiving reduced-dose apixaban. No bleeding or thrombosis occurred in any of the patients on concurrent voriconazole.(10) An article evaluating the clinical significance of efflux transporters like P-gp and BCRP in apixaban exposure analyzed pharmacokinetic data from drug-drug interaction studies and concluded that all apixaban interactions can be explained by inhibition of intestinal CYP3A4. The authors explain that apixaban is a highly permeable and soluble compound, so its ability to undergo passive diffusion renders the role of membrane transporters irrelevant, as evidenced by a lack of change in apixaban absorption rate in the presence of drugs known to inhibit P-gp and BCRP.(11) A review article on DOAC drug-drug interactions suggests that the combination of voriconazole, crizotinib or imatinib with apixaban or rivaroxaban is contraindicated due to the potential for significant increases in DOAC AUC. The authors state that data with voriconazole is missing and thus the interactions are unpredictable.(5) Another review article states that apixaban may be used with voriconazole if no other pharmacokinetic inhibitor is present; otherwise, concurrent use requires a 50% apixaban dose reduction. No dose adjustment is recommended with moderate CYP3A4 inhibitors.(6) Strong CYP3A4 inhibitors linked to this monograph include: boceprevir, ceritinib, ensitrelvir, idelalisib, mibefradil, nefazodone, relacorilant, ribociclib, troleandomycin, and voriconazole.(12,13) Moderate CYP3A4 inhibitors linked to this monograph include: aprepitant, avacopan, berotralstat, clofazimine, crizotinib, duvelisib, fedratinib, fosnetupitant, imatinib, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and voxelotor.(12,13)
Strong And Moderate Cyp3a4 Inhibitors/Etrasimod
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 impair the CYP3A4-mediated metabolism of etrasimod.(1) Etrasimod is metabolized by CYP2C8, CYP2C9, and CYP3A4.(1)
CLINICAL EFFECTS: In patients who are poor metabolizers of CYP2C9 or are also taking a strong or moderate CYP2C9 inhibitor, concurrent use of a strong or moderate inhibitor of CYP3A4 may result in elevated levels of and clinical effects from etrasimod including immunosuppression, decreased lung function, bradycardia, and AV conduction delays.
PREDISPOSING FACTORS: CYP2C9 poor metabolizers (e.g., *2/*3, *3/*3) may have decreased clearance of etrasimod when etrasimod is used concomitantly with strong or moderate inhibitors of CYP3A4. Patients who are also taking a strong or moderate CYP2C9 inhibitor may also have decreased etrasimod clearance.(1)
PATIENT MANAGEMENT: Concomitant use of etrasimod with strong or moderate CYP3A4 inhibitors in patients who are CYP2C9 poor metabolizers is not recommended.(1) Concomitant use with strong or moderate CYP3A4 inhibitors in patients who are also taking a strong or moderate CYP2C9 inhibitor is not recommended. (1)
DISCUSSION: CYP2C9 activity is decreased in individuals with genetic variants such as CYP2C9*2 and CYP2C9*3 alleles. The impact of CYP2C9 genetic variants on the pharmacokinetics of etrasimod has not been directly evaluated. Increased exposure of etrasimod in patients who are CYP2C9 poor metabolizers is expected with concomitant use of moderate to strong inhibitors of CYP3A4.(1) Concomitant use of etrasimod with steady-state fluconazole (a moderate CYP2C9 and CYP3A4 inhibitor) increased etrasimod area-under-curve (AUC) by 84%.(1) Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, ensitrelvir, grapefruit, indinavir, itraconazole, josamycin, ketoconazole, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, relacorilant, telaprevir, tipranavir, troleandomycin, and tucatinib.(2,3) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, fluvoxamine, fosamprenavir, fosnetupitant, isavuconazonium, letermovir, lenacapavir, netupitant, schisandra, stiripentol, tofisopam, and voxelotor.(2,3)
Strong And Moderate Cyp3a4 Inhibitors/Rivaroxaban
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Rivaroxaban is a substrate of CYP3A4 and P-glycoprotein (P-gp). It is about 18% metabolized, mainly by CYP3A4.(1-4) Strong and moderate CYP3A4 inhibitors may inhibit the metabolism of rivaroxaban by CYP3A4.
CLINICAL EFFECTS: Concurrent use of a CYP3A4 inhibitor may result in elevated levels of and clinical effects of rivaroxaban, including an increased risk of bleeding, especially in the setting of concurrent therapy with an agent that inhibits P-gp.(1-4)
PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Patients with renal impairment may be at higher risk of elevated rivaroxaban levels. Drug-associated risk factors include concurrent use of P-gp inhibitors and concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism or have an inherent risk for bleeding (e.g. NSAIDs).
PATIENT MANAGEMENT: The US manufacturer of rivaroxaban provides recommendations regarding concurrent use with strong and moderate inhibitors of both CYP3A4 and P-gp, but does not provide guidance for concurrent use with agents that inhibit CYP3A4 alone.(1) The Canadian manufacturer of rivaroxaban states that increases in rivaroxaban levels by drugs inhibiting only CYP3A4 are expected to be less clinically relevant compared to drugs inhibiting both CYP3A4 and P-gp.(2) The UK manufacturer of rivaroxaban states that drug interactions with agents that inhibit only CYP3A4 are likely not clinically relevant in most patients but may be significant in high-risk patients (e.g., renal impairment).(3) The Australian manufacturer of rivaroxaban states that drug interactions with drugs that inhibit only CYP3A4 are not clinically relevant.(4) Expert opinion on the clinical significance of this interaction is varied and depends on the inhibitor. Some experts state that specific agents (i.e., voriconazole, imatinib, and crizotinib) should be contraindicated.(5) Others state that concurrent use is acceptable if there are no other pharmacokinetic interactions; otherwise, the combination should be avoided.(6) In patients who are also on concurrent P-gp inhibitors, consider the manufacturer recommendations for use with dual CYP3A4 and P-gp inhibitors. The Australian and Canadian manufacturers of rivaroxaban state that the concurrent use of agents that are both an inhibitor of P-gp and a strong inhibitor of CYP3A4 with rivaroxaban is contraindicated.(2,4) The US manufacturer states that concurrent use of strong CYP3A4 and P-gp inhibitors should be avoided(1) while the UK manufacturer states that concurrent use is not recommended.(3) Agents that are not strong inhibitors of both CYP3A4 and P-gp, including fluconazole, are expected to increase rivaroxaban levels to a lesser extent and can be used with rivaroxaban with caution in patients with normal renal function; however, in patients with decreased renal function (CrCL of 15 ml/min to 80 ml/min) these agents should only be used if the benefits of concurrent therapy outweigh the increased risk of bleeding.(1-4) 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 microdose cocktail study using rivaroxaban 25 mcg, voriconazole 400 mg every 12 hours for 2 doses then 200 mg every 12 hours (strong CYP3A4 inhibitor) had "only a minor interaction," increasing the AUC of rivaroxaban by 1.33-fold (p<0.05) while the Cmax and half-life remained unchanged.(7) Another microdose cocktail study with rivaroxaban 25 mcg and voriconazole 400 mg twice daily found that rivaroxaban AUC increased by 1.16-fold with a non-significant change in Cmax.(8) A review article on DOAC drug-drug interactions suggests that the combination of voriconazole, crizotinib or imatinib with apixaban or rivaroxaban is contraindicated due to the potential for significant increases in DOAC AUC. The authors state that data with voriconazole is missing and thus the interactions are unpredictable.(5) Another review article states that rivaroxaban may be used with voriconazole if no other pharmacokinetic inhibitor is present; otherwise, concurrent use should be avoided. No dose adjustment is recommended with moderate CYP3A4 inhibitors.(6) Strong CYP3A4 inhibitors linked to this monograph include: boceprevir, ceritinib, ensitrelvir, idelalisib, mibefradil, nefazodone, relacorilant, ribociclib, troleandomycin, and voriconazole.(9,10) Moderate CYP3A4 inhibitors linked to this monograph include: aprepitant, avacopan, berotralstat, clofazimine, crizotinib, duvelisib, fedratinib, fosnetupitant, imatinib, oral lefamulin, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and voxelotor.(9,10)
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)
Contraindications
*Hypersensitivity to avacopan or its excipients.
There are no contraindication contraindications for this drug.
- Disease of liver
- Severe infection
- Viral hepatitis B
There are no moderate contraindications for this drug.
Adverse reactions
The most common adverse reactions associated with avacopan (>=5%) are nausea, headache, hypertension, diarrhea, vomiting, rash, fatigue, upper abdominal pain, dizziness, increased blood creatinine, and paresthesia.
More Frequent
- Abnormal hepatic function tests
- Hyperbilirubinemia
- Hypertension
- Increased alanine transaminase
- Increased alkaline phosphatase
Less Frequent
- Infection
- Pneumonia
Rare or Very Rare
- Angioedema
- Cholestasis
- Drug-induced hepatitis
- Hypersensitivity drug reaction
- Reactivation of hepatitis B
- Vanishing bile duct syndrome
More Frequent
- Diarrhea
- Dizziness
- Fatigue
- Headache disorder
- Nausea
- Paresthesia
- Skin rash
- Upper abdominal pain
- Vomiting
Less Frequent
- Increased creatine kinase level
- Urinary tract infection
Precautions
No enhanced messaging available.
The safety and efficacy of avacopan have not been studied in pediatric patients.
There are insufficient data in pregnant women to determine whether avacopan is associated with pregnancy-related risks. Animal studies, conducted in hamsters and rabbits, showed no evidence of fetal harm using avacopan doses at 5 and 0.6 times, respectively, the exposure at the maximum recommended human dose. At an exposure 0.6 times the maximum recommended human dose, an increase in the number of abortions was seen in pregnant rabbits.
It is not known whether avacopan is distributed into human milk or if the drug has any effect on milk production or the nursing infant. Avacopan was detected in the plasma of undosed nursing hamsters at a pup to maternal plasma ratio of 0.37, which suggests avacopan is distributed into the milk of lactating hamsters. Consider a risk-benefit assessment prior to using avacopan during breastfeeding.
The manufacturer makes no specific dosage recommendations for geriatric patients. No overall differences in safety or effectiveness were observed between geriatric and younger patients in the phase 3 randomized clinical trial for ANCA-associated vasculitis.
There were 86 patients >=65 years of age included in the ADVOCATE trial: 62 patients 65 to 75 years of age, and 24 patients >=75 years of age. No overall differences in safety or efficacy were observed between geriatric patients and younger adults.
ICD codes
| Code | Type | Description |
|---|---|---|
| Granulomatosis with polyangiitis | ||
| M31.3 | ICD10CM | Wegener's granulomatosis |
| M31.30 | ICD10CM | Wegener's granulomatosis without renal involvement |
| M31.31 | ICD10CM | Wegener's granulomatosis with renal involvement |
| Microscopic polyangiitis | ||
| M31.7 | ICD10CM | Microscopic polyangiitis |
ICD code information from First Databank (FDB).
Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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