Talicia (omeprazole magnesium/amoxicillin trihydrate/rifabutin)

Dosage of amoxicillin, which is available for oral use as the trihydrate, is expressed in terms of anhydrous amoxicillin.

Dosage of omeprazole magnesium is expressed in terms of omeprazole.

In patients with renal impairment, doses and/or frequency of administration of amoxicillin should be modified in response to the degree of renal impairment, severity of the infection, and susceptibility of the causative organisms. The manufacturer states that adults with severe renal impairment and creatinine clearances less than 30 mL/minute should not receive the commercially available film-coated tablets containing 875 mg of amoxicillin. The recommended dosage of amoxicillin for adults with creatinine clearances of 10-30 mL/minute is 250 or 500 mg every 12 hours, depending on the severity of the infection, and the recommended dosage for adults with creatinine clearances less than 10 mL/minute is 250 or 500 mg every 24 hours, depending on the severity of the infection.

Patients undergoing hemodialysis should receive 250 or 500 mg of amoxicillin every 24 hours, depending on the severity of the infection, and should receive an additional dose of the drug during and after each dialysis period.

The manufacturer states that data are insufficient to recommend dosage for pediatric patients with renal impairment.

Rifabutin concentrations reportedly are decreased in patients with impaired renal function as a result of decreased distribution and more rapid elimination of the drug. However, the clinical importance, if any, of this finding has not been determined, and the manufacturer currently makes no specific recommendations for modification of dosage in such patients.

Rifabutin is administered orally. Administration of rifabutin with a high-fat meal decreases the rate but not the extent of absorption. Therefore, the drug generally can be given orally without regard to meals.

Omeprazole delayed-release and immediate-release capsules are administered orally; oral suspensions of the drug are administered orally or through a gastric tube. To avoid decomposition of omeprazole in the acidic pH of the stomach, the commercially available delayed-release capsules and delayed-release oral suspension contain enteric-coated granules of the drug. Immediate-release capsules, immediate-release oral suspension, and the kit for oral suspension (Konvomep(R)) all contain sodium bicarbonate to protect the drug from acid degradation.

Omeprazole magnesium is also available in fixed-combination capsules containing amoxicillin and rifabutin (Talicia(R)). A co-packaged product containing delayed-release omeprazole capsules, clarithromycin tablets, and amoxicillin capsules (Omeclamox-Pak(R)) is also commercially available. See the full prescribing information for administration of these combination products.

Antacids may be administered concomitantly with delayed-release preparations of omeprazole.

For patients receiving continuous feedings via a nasogastric or orogastric tube, enteral feeding should be stopped temporarily for 3 hours before and for 1 hour after administration of preparations of omeprazole oral suspension.

Store omeprazole delayed-release capsules in tight containers or the original carton at 20-25degreesC; protect from light and moisture. Store packets of omeprazole powder for delayed-release suspension at 25degreesC (excursions permitted from 15-30degreesC). Store immediate-release capsules in tight, light-resistant containers at 20-25degreesC and protect from moisture. Store packets of omeprazole powder for immediate-release suspension protected from light and moisture at 25degreesC (excursions permitted from 15-30degreesC). Store omeprazole and sodium bicarbonate powder kit for oral suspension (Konvomep(R)) at 2-8degreesC protected from light; do not freeze.

No dosing information is available for this tab.

Rifabutin, like other rifamycins (e.g., rifampin) can induce hepatic microsomal enzymes which may result in drug interactions. Because of the structural similarity between rifampin and rifabutin and because rifampin is known to interact with numerous other drugs, rifabutin may be anticipated to have some effects on drugs known to be affected by rifampin (e.g., ketoconazole, cyclosporine, oral contraceptives). (See Drug Interactions in Rifampin 8:16.04.) In healthy individuals, rifabutin appears to induce hepatic microsomal enzymes to a lesser extent than rifampin, although the clinical relevance of this finding for drug interactions is not known.

In vivo, omeprazole is a substrate and inhibitor of cytochrome P-450 (CYP) isoenzyme 2C19, and a substrate of CYP3A4. Omeprazole is also an inhibitor of CYP2C19 in vitro.

When co-packaged delayed-release omeprazole capsules, clarithromycin tablets, and amoxicillin capsules (Omeclamox-Pak(R)) are prescribed, drug interactions should be considered for each individual component. Refer to the Omeclamox-Pak(R) prescribing information for drug interaction information.

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

Antimicrobials/Live Typhoid Vaccine

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

MECHANISM OF ACTION: The antimicrobial may be active against the organism in the live-vaccine. Antimicrobial therapy may prevent the vaccine organism from replicating enough to trigger an immune response.(1)

CLINICAL EFFECTS: Vaccination may be ineffective.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Do not give oral typhoid vaccine until 72 hours after the last dose of antimicrobial. If possible, to optimize vaccine effectiveness, do not start antibacterial drugs for 72 hours after the last dose of oral typhoid vaccine. A longer interval should be considered for long-acting antimicrobials, such as azithromycin.(3)

DISCUSSION: Because antimicrobial therapy may prevent sufficient vaccine-organism replication to generate an immune response, the manufacturer of live-attenuated typhoid vaccine and the Centers for Disease Control (CDC) state that the vaccine should not be administered to patients receiving antimicrobial therapy.(1-3)

Cyp1a2 Inducers/Florquinitau F-18

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: Florquinitau F-18 is a CYP1A2 substrate. CYP1A2 inducers may decrease the florquinitau F-18 parent fraction in plasma and reduce brain regional signal intensity.(1)

CLINICAL EFFECTS: Concurrent or recent use of CYP1A2 inducers with florquinitau F-18 may interfere with the interpretation of imaging results using fluoroestradiol F-18.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of florquinitau F-18 states use of CYP1A2 inducers should be avoided. Patients should stop CYP1A2 inducers at least 7 days prior to diagnostic testing with florquinitau F-18.(1)

DISCUSSION: Florquinitau F-18 is a CYP1A2 substrate. CYP1A2 inducers may decrease the florquinitau F-18 parent fraction in plasma and reduce brain regional signal intensity.(1) CYP1A2 inducers linked include: aminoglutethimide, asciminib, carbamazepine, fosphenytoin, leflunomide, marijuana smoking, montelukast, moricizine, nelfinavir, olverembatinib, omeprazole, phenobarbital, phenytoin, primidone, rifampin, ritonavir, teriflunomide, and valproic acid.(2,3)

Cyp3a4 Inducers/Lumateperone

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: Lumateperone is a substrate of CYP3A4. Inducers of CYP3A4 may induce the metabolism of lumateperone.(1)

CLINICAL EFFECTS: The concurrent administration of a CYP3A4 inducer may decrease the exposure to lumateperone.(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 lumateperone states that concurrent use with CYP3A4 inducers should be avoided.(1)

DISCUSSION: Coadministration of lumateperone with rifampin, a strong CYP3A4 inducer, resulted in a 98% reduction in area-under-curve (AUC) and a 90% reduction in concentration maximum (Cmax).(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, repotrectinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 include: amprenavir, armodafinil, aumolertinib, bexarotene, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, garlic, genistein, gingko, ginseng, glycyrrhizin, nevirapine, omaveloxolone, oxcarbazepine, pioglitazone, quercetin, rufinamide, sotorasib, sulfinpyrazone, sunvozertinib, tecovirimat, terbinafine, ticlopidine, troglitazone, vemurafenib, and vinblastine.(2,3)

Cyp3a4 Inducers/Zuranolone

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: Inducers of CYP3A4 may induce the metabolism of zuranolone.(1)

CLINICAL EFFECTS: Concurrent use of a CYP3A4 inducer may result in a loss of zuranolone efficacy.(1)

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 zuranolone with CYP3A4 inducers.(1)

DISCUSSION: Coadministration of zuranolone with rifampin decreased the maximum concentration (Cmax) by 0.31-fold and area-under-curve (AUC) by 0.15-fold.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib. Weak CYP3A4 inducers linked to this monograph include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, flucloxacillin, garlic, genistein, ginseng, glycyrrhizin, methylprednisolone, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)

H2 Antagonists; Proton Pump Inhibit/Posaconazole Suspension

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: H2 antagonists and proton pump inhibitors (PPIs) increase the stomach pH, possibly reducing gastrointestinal absorption of posaconazole suspension.

CLINICAL EFFECTS: Concurrent use of H2 antagonists or proton pump inhibitors (PPIs) may result in decreased effectiveness of posaconazole suspension.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the concurrent use of posaconazole suspension with H2 antagonists or proton pump inhibitors (PPIs).(1) If H2 antagonists or PPI therapy is required, use the tablet formulation or powder mix formulation of posaconazole.

DISCUSSION: Concurrent cimetidine (400 mg twice daily) decreased both posaconazole (200 mg daily) maximum concentration (Cmax) and area-under-curve (AUC) levels by 39%.(1) No significant effects with other H2 blockers have been noted.(1) Esomeprazole (40 mg daily for 3 days) decreased the Cmax and AUC of a single dose of posaconazole suspension (400 mg) by 46% and 32%, respectively.(1) In a study of posaconazole levels in patients with acute myeloid leukemia or myelodysplastic syndrome, use of pantoprazole was associated with decreased posaconazole levels.(3) In a cross-over study in 5 healthy subjects, esomeprazole decreased the Cmax and AUC of posaconazole suspension by 37% and 84%, respectively. Simultaneous intake of Coca-Cola did not completely counteract the effects of esomeprazole.(4) In a study in healthy subjects, esomeprazole decreased the Cmax and AUC of posaconazole suspension by 55% and 49%, respectively. Simultaneous intake of Coca-Cola did not completely counteract the effects of esomeprazole.(5)

H2 Antagonists; Proton Pump Inhibitors/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: The aqueous solubility of defactinib is pH dependent. Higher gastric pH leads to lower solubility which may reduce defactinib absorption.(1)

CLINICAL EFFECTS: Coadministration of H2 antagonists or proton pump inhibitors (PPIs) may reduce the bioavailability of defactinib, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of defactinib states that concurrent use with H2 antagonists or proton pump inhibitors should be avoided.(1) If concurrent use with an acid-reducing agent cannot be avoided, administer defactinib 2 hours before or 2 hours after the administration of a locally acting antacid.(1)

DISCUSSION: In an interaction study, defactinib area-under-the-curve (AUC) decreased by 79% and maximum concentration (Cmax) decreased by 85% following concomitant use of multiple doses of omeprazole 40 mg daily. The AUC and Cmax of N-desmethyl amide (M4), a major metabolite of defactinib, decreased by 83% and 88%, respectively.(1)

H2 Antagonists; Proton Pump Inhibitors/Levoketoconazole

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

MECHANISM OF ACTION: The aqueous solubility of levoketoconazole is pH dependent. Higher gastric pH leads to lower solubility. H2-receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) increase gastric pH and may decrease the absorption of levoketoconazole.(1)

CLINICAL EFFECTS: Coadministration of H2RAs or PPIs may reduce the bioavailability of levoketoconazole, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration of levoketoconazole with PPIs and H2RAs should be avoided.(1)

DISCUSSION: Levoketoconazole is very slightly soluble in water but soluble below pH 2. H2RAs and PPIs raise gastric pH and may impair dissolution and absorption of levoketoconazole.(1)

H2 Antagonists; Proton Pump 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: The aqueous solubility of nirogacestat is pH dependent. Higher gastric pH leads to lower solubility which may reduce nirogacestat absorption.(1)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) or H2 antagonists may reduce the bioavailability of nirogacestat, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration of nirogacestat with proton pump inhibitors, H2 antagonists, and antacids should be avoided. If coadministration with an acid-reducing agent is unavoidable, take nirogacestat 2 hours before or 2 hours after a locally acting antacid.(1)

DISCUSSION: The solubility of nirogacestat is poor at a pH >= 6.(1) Concomitant use of proton pump inhibitors, H2 antagonists, or antacids are expected to reduce concentrations of nirogacestat.(1)

H2 Antagonists; Proton Pump Inhibitors/Secretin

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: H2 antagonists and proton pump inhibitors (PPIs) may result in an incorrect secretin stimulation test result.(1)

CLINICAL EFFECTS: Concurrent use of H2 antagonists and proton pump inhibitors (PPIs) may impact the accuracy of the secretin stimulation test.(1)

PREDISPOSING FACTORS: Patients with alcoholic or other liver disease may be hyperresponsive to stimulation with a secretin stimulation test, masking the presence of coexisting pancreatic disease. Consider additional testing and clinical assessment for diagnosis.(1)

PATIENT MANAGEMENT: The US manufacturer of human secretin states concurrent use of H2 antagonists and proton pump inhibitors (PPIs) at the time of stimulation testing may cause the patient to be hyperresponsive to secretin stimulation and suggest false gastrinoma results. The manufacturer recommends discontinuing H2 antagonists at least 2 days prior to testing. The US manufacturer of vonoprazan recommends stopping vonoprazan at least 4 weeks prior to testing.(2-3) Consult prescribing information for PPIs before administering prior to a secretin stimulation test.(1)

DISCUSSION: Concurrent use of H2 antagonists and proton pump inhibitors (PPIs) may impact the accuracy of the secretin stimulation test.(1)

H2 Antagonists; Proton Pump Inhibitors/Sotorasib

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

MECHANISM OF ACTION: The aqueous solubility of sotorasib is pH dependent. Higher gastric pH leads to lower solubility which may reduce sotorasib absorption.(1)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) or H2 antagonists may reduce the bioavailability of sotorasib, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration of sotorasib with proton pump inhibitors, H2 antagonists, and antacids should be avoided. If coadministration with an acid-reducing agent is unavoidable, take sotorasib 4 hours before or 10 hours after a locally acting antacid.(1) The UK manufacturer of sotorasib states if co-administration with an acid-reducing agent (such as a PPI or an H2 antagonist) is required, sotorasib should be taken with an acidic beverage (such as cola). Alternatively, sotorasib should be taken 4 hours before or 10 hours after administration of a local antacid.(2)

DISCUSSION: The solubility of sotorasib in the aqueous media decreases over the range pH 1.2 to 6.8 from 1.3 mg/mL to 0.03 mg/mL. In an interaction study, coadministration of repeat doses of omeprazole with a single dose of sotorasib decreased sotorasib maximum concentration (Cmax) by 65% and area-under-curve (AUC) by 57% under fed conditions, and decreased sotorasib Cmax by 57% and AUC by 42% under fasted conditions. Under fasted conditions, co-administration of repeat doses of omeprazole with a single dose of sotorasib and 240ml of an acidic beverage (non-diet cola) decreased sotorasib Cmax by 32% and AUC by 23%. The UK manufacturer of sotorasib states the clinical relevance of the decreased sotorasib exposure when co-administered with omeprazole and cola is unclear and sotorasib efficacy might be reduced.(2) Coadministration of a single dose of famotidine given 10 hours prior to and 2 hours after a single dose of sotorasib under fed conditions decreased sotorasib Cmax by 35% and AUC by 38%.(1)

H2 Antagonists; Proton Pump 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: The aqueous solubility of taletrectinib is pH dependent. Higher gastric pH leads to lower solubility which may reduce taletrectinib absorption.(1)

CLINICAL EFFECTS: Coadministration of H2 antagonists or proton pump inhibitors (PPIs) may reduce the bioavailability of taletrectinib, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of taletrectinib states that concurrent use with H2 antagonists or proton pump inhibitors should be avoided.(1) If concurrent use with an acid-reducing agent cannot be avoided, administer taletrectinib 2 hours before or 2 hours after the administration of a locally acting antacid.(1)

DISCUSSION: In an interaction study, taletrectinib area-under-the-curve (AUC) decreased by 40% and maximum concentration (Cmax) decreased by 65% following concomitant use of omeprazole 40 mg daily.(1)

Moderate Cyp3a4 Inducers/Atrasentan

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 inducers of CYP3A4 may induce the metabolism of atrasentan.(1)

CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may reduce the clinical effectiveness of atrasentan.(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 atrasentan states that concurrent use of moderate CYP3A4 inducers should be avoided.(1)

DISCUSSION: In a study, atrasentan trough concentration (Ctrough) decreased by 90% following coadministration of a single dose of 10 mg of atrasentan with rifampin (strong CYP3A4 inducer).(1) The effects of a moderate CYP3A4 inducer on atrasentan concentrations has not been studied. Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Daraxonrasib (< 400 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 CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of daraxonrasib.(1)

CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of daraxonrasib.(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 daraxonrasib states that concomitant use of moderate CYP3A4 inducers requires a dose increase of daraxonrasib to 400 mg once daily.(1)

DISCUSSION: In a clinical study, daraxonrasib area-under-curve (AUC) is predicted to decrease by 50-84% with concomitant use of efavirenz 600 mg once daily and modafinil 400 mg once daily (moderate CYP3A4 inducers).(1) Moderate CYP3A4 inducers linked to this monograph include: asunaprevir, belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lopinavir, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/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: Moderate CYP3A4 inducers may accelerate the metabolism of defactinib by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of defactinib and a moderate CYP3A4 inducer may result in decreased levels and effectiveness of defactinib.(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 defactinib states that the concurrent use of moderate CYP3A4 inducers should be avoided.(1)

DISCUSSION: The impact of moderate CYP3A4 inhibitors on the pharmacokinetics of defactinib has not been investigated in clinical studies. In a study, defactinib maximum concentration (Cmax) decreased by 83% and area-under-curve (AUC) by 87% following coadministration with phenytoin (strong CYP3A4 inducer) three times daily for 23 days and a single dose of defactinib 200 mg (1.0 times the approved recommended dose) on Day 14. The AUC and Cmax of N-desmethyl amide (M4), a major active metabolite of defactinib, decreased by 79% and 70%, respectively.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(2)

Moderate Cyp3a4 Inducers/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: Dordaviprone is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of dordaviprone.(1)

CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of dordaviprone.(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 dordaviprone states that co-administration with moderate inducers of CYP3A4 should be avoided. Monitor patients for loss of efficacy or consider the use of alternative medicinal products.(1)

DISCUSSION: Concurrent use of rifampin (a strong CYP3A4 inducer) is predicted to decrease dordaviprone maximum concentration (Cmax) by 68% and area-under-curve (AUC) by 83%. Concurrent use of efavirenz (a moderate CYP3A4 inducer) is predicted to decrease dordaviprone Cmax by 44% and AUC by 65%.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Entrectinib

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

MECHANISM OF ACTION: Entrectinib is a substrate of CYP3A4. Moderate inducers of CYP3A4 may induce the metabolism of entrectinib.(1)

CLINICAL EFFECTS: The concurrent administration of a moderate CYP3A4 inducer may result in decreased levels and effectiveness of entrectinib.(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 entrectinib states that concurrent use with moderate CYP3A4 inducers should be avoided. (1)

DISCUSSION: Concomitant administration of rifampin (strong CYP3A4 inducer) with a single 600 mg entrectinib dose decreased entrectinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 56% and 77%.(1) Coadministration with a moderate CYP3A4 inducer is predicted to decrease entrectinib's AUC and Cmax by 56% and 43%.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, and tovorafenib.(2-3)

Moderate Cyp3a4 Inducers/Fedratinib

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: Fedratinib is a substrate of CYP3A4. Moderate inducers of CYP3A4 may induce the metabolism of fedratinib.(1)

CLINICAL EFFECTS: The concurrent administration of a moderate CYP3A4 inducer may result in decreased levels and effectiveness of fedratinib.(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 fedratinib states that concurrent use with moderate CYP3A4 inducers should be avoided.(1)

DISCUSSION: Coadministration of efavirenz (moderate CYP3A4 inducer: 600 mg once daily) with a single dose of fedratinib (500 mg; 1.25 times the recommended dose) decreased the area-under-curve (AUC) of fedratinib by approximately 47%.(1) Moderate inducers of CYP3A4 include: belzutifan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad, lorlatinib, modafinil, nafcillin, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(2-3)

Moderate Cyp3a4 Inducers/Fruquintinib

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 inducers of CYP3A4 may induce the metabolism of fruquintinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of fruquintinib.(1)

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

PATIENT MANAGEMENT: If possible, avoid concurrent use of moderate inducers of CYP3A4 with fruquintinib. If concurrent use cannot be avoided, continue to administer fruquintinib at the recommended dosage.(1)

DISCUSSION: Concomitant use with efavirenz (moderate CYP3A4 inducer) is predicted to decrease the fruquintinib maximum concentration (Cmax) by 4% and the area-under-curve (AUC) by 32%.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Glasdegib

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: Glasdegib is a substrate of CYP3A4. Moderate inducers of CYP3A4 may induce the metabolism of glasdegib.(1)

CLINICAL EFFECTS: Concurrent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of glasdegib.(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 glasdegib states to avoid concurrent administration with moderate CYP3A4 inducers. If concurrent use cannot be avoided, increase the daily dose of glasdegib as tolerated as follows: - If current dose of glasdegib is 100 mg once daily, increase to 200 mg once daily - If current dose of glasdegib is 50 mg once daily, increase to 100 mg once daily After the moderate CYP3A4 inducer has been discontinued for 7 days, resume the glasdegib dose that was tolerated prior to initiation of the inducer.(1)

DISCUSSION: A population-based pharmacokinetic model predicts that efavirenz would decrease glasdegib area-under-curve (AUC) by 55% and maximum concentration (Cmax) by 25%.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, and tovorafenib.(2-3)

Moderate Cyp3a4 Inducers/Iberdomide

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: Iberdomide is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of iberdomide.(1)

CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of iberdomide.(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 iberdomide states that concomitant use of moderate CYP3A4 inducers should be avoided.(1)

DISCUSSION: In a PBPK model in patients with cancer, iberdomide area-under-curve (AUC) was predicted to be decreased by 30% and maximum concentration (Cmax) by 50% following concomitant use with efavirenz (moderate CYP3A4 inducer).(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Idelalisib

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 induce the CYP3A4 isoenzyme may induce the metabolism of idelalisib.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inducers may decrease the levels and effectiveness of idelalisib.(1)

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 moderate CYP3A4 inducers in patients receiving therapy with idelalisib.(1) Consider the use of alternative agents with less enzyme induction potential.(1)

DISCUSSION: In a study in healthy subjects, rifampin (600 mg daily for 8 days) decreased the concentration maximum (Cmax) and area-under-curve (AUC) of idelalisib (150 mg single dose) by 58% and 75%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, cenobamate, dipyrone, efavirenz, etravirine, lesinurad, modafinil, nafcillin, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2)

Moderate Cyp3a4 Inducers/Lazertinib

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 inducers of CYP3A4 may induce the metabolism of lazertinib via this pathway.(1)

CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may reduce the clinical effectiveness of lazertinib.(1)

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

PATIENT MANAGEMENT: The US manufacturer of lazertinib states that concurrent use of moderate CYP3A4 inducers should be avoided. Consider an alternative concomitant medication with no potential to induce CYP3A4.(1)

DISCUSSION: In a pharmacokinetic modelling study, concomitant use of efavirenz (moderate CYP3A4 inducer) is predicted to decrease lazertinib steady state concentration maximum (Cmax) and area-under-curve (AUC) by at least 32% and 44%, respectively.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Lirafugratinib

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 inducers of CYP3A4 may induce the metabolism of lirafugratinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of lirafugratinib.(1)

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

PATIENT MANAGEMENT: Avoid concomitant use of moderate CYP3A4 inducers with lirafugratinib.(1)

DISCUSSION: In a pharmacokinetic model, efavirenz (a moderate CYP3A4 inducer) 600 mg daily for 19 days is predicted to reduce lirafugratinib area-under-the-curve (AUC) by 57% and maximum concentration (Cmax) by 15%.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Mavacamten

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 induce the CYP3A4 isoenzyme may increase the metabolism of mavacamten.(1-3)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inducers may decrease the levels and effectiveness of mavacamten.(1-3)

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

PATIENT MANAGEMENT: The US and Canadian manufacturers of mavacamten state concurrent use of mavacamten with moderate CYP3A4 inducers is contraindicated.(1,2) The UK manufacturer of mavacamten states that management of mavacamten during concomitant use with moderate CYP3A4 inducers is dependent on CYP2C19 phenotype. Labeling recommends: -When initiating or increasing the dose of a moderate inducer in patients who are CYP2C19 poor metabolizers, monitor patients closely and adjust mavacamten dose based on clinical response. -When discontinuing or decreasing the dose of a moderate inducer in patients who are CYP2C19 poor metabolizers, decrease the dose of mavacamten to 2.5 mg, or pause therapy if dose is 2.5 mg. -No dose adjustment is warranted with moderate inducers in patients who are CYP2C19 intermediate, normal, rapid, or ultrarapid metabolizers.(3)

DISCUSSION: Concomitant use of mavacamten (a single 15 mg dose) with a strong CYP2C19 and CYP3A4 inducer (rifampin 600 mg daily dose) is predicted to decrease mavacamten area-under-curve (AUC) and maximum concentration (Cmax) by 87% and 22%, respectively, in CYP2C19 normal metabolizers, and by 69% and 4%, respectively, in CYP2C19 poor metabolizers.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, modafinil, nafcillin, pexidartinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(4,5)

Moderate Cyp3a4 Inducers/Nerandomilast (9 Mg)

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

MECHANISM OF ACTION: Moderate CYP3A4 inducers may induce the metabolism of nerandomilast by CYP3A4.

CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may reduce the clinical effectiveness of nerandomilast.(1)

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

PATIENT MANAGEMENT: The recommended dose of nerandomilast with moderate CYP3A4 inducers is 18 mg twice daily. For patients who are unable to tolerate 18 mg twice daily, do not reduce the dosage to 9 mg twice daily in patients taking moderate CYP3A4 inducers.(1)

DISCUSSION: Nerandomilast is primarily metabolized by CYP3A4.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/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 a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of olverembatinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of olverembatinib.(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 olverembatinib states that co-administration with moderate inducers of CYP3A4 should be avoided.(1)

DISCUSSION: In a clinical study of 15 healthy subjects, rifampin (600 mg daily for 8 days), a strong CYP3A4 inducer, decreased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose olverembatinib 40 mg by 75.19% and 61.27%, respectively.(2) In a PBPK model, efavirenz (600 mg daily for 8 days), a moderate CYP3A4 inducer, decreased the AUC and Cmax of olverembatinib 40 mg by 65% and 52%, respectively.(3) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(4,5)

Moderate Cyp3a4 Inducers/Oveporexton

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

MECHANISM OF ACTION: Oveporexton is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of oveporexton.(1)

CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of oveporexton.(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 oveporexton states that concomitant use of moderate CYP3A4 inducers should be avoided.(1)

DISCUSSION: In a PBPK model, oveporexton area-under-curve (AUC) was predicted to be decreased by 73% and maximum concentration (Cmax) by 55% following concomitant use of a moderate CYP3A4 inducer.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Pyrotinib

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

MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of pyrotinib.(1)

CLINICAL EFFECTS: Concurrent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of pyrotinib.(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 pyrotinib states that coadministration with moderate CYP3A4 inducers should be avoided.(1)

DISCUSSION: In a study of healthy subjects, concurrent use of rifampin (a strong CYP3A4 inducer) decreased pyrotinib area-under-curve (AUC) by 96% and maximum concentration (Cmax) by 89%.(1) In a study of healthy subjects, concurrent use of efavirenz (a moderate CYP3A4 inducer) decreased pyrotinib AUC by 80% and Cmax by 66%.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/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: Moderate CYP3A4 inducers may induce the metabolism of remibrutinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may alter the clinical effectiveness of remibrutinib.(1)

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 remibrutinib with moderate CYP3A4 inducers.(1) Monitor patients receiving concurrent therapy for reduced efficacy.

DISCUSSION: Remibrutinib is primarily metabolized by CYP3A4.(1) Remibrutinib concentration maximum (Cmax) is predicted to decrease by approximately 60% and area-under-curve (AUC) is predicted to decrease by approximately 64% following concomitant administration with efavirenz (a moderate CYP3A4 inducer) 600 mg once daily for 14 days.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Revumenib

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 inducers may induce the metabolism of revumenib by CYP3A4 and increase formation of the M1 metabolite which contributes to revumenib's effects on the QTc interval.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inducers may result in decreased levels and effectiveness of revumenib and increased risk of QT prolongation due to increased exposure to revumenib's M1 metabolite. The risk of potentially life-threatening arrhythmias including torsades de pointes may be increased.(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) Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of revumenib states that concomitant use of moderate CYP3A4 inducers should be avoided.(1)

DISCUSSION: Revumenib is primarily metabolized by CYP3A4. Concomitant use of a moderate CYP3A4 inducer may decrease revumenib concentrations and increase M1 systemic exposure, resulting in decreased revumenib efficacy or increased risk of QT prolongation.(1) In clinical trials, QTc interval prolongation was reported as an adverse event in 29% of 135 patients treated with the recommended dosage of revumenib; 12% of patients had Grade 3 QTc prolongation. Revumenib increased the QTc interval in a concentration-dependent manner. At the mean steady-state Cmax using the highest approved recommended dosage of revumenib without CYP3A4 inhibitors, QTc increase was predicted to be 27 msec (upper bound of 90% confidence interval = 30 msec). At the steady-state Cmax using the highest approved recommended dosage of revumenib with CYP3A4 inhibitors, QTc increase was predicted to be 19 msec (upper bound of 90% confidence interval = 22 msec).(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, and tovorafenib.(3)

Moderate Cyp3a4 Inducers/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: Moderate CYP3A4 inducers may induce the metabolism of rilzabrutinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of a moderate CYP3A4 inducer may result in decreased levels and effectiveness of rilzabrutinib.(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 rilzabrutinib states that concomitant use of moderate CYP3A4 inducers should be avoided.(1)

DISCUSSION: Rilzabrutinib is primarily metabolized by CYP3A4.(1) Concomitant administration of rilzabrutinib with efavirenz or rifabutin (moderate CYP3A4 inducers) is predicted to decrease rilzabrutinib area under the curve (AUC) and maximum concentration (Cmax) by up to 70% at steady state.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, lesinurad, lorlatinib, modafinil, nafcillin, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2)

Moderate Cyp3a4 Inducers/Sevabertinib

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: Sevabertinib is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of sevabertinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of sevabertinib.(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 sevabertinib states that co-administration with moderate inducers of CYP3A4 should be avoided. Monitor patients for loss of efficacy or consider the use of alternative medicinal products.(1)

DISCUSSION: In a study, carbamazepine (strong CYP3A4 inducer) decreased sevabertinib's area-under-curve (AUC) 79% and maximum concentration (Cmax) 57%.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Sonrotoclax

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: Sonrotoclax is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of sonrotoclax.(1)

CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of sonrotoclax.(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 sonrotoclax states that co-administration with moderate inducers of CYP3A4 should be avoided.(1)

DISCUSSION: The impact of moderate CYP3A4 inducers on the pharmacokinetics of sonrotoclax has not been investigated in clinical studies. In a clinical study, sonrotoclax area-under-curve (AUC) decreased by 65% and maximum concentration (Cmax) by 42% following concomitant use of phenytoin (strong CYP3A4 inducer).(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Suzetrigine

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

MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of suzetrigine.(1)

CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may reduce the clinical effectiveness of suzetrigine.(1)

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

PATIENT MANAGEMENT: The US manufacturer of suzetrigine states that concurrent use of moderate CYP3A4 inducers should be avoided.(1)

DISCUSSION: Concomitant administration of efavirenz (moderate CYP3A inducer) with suzetrigine is predicted to decrease suzetrigine and active metabolite M6-SUZ area-under-curve (AUC) by 63% and 60%, respectively, while suzetrigine maximum concentration (Cmax) is predicted to decrease by 29% and M6-SUZ Cmax is predicted to increase by 1.3-fold, respectively.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/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: Moderate CYP3A4 inducers may induce the metabolism of taletrectinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of a moderate CYP3A4 inducer may result in decreased levels and effectiveness of taletrectinib.(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 taletrectinib states that concomitant use of moderate CYP3A4 inducers should be avoided.(1)

DISCUSSION: Taletrectinib is primarily metabolized by CYP3A4.(1) Concomitant administration of taletrectinib with a moderate inducer (efavirenz) is predicted to decrease taletrectinib area under the curve (AUC) and maximum concentration (Cmax) by 66% and 40%, respectively.(1) Concomitant administration of taletrectinib with a strong inducer (rifampin; 600 mg once daily) resulted in a decrease in taletrectinib area under the curve (AUC) and maximum concentration (Cmax) by 86% and 42%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, and tovorafenib.(2)

Moderate Cyp3a4 Inducers/Venetoclax

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 inducers of CYP3A4 may induce the metabolism of venetoclax.(1)

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

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

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

DISCUSSION: In a study with 10 healthy subjects, co-administration of rifampin (600 mg daily for 13 days), decreased venetoclax area-under-curve (AUC) by 71% and maximum concentration (Cmax) by 42%.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, telotristat, thioridazine, tipranavir/ritonavir, and tovorafenib.(2-3)

Moderate Cyp3a4 Inducers/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: Zidesamtinib is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of zidesamtinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of zidesamtinib.(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 zidesamtinib states that concurrent use of moderate CYP3A4 inducers should be avoided.(1)

DISCUSSION: Zidesamtinib is a CYP3A4 substrate.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Ziftomenib

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: Ziftomenib is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of ziftomenib.(1)

CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of ziftomenib.(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 ziftomenib states that co-administration with moderate inducers of CYP3A4 should be avoided. Monitor patients for loss of efficacy or consider the use of alternative medicinal products.(1)

DISCUSSION: Efavirenz (moderate CYP3A4 inducer) is estimated to decrease ziftomenib area-under-curve (AUC) and maximum concentration (Cmax) by up to 70%.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Zilurgisertib

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 inducers of CYP3A4 may induce the metabolism of zilurgisertib.(1)

CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of zilurgisertib.(1)

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

PATIENT MANAGEMENT: Avoid concomitant use of moderate CYP3A4 inducers with zilurgisertib.(1)

DISCUSSION: In a pharmacokinetic model, efavirenz (a moderate CYP3A4 inducer) is predicted to decrease zilurgisertib area-under-the-curve (AUC) by 60% and maximum concentration (Cmax) by 25%.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Zoliflodacin

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: Zoliflodacin is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of zoliflodacin.(1)

CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of zoliflodacin.(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 zoliflodacin states that co-administration with moderate inducers of CYP3A4 is contraindicated.(1)

DISCUSSION: Efavirenz, a moderate CYP3A4 inducer, is predicted to decrease the area-under-curve (AUC) of zoliflodacin by approximately 41%.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

P-Glycoprotein (P-Gp) Inducers; Phenobarbital/Ravidasvir

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: Inducers of P-glycoprotein (P-gp) may decrease the absorption of ravidasvir.(1)

CLINICAL EFFECTS: Concurrent or recent use of a P-gp inducer may result in decreased levels and effectiveness of ravidasvir.(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 ravidasvir states concurrent use with P-gp inducers is contraindicated.(1)

DISCUSSION: Interaction studies with P-gp inducers have not been performed. Co-administration with potent inducers of P-gp are expected to decrease ravidasvir plasma concentrations and result in therapeutic failure.(1) Agents linked to this monograph include apalutamide, carbamazepine, fosphenytoin, green tea, lorlatinib, phenobarbital, phenytoin, primidone, quercetin, rifabutin, rifampin, and St. John's wort.(1-3)

Proton Pump Inhibitors/Acalabrutinib Capsules

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

MECHANISM OF ACTION: The aqueous solubility of acalabrutinib capsules is pH dependent. Higher gastric pH leads to lower solubility which may reduce acalabrutinib absorption.(1)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) may reduce the bioavailability of acalabrutinib capsules, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration of proton pump inhibitors is not recommended with acalabrutinib capsules. Separation of doses may not eliminate the interaction with acalabrutinib capsules.(1) Acalabrutinib tablets are not affected by coadministration with proton pump inhibitors and may be used concurrently.(1)

DISCUSSION: In an interaction study, omeprazole (40 mg for 5 days) given simultaneously with acalabrutinib capsules, decreased acalabrutinib area-under-the-curve (AUC) by 43%(1) Proton pump inhibitors linked to this monograph are: dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole.

Proton Pump Inhibitors/Atazanavir; Nelfinavir

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: Proton pump inhibitors increase gastric pH. As gastric pH increases, the solubility of atazanavir and nelfinavir decreases.(1,2) Omeprazole has been shown to inhibit nelfinavir metabolism by CYP2C19.(3)

CLINICAL EFFECTS: Concurrent use of atazanavir(1-2,4-8) or nelfinavir(3,8-9) and a proton pump inhibitor may result in decreased levels and effectiveness of atazanavir or nelfinavir.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US and Australian manufacturer of atazanavir states that treatment naive patients requiring a proton pump inhibitor should receive 300 mg atazanavir with 100 mg ritonavir. The proton pump inhibitor should not exceed a dose comparable to omeprazole 20 mg daily and should be administered 12 hours before atazanavir/ritonavir.(1,2) Atazanavir should not be administered with proton pump inhibitors without concurrent ritonavir in adults or pediatric patients of at least 13 years of age and weighing at least 40 kg.(1,2) The US and Australian manufacturer of atazanavir states that proton pump inhibitors should not be administered with atazanavir in treatment experienced patients.(1,2) Data are insufficient to recommend a dose of atazanavir in patients weighing less than 40 kg and receiving a proton pump inhibitor.(1) The Canadian and UK manufacturer of atazanavir states that the coadministration of atazanavir and proton pump inhibitors is not recommended. If coadministration is necessary, the dose of atazanavir should be increased to 400 mg daily taken with ritonavir 100 mg daily, and the dose of the proton pump inhibitor should not exceed the equivalent of omeprazole 20 mg.(10,11) The UK manufacturer of esomeprazole states that concurrent use with atazanavir is contraindicated.(9) The US manufacturer of esomeprazole(4) and omeprazole(5) states that concurrent use of atazanavir or nelfinavir is not recommended. The US manufacturers of dexlansoprazole (6), lansoprazole,(7) and pantoprazole(8) state that atazanavir and nelfinavir should not be coadministered with proton pump inhibitors.

DISCUSSION: In a study of 16 subjects, atazanavir (400 mg daily) area-under-curve (AUC), maximum concentration (Cmax) and minimum concentration (Cmin) decreased 94%, 96% and 95% respectively, when given with omeprazole (40 mg daily). Omeprazole AUC and Cmax increased 145% and 124% respectively.(1) In a study of 15 subjects, atazanavir AUC, Cmax and Cmin decreased 76%, 72% and 78% respectively, when given with omeprazole (40 mg daily) and ritonavir (100 mg daily).(1) In a study in 13 subjects, administration of omeprazole (20 mg daily) 12 hours before atazanavir/ritonavir (300/100 mg daily) decreased atazanavir Cmax, AUC, and Cmin by 39%, 42%, and 46%, respectively; however, the atazanavir AUC and Cmin were 10% and 2.4-fold higher than average levels seen with atazanavir 400 mg alone.(1) In a study in 14 subjects, administration of omeprazole (20 mg daily) 1 hour before atazanavir/ritonavir (400/100 mg daily) decreased atazanavir Cmax, AUC, and Cmin by 31%, 30%, and 31%, respectively; however, the atazanavir AUC and Cmin were 32% and 3.3-fold higher than average levels seen with atazanavir 400 mg alone.(1) In a study in 10 healthy subjects, concurrent administration of lansoprazole (60 mg daily for 2 days) with atazanavir (400 mg) decreased atazanavir AUC by 94%.(14) In a case report, concurrent esomeprazole decreased atazanavir, but not fosamprenavir levels in a 65 year-old HIV-positive male.(15) In a study in 16 healthy, HIV-negative subjects, the concurrent administration of omeprazole or ranitidine with ritonavir-boosted darunavir had no effect on darunavir pharmacokinetics.(16) In a study in healthy subjects, the concurrent administration of esomeprazole (20 mg daily) with either fosamprenavir (1400 mg twice daily) or fosamprenavir (700 mg twice daily) and ritonavir (100 mg twice daily) for 14 days had no effect on amprenavir pharmacokinetics.(17) In a study in 19 subjects, concurrent omeprazole (40 mg daily) and nelfinavir (1250 mg twice daily) for 4 days decreased nelfinavir AUC, Cmax, and Cmin by 36%, 37%, and 39%.(7,17) The AUC, Cmax, and Cmin of the active M8 metabolite of nelfinavir decreased by 92%, 89%, and 75%, respectively.(4,17) A retrospective review of nelfinavir levels found concurrent use of omeprazole decreased the median M8/nelfinavir ratio.(12) In a case report a 56 year old HIV infected male received omeprazole (40mg daily) and atazanavir/ritonavir (300/100mg) for ten months. Investigators used Bayesian models to determine atazanavir exposure, and found atazanavir levels to be in the 25th percentile of boosted levels, but still above the 75th percentile for unboosted atazanavir.(20) A retrospective review of 76 patients taking proton pump inhibitors and 66 patients not using proton pump inhibitors found no association with a higher virologic failure rate in patients receiving proton pump inhibitors.(21) In a case report, a 50 year-old HIV-infected male with a CD4 count of 1095 cells/ml and an HIV load of 88 copies/ml on a nelfinavir based regimen was switched to an atazanavir/ritonavir (300/100mg daily) regimen. The patient was taking omeprazole (20mg daily) and admitted to taking the atazanavir at 150mg twice daily. The patients CD4 count dropped to 830 cells/ml, but his HIV load dropped to <75 copies/ml. The investigators summarized concurrent use of omeprazole did not adversely affect this patient's virologic load.(22) In a study in 18 healthy subjects, concurrent omeprazole (40 mg daily) with saquinavir/ritonavir (1000/100 mg twice daily) for 4 days increased saquinavir AUC by 83%. No toxicities were noted.(18) In a study in 12 healthy subjects, concurrent omeprazole (40 mg daily) with saquinavir/ritonavir (1000/100 mg twice daily) for 7 weeks increased saquinavir AUC, Cmin, and Cmax by 54%, 73%, 55% respectively. Omeprazole 2 hours prior to saquinavir/ritonavir increased saquinavir AUC, Cmin, and Cmax by 67%, 97%, and 65% respectively. No toxicities were noted.(23) In a study of 14 healthy subjects, concurrent omeprazole (20 mg daily and 40 mg daily) with indinavir (800mg daily) for 7 days decreased indinavir AUC by 34% and 47% respectively and no statistical changes were seen in the Cmax or Tmax of indinavir. When omeprazole (40mg daily) was given with indinavir/ritonavir (800mg/200mg daily) for 7 days indinavir AUC increased by 55% and no statistical changes were seen in indinavir Cmax or Tmax. Omeprazole (40mg daily) showed a Cmax increase of 50% and a half-life increase of 100% in the presence of ritonavir.(24) In a study of 19 healthy subjects, concurrent omeprazole (20 mg daily) with fosamprenavir/ritonavir (1400/200 mg daily) or atazanavir/ritonavir (300/100)for 3 weeks showed no effect on amprenavir pharmacokinetics, but decreased atazanavir AUC and Cmin by 27%.(25) In a retrospective review of 15 HIV-infected patients receiving indinavir (800mg three times daily), nine patients were also receiving omeprazole (20-40mg daily). Of these nine patients, four had plasma concentrations of indinavir below the 95% confidence interval of plasmas concentration in patients receiving indinavir alone, four were within the 95% confidence interval, and one was above the 95% confidence interval.(26) In a case report, a 40 year-old HIV-infected male with extensive antiretroviral history and virological failure began atazanavir/ritonavir (300/100mg daily). The patient was restarted on lansoprazole during atazanavir/ritonavir therapy, and despite lansoprazole and tenofovir therapy the patients plasma concentrations of atazanavir remained consistent with historical values, and the patients Cmin stayed well above the established values for the combination of atazanavir/ritonavir with tenofovir.(27) In a study of 68 healthy subjects, coadministration of omeprazole (40mg daily) with lopinavir/ritonavir (400/100mg twice daily or 800/200mg once daily) showed no statistical change in pharmacokinetics.(28,29) However, when given with atazanavir/ritonavir (300/100 daily) bioavailability of atazanavir decreased by 48-62%.(28) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Proton Pump 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: The aqueous solubility of infigratinib is pH dependent. Higher gastric pH leads to lower solubility which may reduce infigratinib absorption.(1)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) may reduce the bioavailability of infigratinib, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of PPIs, H2 antagonists, and locally acting antacids in patients receiving treatment with infigratinib.(1) If coadministration cannot be avoided and the PPI is replaced with a H2 antagonist, take infigratinib 2 hours before or 10 hours after the H2 antagonist.(1) If coadministration cannot be avoided and the PPI is replaced with an antacid, take infigratinib 2 hours before or 2 hours after the antacid.(1)

DISCUSSION: Infigratinib is practically insoluble at pH 6.8.(1) In a clinical study, lansoprazole decreased the area-under-curve (AUC) and maximum concentration (Cmax) of infigratinib by 45% and 49%, respectively. The AUC and Cmax of the active metabolite BHS697 were decreased by 32% and 44%, respectively, and the active metabolite CQM157's AUC and Cmax were decreased by 72% and 55%, respectively.(1)

Proton Pump 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: The aqueous solubility of olverembatinib is pH dependent. Higher gastric pH leads to lower solubility which may reduce olverembatinib absorption.(1)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) may reduce the bioavailability of olverembatinib leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of olverembatinib states that concurrent use with proton pump inhibitors should be avoided.(1)

DISCUSSION: Olverembatinib has pH-dependent solubility.(1)

Proton Pump Inhibitors/Rilpivirine

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: Rilpivirine requires an acidic medium for absorption. The proton pump inhibitor induced decrease in gastric pH may result in a decrease in rilpivirine absorption.(1)

CLINICAL EFFECTS: Concurrent use of a proton pump inhibitor may result in decreased levels and effectiveness of rilpivirine, as well as the development of resistance.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of rilpivirine states that concurrent use of proton pump inhibitors is contraindicated.(1) When substituting antacids for proton pump inhibitors in patients maintained on rilpivirine, administer the antacid at least 2 hours before or 4 hours after rilpivirine.(1) When substituting H2 antagonists for proton pump inhibitors in patients maintained on rilpivirine, administer the H2 antagonist at least 12 hours before or 4 hours after rilpivirine.(1)

DISCUSSION: In a study in 16 subjects, omeprazole (20 mg daily) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of rilpivirine (150 mg daily) by 40%, 40%, and 33%, respectively. The Cmax and AUC of omeprazole decreased by 14% and 14%, respectively.(1) In a study in 24 subjects, famotidine (40 mg single dose) administered 12 hours before a single dose of rilpivirine (150 mg) had no significant effect on rilpivirine Cmax or AUC.(1) In a study in 23 subjects, famotidine (40 mg single dose) administered 2 hours before a single dose of rilpivirine (150 mg) decreased the rilpivirine Cmax and AUC by 85% and 76%, respectively.(1) In a study in 24 subjects, famotidine (40 mg single dose) administered 4 hours after a single dose of rilpivirine (150 mg) increased the rilpivirine Cmax and AUC by 21% and 13%, respectively.(1)

Proton Pump 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: The aqueous solubility of rilzabrutinib is pH dependent. Higher gastric pH leads to lower solubility which may reduce rilzabrutinib absorption.(1)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) may reduce the bioavailability of rilzabrutinib, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of rilzabrutinib states that concurrent use with proton pump inhibitors should be avoided.(1) If the PPI is replaced with an H2 antagonist, administer rilzabrutinib at least 2 hours before taking the H2 antagonist.(1) If the PPI is replaced with an antacid, administer rilzabrutinib at least 2 hours before taking the antacid.(1)

DISCUSSION: In an interaction study, coadministration of esomeprazole decreased rilzabrutinib maximum concentration (Cmax) by 55% and area-under-the-curve (AUC) by 51%.(1) In an interaction study, coadministration of famotidine decreased rilzabrutinib Cmax by 35% and AUC by 28%.(1)

Proton Pump Inhibitors/Ziftomenib

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

MECHANISM OF ACTION: The aqueous solubility of ziftomenib is pH dependent. Higher gastric pH leads to lower solubility which may reduce ziftomenib absorption.(1)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) may reduce the bioavailability of ziftomenib, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of ziftomenib states that concurrent use with proton pump inhibitors should be avoided.(1) The manufacturer of ziftomenib also states concurrent use with H2 receptor antagonists and antacids should be avoided. If concurrent use cannot be avoided, modify ziftomenib administration time: - Take ziftomenib 2 hours before or 10 hours after administration of an H2 receptor antagonist. - Take ziftomenib 2 hours before or 2 hours after administration of an antacid.(1)

DISCUSSION: In an interaction study, coadministration of proton pump inhibitors (PPIs) decreased ziftomenib area-under-the-curve (AUC) by 53% and maximum concentration (Cmax) by 70%.(1)

Rifabutin/Abiraterone; Cabazitaxel; Vincristine

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

MECHANISM OF ACTION: Rifabutin is an inducer of CYP3A4 and may increase the metabolism of abiraterone,(1) cabazitaxel,(2,3) and vincristine.(4)

CLINICAL EFFECTS: Concurrent or recent use of rifabutin may result in decreased levels and effectiveness of abiraterone,(1) cabazitaxel,(3) and vincristine.(4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concurrent use of rifabutin with abiraterone,(1) cabazitaxel,(3) and vincristine.(4) Consider the use of agents with no or minimal induction potential if possible. Monitor patients for decreased response to therapy. If concurrent administration of abiraterone and rifabutin is required, increase the dosing frequency of abiraterone from once daily to twice daily during the co-administration period. If rifabutin is discontinued, reduce the dose of abiraterone back to the previous dose and frequency.(1)

DISCUSSION: Abiraterone,(1) cabazitaxel,(2,3) and vincristine (3) are metabolized by CYP3A4. Strong inducers of this isoenzyme are expected to decrease levels of these agents. The US manufacturers of abiraterone(1) and vincristine(4) and the UK manufacturer of cabazitaxel(3) include rifabutin on the list of strong CYP3A4 inducers that should be avoided. In a drug interaction trial, concurrent administration of rifampin, a strong CYP3A4 inducer, decreased abiraterone levels by 55%.(1) In a study in 21 advanced cancer patients, rifampin (600mg) decreased the exposure to cabazitaxel (15mg/m2) by 17%.(2)

Rifabutin/Intramuscular Rilpivirine

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: Rifabutin may induce the metabolism of rilpivirine by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent or recent use of rifabutin may result in decreased levels and effectiveness of rilpivirine, as well as the development of resistance.(1)

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

PATIENT MANAGEMENT: The Swedish manufacturer of intramuscular rilpivirine states that concurrent use of rifabutin is contraindicated.(1) It may take several weeks after the discontinuation of an enzyme inducer for enzyme activity to return to normal.(1)

DISCUSSION: Coadministration of rifabutin (300 mg once daily) with rilpivirine (25 mg once daily) decreased rilpivirine's area-under-the-curve (AUC), minimum concentration (Cmin), and maximum concentration (Cmax) by 42%, 48%, and 31%.(1) Coadministration of rifabutin (300 mg once daily) with rilpivirine (50 mg once daily) increased rilpivirine's AUC and Cmax by 16% and 43%.(1)

Rifabutin/Selected Antineoplastic Systemic Enzyme Inhibitors

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: Rifabutin is a moderate inducer of the CYP3A4 isoenzyme and may increase the metabolism of some antineoplastic systemic enzyme inhibitors, including cabozantinib,(1,2) ceritinib,(3) erlotinib,(4) imatinib,(5) lapatinib,(6) and sorafenib.(7)

CLINICAL EFFECTS: Concurrent use of rifabutin may decrease the levels and effectiveness of some antineoplastic systemic enzyme inhibitors, including cabozantinib,(1,2) ceritinib,(3) erlotinib,(4) imatinib,(5) lapatinib,(6) and sorafenib.(7)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the concurrent use of rifabutin in patients receiving therapy with cabozantinib,(1,2) ceritinib,(3) erlotinib,(4) imatinib,(5) lapatinib,(6) and sorafenib.(7) Consider the use of alternative agents with less enzyme induction potential.(1-7) If concurrent use of rifabutin cannot be avoided: Increase the daily dose of cabozantinib TABlets by 20 mg (e.g. from 60 mg to 80 mg daily) as tolerated. The daily dose should not exceed 80 mg. Resume the dose that was used prior to initiating rifabutin 2 to 3 days after discontinuation of rifabutin.(1) Increase the daily dose of cabozantinib CAPsules by 40 mg (from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. The daily dose of cabozantinib should not exceed 180 mg. If rifabutin is discontinued, reduce the dosage of cabozantinib to the dose used prior to initiation of rifabutin 2 to 3 days after discontinuation of rifabutin.(2) Consider increasing the dosage of erlotinib by 50 mg increments as tolerated at two week intervals (to a maximum of 450 mg) while closely monitoring the patient. The highest dosage studied with concurrent rifampin is 450 mg. If the dosage of erlotinib is increased, it will need to be decreased when rifabutin is discontinued.(4) The dose of imatinib should be increased by at least 50% and clinical response should be carefully monitored. Dosages up to 1,200 mg/day (600 mg twice daily) have been used in patients receiving concurrent therapy with strong CYP3A4 inducers.(5) The dose of lapatinib should be gradually titrated from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer indication) or from 1,500 mg/day up to 5,500 mg/day (hormone receptor positive, HER2 positive breast cancer indication) based on patient tolerability. If rifabutin is discontinued, the dose of lapatinib should be adjusted to the normal dose.(6)

DISCUSSION: The US manufacturers of cabozantinib,(2) erlotinib,(4) imatinib,(5) lapatinib,(6) and sorafenib,(7) and the UK manufacturer of ceritinib(3) include rifabutin in their list of strong CYP3A4 inducers to be avoided. Although the combinations of these agents with rifabutin have not been studied, they have been studied with other strong CYP3A4 inducers. In a study in healthy subjects, rifampin (600 mg daily for 31 days) decreased the area-under-curve (AUC) of a single dose of cabozantinib by 77%.(1) In a study in 19 healthy subjects, rifampin (600 mg daily for 14 days) decreased the maximum concentration (Cmax) and AUC of a single dose of ceritinib by 44% and 70%, respectively.(3) Pretreatment and concurrent therapy with rifampin increased erlotinib clearance by 3-fold and decreased the erlotinib AUC by 66% to 80%. This is equivalent to a dose of about 30 mg to 50 mg in NSCLC.(4) In a study, pretreatment with rifampin for 11 days decreased the AUC of a single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single 150 mg dose of erlotinib.(4) In a case report, coadministration of phenytoin (180mg daily) and erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from 1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold (from 3.53 L/h to 41.7 L/h).(8) Pretreatment of 14 healthy subjects with rifampin (600 mg daily for 10 days) increased the clearance of a single dose of imatinib (400 mg) by 3.8-fold. The AUC and Cmax decreased by 74% and 54%, respectively.(5,9) The Cmax of the CGP74588 metabolite increased by 88.6%, but the AUC of CGP74588 decreased by 11%.(9) In healthy subjects, carbamazepine (100 mg twice daily for 3 days and 200 mg twice daily for 17 days), another CYP3A4 inducer, decreased the AUC of lapatinib by 72%. The dose adjustment recommendations are based on pharmacokinetic studies and are predicted to adjust lapatinib AUC to the range observed without concurrent CYP3A4 inducers; however, there are no clinical data with these doses in patients receiving strong CYP3A4 inducers.(6) Concurrent rifampin (600 mg daily for 5 days) decreased the AUC of a single dose of sorafenib (400 mg) by 37%.(7)

Rifabutin/Sofosbuvir-Containing Hepatitis C Products

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: Rifabutin is an inducer of P-glycoprotein (P-gp) and may decrease the absorption of ledipasvir,(1-4) sofosbuvir,(1-12) velpatasvir,(5-12) and voxilaprevir.(9-12)

CLINICAL EFFECTS: Concurrent or recent use of rifabutin may result in decreased levels and effectiveness of ledipasvir,(1-4) sofosbuvir,(1-12) velpatasvir,(5-12) and voxilaprevir.(9-12)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Australian and US manufacturers of ledipasvir-sofosbuvir,(1,4) velpatasvir-sofosbuvir,(5,8) and sofosbuvir-velpatasvir-voxilaprevir,(9,12) and the Canadian manufacturer of velpatasvir-sofosbuvir (6) do not recommend coadministration with rifabutin. The UK manufacturer of ledipasvir-sofosbuvir,(3) velpatasvir-sofosbuvir,(7) and sofosbuvir-velpatasvir-voxilaprevir,(11) and the Canadian manufacturer of sofosbuvir-velpatasvir-voxilaprevir (10) state that concurrent use with rifabutin is contraindicated.

DISCUSSION: In a phase I pharmacokinetic study with 20 healthy subjects, rifabutin (300 mg daily) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of sofosbuvir by 36% and 24%, respectively.(8) The impact of rifabutin on ledipasvir, velpatasvir, and voxilaprevir has not been studied, but rifabutin is expected to lower plasma concentrations of each of these substances. Although a reduction in dose of sofosbuvir of less than 50% is not expected to reduce its efficacy, the potential impact of rifabutin on ledipasvir, velpatasvir, and voxilaprevir warrants caution with concomitant use.(13) In a study in 31 subjects, rifampin (600 mg daily, a strong P-gp inducer) decreased the maximum concentration (Cmax) and AUC of ledipasvir by 35% and 59%, respectively.(4) In a study in 17 subjects, rifampin (600 mg daily) decreased the Cmax and AUC of sofosbuvir by 77% and 72%, respectively.(4) In a study in 12 subjects, rifampin (600 mg daily) decreased the Cmax and AUC of velpatasvir by 71% and 82%, respectively.(8) In a study in 24 subjects, rifampin (600 mg daily) decreased the Cmax and AUC of voxilaprevir by 9% and 73%, respectively.(12)

Rifampin; Rifabutin/Delavirdine

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: Rifampin and rifabutin may induce the metabolism of delavirdine at CYP3A4.(1) Delavirdine may inhibit the metabolism of rifabutin.(1)

CLINICAL EFFECTS: The concurrent administration of rifampin or rifabutin with delavirdine may result in drastically reduced levels of delavirdine and therapeutic failure.(1) The concurrent administration of rifabutin and delavirdine may result in elevated levels of rifabutin.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of delavirdine states that rifampin and rifabutin should not be used in patients receiving delavirdine.(1) The US manufacturer of rifabutin states that concomitant use of rifabutin with delavirdine is contraindicated. (3)

DISCUSSION: In a study in seven HIV-1 infected patients, the concurrent administration of delavirdine (400 mg three times daily) with rifampin (600 mg once daily) resulted in a decrease in the delavirdine area-under-curve (AUC), maximum concentration (Cmax), and minimum concentration (Cmin) by 97%, 90%, and 100%, respectively.(1) In a study in seven HIV-1 infected patients, the concurrent administration of delavirdine (400 mg three times daily) with rifabutin (300 mg once daily) decreased delavirdine AUC, Cmax, and Cmin by 82%, 72%, and 94%, respectively. The AUC, Cmax, and Cmin of rifabutin were increased by 230%, 128%, and 452%, respectively.(1,2)

Selected Cyp3a4 Inducers/Isavuconazonium; Voriconazole

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

MECHANISM OF ACTION: Strong inducers of CYP3A4 and rifabutin may increase the metabolism of isavuconazonium(1,2) and voriconazole.(3)

CLINICAL EFFECTS: The concurrent use of strong inducers of CYP3A4 or rifabutin with isavuconazonium(1,2) or voriconazole(3) may result in severely reduced levels of the azole antifungal and therapeutic failure.

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

PATIENT MANAGEMENT: The concurrent use of isavuconazonium(1,2) or voriconazole(3) with strong inducers of CYP3A4 is contraindicated. The concurrent use of voriconazole with rifabutin is also contraindicated.(3,4) The UK manufacturer of voriconazole states that concurrent use with rifabutin should be avoided. If concurrent use is necessary, the maintenance dose of voriconazole may be increased from 200 mg to 350 mg orally twice daily. If the patient weighs less than 40 kg, the maintenance dose of voriconazole may be increased from 100 mg to 200 mg orally twice daily. If concurrent use is necessary, the maintenance dose of intravenous voriconazole can be increased to 5 mg/kg intravenously twice daily.(9) The US manufacturer of isavuconazonium does not make any recommendations for concurrent use with rifabutin,(1) but the UK manufacturer states that concurrent use of rifabutin is contraindicated.(2)

DISCUSSION: The concurrent use of rifampin (600 mg) with isavuconazonium (multiple doses) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of voriconazole by 75% and 97%, respectively.(1) The concurrent use of rifampin (600 mg once daily) with voriconazole (200 mg every 12 hours for 7 days) decreased the Cmax and AUC of voriconazole by 93% and 96%, respectively. Doubling the dose of voriconazole did not restore adequate exposure to voriconazole during rifampin.(3) The concurrent use of rifabutin (300 mg once daily) with voriconazole (200 mg twice daily) decreased the Cmax and AUC of voriconazole by 67% and 79%, respectively. The concurrent use of rifabutin (300 mg once daily) with voriconazole (400 mg twice daily) increased the Cmax and AUC of voriconazole to twice that seen with voriconazole alone at 200 mg twice daily. However, the Cmax and AUC of rifabutin were 3-fold and 4-fold higher, respectively, when given with voriconazole at 400 mg twice daily.(3) In a study in 16 subjects, subjects received single doses of voriconazole (400 mg) alone, after one dose of St. John's wort (300 mg), and after 15 days of St. John's wort (300 mg daily). After 10 hours of St. John's wort, voriconazole area-under-curve (AUC) increased 22%. After 15 days of St. John's wort, voriconazole AUC decreased 59%.(5) Therapeutic failures have been reported with voriconazole in patients treated concurrently with carbamazepine,(6) phenobarbital,(7) and rifampin.(8) In a study in 12 healthy male subjects, voriconazole (400 mg twice daily for 7 days) with rifabutin (300 mg daily for 7 days) increased rifabutin's AUC and Cmax by 331% and 195%, respectively. The AUC and Cmax of voriconazole were increased by approximately 100%.(4) Selected CYP3A4 inducers linked to this monograph include apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, ivosidenib, lumacaftor, mitotane, phenobarbital, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.

Selected Cyp3a4 Inducers/Nifedipine

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 inducers may induce the hepatic metabolism of nifedipine.(1)

CLINICAL EFFECTS: Concurrent use of an inducer of CYP3A4 may decrease levels and effectiveness of nifedipine.(1)

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

PATIENT MANAGEMENT: The concurrent use of strong CYP3A4 inducers with nifedipine is contraindicated.(1)

DISCUSSION: In a study in 12 healthy males, pretreatment with rifampin (600 mg daily for 14 days) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of nifedipine (20 mg) by 95% and 97%, respectively.(1) In a study of 6 healthy subjects, pretreatment with rifampin (600 mg daily for 7 days) increased the clearance of a single oral dose of nifedipine (20 mg) by 9.28-fold and decrease the nifedipine bioavailability by 87%. There were no significant effects on a single intravenous dose of nifedipine.(2) In a study in 6 healthy subjects, pretreatment with a single dose of rifampin (600 mg) 8 hours before a single oral dose of nifedipine decreased nifedipine bioavailability by 64.2%. Nifedipine half-life decreased by 60%. Nifedipine clearance increased by 1.89-fold.(3) There have been case reports of decreased effectiveness of nifedipine during concurrent rifampin therapy.(4-6) Enzalutamide is a strong inducer of CYP3A4.(7) Selected CYP3A4 inducers linked to this monograph include apalutamide, encorafenib, enzalutamide, ivosidenib, lumacaftor, mitotane, rifabutin, rifampin, and rifapentine.

Selected Moderate Cyp3a4 Inducers/Crizotinib

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 induce the CYP3A4 isoenzyme may induce the metabolism of crizotinib.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inducers may decrease the levels and effectiveness of crizotinib.(1)

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 moderate CYP3A4 inducers in patients receiving therapy with crizotinib.(1) Consider the use of alternative agents with less enzyme induction potential.(1)

DISCUSSION: Rifampin (600 mg daily), a strong CYP3A4 inducer, decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of crizotinib (250 mg) by 69% and 82%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, modafinil, nafcillin, rifabutin, sotorasib, telotristat ethyl, and tovorafenib.(2)

Selected Moderate Cyp3a4 Inducers/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: Moderate inducers of CYP3A4 may induce the metabolism of ensartinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may reduce the clinical effectiveness of ensartinib.(1)

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

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

DISCUSSION: Ensartinib is predominately metabolized by CYP3A4.(1) Moderate CYP3A4 inducers linked to this monograph are: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, pacritinib, repotrectinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3)

Selected P-Gp Inducers/Berotralstat

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: Berotralstat is a substrate of the intestinal efflux transporter P-glycoprotein (P-gp). Inducers of P-gp may decrease systemic absorption of berotralstat.(1)

CLINICAL EFFECTS: Concurrent or recent use of P-gp inducers may result in decreased systemic levels and effectiveness of berotralstat.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of berotralstat states avoid concurrent use of P-gp inducers with berotralstat.(1)

DISCUSSION: Berotralstat is a substrate P-gp. Concomitant administration with a P-gp inducer may decrease berotralstat plasma concentration leading to reduced efficacy of berotralstat.(1) Selected P-gp inducers linked to this monograph include: apalutamide, carbamazepine, efavirenz, fosphenytoin, lorlatinib, phenytoin, rifabutin, rifampin, rifapentine, and St. John's wort.(1)

Slt Moderate And Strong Cyp3a4 Inducers/Ixazomib

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: Ixazomib is primarily metabolized by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of strong or selected moderate CYP3A4 inducers will result in decreased systemic concentrations of ixazomib.(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 ixazomib states that concomitant use with CYP3A4 inducers should be avoided. In an interaction study, rifampin decreased ixazomib exposure(AUC) by 74%.(1) Use an alternative to the inducing agent when possible. The onset of induction is gradual but may begin within one week for potent agents (e.g. rifampin). The time to maximal induction may be 2 or more weeks depending upon the half-life and dose of the inducer.

DISCUSSION: In an interaction study, coadministration with rifampin decreased ixazomib AUC 74% and maximum concentration (Cmax) by 54%(1) Selected moderate and strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, belzutifan, carbamazepine, cenobamate, dabrafenib, elagolix, encorafenib, enzalutamide, fexinidazole, fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin, rifapentine, St. John's Wort, sotorasib, telotristat, and tovorafenib.(2)

Slt Moderate-Strong Cyp3a4 Inducers/Slt Hepatitis C Agents

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 or moderate inducers of CYP3A4 may induce the metabolism of asunaprevir or ombitasvir-paritaprevir-ritonavir treatment for hepatitis C.(1-3) Asunaprevir is also a substrate for the OATP1B1 transporter. OATP1B1 facilitated transport into the liver is thought to be associated with asunaprevir efficacy. While rifampin a strong CYP3A4 inducer, is also an OATP1B1 inhibitor and so may further decrease asunaprevir efficacy by inhibiting its transport into the liver.

CLINICAL EFFECTS: The combination of asunaprevir or ombitasvir-paritaprevir-ritonavir, with or without dasabuvir, may not be effective for the treatment of hepatitis C.(1-3)

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

PATIENT MANAGEMENT: Because of the risk for treatment failure, the manufacturers of asunaprevir, and ombitasvir-paritaprevir-ritonavir state that concomitant use with strong or moderate CYP3A4 inducers is contraindicated.(1-3)

DISCUSSION: In an interaction study with 12 subjects, carbamazepine 200 mg once daily followed by 200 mg twice daily decreased antiviral exposure (area-under-curve or AUC) of ombitasvir by 31%, paritaprevir by 70%, ritonavir by 87%, and dasabuvir by 55%.(1) Strong and moderate CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate, dabrafenib, encorafenib, enzalutamide, etravirine, fexinidazole, fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifapentine, sotorasib, telotristat, and tovorafenib.

Slt Strong & Moderate 2C19 Inhibitor/Cilostazol (> 50Mg 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 CYP2C19 may inhibit the metabolism of cilostazol.(1-4)

CLINICAL EFFECTS: Concurrent use of strong or moderate inhibitors of CYP2C19 may result in elevated levels of 3,4-dehydro-cilostazol, a metabolite of cilostazol that is 4-7 times as active as cilostazol.(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 CYP2C19.(1) The Australian manufacturer of esomeprazole states concomitant use with cilostazol is contraindicated.(5)

DISCUSSION: In a study in 20 subjects examined the effects of omeprazole (40 mg daily) on a single dose of cilostazol (100 mg). Concurrent omeprazole increased the cilostazol maximum concentration (Cmax) and area-under-curve (AUC) by 18% and 26%, respectively. The Cmax and AUC of the 3,4-dehydro-cilostazol metabolite of cilostazol increased 29% and 69%, respectively. The Cmax and AUC of the OPC-13213 metabolite of cilostazol decreased by 22% and 31%, respectively.(4)

Strong & Moderate Cyp3a4 Inducers/Axitinib

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 induce the CYP3A4 isoenzyme may induce the metabolism of axitinib.(1)

CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inducers may decrease the levels and effectiveness of axitinib.(1)

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 strong or moderate CYP3A4 inducers in patients receiving therapy with axitinib.(1) Consider the use of alternatives with little to no induction potential.(1)

DISCUSSION: Rifampin (600 mg daily for 9 days), a strong CYP3A4 inducer, decreased the maximum concentration (Cmax) and area-under-curve (AUC) of axitinib to less than half and less than 25% of levels seen without concurrent rifampin.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, dexamethasone, encorafenib, enzalutamide, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort. Moderate inducers of CYP3A4 include: bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat ethyl, thioridazine and tovorafenib.(1-3)

Strong & Moderate Cyp3a4 Inducers/Bedaquiline

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 inducers may induce the metabolism of bedaquiline.(1)

CLINICAL EFFECTS: Concurrent or recent use of strong or moderate CYP3A4 inducers may result in decreased levels and effectiveness of bedaquiline.(1)

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

PATIENT MANAGEMENT: The concurrent administration of strong or moderate CYP3A4 inducers and bedaquiline should be avoided.(1)

DISCUSSION: In a study in healthy subjects, concurrent administration of rifampin (600 mg daily) and bedaquiline (300 mg daily) for 21 days decreased the area-under-curve (AUC) of bedaquiline by 52%.(1) In a study in healthy subjects, pretreatment with efavirenz (600 mg daily for 27 days) decreased the AUC of a single dose of bedaquiline by 20%. There was no effect on bedaquiline Cmax. The AUC and Cmax of the primary metabolite of bedaquiline increased by 70% and 80%, respectively.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(1-3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, sotorasib, telotristat and tovorafenib.(1-3)

Strong & Moderate Cyp3a4 Inducers/Cobimetinib

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

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

CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inducers may decrease the levels and effectiveness of cobimetinib.(1)

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 strong or moderate CYP3A4 inducers in patients receiving therapy with cobimetinib.(1) Consider the use of alternatives with little to no induction potential.

DISCUSSION: Based upon simulations, coadministration of cobimetinib with a strong CYP3A4 inducer may decrease cobimetinib exposure by 83%, with a moderate CYP3A4 inducer by 73%, leading to a reduction in efficacy.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, cenobamate, encorafenib, enzalutamide, ivosidenib, lorlatinib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort. Moderate inducers of CYP3A4 include: bosentan, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(1-3)

Strong & Moderate Cyp3a4 Inducers/Quizartinib

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 induce the CYP3A4 isoenzyme may induce the metabolism of quizartinib.(1)

CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inducers may decrease the levels and effectiveness of quizartinib.(1)

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 strong or moderate CYP3A4 inducers in patients receiving therapy with quizartinib.(1)

DISCUSSION: The area-under-curve (AUC) of quizartinib decreased by 90% and maximum concentration (Cmax) by 45% following concomitant use of a single 53 mg dose of quizartinib with efavirenz (a moderate CYP3A inducer). The AUC of active metabolite AC886 decreased by 96% and the Cmax by 68%. The effect of concomitant use with a strong CYP3A inducer may result in even greater effect on quizartinib pharmacokinetics based on mechanistic understanding of the drugs involved. 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: bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, and tovorafenib.(2-3)

Strong & Moderate Cyp3a4 Inducers/Sonidegib

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

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

CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inducers may decrease the levels and effectiveness of sonidegib.(1)

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 strong or moderate CYP3A4 inducers in patients receiving therapy with sonidegib.(1) Consider the use of alternatives with little to no induction potential.

DISCUSSION: In an interaction study, 16 healthy subjects received a single dose of sonidegib 800mg alone or 5 days after receiving rifampin 600 mg daily for 14 days. Mean sonidegib area-under-curve (AUC) was decreased by 75% and maximum concentration (Cmax) decreased 54% when taken with rifampin. Based upon population based pharmacokinetic (PBPK) simulations, a moderate CYP3A4 inducer such as efavirenz given for 14 days is predicted to decrease sonidegib AUC 56% in cancer patients taking sonidegib 200 mg daily. Coadministration with a moderate CYP3A4 inducer for 4 months is predicted to decrease sonidegib exposure (AUC) by 69%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate inducers of CYP3A4 include: bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2-3)

Strong And Moderate Cyp3a4 Inducers/Capivasertib

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 inducers of CYP3A4 may increase the metabolism of capivasertib.(1)

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

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

PATIENT MANAGEMENT: Avoid concomitant use of capivasertib with strong and moderate CYP3A4 inducers.(1)

DISCUSSION: Rifampin (strong CYP3A4 inducer) is predicted to decrease capivasertib area-under-curve (AUC) by 70% and maximum concentration (Cmax) by 60%.(1) Efavirenz (moderate CYP3A4 inducer) is predicted to decrease capivasertib AUC by 60% and Cmax by 50%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, and tovorafenib.(2,3)

Strong And Moderate Cyp3a4 Inducers/Capmatinib

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 inducers may increase the metabolism of capmatinib by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of strong and moderate CYP3A4 inducers and capmatinib may result in decreased exposure to capmatinib and decreased anti-tumor activity.(1)

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

PATIENT MANAGEMENT: Avoid concomitant use of strong and moderate CYP3A4 inducers with capmatinib.(1)

DISCUSSION: Coadministration with rifampin (a strong CYP3A4 inducer) decreased capmatinib area-under-curve (AUC) by 67% and maximum concentration (Cmax) by 56%. Coadministration with efavirenz (a moderate CYP3A4 inducer) was predicted to decrease capmatinib AUC by 44% and Cmax by 34%.(1) Strong and moderate CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate, dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, etravirine, fexinidazole, fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin, rifapentine, St. John's wort, sotorasib, telotristat, thioridazine, and tovorafenib.(2)

Strong And Moderate Cyp3a4 Inducers/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: Elacestrant is metabolized by CYP3A4. Strong and moderate inducers of CYP3A4 may increase the metabolism of elacestrant.(1)

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

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

PATIENT MANAGEMENT: The US manufacturer of elacestrant states avoid concomitant use of elacestrant with strong or moderate CYP3A4 inducers.(1) The US manufacturer of elacestrant does not provide dose modification recommendations with strong and moderate CYP3A4 inducers. The Australian and UK manufacturers of elacestrant state concomitant use of strong or moderate CYP3A4 inducers should be avoided and an alternative concomitant medicinal product with no or minimal potential to induce CYP3A4 should be considered. If a strong or moderate CYP3A4 inducer must be used for a short duration of time (i.e. less than or equal to 3 days) or intermittently (i.e. treatment periods less than or equal to 3 days separated by at least 2 weeks or 1 week + 5 half-lives of the CYP3A4 inducer, whichever is longer), continue elacestrant without increasing the dose.(2,3)

DISCUSSION: Coadministration of 200 mg dose of elacestrant with rifampin (a strong CYP3A inducer) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of elacestrant by 73% and 86%, respectively.(1) Efavirenz is predicted to decrease the Cmax and AUC of elacestrant by 44 to 63% and 55% to 73%, respectively.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(4,5) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(4,5)

Strong And Moderate Cyp3a4 Inducers/Fexinidazole

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

MECHANISM OF ACTION: Strong and moderate inducers of CYP3A4 may increase the metabolism of fexinidazole to its active metabolites and result in increased systemic exposure and increased risk for adverse reactions, including the risk of QT prolongation.(1)

CLINICAL EFFECTS: Concurrent use of a strong or moderate CYP3A4 inducer may result in increased levels of fexinidazole's active metabolites (M1 and M2), which may lead to increased risk of adverse reactions and life-threatening cardiac arrhythmias, including torsades des pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2) 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 fexinidazole with medications that induce CYP3A4.(1) Avoid use of fexinidazole in patients who have a baseline QTcF interval greater than 470 msec, a history of torsades de pointes, congenital long QT syndrome, cardiac arrhythmias, uncompensated heart failure, or family history of sudden death, or uncorrected hypokalemia.(1) If patients are, or need to be, treated with drugs known to prolong the QTcF interval or to induce bradycardia, either do not initiate therapy with fexinidazole until such drugs are eliminated from the body (allow a washout period of 5 half-lives for such other drugs). Do not start such drugs until fexinidazole therapy is eliminated (allow a washout period of 7 days).(1) 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: Fexinidazole is metabolized to its active metabolites, M1 and M2, by CYP3A4. M2 plasma concentrations have been associated with the increased risk of QT prolongation.(1) In clinical studies, fexinidazole was associated with a concentration-dependent QTcF prolongation. At recommended therapeutic doses, the mean (upper 90% confidence interval) increase in QTcF is predicted to be 19.0 msec (23.3 msec). The observed increase in QTcF appears to be associated with the M2 (sulfone) metabolite of fexinidazole.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(3,4) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, modafinil, nafcillin, pexidartinib, rifabutin, sotorasib, telotristat ethyl, and tovorafenib.(3,4)

Strong And Moderate Cyp3a4 Inducers/Finerenone

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

MECHANISM OF ACTION: Strong and moderate CYP3A4 inducers may increase the metabolism of finerenone by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of strong or moderate CYP3A4 inducers with finerenone may result in decreased levels and clinical effectiveness of finerenone.(1)

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

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

DISCUSSION: Finerenone is a substrate of CYP3A4. Concurrent use of efavirenz (a moderate CYP3A4 inducer) and rifampicin (a strong CYP3A4 inducer) decreased finerenone area-under-curve (AUC) by 80% and 90%, respectively.(1) Strong and moderate CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate, dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, etravirine, fexinidazole, fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin, rifapentine, St. John's wort, sotorasib, telotristat, thioridazine, and tovorafenib.(2,3)

Strong And Moderate Cyp3a4 Inducers/Ibrexafungerp

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 inducers may increase the metabolism of ibrexafungerp by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of strong or moderate CYP3A4 inducers with ibrexafungerp may result in decreased levels and clinical effectiveness of ibrexafungerp.(1)

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

PATIENT MANAGEMENT: Avoid concomitant use of strong and moderate CYP3A4 inducers with ibrexafungerp.(1)

DISCUSSION: Ibrexafungerp is a substrate of CYP3A4. The manufacturer of ibrexafungerp states that concurrent use of strong or moderate CYP3A4 inducers are likely to significantly reduce ibrexafungerp exposure, but this interaction has not been studied.(1) Strong and moderate CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate, dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, etravirine, fexinidazole, fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin, rifapentine, St. John's wort, sotorasib, telotristat, thioridazine, and tovorafenib.(2,3)

Strong And Moderate Cyp3a4 Inducers/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: Strong and moderate CYP3A4 inducers may increase the metabolism of infigratinib by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of strong and moderate CYP3A4 inducers and infigratinib may result in decreased levels and clinical effectiveness of infigratinib.(1)

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

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

DISCUSSION: Coadministration of multiple doses of rifampin (a strong CYP3A4 inducer) decreased infigratinib area-under-curve (AUC) and maximum concentration (Cmax) by 56% and 44%, respectively.(1) Strong and moderate CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate, dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, etravirine, fexinidazole, fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin, rifapentine, St. John's wort, sotorasib, telotristat, thioridazine, and tovorafenib.(3)

Strong And Moderate Cyp3a4 Inducers/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: Lemborexant is a substrate of CYP3A4. Strong or moderate inducers of CYP3A4 may induce the metabolism of lemborexant.(1)

CLINICAL EFFECTS: The concurrent administration of strong or moderate CYP3A4 inducers may result in decreased levels and effectiveness of lemborexant.(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 lemborexant states that concurrent use with strong or moderate CYP3A4 inducers should be avoided.(1)

DISCUSSION: A pharmacokinetic model predicted that co-administration of rifampin, a strong CYP3A4 inducer, would decrease the AUC of lemborexant by 90%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Strong And Moderate Cyp3a4 Inducers/Leniolisib

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

MECHANISM OF ACTION: Leniolisib is metabolized by CYP3A4. Strong and moderate inducers of CYP3A4 may increase the metabolism of leniolisib.(1)

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

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

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

DISCUSSION: PBPK model-based simulations predicted a maximum decrease of 78% and 58% in leniolisib area-under-curve (AUC) with rifampin (strong CYP3A4 inducer) and efavirenz (moderate CYP3A4 inducer), respectively.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3) Moderate inducers of CYP3A4 include: belzutifan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(2,3)

Strong And Moderate Cyp3a4 Inducers/Lonafarnib

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

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

CLINICAL EFFECTS: Concurrent use of strong and moderate CYP3A4 inducers may decrease the serum levels and effectiveness of lonafarnib.(1)

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

PATIENT MANAGEMENT: The use of strong or moderate CYP3A4 inducers with lonafarnib is contraindicated.

DISCUSSION: With coadministration of a single oral dose of 50 mg lonafarnib (combined with a single oral dose of 100 mg ritonavir) following 600 mg rifampin (a strong CYP3A4 inducer) for 8 days, the area-under-curve (AUC) was reduced by 98% and the maximum concentration (Cmax) was reduced by 92%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, and tovorafenib.(2,3)

Strong And Moderate Cyp3a4 Inducers/Neratinib

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: Inducers of CYP3A4 may induce the metabolism of neratinib.(1)

CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inducers may result in decreased effectiveness of neratinib.(1)

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 neratinib with strong or moderate inducers of CYP3A4.(1) If concurrent use is warranted, monitor patients closely for decreased neratinib effectiveness.

DISCUSSION: Rifampin, a strong CYP3A4 inducer, decreased maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of neratinib (240 mg) by 76% and 87%, respectively.(1) Strong CYP3A4 inducers include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine and St. John's wort.(1,2) Moderate CYP3A4 inducers include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine, and tovorafenib.(1,2)

Strong And Moderate Cyp3a4 Inducers/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: Strong or moderate CYP3A4 inducers may induce the metabolism of nirogacestat.(1)

CLINICAL EFFECTS: Coadministration of nirogacestat with a strong or moderate CYP3A4 inducer decreases nirogacestat plasma concentrations, which may decrease efficacy of nirogacestat.(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 nirogacestat states that concurrent use with strong or moderate CYP3A4 inducers should be avoided.(1)

DISCUSSION: In a PKPB model, coadministration of rifampin, a strong CYP3A4 inducer, following multiple doses of nirogacestat (150 mg BID) is predicted to decrease the area-under-curve (AUC) of nirogacestat by 85%.(1) In a PKPB model, coadministration of efavirenz, a moderate CYP3A4 inducer, following multiple doses of nirogacestat (150 mg BID) is predicted to decrease the AUC of nirogacestat by 67%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, modafinil, nafcillin, pacritinib, pexidartinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Strong And Moderate Cyp3a4 Inducers/Olutasidenib

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 inducers may increase the metabolism of olutasidenib by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of strong and moderate CYP3A4 inducers and olutasidenib may result in decreased levels and clinical effectiveness of olutasidenib.(1)

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

PATIENT MANAGEMENT: Avoid concomitant use of strong and moderate CYP3A4 inducers with olutasidenib.(1)

DISCUSSION: Coadministration of multiple doses of rifampin (a strong CYP3A4 inducer) decreased olutasidenib area-under-curve (AUC) and maximum concentration (Cmax) by 80% and 43%, respectively.(1) Strong and moderate CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, encorafenib, enzalutamide, etravirine, fexinidazole, fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin, rifapentine, St. John's wort, sotorasib, telotristat, thioridazine, and tovorafenib.(2)

Strong And Moderate Cyp3a4 Inducers/Omaveloxolone

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: Omaveloxolone is metabolized by CYP3A4. Strong and moderate inducers of CYP3A4 may increase the metabolism of omaveloxolone.(1)

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

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

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

DISCUSSION: Omaveloxolone is a substrate of CYP3A4. The effect of concomitant use with strong CYP3A4 inducers is unknown. Concurrent administration of a single dose of efavirenz (moderate CYP3A4 inducer) with omaveloxolone decreased the maximum concentration (Cmax) and area-under-the-curve (AUC) of omaveloxolone by 38% and 48%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(2,3)

Strong And Moderate Cyp3a4 Inducers/Palovarotene

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

MECHANISM OF ACTION: Palovarotene is extensively metabolized by CYP3A4. Strong and moderate inducers of CYP3A4 may increase the metabolism of palovarotene.(1)

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

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

PATIENT MANAGEMENT: Avoid concomitant use of palovarotene with strong and moderate CYP3A4 inducers.(1)

DISCUSSION: In a clinical trial, rifampin, a strong CYP3A4 inducer, decreased the maximum concentration (Cmax) and area-under-curve (AUC) of palovarotene by 81% and 89%, respectively.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2)

Strong And Moderate Cyp3a4 Inducers/Pemigatinib

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 inducers may increase the metabolism of pemigatinib by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of strong and moderate CYP3A4 inducers and pemigatinib may result in decreased levels and clinical effectiveness of pemigatinib.(1)

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

PATIENT MANAGEMENT: Avoid concomitant use of strong and moderate CYP3A4 inducers with pemigatinib.(1)

DISCUSSION: Rifampin, a strong CYP3A4 inducer, decreased pemigatinib maximum concentration (Cmax) by 62% and area-under-curve (AUC) by 85% following a single pemigatinib oral dose of 13.5 mg. Concomitant use of a moderate CYP3A4 inducer is predicted to decrease pemigatinib exposure by more than 50%. Strong and moderate CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate, dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, etravirine, fexinidazole, fosphenytoin, ivosidenib, lesinurad, lorlatinib, mavacamten, lumacaftor, mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin, rifapentine, St. John's wort, sotorasib, telotristat, thioridazine, and tovorafenib.(3)

Strong And Moderate Cyp3a4 Inducers/Rimegepant

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

MECHANISM OF ACTION: Strong and moderate CYP3A4 inducers may increase the metabolism of rimegepant by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of strong and moderate CYP3A4 inducers and rimegepant may result in decreased levels and clinical effectiveness of rimegepant.(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 rimegepant recommends avoiding concurrent use with strong or moderate CYP3A4 inducers due to potential decrease in exposure to rimegepant and loss of efficacy.(1) Patients receiving concurrent therapy with strong and moderate CYP3A4 inducers and rimegepant should be observed for decreased clinical effectiveness.

DISCUSSION: In a drug interaction study, rifampin, a strong CYP3A4 inducer, decreased the area-under-curve (AUC) and maximum concentration (Cmax) of rimegepant (75 mg) by 80% and 64%, respectively.(1) Strong and moderate CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate, dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, etravirine, fexinidazole, fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin, rifapentine, St. John's wort, sotorasib, telotristat, thioridazine, and tovorafenib.(1,2)

Strong And Moderate Cyp3a4 Inducers/Selpercatinib

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 inducers may increase the metabolism of selpercatinib.(1)

CLINICAL EFFECTS: Coadministration of selpercatinib with a strong or moderate CYP3A4 inducer decreases selpercatinib plasma concentrations, which may decrease the efficacy of selpercatinib.(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 selpercatinib states that concurrent use with strong and moderate CYP3A4 inducers should be avoided.(1)

DISCUSSION: In a study, multiple doses of rifampin (a strong CYP3A inducer) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of selpercatinib by 87% and 70%, respectively.(1) Coadministration of multiple doses of bosentan or efavirenz (moderate CYP3A inducers) is predicted to decrease the AUC and Cmax of selpercatinib 40-70% and 34-57%, respectively.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, and telotristat ethyl.(2,3)

Strong And Moderate Cyp3a4 Inducers/Selumetinib

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 inducers may increase the metabolism of selumetinib by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of strong and moderate CYP3A4 inducers and selumetinib may result in decreased levels and clinical effectiveness of selumetinib.(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 selumetinib recommends avoiding concurrent use with strong or moderate CYP3A4 inducers due to potential decrease in exposure to selumetinib and loss of efficacy.(1) Patients receiving concurrent therapy with strong and moderate CYP3A4 inducers and selumetinib should be observed for decreased clinical effectiveness.

DISCUSSION: In a study of 22 healthy subjects, rifampin 600 mg daily (a strong CYP3A4 inducer) decreased selumetinib area-under-curve (AUC) and maximum concentration (Cmax) by 51% and 26%, respectively.(2) Concomitant use of efavirenz, a moderate CYP3A4 inducer, is predicted to decrease selumetinib AUC and Cmax by 38% and 22%, respectively.(1) Strong and moderate CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate, dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, etravirine, fexinidazole, fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin, rifapentine, St. John's wort, sotorasib, telotristat, thioridazine, and tovorafenib.(3)

Strong And Moderate Cyp3a4 Inducers/Voclosporin

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

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

CLINICAL EFFECTS: Concurrent use of strong and moderate CYP3A4 inducers may decrease the serum levels and effectiveness of voclosporin.(1)

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

PATIENT MANAGEMENT: The use of strong or moderate CYP3A4 inducers with voclosporin should be avoided.(1)

DISCUSSION: Concurrent use of voclosporin with rifampin 600 mg daily for 10 days (strong CYP3A4 inducer) decreased the concentration maximum (Cmax) and area-under-curve (AUC) by 0.32-fold and 0.13-fold, respectively.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Strong Cyp3a4 & Ugt1a1 Inducers/Cabotegravir-Rilpivirine

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: Apalutamide, barbiturates, carbamazepine, dexamethasone, efavirenz, encorafenib, enzalutamide, eslicarbazepine, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, oxcarbazepine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, ritonavir, or St. John's wort may induce the metabolism of cabotegravir-rilpivirine by CYP3A4 and uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1).(1)

CLINICAL EFFECTS: Concurrent or recent use of apalutamide, barbiturates, carbamazepine, dexamethasone, efavirenz, encorafenib, enzalutamide, eslicarbazepine, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, oxcarbazepine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, ritonavir, or St. John's wort may result in decreased levels and effectiveness of cabotegravir-rilpivirine, as well as the development of resistance.(1)

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

PATIENT MANAGEMENT: The US manufacturer of cabotegravir-rilpivirine states that concurrent use of CYP3A4 inducers and/or UGT1A1 inducers is contraindicated.(1) It may take several weeks after the discontinuation of an enzyme inducer for enzyme activity to return to normal.(1)

DISCUSSION: In a study in 16 subjects, rifampin (600 mg daily) decreased the concentration maximum (Cmax), area-under-curve (AUC), and concentration minimum (Cmin) of rilpivirine (150 mg daily) by 69%, 80%, and 89%, respectively. There were no significant effects on the Cmax or AUC of rifampin or 25-desacetylrifampin.(1) In a study in 15 subjects, rifampin (600 mg daily) decreased the Cmax, AUC, and Cmin of cabotegravir by 6%, 59%, and 50%, respectively.(1) Strong CYP3A4 inducers linked include: apalutamide, barbiturates, carbamazepine, dexamethasone, encorafenib, enzalutamide, eslicarbazepine, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, oxcarbazepine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, or St. John's wort.(1,2) UGT1A1 inducers linked include: carbamazepine, efavirenz, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin, primidone, rifapentine, rifampin, and ritonavir.(1,2)

Strong Cyp3a4 Inducers/Ranolazine

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

MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of ranolazine.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of ranolazine.(1,2)

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

PATIENT MANAGEMENT: The US manufacturer of ranolazine states that the concurrent use of CYP3A4 inducers is contraindicated.(1) The UK manufacturer of ranolazine states that ranolazine should not be used in patients receiving CYP3A4 inducers such as rifampin.(2)

DISCUSSION: Concurrent rifampin (600 mg daily), strong inducer of CYP3A4, decreased ranolazine plasma concentrations by 95%.(1,2) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(1-4)

Strong Cyp3a4 Inducers/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: Inducers of CYP3A4 may induce the metabolism of tolvaptan.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may result in decreased levels and effectiveness of tolvaptan.(1)

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

PATIENT MANAGEMENT: Concurrent administration with strong CYP3A4 inducers should be avoided. If concurrent use is required, the dosage of tolvaptan may need to be increased.(1)

DISCUSSION: Concurrent administration of rifampin, a strong inducer of CYP3A4, decreased tolvaptan exposure by 85%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(1,2)

Strong Cyp3a4 Inducers/Toremifene

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

MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of toremifene.(1) Toremifene may inhibit the metabolism of phenytoin.(1)

CLINICAL EFFECTS: Concurrent or recent use of apalutamide, barbiturates, carbamazepine, dexamethasone, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort may result in decreased levels and effectiveness of toremifene.(1) Concurrent use of toremifene may decrease phenytoin levels.(1)

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

PATIENT MANAGEMENT: Avoid the use of strong inducers of CYP3A4 in patients receiving toremifene. If concurrent toremifene and phenytoin are required, monitor phenytoin levels. The dosage of phenytoin may need to be adjusted.(1)

DISCUSSION: In clinical trials, ten patients on anticonvulsants which included carbamazepine, phenobarbital, and phenytoin experienced a 2-fold increase in clearance and a decrease in the elimination half-life of toremifene.(1,2) The area-under-curve (AUC) and half-life of N-demethyltoremifene, an active metabolite of toremifene, decreased by 61% and 78%, respectively.(2) In a study in healthy males, rifampin (600 mg daily for 5 days) decreased maximum concentration (Cmax) and AUC of a single dose of toremifene (120 mg) by 55% and 87%, respectively. The Cmax of N-demethyltoremifene increased 48% and the AUC of N-demethyltoremifene decreased by 80%.(3) Strong inducers of CYP3A4 include apalutamide, barbiturates, carbamazepine, dexamethasone, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(4,5)

Strong Cyp3a4 Inducers; Rifabutin/Brigatinib

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: Brigatinib is a substrate of CYP3A4. Strong inducers of CYP3A4 and rifabutin may induce the metabolism of brigatinib.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 or rifabutin may result in decreased levels and effectiveness of brigatinib.(1,2)

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 brigatinib states to avoid concurrent administration with strong CYP3A4 inducers.(1,2) The UK manufacturer of brigatinib includes rifabutin on its list of strong CYP3A4 inducers that should be avoided.(2)

DISCUSSION: Brigatinib is a substrate of CYP3A4.(1) Concurrent administration of rifampin (600 mg daily, a strong CYP3A4 inducer) with a single 180 mg dose of brigatinib decreased the brigatinib maximum concentration (Cmax) by 60% and area-under-curve (AUC) by 80% compared to brigatinib alone.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(3-4)

Strong Cyp3a4 Inducers; Rifabutin/Ponatinib

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

MECHANISM OF ACTION: Strong inducers of CYP3A4 and rifabutin may induce the metabolism of ponatinib via this pathway.(1-3)

CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers or rifabutin may reduce the clinical effectiveness of ponatinib.(1-3)

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 ponatinib with strong CYP3A4 inducers.(1-3) The Canadian and UK manufacturers of ponatinib include rifabutin in their list of CYP3A4 inducers that should be avoided.(2-3) When possible, select alternative agents in place of the strong CYP3A4 inducer. Monitor patients receiving concurrent therapy for reduced efficacy.

DISCUSSION: Coadministration of a single ponatinib 45 mg dose with rifampin 600 mg daily in 19 healthy volunteers resulted in a decrease in ponatinib area-under-the-curve (AUC) and maximum concentration (Cmax) by 62% and 42%, respectively. (1) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine and St John's Wort.(4,5)

Strong Cyp3a4 Inducers; Rifabutin/Romidepsin

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

MECHANISM OF ACTION: Strong inducers of CYP3A4 and rifabutin may increase the metabolism of romidepsin.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inducer or rifabutin may result in decreased levels and effectiveness of romidepsin.(1,2)

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 romidepsin recommends avoiding the use of strong inducers of CYP3A4 in patients receiving romidepsin.(1,2) The Canadian manufacturer includes rifabutin on its list of CYP3A4 inducers that should be avoided.(2)

DISCUSSION: In a study in advanced cancer patients, rifampin, a strong inducer of CYP3A4 and an inhibitor and inducer of other CYP enzymes and transporters, unexpectedly increased the maximum concentration (Cmax) and area-under-curve (AUC) of romidepsin (14 mg/m2) by 60% and 80%, respectively. Romidepsin clearance and volume of distribution decreased by 44% and 52%, respectively. This is likely due to inhibition of an undetermined hepatic uptake process responsible for the disposition of romidepsin.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, dexamethasone, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifapentine and St. John's wort.(1-3)

Strong Or Moderate Cyp3a4 Inducers/Avacopan

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)

Strong Or Moderate Cyp3a4 Inducers/Avapritinib

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 or moderate CYP3A4 inducers may induce the metabolism of avapritinib.

CLINICAL EFFECTS: Coadministration of avapritinib with a strong or moderate CYP3A4 inducer decreases avapritinib plasma concentrations, which may decrease efficacy of avapritinib.(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 avapritinib states that concurrent use with strong or moderate CYP3A4 inducers should be avoided.(1)

DISCUSSION: Coadministration of avapritinib 400 mg as a single dose with rifampin 600 mg daily, a strong CYP3A4 inducer, decreased avapritinib concentration maximum (Cmax) by 74% and area-under-curve (AUC) by 92%.(1) Coadministration of avapritinib 300 mg once daily with efavirenz 600 mg once daily, a moderate CYP3A4 inducer, is predicted to decrease avapritinib Cmax by 55% and AUC by 62% at steady state.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine and tovorafenib.(2,3)

Strong Or Moderate Cyp3a4 Inducers/Daridorexant

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

MECHANISM OF ACTION: Daridorexant is a substrate of CYP3A4. Strong or moderate inducers of CYP3A4 may induce the metabolism of daridorexant.(1)

CLINICAL EFFECTS: The concurrent administration of strong or moderate CYP3A4 inducers may result in decreased levels and effectiveness of daridorexant.(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 daridorexant states that concurrent use with strong or moderate CYP3A4 inducers should be avoided.(1)

DISCUSSION: Concomitant use of rifampin, a strong CYP3A4 inducer, with daridorexant 50 mg decreased daridorexant area-under-curve (AUC) by more than 50%. Efavirenz 600 mg, a moderate CYP3A4 inducer, decreased daridorexant AUC and maximum concentration (Cmax) by 60% and 40%, respectively.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Strong Or Moderate Cyp3a4 Inducers/Mobocertinib

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

MECHANISM OF ACTION: Strong or moderate inducers of CYP3A4 may induce the metabolism of mobocertinib.(1)

CLINICAL EFFECTS: Concurrent use of a strong or moderate CYP3A4 inducer may result in a loss of mobocertinib efficacy.(1)

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 mobocertinib with strong or moderate CYP3A4 inducers.(1)

DISCUSSION: Coadministration of mobocertinib with multiple doses of rifampin (a strong CYP3A inducer) is predicted to decrease the steady-state combined molar area-under-curve (AUC) of mobocertinib and its active metabolites by 92%.(1) Coadministration of mobocertinib with multiple doses of efavirenz (a moderate CYP3A inducer) is predicted to decrease the steady-state combined molar AUC of mobocertinib and its active metabolites by 58%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, and tovorafenib.(2,3)

Strong Or Moderate Cyp3a4 Inducers/Repotrectinib

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

MECHANISM OF ACTION: Strong or moderate CYP3A4 inducers may induce the metabolism of repotrectinib.(1)

CLINICAL EFFECTS: Coadministration of repotrectinib with a strong or moderate CYP3A4 inducer decreases repotrectinib plasma concentrations, which may decrease efficacy of repotrectinib.(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 repotrectinib states that concurrent use with strong or moderate CYP3A4 inducers should be avoided.(1)

DISCUSSION: Coadministration of repotrectinib with rifampin, a strong CYP3A4 and P-glycoprotein inducer, decreased concentration maximum (Cmax) by 79% and area-under-curve (AUC) by 92%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, encorafenib, etravirine, lesinurad, modafinil, nafcillin, pacritinib, pexidartinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Strong Or Moderate Cyp3a4 Inducers/Tazemetostat

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 or moderate CYP3A4 inducers may induce the metabolism of tazemetostat.(1)

CLINICAL EFFECTS: Coadministration of tazemetostat with a strong or moderate CYP3A4 inducer may decrease tazemetostat plasma concentrations, which may decrease the efficacy of tazemetostat.(1)

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

PATIENT MANAGEMENT: The US manufacturer of tazemetostat says to avoid coadministration of strong or moderate CYP3A4 inducers with tazemetostat.(1)

DISCUSSION: Tazemetostat is a known substrate of CYP3A4. According to the manufacturer, coadministration with a strong or moderate CYP3A4 inducer may decrease tazemetostat plasma concentrations which may decrease the efficacy of tazemetostat. No clinical studies have been conducted.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Strong Or Moderate Cyp3a4 Inducers/Vonoprazan

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: Vonoprazan is a substrate of CYP3A4. Strong or moderate inducers of CYP3A4 may increase the metabolism of vonoprazan.(1)

CLINICAL EFFECTS: The concurrent administration of strong or moderate CYP3A4 inducers may result in decreased levels and effectiveness of vonoprazan.(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 vonoprazan states that concurrent use with strong or moderate CYP3A4 inducers should be avoided.(1)

DISCUSSION: Strong CYP3A4 inducers like rifampin are predicted to decrease the area-under-curve (AUC) of vonoprazan by 80%, and moderate CYP3A4 inducers like efavirenz are predicted to decrease vonoprazan AUC by 50%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2-3)

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

Esomeprazole; Omeprazole/Select Cyp2c19 Or Cyp3a4 Inducer

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

MECHANISM OF ACTION: Proton pump inhibitors are primarily metabolized by CYP2C19, while CYP3A4 also plays a role in metabolism.(1,2) Enzalutamide, rifampin, and St. John's wort are moderate inducers of CYP2C19 and strong inducers of CYP3A4.(3,4) Apalutamide is a strong inducer of CYP2C19 and CYP3A4.(5) Efavirenz and pacritinib are moderate inducers of CYP2C19 and CYP3A4.(3,6) Sparsentan is a moderate inducer of CYP2C19.(8) Fexinidazole is a moderate inducer of CYP3A4.(3)

CLINICAL EFFECTS: Concurrent use of agents which induce both CYP2C19 and CYP3A4 decrease systemic exposure and may result in decreased effectiveness of proton pump inhibitors.(1-7)

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

PATIENT MANAGEMENT: Avoid concurrent use of esomeprazole or omeprazole with CYP2C19 or CYP3A4 inducers.(1,2) Monitor patients receiving concurrent therapy for reduced proton pump inhibitor (PPI) effectiveness. Although specific dosing recommendations are not available, a higher dose of the proton pump inhibitor may be considered to maintain PPI efficacy.

DISCUSSION: In an interaction study, subjects with prostate cancer received omeprazole before and after enzalutamide 160 mg daily for at least 55 days. Enzalutamide decreased omeprazole area-under-curve (AUC) by 70.5%.(3,4) In an interaction study, rifampin 600 mg daily for 7 days decreased omeprazole AUC by 89.5%.(3,7) In an interaction study, pacritinib 200 mg twice daily at steady state decreased the Cmax and AUC of a single dose of omeprazole (20 mg) by 27% and 51%, respectively.(6) Concomitant use with sparsentan (moderate CYP2C19 inducer) decreased the exposure of omeprazole Cmax by 49% and AUC by 60%.(8) In an interaction study, St. John's wort decreased the maximum concentration (Cmax) and AUC of omeprazole by 37.5% and 49.6%, respectively. The Cmax and AUC of omeprazole sulfone (via CYP2C19) increased by 160.3% and 136.6%, respectively. The Cmax and AUC of 5-hydroxyomeprazole (via CYP3A4) increased by 38.1% and 37.2%, respectively.(9,10)

Esomeprazole; Omeprazole; Cimetidine/Clopidogrel

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

MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2 step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1,2) CYP2C19 contributes to both steps and is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite.(1) Proton pump inhibitors (PPIs) may inhibit CYP2C19 mediated conversion to the active metabolite of clopidogrel. The magnitude and clinical significance of CYP2C19 inhibition is highly variable between agents.(1)

CLINICAL EFFECTS: Concurrent use of esomeprazole, omeprazole, or cimetidine may result in decreased clopidogrel effectiveness, resulting in increased risk of adverse cardiac events.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Evaluate patient risk for gastrointestinal(GI) bleeding. When PPIs are needed, use dexlansoprazole, lansoprazole, pantoprazole or rabeprazole as they have a lower interaction risk.(1,3) Consider the use of H2 blockers (such as famotidine, nizatidine, or ranitidine) in patients with a low bleeding risk and reserve the use of PPIs for patients at higher risk of GI bleeding. US manufacturers for clopidogrel and omeprazole state concurrent use of clopidogrel esomeprazole and omeprazole should be avoided.(1,4-5) As esomeprazole and omeprazole are irreversible inhibitors of CYP2C19, separating clopidogrel from esomeprazole or omeprazole administration times does not change the magnitude of this interaction.(1,4,6) The US manufacturer of clopidogrel states that alternatives to clopidogrel should be considered in patients who are poor metabolizers of CYP2C19.(1) It would be prudent to assume that patients taking strong inhibitors of CYP2C19 are poor metabolizers of this isoenzyme. Moderate CYP2C19 inhibitors, such as omeprazole, and weak CYP2C19 inhibitors, such as cimetidine, may also affect this interaction. Consider alternatives to esomeprazole, omeprazole, and cimetidine in patients stabilized on clopidogrel and alternatives to clopidogrel in patients stabilized on esomeprazole, omeprazole, and cimetidine. If concurrent therapy is warranted, consider appropriate testing to assure adequate inhibition of platelet reactivity.

DISCUSSION: US manufacturer for clopidogrel states omeprazole and esomeprazole have been shown to reduce antiplatelet activity of clopidogrel and recommends against concomitant use. The antiplatelet effect of clopidogrel is reduced by approximately 40% in patients receiving 80 mg per day of omeprazole. Dexlansoprazole, lansoprazole and pantoprazole are described as having less effect on clopidogrel antiplatelet activity.(1,3) In the primary literature, documentation for this interaction is conflicting. However, both in-vitro and retrospective analyses indicate that omeprazole decreases the effectiveness of clopidogrel. Although the half-lives of esomeprazole and omeprazole (a racemic mixture of R- and esomeprazole) are short, the effect on CYP2C19 is long lasting because esomeprazole is an irreversible inhibitor of CYP2C19.(6) In two studies in healthy subjects, concurrent omeprazole decreased the effects of clopidogrel on platelets.(7-8) Several studies have found coadministration of clopidogrel with omeprazole resulted in increased platelet aggregation compared to clopidogrel with pantoprazole, or no PPI.(9-12) In a study, use of omeprazole was associated with a decreased risk of upper gastrointestinal bleeding in patients receiving dual antiplatelet therapy with clopidogrel and aspirin. There was no significant difference between the groups in rate of cardiovascular events.(12) Three studies found that simultaneous omeprazole with clopidogrel reduced clopidogrel concentrations and effects.(13-15) In a cross-over trial, healthy subjects received clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg oral once daily) co-administered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 35% to 40% over this time period.(16) In a study in 39 healthy subjects, the effects of omeprazole and rabeprazole on clopidogrel in patients with different CYP2C19 genotypes was examined. In rapid 2C19 metabolizers, simultaneous omeprazole and rabeprazole significantly decreased clopidogrel response. In decreased 2C19 responders, there was wide variation in clopidogrel response and simultaneous omeprazole and rabeprazole had no significant effect on overall clopidogrel effects; however, some subjects became low responders to clopidogrel while on PPI therapy. Staggered dosing of omeprazole had no effect on clopidogrel response in rapid metabolizers, but decreased clopidogrel response in decreased metabolizers.(17) Several retrospective studies found that patients who took clopidogrel with a PPI had increased incidence of major cardiovascular events compared to patients who took clopidogrel without a PPI.(18-22) A retrospective cohort study of 20,596 patients in the Tennessee Medicaid program, evaluated both cardiovascular disease event and GI bleed risk in patients prescribed clopidogrel with or without concurrent PPI use. Pantoprazole was prescribed in 62% of PPI patients. Concomitant PPI and clopidogrel use decreased the risk of hospitalization from GI bleeding by 50%. There was no clear-cut increase risk for serious cardiovascular disease events; however, the 95% CI for this was wide.(23) A post-hoc analysis of the PRINCIPLE-TIMI 44 trial and the TRITON-TIMI trial examined the effects of PPI use on the pharmacodynamic effects and clinical efficacy of clopidogrel. The PRINCIPLE-TIMI 44 trial examined 201 patients undergoing cardiac catheterization with planned percutaneous coronary intervention, 53 of which were taking a PPI at randomization. Patients receiving a PPI had significantly lower rates of inhibition of platelet aggregation at 0.5 hours, 2 hours, 6 hours, and 18-24 hours post-loading dose of clopidogrel. After 15 days of maintenance therapy, there were significantly more non-responders in the group receiving PPI (50% versus 7.9%). The TRITON-TIMI trial examined 13,608 patients who underwent cardiac catheterization with planned percutaneous coronary intervention, 4529 of which were taking a PPI at randomization. Patients received clopidogrel treatment for 6-15 months. There were no significant differences in occurrence of cardiovascular death, non-fatal MI, or non-fatal stroke between patients taking PPIs at randomization and those not; however, use of PPIs was only assessed at randomization and not during the study.(24) A retrospective cohort study of 16,064 patients evaluated the impact of MACE events in patients taking clopidogrel with PPIs/PCABs. Patients taking concurrent PPIs or PCABs with clopidogrel had a higher incidence of MACE compared to clopidogrel monotherapy. Among MACE, stroke recurrence was the highest risk with the PPI and PCAB groups. The PPIs studied included esomeprazole, dexlansoprazole, omeprazole, pantoprazole, ilaprazole, and rabeprazole, with esomeprazole resulting in the highest risk of MACE and stroke recurrence.(29)

H2 Antagonists;Proton Pump Inhibitors/Methylphenidate Xr-Odt

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

MECHANISM OF ACTION: The solubility of methylphenidate extended release orally disintegrating tablets (XR-ODT) is pH-dependent. At elevated pH, methylphenidate may be released from the tablets more quickly, resulting in increased absorption.(1)

CLINICAL EFFECTS: Coadministration of H2 antagonists or proton pump inhibitors (PPIs) may result in an altered pharmacokinetic profile of methylphenidate XR-ODT, which may change the effectiveness and/or adverse effects of methylphenidate XR-ODT.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration of methylphenidate XR-ODT with H2 antagonists or PPIs is not recommended.(1,2)

DISCUSSION: In in vitro studies, when media pH was increased from 1.2 to 6.8, percentage release of methylphenidate from the XR-ODT tablet was increased by 67% at 0.5 hours, and by 93% at 2.5 hours. The increased dissolution of methylphenidate at higher pH may result in increased drug absorption and change the concentration-time profile of methylphenidate, which is correlated with pharmacological effect.(1)

Long Acting Antacids; H2s;Ppis/Selected Cephalosporins

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

MECHANISM OF ACTION: Absorption of oral cefpodoxime or cefuroxime may be reduced in patients receiving concomitant treatment with acid reducing agents.(1-5)

CLINICAL EFFECTS: Antibiotic efficacy against organisms with a high minimum inhibitory concentration (MIC) to cefpodoxime or cefuroxime could be decreased.

PREDISPOSING FACTORS: Taking cefpodoxime or cefuroxime on an empty stomach magnifies this effect.

PATIENT MANAGEMENT: If possible, avoid the use of H2 antagonists and proton pump inhibitors(PPIs) in patients taking cefpodoxime or cefuroxime. If concurrent therapy is needed with antacids, H2 antagonists, or PPIs, administer cefpodoxime or cefuroxime after eating to maximize oral absorption. Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.

DISCUSSION: In a study of ten subjects, administration of cefpodoxime after single dose famotidine 40 mg decreased both maximum concentration (Cmax) and area-under-curve (AUC) by approximately 40 percent compared with administration of cefpodoxime on an empty stomach.(3) In a study of 17 subjects, administration of cefpodoxime after single dose ranitidine 150 mg decreased Cmax and AUC by approximately 40 percent compared with administration of cefpodoxime on an empty stomach.(4) In a study performed prior to the introduction of PPIs, administration of ranitidine 300 mg and sodium bicarbonate followed by cefuroxime taken on a empty stomach lowered both Cmax and AUC of cefuroxime by approximately 40 per cent compared with administration of cefuroxime alone on an empty stomach. Postprandial administration of cefuroxime in subjects taking ranitidine was similar to that of subjects taking cefuroxime on an empty stomach.(5)

Moderate Cyp2c19 Inhibitors/Mavacamten

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

MECHANISM OF ACTION: Moderate CYP2C19 inhibitors may decrease the metabolism of mavacamten.(1-3)

CLINICAL EFFECTS: Concurrent use of a moderate CYP2C19 inhibitor increases plasma exposure of mavacamten which may increase the incidence and severity of adverse reactions of mavacamten.(1-3)

PREDISPOSING FACTORS: CYP2C19 rapid and ultrarapid metabolizers may experience an increased incidence or severity of adverse effects.(1-3)

PATIENT MANAGEMENT: The US manufacturer of mavacamten recommends initiating mavacamten at one dose below the recommended starting dose in patients who are on stable therapy with a moderate CYP2C19 inhibitor. Reduce dose by one level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients who are on mavacamten treatment and intend to initiate a moderate CYP2C19 inhibitor. Schedule clinical and echocardiographic assessment 4 weeks after inhibitor initiation, and do not up-titrate mavacamten until 12 weeks after inhibitor initiation.(1) Avoid initiation of concomitant moderate CYP2C19 inhibitors in patients who are on stable treatment with the lowest recommended dose of mavacamten because a lower dose is not available.(1) For short-term use (e.g. 1 week), interrupt mavacamten therapy for the duration of the moderate CYP2C19 inhibitor. After therapy with the moderate CYP2C19 inhibitor is discontinued, mavacamten may be reinitiated at the previous dose immediately upon discontinuation.(1) The Canadian manufacturer of mavacamten states concomitant use with moderate CYP2C19 inhibitors is contraindicated.(2) The UK manufacturer of mavacamten states concomitant use with moderate CYP2C19 inhibitors is dependent on CYP2C19 phenotype. Labeling recommends: -In patients who are CYP2C19 poor metabolizers, moderate CYP2C19 inhibitors may be used concurrently without dose adjustment of mavacamten. Monitor left ventricular ejection fraction (LVEF) in 4 weeks then resume usual monitoring schedule. -In patient who are CYP2C19 intermediate, normal, rapid, or ultrarapid metabolizers: Moderate CYP2C19 inhibitors may be used concurrently without dose adjustment of mavacamten starting dose of 5 mg daily. If starting a moderate CYP2C19 inhibitor, reduce mavacamten dose by one dose level or discontinue 2.5 mg. Monitor LVEF in 4 weeks then resume usual monitoring schedule. -If CYP2C19 phenotype is unknown, consider a mavacamten starting dose of 2.5 mg daily. If starting a moderate CYP2C19 inhibitor, reduce mavacamten dose from 5 mg to 2.5 mg or discontinue mavacamten if on 2.5 mg. Monitor LVEF in 4 weeks then resume usual monitoring schedule.(3)

DISCUSSION: Concomitant use of mavacamten (15 mg) with omeprazole (20 mg), a weak CYP2C19 inhibitor, once daily increased mavacamten area-under-curve (AUC) by 48% with no effect on maximum concentration (Cmax) in healthy CYP2C19 normal metabolizers and rapid metabolizers.(1) Moderate CYP2C19 inhibitors linked to this monograph include: abrocitinib, cannabidiol, esomeprazole, moclobemide, omeprazole, stiripentol, triclabendazole.(4,5)

Moderate Cyp3a4 And P-Gp Inducers/Glecaprevir-Pibrentasvir

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

MECHANISM OF ACTION: Glecaprevir and pibrentasvir are substrates of the P-glycoprotein (P-gp) transporter. Glecaprevir is also a minor substrate of CYP3A4. Agents that are inducers of P-gp and CYP3A4 may induce efflux and decrease the absorption as well as induce the metabolism of glecaprevir-pibrentasvir.(1)

CLINICAL EFFECTS: The combination of glecaprevir-pibrentasvir may not be effective for the treatment of hepatitis C.(1)

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

PATIENT MANAGEMENT: Because of the risk of treatment failure, the UK manufacturer of glecaprevir-pibrentasvir states that concomitant use with moderate CYP3A4 and P-gp inducers is not recommended.(1)

DISCUSSION: While not designed to evaluate effects on glecaprevir-pibrentasvir, a study of the effects of glecaprevir-pibrentasvir on efavirenz-emtricitabine-tenofovir observed that geometric mean exposures of glecaprevir and pibrentasvir were 47% lower than historical controls.(2) In a single dose study in 12 subjects, a single dose of rifampin (600 mg, a strong CYP3A4 and P-gp inducer) with glecaprevir/pibrentasvir (300mg/120 mg single dose) increased glecaprevir's maximum concentration (Cmax) and area-under-the-curve (AUC) by 6.52-fold and 8.55-fold, respectively. In another single dose study in 12 subjects, rifampin (600 mg daily) with glecaprevir/pibrentasvir (300 mg/120 mg single dose) decreased glecaprevir's Cmax and AUC by 86% and 88% and pibrentasvir's Cmax and AUC by 83% and 87%, respectively.(1) In a study in 10 subjects, carbamazepine (200 mg twice daily, a strong CYP3A4 and P-gp inducer) administered concomitantly with glecaprevir/pibrentasvir (300/120 mg daily) decreased the Cmax and AUC of glecaprevir by 67% and 66%, and the Cmax and AUC of pibrentasvir by 50% and 51%, respectively.(1) Moderate CYP3A4 and P-gp inducers linked to this monograph include: lorlatinib and rifabutin.(3)

Moderate Cyp3a4 Inducer/Vanzacaftor-Tezacaftor-Deutivacaftor

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

MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of vanzacaftor, tezacaftor, and deutivacaftor.(1)

CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of vanzacaftor, tezacaftor, and deutivacaftor.(1)

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

PATIENT MANAGEMENT: Concurrent use of moderate CYP3A4 inducers in patients maintained on vanzacaftor-tezacaftor-deutivacaftor is not recommended.(1)

DISCUSSION: Concurrent administration with efavirenz (a moderate inducer of CYP3A4) is predicted to decrease vanzacaftor and deutivacaftor area-under-curve (AUC) by 69% and 73%, respectively, and maximum concentration (Cmax) by 65% and 56%, respectively.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Abemaciclib

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

MECHANISM OF ACTION: Abemaciclib is a substrate of CYP3A4. Moderate inducers of CYP3A4 may induce the metabolism of abemaciclib.(1)

CLINICAL EFFECTS: Concurrent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of abemaciclib.(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 abemaciclib states to avoid concurrent administration with moderate CYP3A4 inducers and consider alternative agents.(1)

DISCUSSION: Abemaciclib is a substrate of CYP3A4.(1) Concurrent administration of rifampin (600 mg once daily, a strong CYP3A4 inducer) with a single 200 mg dose of abemaciclib decreased the relative potency adjusted unbound area-under-curve (AUC) of abemaciclib and its active metabolites (M2, M18, and M20) by 70% in healthy subjects.(1) Concurrent administration of efavirenz, bosentan, and modafinil (moderate CYP3A4 inducers) are predicted to decrease the relative potency adjusted unbound AUC of abemaciclib and its active metabolites (M2, M18, and M20) by 53%, 41%, and 29%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, tipranavir/ritonavir and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Atogepant

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

MECHANISM OF ACTION: Moderate CYP3A4 inducers may increase the metabolism of atogepant by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of moderate CYP3A4 inducers with atogepant may result in decreased levels and clinical effectiveness of atogepant.(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 atogepant recommends that patients on concomitant moderate CYP3A4 inducers receive atogepant 60 mg once daily for prevention of episodic migraines and use of atogepant is not recommended for prevention of chronic migraines.(1) Patients receiving concurrent therapy with CYP3A4 inducers and atogepant should be observed for decreased clinical effectiveness.

DISCUSSION: In a study of healthy subjects, rifampin, a strong CYP3A4 inducer, decreased the area-under-curve (AUC) and maximum concentration (Cmax) of atogepant by 60% and 30%, respectively. Topiramate, a weak CYP3A4 inducer, decreased atogepant AUC and Cmax by 25% and 24%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine and tovorafenib.(1,2)

Moderate Cyp3a4 Inducers/Aumolertinib

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

MECHANISM OF ACTION: Aumolertinib is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of aumolertinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of aumolertinib.(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 aumolertinib states that concomitant use of moderate CYP3A4 inducers is not recommended.(1)

DISCUSSION: The impact of moderate CYP3A4 inducers on the pharmacokinetics of aumolertinib has not been investigated in clinical studies. In a clinical study, aumolertinib area-under-curve (AUC) decreased by approximately 90% following concomitant use of rifampin (strong CYP3A4 inducer).(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, telotristat, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Bictegravir-Lenacapavir

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

MECHANISM OF ACTION: Agents that induce the CYP3A4 isoenzyme may accelerate the metabolism of lenacapavir.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inducers may decrease the levels and effectiveness of lenacapavir.(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 bictegravir-lenacapavir for HIV treatment states that concurrent use of moderate CYP3A4 inducers is not recommended.(1)

DISCUSSION: In a study, efavirenz 600 mg once daily (inducer of CYP3A4 [moderate] and P-glycoprotein) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of lenacapavir by 36% and 56%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: barbiturates, cenobamate, dabrafenib, dipyrone, elagolix, lesinurad, lorlatinib, modafinil, nafcillin, nevirapine, oxcarbazepine, phenobarbital, primidone, rifabutin, rifapentine, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Cabozantinib Lauryl Sulfate

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

MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of cabozantinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of cabozantinib.(1)

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 moderate CYP3A4 inducers in patients receiving therapy with cabozantinib. Consider the use of alternative agents with less enzyme induction potential.(1) If concurrent use of a moderate CYP3A4 inducer cannot be avoided, increase the daily dose of cabozantinib CAPsules by 11.5 mg (from 34.5 mg to 46 mg daily, or from 23 mg to 34.5 mg daily, or from 11.5 mg to 23 mg daily) as tolerated. The daily dose of cabozantinib should not exceed 46 mg. If the CYP3A4 inducer is discontinued, reduce the dosage of cabozantinib to the dose used prior to initiation of the inducer 2 to 3 days after discontinuation of the moderate inducer.(1)

DISCUSSION: The impact of moderate CYP3A4 inducers on the pharmacokinetics of cabozantinib has not been investigated in clinical studies. In a study in healthy subjects, rifampin (strong CYP3A4 inducer, 600 mg daily for 31 days) decreased the AUC of a single dose of cabozantinib by 77%.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Cabozantinib S-Malate Tablets

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

MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of cabozantinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of cabozantinib.(1)

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 moderate CYP3A4 inducers in patients receiving therapy with cabozantinib. Consider the use of alternative agents with less enzyme induction potential.(1) If concurrent use of a moderate CYP3A4 inducer cannot be avoided, increase the daily dose of cabozantinib TABlets by 20 mg (e.g. from 60 mg to 80 mg daily) as tolerated. The daily dose should not exceed 80 mg. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the moderate inducer.(1)

DISCUSSION: The impact of moderate CYP3A4 inducers on the pharmacokinetics of cabozantinib has not been investigated in clinical studies. In a study in healthy subjects, rifampin (strong CYP3A4 inducer, 600 mg daily for 31 days) decreased the AUC of a single dose of cabozantinib by 77%.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Camizestrant

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

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

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inducers may decrease the levels and effectiveness of camizestrant.(1)

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

PATIENT MANAGEMENT: Dosage modifications for concomitant use of moderate CYP3A4 inducers differ depending on the CDK4/6 inhibitor used in combination with camizestrant.(1) Avoid the use of moderate CYP3A4 inducers for patients who are receiving camizestrant in combination with abemaciclib or palbociclib.(1) If concomitant use of a moderate CYP3A4 inducer cannot be avoided in patients who are receiving camizestrant in combination with abemaciclib or palbociclib, increase the camizestrant dosage from 75 mg once daily to 150 mg once daily. After the moderate CYP3A4 inducer has been discontinued for at least 14 days, resume the camizestrant dosage used prior to initiation of the moderate CYP3A4 inducer. For patients who are receiving camizestrant in combination with ribociclib concomitantly with a moderate CYP3A4 inducer, no camizestrant dosage modification is recommended.(1)

DISCUSSION: Camizestrant maximum concentration (Cmax) is predicted to decrease to 58%, and the area-under-curve (AUC) is predicted to decrease to 43% following concomitant administration of phenobarbital (moderate CYP3A4 inducer) 100 mg once daily for 17 days. Phenobarbital or efavirenz (moderate CYP3A4 inducer) are predicted to have minimal effects on camizestrant AUC and Cmax when camizestrant is given in combination with 400 mg or 600 mg ribociclib. Moderate inducers of CYP3A4 include: barbiturates, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, phenobarbital, primidone, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Duvelisib

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

MECHANISM OF ACTION: Moderate inducers of CYP3A4 may accelerate the metabolism of duvelisib.(1)

CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may alter the clinical effectiveness of duvelisib.(1)

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 duvelisib with moderate CYP3A4 inducers.(1) When possible, select alternative agents in place of the moderate CYP3A4 inducer. If the moderate CYP3A4 inducer cannot be avoided, increase the dose of duvelisib on day 12 of concurrent therapy as follows: - If the initial dose of duvelisib is 25 mg twice daily, increase the duvelisib dose to 40 mg twice daily. - If the initial dose of duvelisib is 15 mg twice daily, increase the duvelisib dose to 25 mg twice daily. Monitor patients receiving concurrent therapy for reduced efficacy.(1) If the moderate CYP3A4 inducer is discontinued, reduce the dose of duvelisib back to the initial dose 14 days after discontinuation of the moderate CYP3A4 inducer.(1)

DISCUSSION: The primary metabolism pathway for duvelisib is CYP3A4.(1) In an interaction study, etravirine (a moderate CYP3A inducer) 200 mg twice daily decreased the maximum concentration (Cmax) and area-under-curve (AUC) of single dose duvelisib 25 mg by 16% and 35%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad, lorlatinib, modafinil, nafcillin, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2-4)

Moderate Cyp3a4 Inducers/Elbasvir-Grazoprevir

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

MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of elbasvir and grazoprevir.(1,2)

CLINICAL EFFECTS: Concurrent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of elbasvir and grazoprevir.(1,2)

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

PATIENT MANAGEMENT: Concurrent use of elbasvir-grazoprevir and a moderate CYP3A4 inducers is not recommended.(1,2) If concurrent use is required, monitor the patient for potential treatment failure and decreased elbasvir and grazoprevir levels.

DISCUSSION: In single dose studies, rifampin increased levels of both elbasvir and grazoprevir. In a study in 14 subjects, rifampin (600 mg single IV dose) increased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of a single dose of elbasvir (50 mg) by 41%, 22%, and 31%, respectively. In a study in 14 subjects, rifampin (600 mg single oral dose) increased the Cmax, AUC, and Cmin of a single dose of elbasvir (50 mg) by 29%, 17%, and 21%, respectively. In a study in 12 subjects, rifampin (600 mg single IV dose) increased the Cmax, AUC, and Cmin of a single dose of grazoprevir (200 mg) by 10.94-fold, 10.21-fold, and 1.77-fold, respectively. In a study in 12 subjects, rifampin (600 mg single oral dose) increased the Cmax, AUC, and Cmin of a single dose of grazoprevir (200 mg) by 6.52-fold, 8.35-fold, and 1.61-fold, respectively.(1) However, multiple dose studies with rifampin showed decreased grazoprevir levels. In a study in 12 subjects, rifampin (600 mg orally) decreased the AUC and Cmin of grazoprevir (200 mg daily) by 7% and 90%, respectively. Cmax increased 16%.(1) In a study in 12 subjects, efavirenz (600 mg daily) decreased the Cmax, AUC, and Cmin of elbasvir (50 mg daily) by 45%, 34%, and 59%, respectively.(1) In a study in 12 subjects, efavirenz (600 mg daily) decreased the Cmax, AUC, and Cmin of grazoprevir (200 mg daily) by 87%, 82%, and 69%, respectively.(1) Moderate inducers of CYP3A4 include belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(1-4)

Moderate Cyp3a4 Inducers/Elinzanetant

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

MECHANISM OF ACTION: Moderate CYP3A4 inducers may induce the metabolism of elinzanetant by CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may reduce the clinical effectiveness of elinzanetant.(1,2)

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

PATIENT MANAGEMENT: The US manufacturer of elinzanetant states concurrent use with moderate CYP3A4 inducers should be avoided.(1) The Canadian manufacturer of elinzanetant states no dose adjustment is recommended for the concomitant use of elinzanetant with CYP3A4 and P-gp inducers.(2)

DISCUSSION: Elinzanetant maximum concentration (Cmax) reduced by 44% and area-under-curve (AUC) reduced by 64% following concomitant use with carbamazepine (moderate to strong CYP3A4 inducer) 600 mg administered twice daily.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(3,4)

Moderate Cyp3a4 Inducers/Erdafitinib

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

MECHANISM OF ACTION: Erdafitinib is a substrate of CYP2C9 and CYP3A4. Moderate inducers of CYP3A4 may induce the metabolism of erdafitinib.(1)

CLINICAL EFFECTS: Concurrent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of erdafitinib.(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 erdafitinib states that if a moderate CYP3A4 inducer must be co-administered, increase the erdafitinib dose to 9 mg daily. If a moderate CYP3A4 inducer is discontinued, continue erdafitinib at the same dose in the absence of drug-related toxicity.(1)

DISCUSSION: Carbamazepine (a strong CYP3A4 inducer and weak CYP2C9 inducer) decreased the mean maximum concentration (Cmax) and area-under-curve (AUC) of erdafitinib by 78% and 45%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2-3)

Moderate Cyp3a4 Inducers/Gepotidacin

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

MECHANISM OF ACTION: Moderate CYP3A4 inducers may induce the metabolism of gepotidacin.(1)

CLINICAL EFFECTS: Concurrent or recent use of a moderate CYP3A4 inducer may result in decreased antimicrobial activity of gepotidacin.(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 gepotidacin states that concomitant use of moderate CYP3A4 inducers 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 inducers.(1)

DISCUSSION: Gepotidacin is primarily metabolized by CYP3A4.(1) Concomitant administration of efavirenz (moderate CYP3A4 inducer) and a single 1,500 mg dose of gepotidacin is predicted to decrease area-under-curve (AUC) and maximum concentration (Cmax) by 49% and 34%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, lesinurad, lorlatinib, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Ibrutinib

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

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

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inducers may decrease the levels and effectiveness of ibrutinib.(1)

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 moderate CYP3A4 inducers in patients receiving therapy with ibrutinib.(1) Consider the use of alternative agents with less enzyme induction potential.(1)

DISCUSSION: The coadministration of rifampin decreased the maximum concentration (Cmax) and area-under-curve (AUC) of ibrutinib by more than 13-fold and 10-fold.(1) In a pharmacokinetic model, efavirenz (600 mg daily), a moderate CYP3A4 inducer, was predicted to decrease the Cmax and AUC of ibrutinib (560 mg) by 2.4-fold and 2.5-fold, respectively.(2) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(4)

Moderate Cyp3a4 Inducers/Iv And Oral Lefamulin

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

MECHANISM OF ACTION: Lefamulin is a substrate of CYP3A4. Moderate inducers of CYP3A4 may induce the metabolism of lefamulin.(1) Oral lefamulin tablets may inhibit the metabolism of agents that are also sensitive CYP3A4 substrates.(1-3)

CLINICAL EFFECTS: The concurrent administration of a moderate CYP3A4 inducer may result in decreased levels and effectiveness of lefamulin.(1) Coadministration of oral lefamulin with agents that are also sensitive CYP3A4 substrates may result in elevated levels and toxicities of the sensitive CYP3A4 substrate.

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 lefamulin states that concurrent use with moderate CYP3A4 inducers should be avoided.(1) Concomitant use of lefamulin tablets with sensitive CYP3A4 substrates requires close monitoring for adverse effects of these drugs.(1)

DISCUSSION: In a study, concurrent administration of rifampin (a strong inducer) with lefamulin injection decreased lefamulin area-under-the-curve (AUC) and maximum concentration (Cmax) by 28% and 8%.(1) In a study, concurrent administration of rifampin (a strong inducer) with oral lefamulin (tablets) decreased lefamulin AUC and Cmax by 72% and 57%.(1) In a study, oral lefamulin tablets administered concomitantly with and at 2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200% and 100%, respectively. No clinically significant effect on midazolam pharmacokinetics was observed when co-administered with lefamulin injection.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, lesinurad, lorlatinib, modafinil, nafcillin, rifabutin, telotristat, and tovorafenib.(2-3)

Moderate Cyp3a4 Inducers/Lenacapavir

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

MECHANISM OF ACTION: Agents that induce the CYP3A4 isoenzyme may accelerate the metabolism of lenacapavir.(1-3)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inducers may decrease the levels and effectiveness of lenacapavir.(1-3)

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 lenacapavir for HIV treatment states that concurrent use of moderate CYP3A4 inducers is not recommended.(1-3)

DISCUSSION: In a study, efavirenz 600 mg once daily (inducer of CYP3A4 [moderate] and P-glycoprotein) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of lenacapavir by 36% and 56%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: barbiturates, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad, lorlatinib, modafinil, nafcillin, nevirapine, oxcarbazepine, phenobarbital, primidone, rifabutin, rifapentine, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(4,5)

Moderate Cyp3a4 Inducers/Lorlatinib

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

MECHANISM OF ACTION: Moderate inducers of CYP3A4 are expected to increase the metabolism of lorlatinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of moderate inducers of CYP3A4 may result in decreased levels and effectiveness of lorlatinib.(1)

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

PATIENT MANAGEMENT: Avoid concurrent administration of moderate inducers of CYP3A4 with lorlatinib.(1) If concurrent use of lorlatinib and moderate CYP3A4 inducers cannot be avoided, increase the dose of lorlatinib to 125 mg daily.(1)

DISCUSSION: Modafinil (a moderate CYP3A4 inducer) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single 100 mg dose of lorlatinib by 23% and 22%, respectively.(1) Moderate inducers of CYP3A4 include belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad, modafinil, nafcillin, pacritinib, pexidartinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(1)

Moderate Cyp3a4 Inducers/Mitapivat

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

MECHANISM OF ACTION: Moderate inducers of CYP3A4 may increase the metabolism of mitapivat.(1)

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

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

PATIENT MANAGEMENT: Consider alternative therapies that are not moderate CYP3A4 inducers in patients who are on mitapivat. If concurrent use is necessary, monitor hemoglobin closely and titrate mitapivat dose, not to exceed a maximum dose of 100 mg twice daily.(1)

DISCUSSION: Mitapivat is a CYP3A4 substrate. In a pharmacokinetic study with 5 or 20 mg twice daily of mitapivat, efavirenz decreased area-under-curve (AUC) and concentration maximum (Cmax) by 60% and 30%, respectively. After mitapivat doses of 50 mg twice daily, efavirenz decreased AUC and Cmax by 55% and 24%, respectively.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad, modafinil, nafcillin, pacritinib, pexidartinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Pirtobrutinib

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

MECHANISM OF ACTION: Pirtobrutinib is metabolized by CYP3A4. Moderate inducers of CYP3A4 may increase the metabolism of pirtobrutinib.(1)

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

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

PATIENT MANAGEMENT: Avoid concomitant use of pirtobrutinib with moderate CYP3A4 inducers.(1) If concomitant use of moderate CYP3A4 inducers is unavoidable, and the current dose of pirtobrutinib is 200 mg daily, increase the dose to 300 mg daily. If the current pirtobrutinib dosage is 50 mg or 100 mg once daily, increase the dose by 50 mg.(1)

DISCUSSION: Efavirenz and bosentan (moderate CYP3A inducers) are predicted to decrease the area-under-curve (AUC) of pirtobrutinib by 49% and 27%, respectively.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, and thioridazine.(2,3)

Moderate Cyp3a4 Inducers/Pralsetinib

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

MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of pralsetinib.(1)

CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inducer may result in a loss of pralsetinib efficacy.(1)

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 pralsetinib with moderate CYP3A4 inducers.(1) If coadministration with a moderate CYP3A4 inducer cannot be avoided, increase the dose of pralsetinib on day 7 of coadministration with pralsetinib as follows: -If the current dose is 400 mg once daily, increase the dose to 600 mg daily. -If the current dose is 300 mg once daily, increase the dose to 500 mg daily. -If the current dose is 200 mg once daily, increase the dose to 300 mg daily. After discontinuation of a moderate CYP3A4 inducer for at least 14 days, resume the previous pralsetinib dose prior to initiating the moderate CYP3A4 inducer.(1) Monitor patients receiving concurrent therapy for reduced efficacy.

DISCUSSION: Coadministration of efavirenz 600 mg once daily is expected to decrease pralsetinib concentration maximum (Cmax) by 18% and area-under-curve (AUC) by 45%.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2-3)

Moderate Cyp3a4 Inducers/Praziquantel

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

MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of praziquantel.(1,2)

CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of praziquantel.(1,2)

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

PATIENT MANAGEMENT: The US manufacturer of praziquantel recommends avoiding concomitant administration with moderate CYP3A4 inducers due to the risk of a clinically significant decrease in praziquantel plasma concentration which may lead to reduced therapeutic effect of praziquantel.(2) In patients receiving a clinically significant CYP3A4 inducer drug who need immediate treatment for schistosomiasis, alternative agents for schistosomiasis should be considered, where possible. If praziquantel treatment is necessary immediately, increase monitoring for reduced anthelmintic efficacy associated with praziquantel, when used in combination with a moderate CYP3A4 inducer.(2) In patients receiving a clinically significant CYP3A4 inducer drug whose treatment could be delayed, discontinue the CYP3A4 inducer drug at least 2 to 4 weeks before administration of praziquantel and, where possible, consider starting alternative medications that are not CYP3A4 inducers. The CYP3A4 inducer drug can be restarted 1 day after completion of praziquantel treatment, if needed.(2)

DISCUSSION: In a crossover study, 20 healthy subjects ingested a single 40 mg/kg oral dose of praziquantel following pre-treatment with oral efavirenz (400 mg daily for 13 days). Oral efavirenz reduced the mean praziquantel area-under-curve (AUC) by 77% and maximum concentration (Cmax) by 79%, when coadministered with praziquantel compared to praziquantel given alone.(2) Moderate CYP3A4 inducers include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(3-4)

Moderate Cyp3a4 Inducers/Ripretinib

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

MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of ripretinib via this pathway.(1) Ripretinib and the active metabolite DP-5439 contribute to anticancer activity. CYP3A4 is the primary metabolism pathway for both ripretinib and the active metabolite DP-5439.(1)

CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may alter the clinical effectiveness of ripretinib.(1)

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 ripretinib with moderate CYP3A4 inducers.(1-3) When possible, select alternative agents in place of the moderate CYP3A4 inducer. If the moderate CYP3A4 inducer cannot be avoided, increase the dose of ripretinib from 150 mg once daily to 150 mg twice daily during concurrent therapy. Monitor patients receiving concurrent therapy for reduced efficacy.(1-3) If the moderate CYP3A4 inducer is discontinued, reduce the dose of ripretinib back to 150 mg once daily 14 days after discontinuation of the moderate CYP3A4 inducer.(1-3) If a dose of ripretinib is missed (in patients taking twice daily dosing): -If less than 4 hours have passed since missed dose, patient should take the dose as soon as possible and then take the next dose at the regularly scheduled time. -If more than 4 hours have passed since missed dose, patient should skip the missed dose and then take the next dose at the regularly scheduled time.(1-3)

DISCUSSION: The primary metabolism pathway for ripretinib and DP-5439 is via CYP3A4.(1) In an interaction study of rifampin (a strong CYP3A inducer) and ripretinib, concurrent use decreased ripretinib concentration maximum (Cmax) by 18% and area-under-curve (AUC) by 61%, as well as decreased the active metabolite DP-5439 AUC by 57% and increased Cmax by 37%.(1) In a pharmacokinetic model of efavirenz (a moderate CYP3A inducer), concurrent use was predicted to decrease ripretinib Cmax by 24% and decrease AUC by 56%.(1) In the presence of a moderate CYP3A inducer, a doubled ripretinib dose (twice daily rather than once daily), is predicted to result in a 17% reduction in combined AUC of ripretinib and active metabolite DP-5439, compared to the usual recommended once daily dose with no inducer present.(2) In an interaction study of itraconazole (a strong CYP3A4 inhibitor) and ripretinib, concurrent use increased ripretinib Cmax by 36% and AUC by 99%. Concurrent use increased the AUC of DP-5439 by 99% with no change in Cmax.(1) Moderate CYP3A4 inducers linked to this monograph are: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(4,5)

Moderate Cyp3a4 Inducers/Sebetralstat

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

MECHANISM OF ACTION: Moderate CYP3A4 inducers may accelerate the metabolism of sebetralstat by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of sebetralstat and a moderate CYP3A4 inducer may result in decreased levels and effectiveness of sebetralstat.(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 sebetralstat states that the concurrent use of moderate CYP3A4 inducers should be avoided.(1)

DISCUSSION: Sebetralstat maximum concentration (Cmax) decreased by 63% and area-under-curve (AUC) decreased by 79% following concomitant administration with efavirenz (a moderate CYP3A4 inducer) 600 mg once daily for 14 days. Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(2)

Moderate Cyp3a4 Inducers/Sunvozertinib

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

MECHANISM OF ACTION: Moderate CYP3A4 inducers may induce the metabolism of sunvozertinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of a moderate CYP3A4 inducer may result in decreased levels and effectiveness of sunvozertinib.(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 sunvozertinib states that concomitant use of moderate CYP3A4 inducers should be avoided.(1) If concurrent use cannot be avoided, increase sunvozertinib dose from 200 mg to 400 mg.(1) After stopping the CYP3A4 inducer, resume the prior sunvozertinib dose 7-14 days after stopping the CYP3A4 inducer.(1)

DISCUSSION: Sunvozertinib is primarily metabolized by CYP3A4.(1) Concomitant administration of sunvozertinib with a strong inducer (carbamazepine) resulted in a decrease in sunvozertinib area under the curve (AUC) and maximum concentration (Cmax) by 48% and 38%, respectively.(1) Sunvozertinib's AUC is predicted to decrease 44% with concurrent administration of efavirenz (600 mg daily; moderate CYP3A4 inducer).(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, rifabutin, repotrectinib, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2)

Moderate Cyp3a4 Inducers/Zanubrutinib

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

MECHANISM OF ACTION: Zanubrutinib is a substrate of CYP3A4. Moderate inducers of CYP3A4 may induce the metabolism of zanubrutinib.(1)

CLINICAL EFFECTS: The concurrent administration of moderate CYP3A4 inducers may result in decreased levels and effectiveness of zanubrutinib.(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 zanubrutinib states that concurrent use with moderate CYP3A4 inducers should be avoided. If concurrent use cannot be avoided, increase zanubrutinib dosage to 320 mg twice daily.(1)

DISCUSSION: Co-administration of multiple doses of efavirenz, a moderate CYP3A4 inducer, is predicted to decrease zanubrutinib Cmax by 58% and AUC by 60%.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, suzetrigine, telotristat ethyl, thioridazine, and tovorafenib.(2-3)

Omeprazole; Esomeprazole/Hydantoins

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

MECHANISM OF ACTION: Omeprazole and esomeprazole may inhibit the CYP2C19 metabolism of hydantoins.(1-3) Hydantoins may induce the CYP3A4 metabolism of omeprazole and esomeprazole.(1-3)

CLINICAL EFFECTS: Concurrent administration of omeprazole or esomeprazole and hydantoins may result in elevated levels of the hydantoin. Phenytoin has a narrow therapeutic range. Early symptoms of phenytoin toxicity may include nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting. Severe toxicity may produce organ dysfunction (e.g. coma, irreversible cerebellar dysfunction and atrophy, hypotension, bradycardia, seizures, and cardiac arrest) and may be fatal.(1) Concurrent use of omeprazole or esomeprazole with CYP3A4 inducers may result in decreased levels and effectiveness of omeprazole or esomeprazole.(1-3)

PREDISPOSING FACTORS: Renal impairment, hepatic impairment, or hypoalbuminemia.

PATIENT MANAGEMENT: Avoid concomitant use of CYP3A4 inducers with omeprazole or esomeprazole.(2,3) Patients should be monitored for changes in response to hydantoins when omeprazole or esomeprazole are added to or discontinued from hydantoin therapy. Serum hydantoin concentration should be monitored to assist in dosage adjustments.(1) Monitor the patient for signs of hydantoin toxicity (e.g. nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting).

DISCUSSION: In a double-blind cross-over study in ten healthy subjects, concurrent phenytoin (300 mg single dose on day seven of omeprazole therapy) and omeprazole (40 mg daily for nine days) therapy resulted in area-under-curve (AUC) increasing 19% when compared to phenytoin and placebo. There were no significant changes in phenytoin peak concentration, (Cmax) time to Cmax, or half-life.(4) In another cross-over study on eight healthy subjects, concurrent phenytoin (250 mg single dose administered intravenously over 30 minutes on day seven of omeprazole therapy) and omeprazole (40 mg daily for eight days) resulted in plasma clearance decreasing 15% and half-life increasing 27% when compared to phenytoin and placebo. There was a small, but not significant, increase in phenytoin plasma concentrations during concurrent omeprazole therapy.(5) The results of these studies are disputed in a study of eight epileptic patients maintained on phenytoin (dosage range 200-450 mg daily). There were no significant changes in phenytoin levels or phenytoin urinary excretion after three weeks of concurrent omeprazole (20 mg daily) therapy when compared to previous steady-state values. The authors speculated that the low dose of omeprazole (20 mg daily) was not enough to produce the inhibition of phenytoin metabolism seen in other studies.(6) In an interaction study, rifampin 600 mg daily for 7 days decreased omeprazole AUC by 89.5%.(8,9)

P-Glycoprotein (P-Gp) Inducers/Etoposide

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

MECHANISM OF ACTION: Etoposide is a substrate of the efflux transporter P-glycoprotein (P-gp).(1-5) P-gp induction may decrease cellular concentrations of etoposide, increase biliary or renal elimination of etoposide, and decrease systemic absorption of oral etoposide.

CLINICAL EFFECTS: Concurrent or recent use of P-glycoprotein inducers may result in decreased levels and effectiveness of etoposide.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concurrent use of an inducer of P-gp in patients treated with etoposide and consider use of alternative agents when possible. If therapy with a P-gp inducer is required, consider therapeutic drug monitoring of etoposide to assure treatment efficacy. The time to maximal induction may be delayed 1-2 weeks depending upon the half-life and dose of the inducer. After discontinuation of the inducer the offset of induction is also gradual.

DISCUSSION: This monograph is based upon the relatively recent understanding of the role of transporters in the absorption, distribution and elimination of etoposide.(1-3) Apalutamide, carbamazepine, efavirenz, fosphenytoin, lorlatinib, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort may induce production of P-gp and lead to decreased systemic or cellular exposure to etoposide.(4,6)

P-Gp & Moderate Cyp3a4 Inducer/Emtricitabine-Rilpivirine-Taf

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

MECHANISM OF ACTION: Moderate CYP3A4 inducers may induce the metabolism of rilpivirine. P-glycoprotein (P-gp) inducers may decrease the absorption of tenofovir alafenamide (TAF).(1)

CLINICAL EFFECTS: Concurrent or recent use of dual P-gp and moderate CYP3A4 inducers may result in decreased levels and effectiveness of rilpivirine and TAF, as well as the development of resistance.(1)

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

PATIENT MANAGEMENT: The US manufacturer of emtricitabine-rilpivirine-TAF states that concurrent use of P-gp and moderate CYP3A4 inducers is not recommended.(1)

DISCUSSION: In a study in 18 subjects, rifabutin (300 mg daily) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of rilpivirine (25 mg orally daily) by 31%, 42%, and 48%, respectively.(1) P-gp and moderate CYP3A4 inducers linked to this monograph include: efavirenz, lorlatinib, and rifabutin.(2)

P-Gp And Moderate Cyp3a4 Inducers/Darolutamide

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

MECHANISM OF ACTION: Agents that are combined P-gp and moderate CYP3A4 inducers may induce the metabolism of darolutamide by both pathways.(1)

CLINICAL EFFECTS: Concurrent or recent use of inducers of both P-gp and CYP3A4 may result in decreased levels and effectiveness of darolutamide.(1)

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

PATIENT MANAGEMENT: If possible, avoid the concurrent use of agents that are combined P-gp and moderate CYP3A4 inducers in patients receiving darolutamide.(1)

DISCUSSION: Concurrent rifampin (combined P-gp and strong CYP3A4 inducer) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of darolutamide by 72% and 52%, respectively. Combined P-gp and moderate CYP3A4 inducers are expected to decrease the AUC by 36-58%.(1) Agents that are combined P-gp and moderate CYP3A4 inducers linked to this monograph include: efavirenz, lorlatinib and rifabutin.(2)

Penicillins/Methotrexate

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

MECHANISM OF ACTION: Penicillins may compete with the renal tubular secretion of methotrexate.

CLINICAL EFFECTS: The concurrent use of methotrexate and penicillins may result in elevated levels of methotrexate and methotrexate toxicity, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression.

PREDISPOSING FACTORS: Risk factors for methotrexate toxicity include: - High-dose oncology regimens - Impaired renal function, ascites, or pleural effusions

PATIENT MANAGEMENT: Patients receiving concurrent therapy with methotrexate and penicillins should be monitored closely for elevated methotrexate levels and methotrexate toxicity. The dose and duration of leucovorin rescue therapy may need to be increased.

DISCUSSION: Elevated methotrexate levels, signs of methotrexate toxicity, and death have been reported following the concurrent use of methotrexate (both low dose and high dose) and penicillin derivatives. In a patient being treated with high-dose methotrexate (8 G/m2), the concurrent use of amoxicillin resulted in a 56% decrease in the clearance of methotrexate and signs of methotrexate toxicity.(1) There are two cases of methotrexate toxicity following the addition of amoxicillin to low-dose methotrexate therapy (7.5 mg-10 mg weekly) for psoriasis. In another case, a patient was found to have a toxic methotrexate level 12 days after her last dose of weekly methotrexate (7.5 mg). The patient had been treated with amoxicillin followed by flucloxacillin.(2) In a case report, dicloxacillin decreased methotrexate clearance 93%.(4) Flucloxacillin was shown to increase the area-under-curve (AUC) of methotrexate by 7.3% in a study in 10 subjects.(5) In a case report, a patient on low-dose methotrexate (5 mg) developed methotrexate pneumonia following the addition of flucloxacillin to his regimen.(5) In a patient being treated with high-dose methotrexate (12 G/m2), the concurrent use of mezlocillin increased the half-life of methotrexate from 10.1 to 27.2 hours.(6) In a case report, a patient developed methotrexate toxicity following the addition of penicillin V potassium to his methotrexate (50 mg weekly).(7) In a case report, penicillin decreased methotrexate clearance 36%.(4) In one report, leucovorin rescue therapy had to be continued for 192 hours following the concurrent use of methotrexate (3 G/m2) and piperacillin. During cycles without concurrent piperacillin, leucovorin rescue therapy was only required for 72 hours.(8) There are two reports of neutropenia and death following the concurrent use of piperacillin and low-dose methotrexate (2.5 mg three times weekly in one patient, 5 mg weekly in another) for psoriasis. One of these patients also received flucloxacillin. (3) In another case report, the concurrent use of piperacillin decreased methotrexate clearance by 67%.(4) In a case report, ticarcillin decreased methotrexate clearance by 60%.(4)

Proton Pump Inhibitors/Capecitabine

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

MECHANISM OF ACTION: The aqueous solubility of capecitabine is pH dependent. Higher gastric pH leads to lower solubility and altered tablet dissolution which may reduce capecitabine absorption.(1,2)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) may reduce the bioavailability of capecitabine, leading to decreased systemic levels and effectiveness.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration of proton pump inhibitors with capecitabine may decrease bioavailability. When clinically appropriate, consider using H2 blockers or antacids.

DISCUSSION: A retrospective study in early stage colorectal cancer patients treated with adjuvant monotherapy capecitabine examined recurrence-free survival (RFS) and overall survival (OS) in 1335 patients with and without concurrent proton pump inhibitor (PPI) therapy. The PPI group was defined as a prescription for a PPI filled at any point in time during capecitabine treatment. Patients in the capecitabine with concurrent PPI group had a statistically significant decrease in 5-year RFS (74% v 83%; hazard ratio (HR) 1.89; 95% confidence interval (CI) 1.07-3.35; p=0.03) compared to capecitabine without PPI therapy. OS was not significantly different between groups (81% PPI v 78% non-PPI; HR 1.13; 95% CI 0.6-2.14; p=0.7). After adjusting for male gender, stage III colorectal cancer, advance age >68, poorer ECOG PS, there was a trend toward decreased RFS in PPI patients (HR 1.65; 95% CI 0.93-2.94; p=0.09).(1) An ad hoc analysis of the TRIO-013/LOCiC trial examined coadministration of PPI therapy, defined as 20% or more overlap between a PPI prescription and trial treatment duration with capecitabine and/or lapatinib, on progression-free survival (PFS) and overall survival (OS). The secondary analysis examined 545 patients in which 42% were on concurrent PPI therapy. Patients in the non-PPI group had an improved median PFS (5.7 v 4.2 months; HR 1.55; 95% CI 1.29-1.81; p<0.001) and median OS (11.3 v 9.2 months; HR 1.34; 95% CI 1.06-1.62; p=0.04) compared with PPI users. A multivariate analysis reviewed effects of PPIs on both PFS and OS with capecitabine alone and found effects of PPI use on both PFS and OS was still significant (HR 1.68; p<0.001 and HR 1.41; p=0.001, respectively).(2) In a study in 12 subjects, concomitant administration of capecitabine with aluminum-magnesium hydroxide containing antacid 20 mL increased area-under-curve (AUC) and concentration maximum (Cmax) by 16% and 35%, respectively.(3) Proton pump inhibitors linked to this monograph include: dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole.

Proton Pump Inhibitors/Indinavir

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

MECHANISM OF ACTION: The aqueous solubility of indinavir is pH dependent. Higher gastric pH leads to lower solubility which may reduce indinavir absorption.(1-2)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors may reduce the bioavailability of indinavir, leading to decreased systemic levels and effectiveness.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concomitant administration of indinavir and proton pump inhibitors is not recommended unless indinavir is accompanied by ritonavir, typically dosed as indinavir 800 mg twice daily with ritonavir 100 mg twice daily. Monitor patients receiving concurrent therapy for changes in indinavir effectiveness.(1)

DISCUSSION: A retrospective analysis in 9 HIV+ patients found that indinavir administration with omeprazole (20 mg) decreased the maximum concentration (Cmax) of indinavir by 29%. Indinavir administration with omeprazole (40 mg) decreased the Cmax of indinavir by 41%.(1) In a crossover study in 16 healthy volunteers, concurrent administration of omeprazole (20 mg to 40 mg for 7 days) decreased the indinavir (800 mg single dose) Cmax and area-under-the-curve (AUC) by 29-41% and 34-47%, respectively.(2) Coadministration of omeprazole (40 mg) and indinavir (800 mg single dose) to 14 HIV+ subjects resulted in a 47% decrease in indinavir AUC and a 55% decrease in minimum concentration (Cmin). The addition of ritonavir (200 mg single dose) reversed the effects of omeprazole.(3) In a crossover study in 5 healthy volunteers, concurrent administration of indinavir (400 mg single dose) with a proton pump inhibitor resulted in increased gastric pH and a smaller fraction of indinavir being dissolved and lower intestinal concentrations.(4) In an animal study investigating the solubility of indinavir, solubility of indinavir in aqueous media decreased from more than 100 mg/mL at pH 3 to less than 0.1 mg/mL at pH 5 or above.(5)

Proton Pump Inhibitors/Ledipasvir; Velpatasvir

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

MECHANISM OF ACTION: The aqueous solubility of ledipasvir and velpatasvir is pH dependent. Higher gastric pH leads to lower solubility which may reduce ledipasvir and velpatasvir absorption.(1-3)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) may reduce the bioavailability of ledipasvir and velpatasvir, leading to decreased systemic levels and effectiveness.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Omeprazole 20 mg daily, or comparable doses of other PPIs, may be administered simultaneously with ledipasvir-sofosbuvir under fasting conditions.(1) Coadministration of proton pump inhibitors is not recommended with sofosbuvir-velpatasvir. When concomitant proton pump inhibitor use is necessary in patients receiving sofosbuvir-velpatasvir, velpatasvir-sofosbuvir should be administered with food and taken 4 hours before omeprazole 20 mg. Use with other proton pump inhibitors has not been studied.(2) Omeprazole 20 mg daily may be administered with sofosbuvir-velpatasvir-voxilaprevir. Use with other proton pump inhibitors has not been studied.(3) When clinically appropriate, consider use of H2 blockers or antacids.(1-3)

DISCUSSION: In an interaction study, omeprazole 20 mg given once daily simultaneously with ledipasvir-sofosbuvir, decreased ledipasvir exposure (AUC) by 4%. When omeprazole 20 mg once daily was given 2 hours prior to ledipasvir-sofosbuvir dose, ledipasvir exposure (AUC) decreased approximately 50%.(1) In an interaction study, omeprazole 20 mg given once daily simultaneously with sofosbuvir-velpatasvir decreased velpatasvir exposure (AUC) by 37%. When omeprazole 20 mg once daily was given 12 hours prior to sofosbuvir-velpatasvir dose, velpatasvir exposure (AUC) decreased 57%. When omeprazole 20 mg once daily was given 2 hours prior to sofosbuvir-velpatasvir dose, velpatasvir AUC decreased 48%. When omeprazole 20 mg once daily was given 4 hours after sofosbuvir-velpatasvir dose, velpatasvir AUC decreased 33%. When omeprazole 40 mg once daily was given 4 hours after sofosbuvir-velpatasvir dose, velpatasvir AUC decreased 56%.(2) In an interaction study, when omeprazole 20 mg once daily was given 2 hours prior to the sofosbuvir-velpatasvir-voxilaprevir dose, sofosbuvir AUC, velpatasvir AUC, and voxilaprevir AUC decreased 27%, 54%, and 20%, respectively. When omeprazole 20 mg once daily was given 4 hours after the sofosbuvir-velpatasvir-voxilaprevir dose, sofosbuvir AUC, velpatasvir AUC, and voxilaprevir AUC decreased 18%, 51%, and 5%, respectively %.(3) Proton pump inhibitors linked to this monograph are: dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole.

Proton Pump Inhibitors/Methotrexate (Oncology-Injection )

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

MECHANISM OF ACTION: Proton pump inhibitors may inhibit the active secretion of methotrexate from the kidney via inhibition of the hydrogen-potassium ATPase(1) and may reduce uptake of methotrexate into breast cancer resistance protein via competitive inhibition.(2,3)

CLINICAL EFFECTS: The concurrent use of methotrexate and proton pump inhibitors may result in elevated levels of methotrexate and increased methotrexate-related adverse effects and toxicities, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia.

PREDISPOSING FACTORS: Risk factors for methotrexate toxicity include: - High-dose oncology regimens - Impaired renal function, ascites, or pleural effusions

PATIENT MANAGEMENT: For patients receiving high dose methotrexate with leucovorin rescue, consider discontinuation of proton pump inhibitors for the duration of therapy. Patients receiving concurrent use of methotrexate and proton pump inhibitors should be monitored closely for elevated methotrexate levels and methotrexate toxicity. The US manufacturer of omeprazole states that secretory ability returns gradually over three to five days following discontinuation.(4) Therefore, it would seem prudent to discontinue proton pump inhibitors several days prior to methotrexate therapy.

DISCUSSION: In a clinical trial in 74 patients on high dose (1-5 G/m2) methotrexate therapy, data was examined to determine if proton pump inhibitor (omeprazole, pantoprazole, rabeprazole) use affects methotrexate elimination. Delayed elimination was found to be more frequent in those with co-administration of a proton pump inhibitor (31.7% vs. 13.8%), resulting in higher plasma methotrexate concentrations at 24, 48, and 74 hours. The effect was seen with lansoprazole, omeprazole, pantoprazole, and rabeprazole.(2) There are three case reports(1,5,6) of elevated methotrexate levels or delayed methotrexate elimination resulting from concurrent administration of high dose methotrexate and omeprazole, including one patient(6) that developed severe mucositis. In each case, omeprazole was discontinued and normal methotrexate kinetics were observed on subsequent cycles with no further adverse effects noted. In a case report of a 59 year-old male on low dose (15 mg weekly) methotrexate, administration of pantoprazole (20 mg daily) was found to increase the AUC of the metabolite 7-hydroxymethotrexate by 70%.(7) In a clinical trial, 28 adults with rheumatoid arthritis on low dose (7.5-15 mg weekly) methotrexate were assigned to receive lansoprazole (30 mg daily) and naproxen (500 mg twice daily) on Days 1-7 of therapy. The half life of the metabolite 7-hydroxymethotrexate was prolonged with concurrent administration, but no other statistically significant differences were found in regards to the plasma concentration profiles of methotrexate or 7-hydroxymethotrexate.(8)

Proton Pump Inhibitors/Paltusotine (>= 60 Mg)

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

MECHANISM OF ACTION: The aqueous solubility of paltusotine is pH dependent. Higher gastric pH leads to lower solubility which may reduce paltusotine absorption.(1)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) may reduce the bioavailability of paltusotine, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of paltusotine states that concomitant use of paltusotine with PPIs may require an increased dosage of paltusotine. Patients who are already on paltusotine 60 mg daily should avoid concomitant use with PPIs.(1)

DISCUSSION: In an interaction study, paltusotine area-under-the-curve (AUC) was decreased by 21% with 20 mg dose and 42% with 60 mg dose levels.(1)

Proton Pump Inhibitors/Pemetrexed

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

MECHANISM OF ACTION: Proton pump inhibitors may inhibit the active secretion of pemetrexed from the kidney via the organic anion transporter 3 (OAT3).(1,2,3)

CLINICAL EFFECTS: The concurrent use of pemetrexed and proton pump inhibitors may result in increased levels and toxicities of pemetrexed, including severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia.

PREDISPOSING FACTORS: Risk factors for pemetrexed toxicity include high-dose oncology regimens, impaired renal function, and concurrent use of nephrotoxic medications.

PATIENT MANAGEMENT: For patients receiving pemetrexed, consider discontinuation of proton pump inhibitors for the duration of pemetrexed therapy. If concurrent use cannot be avoided, monitor closely for elevated pemetrexed levels and toxicity.

DISCUSSION: A prospective observational study of 156 patients receiving pemetrexed-based therapy found that severe hematological toxicity, namely neutropenia and anemia, occurred in 34/55 patients (61.8%) taking concurrent proton pump inhibitors (PPIs) and in 36/101 patients (35.6%) who did not consume PPIs. In Cox regression multivariable analysis, the hazard ratio for severe hematological toxicity with PPI use was 2.51 (95% CI = 1.47-4.26). Esomeprazole, pantoprazole, and lansoprazole were the most consumed PPIs in the study, but no correlation was investigated.(1) A retrospective review of 61 patients investigated medication-related causes of severe hematological toxicity in patients on pemetrexed/carboplatin chemotherapy. Twenty-three patients took PPIs: lansoprazole (n=16), esomeprazole (n=5), omeprazole (n=1), and rabeprazole (n=1). In a multiple logistic regression analysis, use of PPIs in patients receiving pemetrexed/carboplatin combination chemotherapy was associated severe hematotoxicity (odds ratio: 5.34, 95% CI: 1.06-26.94, P = 0.042).(2) In an in vitro analysis and retrospective study, lansoprazole, rabeprazole, pantoprazole, esomeprazole, omeprazole, and vonoprazan were shown to inhibit OAT3-mediated uptake of pemetrexed, with lansoprazole having the greatest inhibitory effect. In the multivariate analysis of 108 patients, concurrent use of lansoprazole (but not other PPIs) and pemetrexed/carboplatin was a significant risk factor for the development of hematological toxicity (odds ratio: 10.004, P = 0.005).(3) In a retrospective study of 74 patients who received pemetrexed, 24 patients (32%) were on concomitant PPIs. Pemetrexed toxicity was associated with cystatin clearance (p=0.0135), albumin level (p=0.0333), and proton pump inhibitors (p=0.035) on multivariate analysis. Most patients (n=14) took esomeprazole or omeprazole, with the remainder taking lansoprazole (n=5), pantoprazole (n=4) or an unspecified agent.(4)

Proton Pump Inhibitors/Selected Kinase Inhibitors

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

MECHANISM OF ACTION: The solubility of bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) pazopanib(8), and pexidartinib (9) is pH dependent. Changes in gastric pH from proton pump inhibitors may decrease the absorption of bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) pazopanib,(8) and pexidartinib.(9)

CLINICAL EFFECTS: Use of proton pump inhibitors may result in decreased levels and effectiveness of bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) pazopanib,(8) and pexidartinib.(9)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of proton pump inhibitors (PPIs) in patients receiving treatment with bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) pazopanib,(8) and pexidartinib.(9) Consider the use of short-acting antacids in these patients.(1-9) If antacids are used, separate the administration times by several hours(1-9) but at least 2 hours for bosutinib,(1) dasatinib,(3) nilotinib,(7) and pexidartinib(9), 6 hours for gefitinib,(5) and 3 hours for neratinib.(6) If PPIs are required with gefitinib, administer gefitinib 12 hours after the last dose or 12 hours before the next dose of the PPI. Administer gefitinib 6 hours before or after H2-antagonists or antacids.(5) If H2 antagonist therapy is used with bosutinib, separate administration by at least 2 hours.(1) If H2 antagonist therapy is required with dacomitinib, dacomitinib must be given once daily 10 hours after the H2 blocker and 6 hours before the next dose of the H2 blocker.(2) If H2 antagonist therapy is required with erlotinib, neratinib, nilotinib, or pexidartinib, the kinase inhibitor must be given 10 hours after the H2 blocker and at least 2 hours before the next dose of the H2 blocker.(4,6,7,9) If H2 antagonist therapy is required with gefitinib, gefitinib should be given at least 6 hours before or after the H2 antagonist.(5) The manufacturer of Phyrago states that it can be administered with gastric acid reducing agents. Administration times should be separated with antacids.

DISCUSSION: In a study, concurrent rabeprazole decreased the Cmax and AUC of dacomitinib by 51% and 39%, respectively.(2) In a study in 24 healthy subjects, administration of a single dose of dasatinib (50 mg) 10 hours after famotidine decreased dasatinib area-under-curve (AUC) and maximum concentration (Cmax) by 61% and 63%, respectively.(3) In a study in 14 healthy subjects, administration of a single dose of dasatinib (100 mg) 22 hours after omeprazole (40 mg at steady state) decreased dasatinib AUC and Cmax by 43% and 42%, respectively.(3) In a study in 24 healthy subjects, simultaneous administration of dasatinib (50 mg) with aluminum hydroxide/magnesium hydroxide (30 ml) decreased dasatinib AUC and Cmax by 55% and 58%, respectively. In the same subjects, administration of the antacid 2 hours before dasatinib decreased dasatinib Cmax by 26%, but had no effect on dasatinib AUC.(3) In a study, concurrent omeprazole decreased the AUC and Cmax of erlotinib by 46% and 61%, respectively.(4) In a study, administration of erlotinib two hours after a dose of ranitidine (300 mg), erlotinib AUC and Cmax decreased by 33% and 54%, respectively. Administration of erlotinib 10 hours after and two hours before ranitidine (150 mg twice daily), erlotinib AUC and Cmax decreased by 15% and 17%, respectively.(4) In a case report, a patient that was given erlotinib (150 mg daily,) with algeldrate/magnesium hydroxide (800/400 mg four times daily 4 hours before or 2 hours after erlotinib) did not see a significant reduction in serum trough concentrations of erlotinib. When the patient was switched to intravenous pantoprazole via continuous infusion (8 mg per hour), serum erlotinib levels decreased significantly below minimal trough concentrations for effective tyrosine kinase inhibition. When the patient was switched to oral pantoprazole (40 mg twice daily), serum trough levels of erlotinib returned to therapeutic levels.(9) In a study in healthy subjects, high dose ranitidine with sodium carbonate was administered to maintain gastric pH above 5.0 and gefitinib AUC decreased 47%.(5) In a study in 15 healthy subjects, lansoprazole (30 mg at steady state) decreased the Cmax and AUC of a single dose of neratinib (240 mg) by 71% and 65%, respectively.(6) In a study in 22 healthy subjects, pretreatment with esomeprazole (40 mg daily), decreased the Cmax and AUC of a single dose of nilotinib (400 mg) by 27% and 34%, respectively.(7,10) Increasing the dosage of nilotinib or separating the administration time of nilotinib and the proton pump inhibitor is not expected to eliminate the interaction.(7) There were no significant changes in nilotinib pharmacokinetics when famotidine was administered 10 hours before or 2 hours after nilotinib.(7) There were no significant changes in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered 2 hours before or after nilotinib.(7) In a study in 13 patients, esomeprazole (40 mg daily for 5 days) decreased the Cmax and AUC of pazopanib (400 mg daily) by 42% and 40%, respectively, when compared to the administration of pazopanib alone.(11) In an open-label, crossover study in 17 evaluable patients, omeprazole (40 mg daily) had no significant effects on the pharmacokinetics, pharmacodynamics, or safety of bortezomib (1.3 mg/m2).(12) Coadministration of esomeprazole decreased pexidartinib Cmax and AUC by 55% and 50%. (13) Phyrago is not sensitive to increased gastric pH due to its polymer formulation. No clinically significant dasatinib pharmacokinetic changes were seen with concurrent administration of Phyrago with omeprazole (proton pump inhibitor) or famotidine (H2 receptor antagonist).(14)

Proton Pump Inhibitors/Selpercatinib

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

MECHANISM OF ACTION: The solubility of selpercatinib is pH dependent. Increase in gastric pH from proton pump inhibitors (PPIs) may decrease the solubility and absorption of selpercatinib.(1)

CLINICAL EFFECTS: Use of proton pump inhibitors may result in decreased levels and effectiveness of selpercatinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of proton pump inhibitors (PPIs), H2 antagonists, and locally acting antacids in patients receiving treatment with selpercatinib. If coadministration with PPIs cannot be avoided, take selpercatinib with food.(1) If the PPI is replaced with a H2 antagonist, take selpercatinib 2 hours before or 10 hours after the H2 antagonist.(1) If the PPI is replaced with an antacid, take selpercatinib 2 hours before or 2 hours after the antacid.(1)

DISCUSSION: In a study, omeprazole decreased the area-under-curve (AUC) and maximum concentration (Cmax) of selpercatinib (administered fasting) by 69% and 88%, respectively. When selpercatinib was administered with food, omeprazole did not significantly affect selpercatinib levels.(1)

Rifabutin/Atovaquone

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

MECHANISM OF ACTION: The exact mechanism is unknown but likely involves rifabutin-induced increase in the metabolism of atovaquone.(1,2)

CLINICAL EFFECTS: Concurrent administration of atovaquone with rifabutin may result in decreased levels and clinical effects of atovaquone(1,2).

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The administration of rifabutin during atovaquone therapy is not recommended.(1,2) Consider alternative agents to rifabutin during atovaquone therapy.(1) If coadministration is necessary, the National Institute of Health Opportunistic Infections guidelines recommend patients take atovaquone with a fatty meal and monitor for decreased atovaquone efficacy.(3)

DISCUSSION: In a study of 13 HIV-positive patients, rifampin (600 mg every 24 hours) and atovaquone (750 mg every 12 hours) resulted in a decrease in average atovaquone steady-state plasma concentration by 52% and an increase in average rifampin steady-state plasma concentration by 37%.(1) In a trial of 24 healthy volunteers, rifabutin 300 mg once daily with atovaquone oral suspension 750 mg twice daily resulted in a 34% decrease in the mean steady-state plasma atovaquone concentration and a 19% decrease in the mean steady-state plasma rifabutin concentration.(1)

Rifabutin/Etravirine

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

MECHANISM OF ACTION: Etravirine and rifabutin may induce the metabolism of each other.(1)

CLINICAL EFFECTS: Concurrent use may result in decreased levels and effectiveness of both etravirine and rifabutin.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of etravirine recommends a rifabutin dose of 300 mg daily in patients not receiving concurrent therapy with a protease inhibitor.(1) The US manufacturer of etravirine recommends that rifabutin not be administered to patients receiving concurrent etravirine with darunavir/ritonavir, lopinavir/ritonavir, or saquinavir/ritonavir.(1)

DISCUSSION: In a study in 12 subjects, concurrent rifabutin (300 mg daily) decreased etravirine maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) by 37%, 37%, and 35%. Rifabutin Cmax, AUC, and Cmin decreased by 10%, 17%, and 24%. The Cmax, AUC, and Cmin of 25-O-desacetylrifabutin decreased by 15%, 17%, and 22%, respectively.(1)

Rifabutin/Intramuscular Cabotegravir

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

MECHANISM OF ACTION: Rifabutin may induce the metabolism of cabotegravir by CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent or recent use of rifabutin may result in decreased levels and effectiveness of cabotegravir.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The implications of this interaction differs depending on the indication for cabotegravir. If cabotegravir is used with rilpivirine for treatment of HIV infection: - Rifabutin should be avoided.(1) If cabotegravir is used alone for pre-exposure prophylaxis: - In a patient already on or just starting rifabutin, increase the frequency of cabotegravir doses to 600 mg every 2 weeks for the first 2 doses, then 600 mg monthly thereafter while on rifabutin. - In a patient starting rifabutin after the second injection or later of cabotegravir, increase cabotegravir injections to 600 mg monthly while on rifabutin. After stopping rifabutin, the recommended dosing schedule of cabotegravir is 600 mg every 2 months.(2)

DISCUSSION: Coadministration of rifabutin (300 mg once daily) with cabotegravir (30 mg once daily) decreased cabotegravir's area-under-the-curve (AUC), minimum concentration (Cmin), and maximum concentration (Cmax) by 23%, 26%, and 17%.(1,2)

Rifabutin/Letermovir

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

MECHANISM OF ACTION: Letermovir is a substrate of the efflux transporter P-glycoprotein (P-gp) and of UDP-glucuronosyltransferase (UGT) 1A1/3 enzymes. P-gp induction may decrease systemic absorption of letermovir, while UGT1A1/3 induction may increase the metabolism of letermovir.(1) Rifabutin is an inducer of P-gp and UGT.(2,3) Rifabutin is a CYP3A4 substrate.(2) Letermovir may inhibit the CYP3A4 metabolism of rifabutin.(1,3)

CLINICAL EFFECTS: Concurrent or recent use of P-glycoprotein or UGT1A1/3 inducers may result in decreased levels and loss of effectiveness of letermovir.(1) The levels and toxicities of rifabutin may increase, including uveitis.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of letermovir states that coadministration of P-gp inducers or UGT1A1/3 inducers is not recommended.(1) Monitor for rifabutin-associated adverse events. Reduce the rifabutin dose or suspend rifabutin use if toxicity is suspected.(1) If uveitis occurs, temporary discontinuance of rifabutin and ophthalmologic evaluation are recommended. In most mild cases, rifabutin may be restarted; however, if signs or symptoms recur, use of rifabutin should be discontinued.(2)

DISCUSSION: In a study, at 24 hours after the last dose of rifampin (600 mg daily), a P-gp and UGT inducer, the area-under-curve (AUC) of letermovir was decreased by 85 %, compared to letermovir when taken alone.(1) In a study of five healthy subjects, concurrent use of rifabutin (150 mg daily for 16 days) and ritonavir (500 mg BID for 10 days), a CYP3A4 inhibitor, increased the AUC and concentration maximum (Cmax) by 300% and 150%, respectively.(2)

Rifabutin/Nirmatrelvir-Ritonavir

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

MECHANISM OF ACTION: Nirmatrelvir-ritonavir may inhibit the metabolism of rifabutin by CYP3A4.(1,2)

CLINICAL EFFECTS: The concurrent use of nirmatrelvir-ritonavir with rifabutin may result in increased levels, clinical effects, and side effects (including neutropenia, lymphopenia, and influenza-like illness) of rifabutin.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of nirmatrelvir with rifabutin may require a dose adjustment of rifabutin. The US manufacturer of rifabutin recommends a rifabutin dose reduction of 75% (to a maximum of 150 mg every other day or 3 times weekly) with concomitant ritonavir-boosted protease inhibitors.(1,2) In the HIV setting, subtherapeutic rifabutin levels have been observed with a 75% dose reduction.(3-8) Given the risk of rifamycin resistance, the Department of Health and Human Services (DHHS) Guidelines for the Use of Antiretroviral Agents(9) and the CDC's guidelines on managing drug interactions in HIV-related tuberculosis (TB)(10) both recommend that the dose of rifabutin be reduced to 150 mg once daily, or 300 mg three times weekly (a 50% reduction), when used with protease inhibitors. Clinicians should recognize that there are limited safety data with this dose and patients need to be closely monitored for rifabutin-related toxicities. Consider increased monitoring for increased side effects of rifabutin including uveitis, thrombocytopenia, and neutropenia, and consider monitoring rifabutin concentrations.(2)

DISCUSSION: Nirmatrelvir-ritonavir is a strong CYP3A4 inhibitor.(1)

Rifabutin/Oral Rilpivirine

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

MECHANISM OF ACTION: Rifabutin may induce the metabolism of rilpivirine by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent or recent use of rifabutin may result in decreased levels and effectiveness of rilpivirine, as well as the development of resistance.(1)

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

PATIENT MANAGEMENT: The US manufacturer of oral rilpivirine states that concurrent use of CYP3A4 inducers such as rifabutin warrants dose adjustment. When administering rifabutin with oral rilpivirine, increase the dose of rilpivirine to 50 mg once daily. When rifabutin co-administration is stopped, the rilpivirine dose should be decreased to 25 mg once daily. It may take several weeks after the discontinuation of an enzyme inducer for enzyme activity to return to normal.(1)

DISCUSSION: In a study in 18 subjects, rifabutin (300 mg daily) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of rilpivirine (25 mg orally daily) by 31%, 42%, and 48%, respectively.(1) A study in 18 subjects compared rilpivirine administered alone (25 mg orally daily) to coadministration with rifabutin (300 mg daily) and rilpivirine (50 mg orally daily). A significant difference was not found with the Cmax (1.43), AUC (1.16), or Cmin (0.93) of rilpivirine. (1)

Rifabutin/Selected Azole Antifungal Agents

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

MECHANISM OF ACTION: Multiple mechanisms may be involved: 1) Rifabutin may induce the CYP3A4 metabolism of the azole antifungal agents. 2) The azole antifungals may inhibit the CYP3A4 metabolism of rifabutin.(1)

CLINICAL EFFECTS: The levels and effectiveness of the azole antifungals may decrease. The levels and toxicities of rifabutin may increase, including uveitis.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Rifabutin is not recommended two weeks before, during, and two weeks after treatment with itraconazole or ketoconazole.(2,3) If co-administration cannot be avoided, observe the patient for a decrease in the therapeutic effect of the antifungal agent. It may be necessary to increase the dose of the antifungal agent. Monitor for rifabutin-associated adverse events. Reduce the rifabutin dose or suspend rifabutin use if toxicity is suspected.(1) If uveitis occurs, temporary discontinuance of rifabutin and ophthalmologic evaluation are recommended. In most mild cases, rifabutin may be restarted; however, if signs or symptoms recur, use of rifabutin should be discontinued.(1)

DISCUSSION: Concurrent itraconazole (200 mg daily) with rifabutin (300 mg daily) in six HIV-infected patients resulted in an increased effect on rifabutin and a decrease in itraconazole's area-under-curve (AUC) and maximum concentration (Cmax) by 70% and 75%, respectively.(2)

Rifabutin/Telithromycin

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

MECHANISM OF ACTION: Rifabutin may induce the metabolism of telithromycin by CYP3A4.(1-3) Additionally, telithromycin may inhibit the metabolism of rifabutin by CYP3A4.(1-3)

CLINICAL EFFECTS: Concurrent use of rifabutin may result in decreased levels and effectiveness of telithromycin.(1-3) Concurrent use may also result in increased levels of and side effects from rifabutin.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The UK manufacturer of telithromycin states that treatment with CYP3A4 inducers should be avoided during and for two weeks after treatment with the CYP3A4 inducer.(2) The US manufacturer of telithromycin states that concurrent treatment with CYP3A4 inducers should be avoided.(3) Monitor patients receiving concurrent therapy for decrease antibiotic efficacy.

DISCUSSION: Concurrent use of telithromycin with rifampin (strong CYP3A4 inducer) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of telithromycin by 79% and by 86%, respectively.(2) The induction effect decreases during the two weeks following the discontinuation of the inducer.(2)

Rifabutin/Voxelotor

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

MECHANISM OF ACTION: Voxelotor is a substrate of CYP3A4. Strong or moderate inducers of CYP3A4 may induce the metabolism of voxelotor.(1) Rifabutin is a CYP3A4 substrate.(2) Voxelotor may inhibit the CYP3A4 metabolism of rifabutin.(1,3)

CLINICAL EFFECTS: The concurrent administration of strong or moderate CYP3A4 inducers may result in decreased levels and effectiveness of voxelotor.(1) The levels and toxicities of rifabutin may increase, including uveitis.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of voxelotor states that concurrent use with strong or moderate CYP3A4 inducers should be avoided. If concomitant rifabutin is unavoidable in patients 12 years and older, increase the dose of voxelotor to 2,000 mg daily. For patients 4 years to less than 12 years who require concurrent rifabutin, refer to voxelotor prescribing information for recommended weight-based voxelotor dosage adjustments.(1) Monitor for rifabutin-associated adverse events. Reduce the rifabutin dose or suspend rifabutin use if toxicity is suspected.(1) If uveitis occurs, temporary discontinuance of rifabutin and ophthalmologic evaluation are recommended. In most mild cases, rifabutin may be restarted; however, if signs or symptoms recur, use of rifabutin should be discontinued.(2)

DISCUSSION: A pharmacokinetic model predicted that co-administration of rifampin, a strong CYP3A4 inducer, would decrease the area-under-curve (AUC) of voxelotor by 40%. Co-administration of efavirenz, a moderate CYP3A4 inducer, is predicted to decrease the AUC of voxelotor by 24%.(1) In a study of five healthy subjects, concurrent use of rifabutin (150 mg daily for 16 days) and ritonavir (500 mg BID for 10 days), a CYP3A4 inhibitor, increased the AUC and concentration maximum (Cmax) by 300% and 150%, respectively.(2)

Rifabutin; Rifapentine/Selected Protease Inhibitors

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

MECHANISM OF ACTION: Protease inhibitors may inhibit the metabolism of rifabutin by CYP3A4.(1-29) Rifabutin may induce the metabolism of some protease inhibitors.(1-14) Rifabutin may decrease the metabolism of darunavir by competitive inhibition at CYP3A4.(17-19) Rifapentine may induce the metabolism of the protease inhibitor by CYP3A4.(14)

CLINICAL EFFECTS: The concurrent administration of amprenavir, atazanavir, boceprevir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, telaprevir or tipranavir with rifabutin may result in increased levels, clinical effects, and side effects (including neutropenia, lymphopenia, and influenza-like illness) of rifabutin.(1-29) Levels of amprenavir, indinavir, nelfinavir, and saquinavir may be decreased.(1-14) The increased levels of darunavir seen with concurrent rifabutin are not expected to be clinically significant.(17-19) Concurrent or recent use of rifapentine may result in decreased levels and effectiveness of the protease inhibitor.(14)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Department of Health and Human Services (DHHS) Guidelines for the Use of Antiretroviral Agents,(27) the CDC/NIH guidelines on treatment of opportunistic infections (OI) in HIV(28), and the CDC's guidelines on managing drug interactions in HIV-related tuberculosis (TB)(29) all recommend that the dose of rifabutin be reduced to 150 mg once daily, or 300 mg three times weekly (a 50% reduction), when used with boosted or unboosted protease inhibitors. Previous iterations of the guidelines recommended a rifabutin dose of 150 mg three times weekly, but some studies have found subtherapeutic rifabutin levels as a result.(30-35) Given the risk of rifamycin resistance, the guidelines now recommend a higher dose of rifabutin than previously, but state that clinicians should recognize that there are limited safety data with this dose and patients need to be closely monitored for rifabutin-related toxicities. The Australian, UK, and US manufacturers of amprenavir,(1,2,3) fosamprenavir,(4,6) indinavir,(7,8,9) and nelfinavir(10,11,12) recommend reducing the dose of rifabutin by at least 50% when used concurrently. The Australian(7) and US(9) manufacturers of indinavir recommend that the dosage of indinavir be increased to 1,000 mg every eight hours. The UK manufacturer of indinavir recommends that the dosage of indinavir be increased to 1,000 mg or 1,200 mg every eight hours.(8) The US manufacturer of nelfinavir(12) and the US manufacturer of rifabutin(14) recommend a dosage of nelfinavir of 1,250 mg twice daily when used with rifabutin. Monitoring of patients should be increased. Monitor for neutropenia, liver enzyme levels, and consider monitoring rifabutin concentrations. The Australian, Canadian, UK, and US manufacturers of atazanavir,(15,16,17) darunavir,(18,19,20) fosamprenavir when used with ritonavir,(4,5,6) lopinavir-ritonavir,(21,22,23) saquinavir,(13) and tipranavir (24) recommend that the dosage of rifabutin be reduced by 75% (e.g. 150 mg every other day or 3 times per week) with careful monitoring. Additional dose adjustment may be warranted. In Australia, the combination of atazanavir with cobicistat is contraindicated with rifabutin.(15) Monitoring of patients should be increased. Monitor for neutropenia, liver enzyme levels, and consider monitoring rifabutin concentrations. When ritonavir is used as an antiretroviral agent at 500 mg bid or above, it is contraindicated with rifabutin.(25,26) When used as a boosting agent, refer to the dosing for the primary protease inhibitor. Consider alternatives to rifapentine in patients receiving protease inhibitors. DHHS guidelines state that rifapentine should not be coadministered with any protease inhibitors.(27) In Australia, the combination of atazanavir with cobicistat is contraindicated with rifapentine.(15) Selected protease inhibitors linked to this monograph include: amprenavir, atazanavir, boceprevir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and telaprevir.

DISCUSSION: Two open-label, randomized, cross-over studies, one in South Africa(30) and one in Vietnam(31), comparing rifabutin doses of 300 mg daily alone with 150 mg 3 times weekly or 150 mg daily given with lopinavir-ritonavir (LPVr) found that the 150 mg daily dose with LPVr attained higher rifabutin levels than 300 mg daily alone, and the 150 mg 3 times weekly dose with LPVr led to lower rifabutin levels than 300 mg daily alone. The levels of the rifabutin active metabolite 25-O-desacetylrifabutin was markedly elevated with both dosages in both studies. All 16 patients in the South Africa study and 22/24 patients in the Vietnam study had negative cultures at the end of TB therapy. Mild adverse events were common. Two cases of uveitis occurred in the South Africa study and none in the Vietnam study. Grade 3 neutropenia occurred in 5 patients and 1 patient in the South Africa and Vietnam study, respectively. A retrospective cohort study of HIV-TB co-infected patients on ritonavir-boosted atazanavir compared the use of rifabutin 150 mg 3 times weekly (n=118) with rifabutin 150 mg daily (n=174). Significantly more patients in the rifabutin daily group than the rifabutin three times weekly group achieved clinical cure (73% vs. 44.1%, p<0.001).(36) A number of other small studies in HIV-TB co-infected patients on ritonavir-based antiretroviral therapy have also found that a rifabutin dose of 150 mg 3 times weekly led to inadequate rifabutin levels but high 25-O-desacetylrifabutin levels. Many patients achieved clinical cure despite the low rifabutin levels, but studies did report patient deterioration, deaths, relapse, or resistance in patients with low rifabutin levels.(32-35) A case series of 3 patients with AIDS and TB reported that the patients developed acquired rifamycin resistance despite receiving directly observed therapy for TB. All the patients had been on ritonavir-boosted protease inhibitors and had a rifabutin dose of 150 mg every other day.(37) In a study in 7 subjects, atazanavir/ritonavir (300/100 mg daily) and rifabutin (150 mg twice weekly) increased the Cmax, AUC, and Cmin of rifabutin by 2.49-fold, 1.48-fold, and 1.40-fold, respectively, when compared to the administration of 150 mg daily of rifabutin. The Cmax, AUC, and Cmin of 25-O-desacetylrifabutin increased by 7.77-fold, 10.90-fold, and 11.45-fold, respectively.(15) Concurrent darunavir/ritonavir (600/100 mg twice daily) and rifabutin (150 mg every other day) decreased rifabutin Cmax and AUC by 28% and 7%, respectively, and increased rifabutin Cmin by 64% when compared to the administration of rifabutin (300 mg daily) alone. The Cmax, AUC, and Cmin of 25-O-desacetylrifabutin increased by 4.77-fold, 9.81-fold, and 27.1-fold, respectively. The Cmax, AUC, and Cmin of darunavir increased 42%, 57%, and 75%, respectively.(20) In a study using concurrent rifabutin (150 mg daily) with darunavir/ritonavir (400/100 mg twice daily), lymphopenia and influenza-like illnesses were reported at a higher frequency than in patients who received rifabutin alone. One patient experienced a grade 3 decrease in white blood cell count during concurrent therapy.(19) Concurrent fosamprenavir/ritonavir (700/100 mg twice daily) and rifabutin (150 mg every other day) increased amprenavir Cmax, AUC, and Cmin by 36%, 35%, and 17%, respectively. Rifabutin Cmax decreased by 14% and rifabutin Cmin increased by 28%. The Cmax, AUC, and Cmin of 25-O-desacetylrifabutin increased by 579%, 1120%, and 2510%, respectively. The AUC of rifabutin plus 25-O-desacetylrifabutin increased by 64%.(6) In a study in 14 healthy, HIV-negative subjects, concurrent rifabutin (150 mg once daily) and indinavir (800 mg every 8 hours) decreased indinavir Cmax, AUC, and Cmin by 20%, 32%, and 40%, respectively. Rifabutin Cmax, AUC, and Cmin increased by 1.29-fold, 1.54-fold, and 1.99-fold, respectively.(9,28) In a study in 18 healthy subjects, concurrent indinavir (1,000 mg three times daily) with rifabutin (150 mg daily) increased rifabutin and 25-O-desacetylrifabutin AUC by 70% and 120%, respectively, when compared to the administration of rifabutin (300 mg daily) alone. In a study in 10 HIV-positive subjects, concurrent administration of indinavir (1,000 mg three times daily) with rifabutin (150 mg daily) produced indinavir levels similar to indinavir (800 mg three time daily) administered alone.(39) Concurrent lopinavir/ritonavir (400/100 mg twice daily) with rifabutin (150 mg daily) increased lopinavir Cmax, AUC, and Cmin by 1.08-fold, 1.17-fold, and 1.20-fold, respectively. The Cmax, AUC, and Cmin of rifabutin increased by 2.12-fold, 3.03-fold, and by 4.90-fold, respectively. The Cmax, AUC, and Cmin of 25-O-desacetylrifabutin increased by 23.6-fold, 47.5-fold, and by 94.9-fold, respectively. The Cmax, AUC, and Cmin of rifabutin plus 25-O-desacetylrifabutin increased by 3.46-fold, 5.73-fold, and 9.53-fold, respectively.(23) Concurrent rifabutin (300 mg daily) and nelfinavir (750 mg every 8 hours) increased rifabutin AUC, Cmax, and Cmin by 207%, 146%, and 305%, respectively. Nelfinavir AUC, Cmax, and Cmin decreased by 32%, 24%, and 53%, respectively. Concurrent rifabutin (150 mg once daily) and nelfinavir (750 mg every 8 hours) increased rifabutin AUC, Cmax, and Cmin by 83%, 19%, and 177%, respectively. Nelfinavir AUC, Cmax, and Cmin decreased by 23%, 18%, and 25%, respectively. Concurrent rifabutin (150 mg once daily) and nelfinavir (1,250 mg every 12 hours) decreased nelfinavir Cmin by 15%. There was no effect on nelfinavir AUC or Cmax.(12) Rifapentine (600 mg twice weekly for 28 days) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of indinavir (800 mg 3 times daily on Days 15-28) by 70% and 55%, respectively. Indinavir clearance increased 3-fold. There was no affect on indinavir half-life. There were no effects on rifapentine pharmacokinetics.(14) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Rifamycins/Dapsone

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

MECHANISM OF ACTION: The exact mechanism is unknown but likely involves induction of hepatic enzymes resulting in increased clearance of dapsone.(1-3)

CLINICAL EFFECTS: Concurrent use may lead to decreased levels and clinical effects of dapsone when it is used for treatment or prophylaxis of Pneumocystis jiroveci pneumonia (PCP).(1-5) Since dapsone is extremely potent for treatment of leprosy, this interaction is not clinically relevant in the setting of leprosy.(5)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US Department of Health and Human Service guidelines for prevention and treatment of opportunistic infections in patients with HIV recommend avoiding concomitant administration of dapsone with rifamycins if possible and considering use of alternatives to dapsone.(4) Since dapsone is extremely potent for treatment of leprosy, this interaction is not clinically relevant in the setting of leprosy.(5)

DISCUSSION: When given with rifampin, dapsone levels have been found to decrease by 7- to 10-fold.(3,4) In a trial of 16 HIV-positive patients, rifabutin (300 mg daily) lowered the area-under-curve (AUC) of dapsone (50 mg daily) by 27% to 40%.(2,4) Although dapsone dose adjustment is not necessary when it is used for leprosy, the implications of this interaction when dapsone is used for PCP is unknown. Mycobacterium leprae is very sensitive to dapsone, with a minimum inhibitory concentration (MIC) of 2.5 to 10 mcg/L. In contrast, the MIC of dapsone against P. jiroveci is 100 to 10,000 mcg/L. Dapsone concentrations reached with typical PCP therapy is in the range of 100 to 7,000 mcg/L. Thus, a 10-fold reduction in dapsone levels could result in dapsone levels below the MIC for PCP.(5)

Rifamycins/Hormonal Contraceptives

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

MECHANISM OF ACTION: Rifamycins (rifampin, rifabutin and rifapentine) induce the CYP3A4 mediated metabolism of both estrogen and progestin components of hormonal contraceptives.

CLINICAL EFFECTS: Concurrent use of rifampin, rifabutin, or rifapentine may result in reduced levels and clinical effectiveness of hormone containing contraceptives. Breakthrough bleeding and contraceptive failure/pregnancy may result. Effects may be seen for several weeks after discontinuation of the rifamycin.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving rifamycins should be alerted to the risk for decreased effectiveness(e.g. contraceptive failure) of their hormonal contraceptive therapy. It is recommended that alternative or additional contraceptive methods be used during and for several weeks after rifamycin therapy. If a combined oral contraceptive is used, the preparation should contain at least 30 mcg of ethinyl estradiol should be used. The patient should be asked to report any spotting or bleeding. For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.

DISCUSSION: In an open-label, randomized crossover study, 22 healthy females received oral contraceptives for 21 days, then were randomized to receive rifampin or rifabutin (300 mg/d for 10 days). Rifampin and rifabutin decreased the area-under-curve (AUC) of ethinyl estradiol by 64% and 35%, respectively, and maximum concentration (Cmax) by 42% and 20%, respectively. Rifampin and rifabutin decreased the AUC of norethindrone by 60% and 20%, respectively. Incidences of spotting were much greater in the rifampin co-administration group. In a study, a single dose of oral contraceptive (ethinyl estradiol 50 mcg and norethindrone acetate 1 mg) was administered to 7 female patients with tuberculosis, both during TB treatment and one month after stopping rifampin (450-600 mg/d). Upon cessation of rifampin therapy, the AUC for ethinyl estradiol significantly increased by 70%, and terminal plasma half-life more than doubled. A similar study design analyzed the pharmacokinetics of norethisterone (1 mg) in 8 women receiving rifampin (450-600 mg/d). Upon termination of TB treatment, it was found that rifampin reduced the AUC of a single dose of norethisterone (1 mg) by approximately 40%, with a half-life reduction of 50%. In a study, male volunteers received 50 mcg iv of ethinyl estradiol, followed by rifampin (600 mg for 6 days). Ethinyl estradiol half-life decreased by approximately 55%. The upward titration of ethinyl estradiol to 100 mcg resulted in a more than 2-fold increase in ethinyl estradiol metabolism caused by rifampicin treatment. An analytical trial evaluated liver biopsies from four patients treated with rifampin 600 mg for a period of 6-10 days. Hepatic microsomes from the biopsies were incubated with hormone substrates, including oestradiol and ethinyl estradiol. Rifampin resulted in a fourfold increase in hydroxylation. Not only did rifampin increase the rate of hydroxylation through enzyme induction, it also caused an increase in cytochrome P-450. There are reports of breakthrough bleeding and unintended pregnancy during concurrent use. A study of 118 HIV-positive females compared levonorgestrel pharmacokinetics and safety between the following groups: 1. levonorgestrel 1.5 mg with dolutegravir-based antiretrovirals (ART)(control group), 2. levonorgestrel 1.5 mg with efavirenz-based ART, 3. levonorgestrel 3 mg with efavirenz-based ART, and 4. levonorgestrel 3 mg with rifampin. While both levonorgestrel 3 mg groups had Cmax and AUC(0-8h) similar to the control group, the half life of levonorgestrel was shorter, resulting in an AUC(inf) that was 53% lower in the efavirenz group and 37% lower in the rifampin group than the control group. Tolerability was similar between groups. No pregnancies were reported but it is unknown whether the correction of levonorgestrel levels early in the dosing period is sufficient to maintain overall emergency contraceptive effectiveness.(25)

Rifamycins/Ixabepilone

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

MECHANISM OF ACTION: Rifamycins may induce the metabolism of ixabepilone by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent or recent use of rifamycins may result in decreased levels and effectiveness of ixabepilone.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of ixabepilone states that concurrent use of strong inducers of CYP3A4, such as rifampin, rifapentine, and rifabutin, should be avoided. If concurrent therapy is required, the dose of ixabepilone may be gradually increased from 40 mg/m2 to 60 mg/m2, depending on tolerance. If the dose is increased, ixabepilone should be given as a 4 hour infusion. Monitor patients closely for toxicity. If the inducer is discontinued, the dose of ixabepilone should be returned to the dose used prior to concurrent therapy.(1)

DISCUSSION: Concurrent use of rifampin increased ixabepilone area-under-curve (AUC) by 43%, compared to treatment with ixabepilone alone.(1) Adjustment of the ixabepilone dose in the presence of a strong CYP3A4 inducer to 60 mg/m2 given over 4 hours is predicted to adjust the ixabepilone AUC to the range observed without inducers; however, there is no clinical data with this dose.(1)

Rifamycins/Posaconazole

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

MECHANISM OF ACTION: Posaconazole is primarily metabolized via glucuronidation (UGT). Rifamycins induce one or more UGT pathways.(1,2) Posaconazole may inhibit the metabolism of rifabutin.(1,2)

CLINICAL EFFECTS: Concurrent use of rifamycins may result in decreased levels and clinical effectiveness of posaconazole.(1,2) Concurrent use of posaconazole may result in elevated levels of and toxicity from rifabutin, including uveitis and leukopenia.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The UK manufacturer of posaconazole states that concurrent use of rifamycins should be avoided unless the benefit to the patient outweighs the risk of concurrent therapy.(1) The US manufacturer of posaconazole states that concurrent use of rifabutin should be avoided unless benefit outweighs the risk. If concurrent use is warranted, frequent monitoring of full blood counts and for adverse effects such as uveitis and leucopenia should be performed.(2)

DISCUSSION: Concurrent rifabutin (300 mg daily) decreased posaconazole area-under-curve (AUC) and maximum concentration (Cmax) by 51% and 57%, respectively.(1) Concurrent rifabutin (300 mg daily) with posaconazole (200 mg daily) decreased posaconazole AUC and Cmax by 43% and 49%, respectively. Rifabutin AUC and Cmax increased by 72% and by 31%, respectively.(2)

Rifamycins/Selected Anticoagulants (Vitamin K Antagonists)

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

MECHANISM OF ACTION: Rifamycins may induce the hepatic metabolism of the anticoagulants.

CLINICAL EFFECTS: Concurrent or recent use of a rifamycin may result in decreased levels of and clinical effects from anticoagulants. If the rifamycin is withdrawn, levels and effects of the anticoagulant may increase, increasing the risk of hemorrhage. This effect may be dose-related and continue beyond discontinuation of the rifamycin.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If concurrent use of rifamycins and warfarin is warranted, use caution during concurrent use and monitor patients closely. The dose of the anticoagulant will need to be adjusted when the rifamycin is initiated or discontinued. If concurrent use of rifampin and warfarin is warranted, monitor INR closely to maintain target INR. The dose of warfarin may need to be increased 3-5 times higher than a stable baseline dose. Goal INR may be delayed and labile for months after starting rifampin. After discontinuation of rifampin, INR requires close monitoring to de-escalate warfarin dose as induction effects fade. Evaluate patients closely for benefits of bridging with LMWH with risks of additional bleeding.(2) The time of highest risk for an anticoagulant drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose, or discontinuing either drug.

DISCUSSION: In a study in 4 healthy subjects, concurrent rifampin (300 mg twice daily) decreased warfarin (0.75 mg/kg) area-under-curve (AUC) by 70%.(1) In a study in 10 healthy males, concurrent rifampin (600 mg daily) decreased oral warfarin (1.5 mg/kg) AUC by 57%. Prothrombin time decreased by 52%. Intravenous warfarin AUC decreased by 58%. Prothrombin time decreased by 56%.(3) In a study in 8 healthy subjects, concurrent rifampin (600 mg daily) decreased warfarin (dosed to therapeutic effect) plasma levels by 85%. On warfarin alone, subjects averaged 25% of normal prothrombin activity. On concurrent rifampin, subjects averaged 85% of normal prothrombin activity.(4) There are several case reports of decreased warfarin(5-8) and phenprocoumon(9) effects during concurrent rifampin therapy. A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of warfarin and rifampin resulted in a ratio of rate ratios (RR) (95% CI) of 2.25 (1.1-4.61).(10)

Rifamycins/Selected Calcium Channel Blockers

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

MECHANISM OF ACTION: Multiple mechanisms appear to be involved. Rifampin may increase the hepatic metabolism of the calcium channel blockers, increase first-pass hepatic metabolism of oral calcium channel blockers, and decrease the protein binding of calcium channel blockers.(1-8)

CLINICAL EFFECTS: Concurrent use of rifampin may decrease levels and effectiveness of the calcium channel blocker.(1-8)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Observe the patient for a decrease in the therapeutic effects of the calcium channel blocker if rifampin is initiated. The dose of the calcium channel blocker may need to be adjusted if rifampin is initiated or discontinued.(1-7) The US manufacturer of diltiazem states that concurrent use should be avoided.(2) The manufacturer of lercanidipine states that concurrent use is not recommended.(10)

DISCUSSION: In healthy subjects, pretreatment with rifampin (600 mg daily) reduced the concentration of a single dose of isradipine (5 mg) below a detectable level. The study concluded that the concentrations and effects of isradipine may be either reduced or absent as a result of increased isradipine metabolism.(1) Concurrent administration of rifampin has been shown to lower diltiazem levels below detectable limits.(2) In a study in 5 healthy subjects, pretreatment with rifampin (6 days) decreased the area-under-curve (AUC) of a single oral dose of nilvadipine (4 mg) by 96.5%. Pretreatment with rifampin abolished nilvadipine-induced hypotensive effects and tachycardia.(3) A study in six subjects examined the effects of pretreatment with rifampin (600 mg daily for 15 days) on single doses of verapamil (10 mg intravenously or 120 mg orally). Rifampin significantly decreased the maximum concentration (Cmax) and AUC of oral verapamil and resulted in no changes in the P-R interval. There were small decreases in the AUC of intravenous verapamil.(4) In a study in 8 male subjects, pretreatment with rifampin (600 mg daily for 15 days) increased the systemic clearance of S-verapamil by 1.3-fold and the apparent oral-clearance of S-verapamil by 32-fold. The bioavailability of S-verapamil decreased 25-fold. The effect of oral verapamil on AV conduction was almost abolished. No significant changes were noted for intravenous administration of verapamil.(5) In a study in 16 hypertensive chronic kidney disease patients, amlodipine levels decreased an average of 82% after initiation of rifampin. In eight of the 16 patients, the levels were undetectable.(9) There have been case reports of decreased effectiveness of barnidipine,(6) manidipine,(6) nisoldipine,(6) and verapamil(7,8) during concurrent rifampin therapy.

Rifamycins/Ulipristal

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

MECHANISM OF ACTION: Rifamycins (rifabutin, rifampin, rifapentine) may induce the metabolism of ulipristal by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use or use of rifamycins within the previous 2-3 weeks may result in decreased levels and effectiveness of ulipristal.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US and UK manufacturers of ulipristal state that concurrent use with CYP3A4 inducers such as rifampin is not recommended. Decreased effectiveness of ulipristal may occur even 2-3 weeks after discontinuation of rifamycins.(1,2) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.

DISCUSSION: CYP3A4 inducers may decrease levels and effectiveness of ulipristal. Enzyme induction may take 2-3 weeks to wear off. Plasma levels of ulipristal may be reduced even if the CYP3A4 inducer was discontinued in the previous 2-3 weeks.(1) Concurrent administration of ulipristal 30 mg and rifampin 600 mg for 9 days decreased the maximum concentration (Cmax) and area-under-the-curve (AUC) by 90% and 93%, respectively. The Cmax and AUC of monodemethyl-ulipristal decreased by 84% and 90% respectively.(2)

Select Cyp2c19 Inhibitors/Citalopram (>20 Mg)

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

MECHANISM OF ACTION: Citalopram is primarily metabolized by the CYP2C19 isoenzyme.(1)

CLINICAL EFFECTS: Concurrent use of an agent that inhibits CYP2C19 may result in elevated levels of and toxicity from citalopram, including including risks for serotonin syndrome or prolongation of the QTc interval.(1-5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(5)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age, poor metabolizer status at CYP2C19, or higher blood concentrations of citalopram.(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) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,5) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

PATIENT MANAGEMENT: The dose of citalopram should be limited to 20 mg in patients receiving concurrent therapy with an inhibitor of CYP2C19.(1,4) Evaluate the patient for other drugs, diseases and conditions which increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, discontinue other QT prolonging drugs) when possible.(1,2) Weigh the specific benefits versus risks for each patient. The US manufacturer recommends ECG monitoring for citalopram patients with congestive heart failure, bradyarrhythmias, taking concomitant QT prolonging medications or receiving concurrent therapy.(4) Citalopram should be discontinued in patients with persistent QTc measurements greater than 500 ms.(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. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: Concurrent use of citalopram (40 mg daily) and cimetidine (400 mg twice daily) for 8 days increased the maximum concentration (Cmax) and area-under-curve (AUC) of citalopram by 39% and 43%, respectively.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), armodafinil, asciminib, berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, elagolix, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, tecovirimat, treosulfan, and vonoprazan.(7,8)

Selected Antimycobacterials/Live Bcg

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

MECHANISM OF ACTION: Bacillus Calmette-Guerin (BCG) is a live, attenuated strain of Mycobacterium bovis (M.bovis) used to induce a granulomatous response in the treatment of localized bladder cancer and as a vaccine to prevent tuberculosis.(1-2) Co-treatment with antibacterial agents active against M.bovis may lead to an attenuation of the immune response associated with BCG administration.(1-2)

CLINICAL EFFECTS: The effectiveness of chemotherapy may be impaired, or the vaccine may be ineffective. Agents linked to this monograph may have activity against M.bovis: amikacin, capreomycin, ciprofloxacin, clofazimine, cycloserine, ethambutol, ethionamide, gatifloxacin, isoniazid, kanamycin, levofloxacin, moxifloxacin, ofloxacin, rifabutin, rifampin, rifapentine, and streptomycin.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Intravesical instillation of BCG should be postponed during treatment with antibacterials which may decrease effectiveness.(2) Administration of BCG vaccine to patients receiving antibiotic therapy should only be done under close medical supervision.(1) If a patient develops a systemic BCG infection due to intravesicular or vaccine administration, treatment with multiple antimycobacterial agents may be required.

DISCUSSION: Because antibiotic therapy may prevent sufficient vaccine-organism replication to generate an immune response, the manufacturer of BCG vaccine states that administration of BCG vaccine to patients receiving antibiotic therapy should only be done under close medical supervision.(1) Pyrazinamide is not included in this interaction as BCG is not sensitive to pyrazinamide.(2)

Selected Cyp3a4 Inducers/Cobicistat-Elvitegravir

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

MECHANISM OF ACTION: Cobicistat may inhibit rifabutin and rifapentine metabolism by CYP3A4. Apalutamide, encorafenib, enzalutamide, lumacaftor, mitotane, oxcarbazepine, rifabutin, and rifapentine may induce the metabolism of cobicistat and elvitegravir.(1)

CLINICAL EFFECTS: Concurrent use of cobicistat-elvitegravir with apalutamide, encorafenib, enzalutamide, lumacaftor, mitotane, oxcarbazepine, rifabutin, or rifapentine may result decreased levels of elvitegravir and development of resistance.(1) Concurrent use of cobicistat-elvitegravir may result in elevated levels of apalutamide, oxcarbazepine, rifabutin, or rifapentine, as well as ivacaftor (which is coformulated with lumacaftor).(1)

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

PATIENT MANAGEMENT: Concurrent use of combination product containing cobicistat-elvitegravir-emtricitabine-tenofovir and rifabutin or rifapentine is not recommended.(1) Consider the use of alternative anticonvulsants to oxcarbazepine.(1) Concurrent use with carbamazepine, phenobarbital, or phenytoin is contraindicated.(1)

DISCUSSION: Concurrent cobicistat-elvitegravir (150 mg each daily) increased the maximum concentration (Cmax) of rifabutin (150 mg every other day) by 1.09-fold. The area-under-curve (AUC) and minimum concentration (Cmin) of rifabutin decreased by 8% and 6%, respectively, when compared to the administration of 300 mg daily of rifabutin. The Cmax, AUC, and Cmin of 25-O-desacetyl-rifabutin increased by 4.84-fold, 6.25-fold, and 4.94-fold, respectively, when compared to the administration of 300 mg daily of rifabutin. The Cmax, AUC, and Cmin of elvitegravir decreased by 9%, 21%, and 67%, respectively.(1) Concurrent cobicistat-elvitegravir (150 mg each daily) with carbamazepine (200 mg twice daily) decreased the Cmax, AUC, and Cmin of elvitegravir by 45%, 69%, and 97%, respectively. Concurrent cobicistat-elvitegravir (150 mg each daily) with carbamazepine (200 mg twice daily) increased the Cmax, AUC, and Cmin of carbamazepine by 40%, 43%, and 51%, respectively. The Cmax, AUC, and Cmin was decreased for carbamazepine-10,11-epoxide by 29%, 35%, and 41%, respectively. (2)

Selected P-Glycoprotein (P-Gp) Inducers/Edoxaban

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

MECHANISM OF ACTION: Edoxaban is a P-glycoprotein (P-gp) substrate. P-gp induction may reduce systemic exposure to edoxaban.(1)

CLINICAL EFFECTS: Concurrent or recent use of apalutamide, carbamazepine, efavirenz, fosphenytoin, lorlatinib, phenytoin, rifapentine, or St. John's wort may result in decreased effectiveness of edoxaban.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of edoxaban states that concomitant use of rifampin should be avoided. Although there are no recommendations for other P-gp inducers, a similar precaution is reasonable.(4) The UK manufacturer of edoxaban recommends caution with co-administration of P-gp inducers such as carbamazepine, phenytoin, or St. John's wort.(1,3) Consider alternatives to the P-gp inducing agent. If therapy with an inducer of P-gp is required, alternatives to edoxaban may need to be considered. If a P-gp inducer is discontinued, edoxaban exposure will remain impaired for at least one week after the completion of therapy.

DISCUSSION: Co-administration of another P-gp inducer, rifampin 600 mg QD for 7 days with a single dose of edoxaban 60 mg on Day 7, decreased total systemic exposure to edoxaban by 40% without having an apparent effect on peak exposure.(5) A 76-year-old male on apixaban for atrial fibrillation s/p pulmonary embolism 1 month prior was started on rifabutin 300 mg daily for tuberculosis. Apixaban was switched to edoxaban due to a drug interaction with rifabutin. At 1 month, rifabutin was increased to 450 mg daily. After another 8 weeks, the patient suffered a DVT that was thought to be a result of a drug-drug interaction with rifabutin.(6) Other inducers of P-glycoprotein linked to this monograph include apalutamide, carbamazepine, fosphenytoin, lorlatinib, phenytoin, rifabutin, rifapentine, and St. John's wort.(2,3)

Selected Strong Cyp2c19 Inducers/Clopidogrel

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

MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2 step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1-3) As CYP2C19 contributes to both steps, it is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite. Strong inducers of CYP2C19 may increase the conversion of clopidogrel to its active metabolite.(1,2)

CLINICAL EFFECTS: Concurrent use of strong CYP2C19 inducers with clopidogrel may increase the effects and toxicity of clopidogrel, including bleeding.(1,2)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patient 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). Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of clopidogrel states that concomitant use of strong CYP2C19 inducers should be avoided.(1,2) If concurrent therapy cannot be avoided, monitor patients for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue clopidogrel in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: In a study of 12 healthy volunteers, rifampin (300 mg twice daily for 7 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of the active metabolite of clopidogrel by approximately 4-fold. In conjunction with this, there was a higher level of P2Y12 receptor blockade by clopidogrel after rifampin pre-treatment. Clopidogrel 600 mg alone decreased the number of unblocked receptors at 4 hours from 248 +/- 40 to 48 +/- 24 per platelet. After rifampin pre-treatment, clopidogrel decreased the number of unblocked receptors from 266 +/- 63 to 4 +/- 2 (p < 0.0001).(4) A study of 10 healthy volunteers found that rifampin 300 mg twice daily for 4 days then combined with clopidogrel 75 mg daily for 6 days led to a significantly greater inhibition of platelet aggregation compared to clopidogrel alone (56% versus 33%, respectively). Three subjects who were initially clopidogrel nonresponders and 1 subject who was a low responder all became responders after treatment with rifampin.(5) Strong CYP2C19 inducers linked to this monograph include: apalutamide, rifabutin and rifampin.(6,7)

Selected Strong Cyp3a4 Inducers/Irinotecan

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

MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of irinotecan by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may result in decreased levels of irinotecan, as well as its active metabolites, and decreased clinical effectiveness.

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

PATIENT MANAGEMENT: The manufacturer states do not administer strong CYP3A4 inducers with irinotecan unless there are no therapeutic alternatives. Consideration should be given to substituting non-enzyme inducing therapies at least 2 weeks prior to irinotecan therapy.(1) Levels of irinotecan and the active metabolites should be monitored in patients receiving concurrent use of strong CYP3A4 inducers. If strong CYP3A4 inducers are added to or discontinued from concurrent irinotecan, the dosage of irinotecan may need to be adjusted to ensure therapeutic effects or prevent toxicity.

DISCUSSION: The manufactures states that irinotecan may interact with strong CYP3A4 inducers which may result in increased irinotecan metabolism.(1) In a clinical trial, irinotecan clearance values were 65.4% higher in patients receiving phenytoin when compared to patients who were not taking enzyme-inducing anticonvulsants.(2) In another clinical trial, irinotecan clearance was 117% higher in patients receiving anticonvulsants that included phenytoin.(5) Data from another clinical trial also suggested that phenytoin increases irinotecan clearance.(6) Case reports have also noted increased irinotecan clearance by 4-fold(3) and by 62.7%(4) in patients receiving concurrent phenytoin. Levels of irinotecan and its active metabolite, SN-38 were both decreased. Selected strong CYP3A4 inducers linked include: apalutamide, encorafenib, enzalutamide, ivosidenib, lumacaftor, mitotane, rifabutin, rifampin, and rifapentine.

Str 3A4 & P-Gp Inducers;Rifabutin/Bictegravir-Emtricitab-Taf

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

MECHANISM OF ACTION: Bictegravir is a CYP3A4 substrate and tenofovir alafenamide (TAF) is a substrate of the intestinal efflux transporter P-glycoprotein (P-gp). Concurrent use of agents that are both CYP3A4 and P-gp inducers may induce the metabolism of bictegravir and decrease systemic absorption of TAF.(1) Phenobarbital may also induce the metabolism of TAF.(1) Primidone is metabolized to phenobarbital.

CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 and P-gp inducers, phenobarbital, primidone, or rifabutin may result in decreased systemic levels of bictegravir and tenofovir alafenamide, virologic failure, and development of resistance.(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 bictegravir recommends considering alternatives to carbamazepine, phenobarbital, and phenytoin for patients on bictegravir.(1) The National Institute of Health HIV guidelines do not recommend coadministration of carbamazepine, phenobarbital or phenytoin with bictegravir.(2) Fosphenytoin and primidone are metabolized to phenytoin and phenobarbital, respectively. Other CYP3A4 inducers are not recommended to be coadministered with bictegravir.(1,2)

DISCUSSION: Coadministration of rifampin (600 mg daily, a strong CYP3A4 inducer) decreased bictegravir area-under-curve (AUC) by 75% and maximum concentration (Cmax) by 28%.(1) Although the other strong CYP3A4 inducers linked to this monograph have not been studied with bictegravir, a similar effect is expected. Coadministration of rifabutin (300 mg daily) with bictegravir decreased bictegravir AUC and Cmax by 38% and 20%, respectively.(1) When tenofovir alafenamide (TAF) was coadministered with carbamazepine, the maximum concentration (Cmax) and area-under-curve (AUC) were decreased 57% and 55%, respectively.(1-4) A subsequent study suggests that this interaction may not have clinically significant effects on intracellular levels of tenofovir diphosphate, the active metabolite of tenofovir alafenamide. In a study of 23 healthy volunteers, the intracellular Cmax and AUC of tenofovir diphosphate were 38% and 36% lower, respectively, when tenofovir alafenamide was coadministered with rifampin than without rifampin. However, these levels of tenofovir diphosphate were 4.4- and 4.21-fold higher, respectively, than levels obtained from tenofovir disoproxil 300 mg daily without rifampin.(3) CYP3A4 and P-gp inducers linked to this monograph include: apalutamide, carbamazepine, fosphenytoin, phenytoin, rifabutin, rifapentine, and St. John's wort.(1,4) Phenobarbital and primidone are known strong CYP3A4 inducers (4) and the manufacturer of bictegravir also classifies phenobarbital as a P-gp inducer.(1)

Str Or Mod 3A4 Inducer & Substrate/Vonoprazan-Clarithro-Amox

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

MECHANISM OF ACTION: Bosentan, carbamazepine, dabrafenib, elagolix, ivosidenib, lorlatinib, lumacaftor, and mitapivat are both moderate to strong inducers and substrates of CYP3A4.(1,2) Moderate and strong inducers of CYP3A4 may increase the CYP3A4-mediated metabolism of vonoprazan and clarithromycin.(3) Clarithromycin is a strong inhibitor of CYP3A4 and may decrease the metabolism of CYP3A4 substrates.(3)

CLINICAL EFFECTS: Concurrent use of moderate to strong CYP3A4 inducers may result in decreased levels and effectiveness of vonoprazan and clarithromycin.(3) Concurrent use of CYP3A4 substrates with clarithromycin may result in elevated levels of and toxicity from the substrate.(3)

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 vonoprazan states that concurrent use with strong or moderate CYP3A4 inducers should be avoided.(3)

DISCUSSION: Vonoprazan and clarithromycin are CYP3A4 substrates. Strong CYP3A4 inducers like rifampin are predicted to decrease the area-under-curve (AUC) of vonoprazan by 80%, and moderate CYP3A4 inducers like efavirenz are predicted to decrease vonoprazan AUC by 50%.(1) Strong inducers of CYP3A4 that are CYP3A4 substrates include: carbamazepine, ivosidenib, and lumacaftor. Moderate inducers of CYP3A4 that are CYP3A4 substrates include: bosentan, dabrafenib, elagolix, lorlatinib, mitapivat, and rifabutin.(2-3)

Strong & Moderate Cyp3a4 Inducers/Guanfacine

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

MECHANISM OF ACTION: Strong or moderate inducers of CYP3A4 may induce the metabolism of guanfacine.(1)

CLINICAL EFFECTS: The concurrent administration of a strong or moderate CYP3A4 inducer may result in decreased levels and effectiveness of guanfacine.(1)

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

PATIENT MANAGEMENT: Patients maintained on guanfacine may need dosage adjustments if strong or moderate inducers of CYP3A4 are initiated or discontinued. The manufacturer of extended-release guanfacine recommends a starting dose of extended-release guanfacine initiated at up to double the recommended level of the weight based dosing in patients receiving strong or moderate inducers of CYP3A4. If a patient has been maintained on extended-release guanfacine and is started on a strong or moderate CYP3A4 inducer, the dose of extended-release guanfacine should be increased up to double the recommended weight based dose over 1 to 2 weeks. If a patient has been maintained on extended-release guanfacine and a strong or moderate CYP3A4 inducer, and the strong or moderate CYP3A4 inducer is discontinued, the dose of extended-release guanfacine may need to be decreased to the recommended weight based dose over 1 to 2 weeks. 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: Rifampin (dosage not stated), a strong inducer of CYP3A4, decreased the maximum concentration (Cmax) and area-under-curve (AUC) of guanfacine (dosage not stated) by approximately 50%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(1-3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine, and tovorafenib.(1-3)

Strong & Moderate Cyp3a4 Inducers/Olaparib

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

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

CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inducers may decrease the levels and effectiveness of olaparib.(1)

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 strong or moderate CYP3A4 inducers in patients receiving therapy with olaparib.(1) Consider the use of alternatives with little to no induction potential.

DISCUSSION: In a drug interaction trial, olaparib area-under-curve (AUC) and maximum concentration (Cmax) decreased 87% and 71% respectively when olaparib was administered with rifampin. Based upon simulated models, a moderate CYP3A4 inducer is predicted to decrease olaparib AUC by 50-60% and Cmax by 20-30%.(1-3) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate inducers of CYP3A4 include: bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(4-5)

Strong And Moderate Cyp3a4 Inducers/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. Strong and moderate inducers of CYP3A4 may accelerate the metabolism of cariprazine.(1-4)

CLINICAL EFFECTS: Concurrent use of a strong or moderate inducer of CYP3A4 may result in decreased levels and effectiveness of cariprazine.(1-4)

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

PATIENT MANAGEMENT: The US manufacturer of cariprazine does not recommend concurrent use of strong CYP3A4 inducers.(1) The Australian, Canadian, and UK manufacturers of cariprazine state that concurrent use of strong and moderate CYP3A4 inducers is contraindicated.(2-4)

DISCUSSION: Cariprazine and its active metabolites are primarily metabolized by CYP3A4. Coadministration with CYP3A4 inducers has not been studied and the net effect is unclear. Due to the long half life of the active metabolites, it takes several weeks for cariprazine to reach steady state after dosage changes.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(5-6) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(5-6)

Strong And Moderate Cyp3a4 Inducers/Pimavanserin

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

MECHANISM OF ACTION: Strong or moderate inducers of CYP3A4 may induce the metabolism of pimavanserin.(1)

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

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

PATIENT MANAGEMENT: The US manufacturer of pimavanserin recommends avoiding concomitant use of strong or moderate CYP3A4 inducers.(1)

DISCUSSION: Pimavanserin is primarily metabolized by CYP3A4 while other metabolic enzymes CYP2J2, CYP2D6 and FMO play a lesser role.(1) In a study of subjects pretreated with 7 days of rifampin (600 mg daily, a strong CYP3A4 inducer), a single dose of pimavanserin (34 mg) produced an area-under-curve (AUC) and maximum concentration (Cmax) that was 91 % and 71 % lower, respectively, than when pimavanserin is given without rifampin.(1) A physiology-based pharmacokinetic model predicted that efavirenz (a moderate CYP3A4 inducer) would decrease pimavanserin AUC and Cmax by 70 % and 60 %, respectively.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(3-4) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, and tovorafenib.(3-4)

Strong And Moderate Cyp3a4 Inducers/Pretomanid

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

MECHANISM OF ACTION: Strong and moderate CYP3A4 inducers may induce the metabolism of pretomanid by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of strong and moderate CYP3A4 inducers and pretomanid may result in decreased levels and clinical effectiveness of pretomanid.(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 pretomanid recommends avoiding concurrent use with strong or moderate CYP3A4 inducers during pretomanid therapy.(1) Patients receiving concurrent therapy with strong and moderate CYP3A4 inducers and pretomanid should be observed for decreased levels and clinical effectiveness.

DISCUSSION: In a clinical study, concurrent use of pretomanid 200 mg with efavirenz 600 mg for 7 days resulted in decreased mean area-under-curve (AUC) by 35% and maximum concentration (Cmax) by 28%.(1) In a clinical study, concurrent use of pretomanid 200 mg with rifampin 600 mg for 7 days resulted in decreased mean AUC by 66% and Cmax by 53%.(1) Strong and moderate CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate, dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, etravirine, fexinidazole, fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin, rifapentine, St. John's wort, sotorasib, telotristat, thioridazine, and tovorafenib.(1,2)

Strong Cyp3a4 Inducers/Cabozantinib S-Malate Capsules

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

MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of cabozantinib.(1)

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

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 strong CYP3A4 inducers in patients receiving therapy with cabozantinib. Consider the use of alternative agents with less enzyme induction potential.(1) Dosage adjustments are specific to the formulation of cabozantinib prescribed. If concurrent use of a CYP3A4 inducer cannot be avoided, increase the daily dose of cabozantinib CAPsules by 40 mg (from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. The daily dose of cabozantinib should not exceed 180 mg. If the CYP3A4 inducer is discontinued, reduce the dosage of cabozantinib to the dose used prior to initiation of the inducer 2 to 3 days after discontinuation of the strong inducer.(1)

DISCUSSION: In a study in healthy subjects, rifampin (600 mg daily for 31 days) decreased the AUC of a single dose of cabozantinib by 77%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, and rifapentine.(1-3)

Strong Cyp3a4 Inducers/Flibanserin

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

MECHANISM OF ACTION: Flibanserin is primarily metabolized by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers and flibanserin will result in decreased systemic concentrations of flibanserin and may lead to therapeutic failure.(1,6)

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 flibanserin states that concomitant use with CYP3A4 inducers is not recommended. In an interaction study, rifampin decreased flibanserin exposure(AUC) 95%.(1) The onset of induction is gradual but may begin within one week for potent agents (e.g. rifampin). The time to maximal induction may be 2 or more weeks depending upon the half-life and dose of the inducer.

DISCUSSION: In an interaction study described in prescribing information, rifampin decreased flibanserin exposure (AUC) 95%.(1) FDA defines strong CYP inducers as agents which cause a > or = to 80% decrease in systemic exposure (area-under-curve or AUC) of a drug metabolized by a specific CYP enzyme.(2) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenytoin, primidone, rifabutin, rifampin, rifapentine and St. John's Wort.(3)

Strong Cyp3a4 Inducers/Selected Immunosuppressants

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

MECHANISM OF ACTION: Strong inducers of CYP3A4 may increase the metabolism of cyclosporine, everolimus, sirolimus, tacrolimus, and temsirolimus.(1)

CLINICAL EFFECTS: Concurrent use of strong inducers of CYP3A4 may result in decreased levels and effectiveness of cyclosporine, everolimus, sirolimus, tacrolimus, and temsirolimus.(1)

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

PATIENT MANAGEMENT: The American Society of Transplantation guidelines state that cyclosporine and tacrolimus should be avoided in combination with rifabutin and rifampin. Everolimus should be avoided in combination with rifampin and is contraindicated with rifabutin. Sirolimus is contraindicated with rifabutin and rifampin. If concurrent therapy of cyclosporine, everolimus, sirolimus, or tacrolimus with rifampin is needed, increase the dose of the immunosuppressant by 2-fold when the combination is initiated and monitor immunosuppressant concentrations frequently with rapid subsequent dose increases as needed. The reverse is recommended when rifampin is discontinued.(62) The US manufacturer of everolimus states that concurrent use with strong CYP3A4 inducers should be avoided. If concurrent use is warranted, consider increasing the dose of everolimus. In patients with advanced hormone receptor-positive, HER2-negative breast cancer (HR+BC); advanced pancreatic neuroendocrine tumors (PNET); or advanced renal cell carcinoma; or renal angiomyolipoma with TSC, double the daily dose of everolimus using 5 mg increments or less. If the inducer is discontinued, return the dose to that used prior to inducer therapy once the inducer has been stopped for 5 days. In patients with subependymal giant cell astrocytoma with TSC, double the dose of everolimus using 5 mg increments or less. Subsequent dosing should be individualized based on therapeutic drug monitoring. If the inducer is discontinued, return the dose of everolimus to the dose used prior to the inducer once the inducer has been stopped for 5 days, and assess everolimus trough levels 2 weeks later.(1) St. John's wort may decrease everolimus levels unpredictably and should be avoided entirely.(1) The US manufacturer of temsirolimus states that concurrent use of strong inducers of CYP3A4, such as carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, or rifampin should be avoided. If concurrent therapy is warranted, consider increasing the dosage of temsirolimus from 25 mg/week to 50 mg/week. If the inducer is discontinued, the dosage of temsirolimus should be returned to the previous dose.(2) If possible, consider alternatives to strong CYP3A4 inducers in patients maintained on cyclosporine, sirolimus, and tacrolimus. If concurrent therapy is warranted, monitor cyclosporine, sirolimus, and tacrolimus serum levels and observe the patient for graft rejection. The dosage of cyclosporine, sirolimus, and tacrolimus may need to be adjusted following the initiation or discontinuation of these agents. Strong CYP3A4 inducers linked to this monograph include: allobarbital, amobarbital, apalutamide, aprobarbital, barbexaclone, barbital, brallobarbital, butabarbital, butalbital, butethal, carbamazepine, cyclobarbital, difebarbamate, ethotoin, febarbamate, fosphenytoin, hexobarbital, lumacaftor, mephenytoin, mephobarbital, metharbital, mitotane, natisedine, pentobarbital, phenobarbital, phenytoin, primidone, probarbital, proxibarbal, rifabutin, rifampin, rifapentine, secobarbital, St. John's wort, talbutal, vinbarbital, and vinylbital.

DISCUSSION: In a study in 10 lung transplant patients, significantly higher doses of cyclosporine were required during nafcillin therapy to maintain therapeutic trough levels. Patients also developed higher serum creatinine levels and more renal dysfunction than patients not receiving nafcillin. In a case report, a patient experienced 70% and 85% drops in cyclosporine levels during two separate courses of nafcillin therapy. Trough cyclosporine concentrations have been found to decrease within 48 hours after starting phenytoin even when the dose of cyclosporine is increased. Conversely, cyclosporine concentrations may increase when the hydantoin is discontinued. The effect of the hydantoin on cyclosporine may reverse over a period of one to three weeks after stopping the hydantoin. Concurrent administration of cyclosporine and rifampin has been associated with lowering of cyclosporine to undetectable serum levels. Decreases in cyclosporine levels have been observed within 2 days of concomitant therapy but will probably not be maximal for 1 week. The effects of the interaction may persist for up to 3 weeks after rifampin is stopped. In an open-label study in 11 renal transplant patients, subjects received St. John's wort (600 mg daily) for 14 days in addition to their normal cyclosporine regimen. After 14 days of St. John's wort, dose-corrected cyclosporine area-under-curve (AUC), maximum concentration (Cmax), and minimum concentration (Cmin) decreased by 46%, 42%, and 41%, respectively. Mean cyclosporine dose increased from 2.7 mg/kg/day at 4.2 mg/kg/day at the end of the study. Subjects required their first cyclosporine dosage adjustment at Day 3. There are several case reports of decreased cyclosporine with concurrent carbamazepine, phenobarbital, and St. John's wort. In healthy subjects, concurrent use of rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 64% and 58%, respectively. Increasing the dosage of everolimus to 20 mg daily in patients taking a strong inducer of CYP3A4 is expected to increase the AUC of everolimus to levels seen without a concurrent inducer; however, there are no clinical data available with this dosage in patients receiving strong CYP3A4 inducers. In an open-label clinical trial, 10 male patients received ridaforolimus (40 mg daily, days 1 and 14) and rifampin (600 mg daily, days 1-21). Administration of rifampin resulted in a reduction in the mean whole-blood concentration of ridaforolimus (AUC-GMR 0.57, Cmax- GMR 0.66). The mean whole-blood concentration of ridaforolimus increased 1.5-fold following ketoconazole administration. In a study in 14 healthy subjects, pretreatment with rifampin (600 mg daily for 14 days) decreased the AUC and Cmax of a single dose of sirolimus (20 mg) by 82% and 71%, respectively. The oral clearance of sirolimus increased by 5.5-fold. There are case report of decreased sirolimus levels with concurrent phenytoin and rifampin. A study in six healthy subjects examined the effects of rifampin on single doses of oral (0.1 mg/kg) and intravenous (0.025 mg/kg/4 hours) tacrolimus. Rifampin increased tacrolimus clearance by 47% and decreased tacrolimus bioavailability by 51%. In a study in 10 healthy subjects, pretreatment with St. John's wort (300 mg 3 times daily for 18 days) decreased the AUC of a single dose of tacrolimus (0.1 mg/kg) by 35.3%. Tacrolimus apparent oral clearance and volume of distribution increased by 68% and 53%, respectively. In a study in 10 renal transplant patients, concurrent St. John's wort (600 mg daily) for 2 weeks increased tacrolimus dose requirements from a baseline of 4.5 mg/day to 8.0 mg/day. Dose-correct tacrolimus AUC decreased by 57.8%. There have been several case reports of decreased tacrolimus levels with concurrent carbamazepine, phenobarbital, phenytoin, rifampin, and St. John's wort. Phenobarbital and phenytoin have been used successfully to treat tacrolimus overdose. Concurrent rifampin had no significant effects on the AUC or Cmax of temsirolimus; however, sirolimus AUC and Cmax decreased by 56% and 65%, respectively. A dosage adjustment to 50 mg/week of temsirolimus in the presence of strong CYP3A4 inducers is predicted to adjust levels to those seen without inducers; however, there are no clinical data in patients using this dose. There is a case report of decreased temsirolimus effectiveness with concurrent rifampin.

Strong Cyp3a4 Inducers; Rifabutin/Larotrectinib

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

MECHANISM OF ACTION: Strong inducers of CYP3A4 and rifabutin may increase the metabolism of larotrectinib.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 or rifabutin may result in decreased levels and effectiveness of larotrectinib.(1,2)

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 larotrectinib states that the concurrent use of strong CYP3A4 inducers should be avoided, and that alternative treatments with less CYP3A4 induction should be considered.(1,2) The Canadian manufacturer includes rifabutin on its list of CYP3A4 inducers that should be avoided.(2) If coadministration of a strong 3A4 inducer cannot be avoided, double the larotrectinib dose. After the strong 3A4 inducer has been discontinued for 3 to 5 elimination half-lives, resume the larotrectinib dose at the dose taken prior to initiating the 3A4 inducer.(1,2)

DISCUSSION: In a study with healthy subjects, co-administration of rifampin (strong 3A4 inducer) with a single dose of larotrectinib (100 mg), decreased larotrectinib area-under-curve (AUC) by 81% and maximum concentration (Cmax) by 71%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(3-4)

Strong Cyp3a4 Inducers; Rifabutin/Vemurafenib

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

MECHANISM OF ACTION: Vemurafenib is a substrate of CYP3A4. Strong inducers of CYP3A4 and rifabutin may increase the metabolism of vemurafenib.(1-3)

CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 or rifabutin may result in decreased levels and effectiveness of vemurafenib.(1-3)

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 vemurafenib states to avoid concurrent use with strong CYP3A4 inducers and replace these drugs with alternative drugs when possible.(1-3) The Canadian and UK manufacturers include rifabutin on their lists of CYP3A4 inducers that are to be avoided.(2,3) If concurrent administration with a strong CYP3A4 inducer is unavoidable, increase the dose of vemurafenib by 240 mg (one tablet) as tolerated.(1) If concurrent use of a strong CYP3A4 inducer is discontinued, allow a 2 week period to lapse and then resume the dose of vemurafenib that was taken prior to initiation of the strong CYP3A4 inducer.(1)

DISCUSSION: In a study in healthy subjects, coadministration of single dose vemurafenib 960 mg with rifampin (600 mg daily, a strong CYP3A inducer) decreased vemurafenib area-under-curve (AUC) by 40% (90% CI: 24%, 53%) with no effect on maximum concentration (Cmax), when compared to vemurafenib alone.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(4-5)

Strong Or Moderate Cyp3a4 Inducers/Ganaxolone

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

MECHANISM OF ACTION: Ganaxolone is a substrate of CYP3A4. Strong or moderate inducers of CYP3A4 may induce the metabolism of ganaxolone.(1)

CLINICAL EFFECTS: The concurrent administration of strong or moderate CYP3A4 inducers may result in decreased levels and effectiveness of ganaxolone.(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 ganaxolone states that concurrent use with strong or moderate CYP3A4 inducers should be avoided. If concurrent use is unavoidable, consider increasing the dose of ganaxolone. Do not exceed the recommended maximum daily dose.(1) In patients who are stable on ganaxolone and are initiated on anticonvulsants that are CYP3A4 inducers, consider increasing the dose of ganaxolone. Do not exceed the recommended maximum daily dose.(1)

DISCUSSION: Co-administration of rifampin, a strong CYP3A4 inducer, decreased the ganaxolone concentration maximum (Cmax) by 57% and area-under-curve (AUC) by 68%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2-3)

Strong Or Moderate Cyp3a4 Inducers/Simeprevir

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

MECHANISM OF ACTION: Strong or moderate inducers of CYP3A4 may induce the metabolism of simeprevir.(1)

CLINICAL EFFECTS: Concurrent or recent use of strong or moderate CYP3A4 inducers may lower simeprevir minimum concentrations (Cmin) leading to a loss of virologic response to simeprevir.(1)

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

PATIENT MANAGEMENT: The US manufacturer of simeprevir states that concurrent administration of strong or moderate inducers of CYP3A4 is not recommended due risk for simeprevir treatment failure.(1)

DISCUSSION: In a study in 18 subjects, rifampin (600 mg daily for 7 days) decreased the area-under-curve (AUC) and Cmin of simeprevir (200 mg daily for 7 days) by 48% and 92%, respectively. The simeprevir maximum concentration (Cmax) increased 1.31-fold.(1) Strong and moderate inducers of CYP3A4 linked to this monograph include apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate, dabrafenib, dexamethasone, elagolix, encorafenib, enzalutamide, fosphenytoin, ivosidenib, fexinidazole, lesinurad, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, modafinil, nafcillin, oxcarbazepine, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifampin, rifabutin, rifapentine, St. John's wort, sotorasib, telotristat, and tovorafenib.(1-3)

Strong P-Gp Or Cyp3a4 Inducer/Linagliptin

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

MECHANISM OF ACTION: Strong P-gp or CYP3A4 inducers may increase the metabolism of linagliptin.(1)

CLINICAL EFFECTS: Concurrent or recent use of strong P-gp or CYP3A4 inducers may result in decreased levels and effectiveness of linagliptin.(1)

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

PATIENT MANAGEMENT: If possible, use an alternative agent to strong P-gp or CYP3A4 inducers in patients maintained on linagliptin. If concurrent therapy is required, patients may need adjustment to their diabetes therapy, including replacement of linagliptin.(1)

DISCUSSION: Concurrent rifampin (600 mg daily) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of linagliptin (5 mg daily) by 40% and 44%, respectively.(1) Strong P-gp or CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, efavirenz, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lorlatinib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(2)

Strong; Selected Moderate Cyp2c19 Inhibitors/Clobazam

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

MECHANISM OF ACTION: Clobazam's active metabolite, N-desmethylclobazam, is metabolized by the CYP2C19 isoenzyme.(1) The FDA categorizes N-desmethylclobazam as a sensitive substrate for CYP2C19. Sensitive substrates are drugs whose plasma area-under-curve (AUC) have been shown to increase 5-fold or higher when co-administered with a strong inhibitor of the enzyme.(2)

CLINICAL EFFECTS: Concurrent use of a strong or selected moderate inhibitor of CYP2C19 may result in elevated levels of and toxicity from the active metabolite of clobazam, including profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The dosage of clobazam may need to be adjusted when initiating or discontinuing a strong or selected moderate inhibitor of CYP2C19.(1) When initiating a strong or selected moderate inhibitor of CYP2C19 in a patient maintained on clobazam, monitor closely for increased effects from clobazam and adjust dose accordingly.(1) If possible, use an alternative treatment which does not inhibit CYP2C19. When initiating clobazam in a patient maintained on a strong or moderate inhibitor of CYP2C19, it would be prudent to follow the manufacturer's recommendations for dosage adjustments in patients who are CYP2C19 poor metabolizers. In these patients, consider a starting dose of 5 mg/day and reduce weekly dosage adjustments to half the normal increase. Based on clinical response, the dosage may be titrated to normal dosage levels based on weight group at Day 21.(1)

DISCUSSION: The active metabolite of clobazam, N-desmethylclobazam, is metabolized by CYP2C19. Levels of N-desmethylclobazam are 3-5 times higher in poor metabolizers of CYP2C19 and 2 times higher in intermediate metabolizers of CYP2C19. Thus, strong and moderate inhibitors of CYP2C19 are expected to result in a 3 to 5-fold increase in levels of N-desmethylclobazam as well.(1) Strong and selected moderate inhibitors of CYP2C19 include: camizestrant, esomeprazole, fluconazole, fluvoxamine, omeprazole, stiripentol, and ticlopidine.(2) Esomeprazole and omeprazole are irreversible inhibitors of CYP2C19. Although intermittent use may lead to moderate CYP2C19 inhibition, routine use may lead to inactivation of all available CYP2C19, converting patient to the CYP2C19 poor metabolizer phenotype.(3) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Agents Affecting Gastric Ph/Itraconazole; Ketoconazole

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Antacids, buffers in didanosine products, H2 antagonists, and proton-pump inhibitors increase the stomach pH. Quinapril tablets may contain a high percentage of magnesium. Since some orally administered azole antifungal agents require an acidic medium for optimal absorption, agents may decrease the absorption of azole antifungal agents.

CLINICAL EFFECTS: Simultaneous administration of an antacid, buffered didanosine, a H2 antagonist, or a proton-pump inhibitor may result in decreased therapeutic effects of the azole antifungal.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If the concurrent administration of these two agents cannot be avoided, consider administering two capsules of glutamic acid hydrochloride 15 minutes before administering the antifungal and separate the administration times of the antifungal and the agent affecting gastric pH by at least two hours.

DISCUSSION: Itraconazole, ketoconazole, and posaconazole require an acidic medium for predictable dissolution and absorption decreases as pH increases and proton pump inhibitors are expected to decrease their absorption.(1-4) In a study in 11 healthy subjects, omeprazole (40 mg daily) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of itraconazole (200 mg single dose) by 66% and 64%, respectively.(5) In a study in 15 healthy subjects, omeprazole (40 mg daily) had no effect on the pharmacokinetics of itraconazole solution.(6) In a study in 9 healthy subjects, omeprazole (60 mg) decreased the AUC of ketoconazole (200 mg single dose) by 83.4% compared to control (ketoconazole alone). Administration of Coca-Cola (240 ml) with ketoconazole and omeprazole raised ketoconazole AUC to 65% of control values.(7) Omeprazole has been shown to have no significant effect on the absorption of fluconazole(8) or voriconazole.(9) Case reports and in-vivo studies have documented significant decreases in ketoconazole levels during concurrent therapy with H-2 antagonists, including cimetidine and ranitidine. Concurrent administration of itraconazole and famotidine resulted in a significant decrease in itraconazole levels, but no significant changes in famotidine levels. An interaction should be expected to occur between both ketoconazole or itraconazole and the other H-2 antagonists.(10-14) In randomized, open-labeled, cross-over study in 12 healthy subjects, simultaneous administration of an antacid decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of itraconazole (200 mg) by 66% and 70%, respectively. Time to Cmax (Tmax) increased by 70%.(15) This interaction has also been reported in a case report.(16) In a study in 3 subjects, simultaneous administration of a combination aluminum hydroxide/magnesium hydroxide (30 ml) decreased the AUC of a single dose of ketoconazole (200 mg) by 41%.(172) In a case report, a patient receiving concurrent ketoconazole with aluminum hydroxide, cimetidine, and sodium bicarbonate did not respond to therapy until cimetidine was discontinued and the administration time of aluminum hydroxide and cimetidine was changed to 2 hours after ketoconazole. In a follow-up study in 2 subjects, concurrent cimetidine and sodium hydroxide lowered ketoconazole levels.(18) In a study in 14 subjects, simultaneous administration of aluminum hydroxide/magnesium hydroxide (20 ml, 1800 mg/1200 mg) had no significant effects on fluconazole pharmacokinetics.(3) In a randomized, open-label, cross-over study in 6 subjects, simultaneous administration of itraconazole with buffered didanosine tablets resulted in undetectable levels of itraconazole.(19) In a randomized cross-over study in 12 HIV-positive subjects, administration of buffered didanosine tablets 2 hours after ketoconazole had no effects on ketoconazole levels.(20) In a randomized, cross-over, open-label study in 24 healthy subjects, simultaneous administration of enteric-coated didanosine had no effect on ketoconazole pharmacokinetics.(21) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Amoxicillin, Ampicillin, Bendamustine/Allopurinol

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown. Allopurinol, amoxicillin, ampicillin, and bendamustine have been documented to cause cases of Stevens-Johnson syndrome (SJS), Toxic epidermal necrolysis (TEN), and Drug reaction with eosinophilia and systemic symptoms (DRESS).(1)

CLINICAL EFFECTS: Concurrent administration of allopurinol with amoxicillin, ampicillin or bendamustine may result in an increased incidence of rash which may be severe.

PREDISPOSING FACTORS: Patients who are HLA-B*58:01 positive may be at increased risk.

PATIENT MANAGEMENT: Consider an alternative to amoxicillin, ampicillin, or bendamustine in patients with a history of serious skin rashes, such as SJS, TEN, or DRESS. Discontinue allopurinol at the first appearance of skin rash or other signs which may indicate a hypersensitivity reaction when used with amoxicillin or ampicillin or bendamustine. Instruct patients to seek medical attention for any peeling skin rash or blisters.(1)

DISCUSSION: In the Boston Collaborative Drug Surveillance Program, drug rash was seen in 22.4% of 67 hospitalized patients (relative risk 3.0) receiving concurrent allopurinol and ampicillin compared to 7.5% of 1257 patients receiving only ampicillin and 2.1% of 283 patients rceiving only allopurinol.(4) A hospital drug monitoring program found the observed risk of developing an exanthema with concurrent use is as follows: aminopenicillin without allopurinol 10.1%, aminopenicillin combined with allopurinol 7.2%, allopurinol without aminopenicillin 3.0%, or neither of the two drugs 1.5%.(6) A case-control study did not find a statistically significant increased risk of SJS with concurrent use of allopurinol and amoxicillin or ampicillin (allopurinol alone 4.4% vs. with amoxicillin 6.8%; allopurinol alone 0.1% vs. with ampicillin 2.7% at 1 month)(allopurinol alone 4.4% vs. with amoxicillin 5.7% or allopurinol alone 0.2% vs. with ampicillin 2.9% at 3 months).(8) In a retrospective study looking at mortality data, records were screened for administration of high risk drugs associated with SJS. Allopurinol and ampicillin was one of the drug combinations listed as contributing to mortality in patients (p = 0.049).(9)

Esomeprazole; Omeprazole/Carbamazepine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Esomeprazole and omeprazole are primarily metabolized by CYP2C19. CYP3A4 plays a smaller role in metabolism.(1,2) Carbamazepine is a strong inducer of CYP2C19 and CYP3A4.(2) Esomeprazole and omeprazole are weak CYP3A4 inhibitors and may also affect the metabolism of carbamazepine by CYP3A4.(2)

CLINICAL EFFECTS: Concurrent use of agents which induce both CYP2C19 and CYP3A4 decrease systemic exposure and may result in decreased effectiveness of esomeprazole and omeprazole. Concurrent use of esomeprazole or omeprazole with carbamazepine may increase systemic exposure and may result in increased toxicity of carbamazepine.(1-8)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with carbamazepine for reduced proton pump inhibitor (PPI) effectiveness. Although specific dosing recommendations are not available, a higher dose of esomeprazole or omeprazole may be considered to maintain PPI efficacy. Monitor patients receiving concurrent therapy for increased carbamazepine effects. Therapeutic drug monitoring should be completed routinely when carbamazepine is coadministered with esomeprazole or omeprazole.(7,8)

DISCUSSION: In an interaction study, omeprazole increased the maximum concentration (Cmax), area-under-curve (AUC) and elimination half-life (t1/2) of carbamazepine. The effect of carbamazepine on omeprazole was not studied in these trials (3,4) or in other investigations. The effects of other CYP2C19 inducers on the pharmacokinetics of omeprazole have been reported. In an interaction study, subjects with prostate cancer received omeprazole before and after enzalutamide 160 mg daily (an inducer of CYP2C19 and CYP3A4) for at least 55 days. Enzalutamide decreased omeprazole AUC by 70.5%.(2,5) In an interaction study, rifampin 600 mg daily (an inducer of CYP2C19 and CYP3A4) for 7 days decreased omeprazole AUC by 89.5%.(2,6) In an interaction study, St. John's wort (an inducer of CYP2C19 and CYP3A4) decreased the Cmax and AUC of omeprazole by 37.5% and 49.6%, respectively. The Cmax and AUC of omeprazole sulfone (via CYP2C19) increased by 160.3% and 136.6%, respectively. The Cmax and AUC of 5-hydroxyomeprazole (via CYP3A4) increased by 38.1% and 37.2%, respectively.(7,8)

H2 Antagonists; Proton Pump Inhibitors/Amphetamines

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: H2 antagonists and proton pump inhibitors (PPIs) may alter the timing of absorption of amphetamines.

CLINICAL EFFECTS: Concurrent use of amphetamines and H2 antagonists or PPIs may result in an increased absorption rate and a change in timing of peak amphetamine levels.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer states that patients receiving concurrent amphetamines and H2 antagonists or PPIs should be monitored for changes in the timing and clinical effects of amphetamines.(1) Monitor patients receiving concurrent therapy for changes in amphetamine effectiveness and side effects. The Canadian manufacturer states that concurrent use of proton pump inhibitors and amphetamines should be avoided.(3)

DISCUSSION: During concurrent use of a proton pump inhibitor, the median time to maximum concentration (Tmax) of Adderall XR decreased from 5 hours to 2.75 hours.(3) In a 4-way crossover study in healthy subjects, omeprazole had no effect on the total exposure a single dose of mixed amphetamine salts (20 mg); however median Tmax decreased from 5 hours to 2.75 hours. Approximately 50% of subjects had a decrease in Tmax of equal to or greater than 1 hour.(4)

Moderate And Weak Cyp3a4 Inducers/Ubrogepant

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate or weak CYP3A4 inducers may induce the metabolism of ubrogepant.(1)

CLINICAL EFFECTS: Concurrent use of a moderate or weak CYP3A4 inducer may result in decreased levels and effectiveness of ubrogepant.(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 recommends a dosage adjustment of ubrogepant when coadministered with moderate or weak CYP3A4 inducers. Initial dose of ubrogepant should be 100 mg. If a second dose is needed, the dose of ubrogepant should be 100 mg.(1)

DISCUSSION: Coadministration of ubrogepant with rifampin, a strong CYP3A4 inducer, resulted in an 80% reduction in ubrogepant exposure. No dedicated drug interaction studies were conducted to assess concomitant use with moderate or weak CYP3A4 inducers. Dose adjustment for concomitant use of ubrogepant with moderate or weak CYP3A4 inducers is recommended based on a conservative prediction of 50% reduction in exposure of ubrogepant.(1) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, dexamethasone, dicloxacillin, echinacea, elafibranor, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, meropenem-vaborbactam, methylprednisolone, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, relugolix, repotrectinib, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)

Moderate Cyp3a4 Inducers/Aficamten

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Aficamten is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of aficamten.(1)

CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may decrease the levels and effectiveness of aficamten and increase the risk of developing heart failure due to systolic dysfunction.(1)

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

PATIENT MANAGEMENT: In patients who are on stable concurrent therapy with aficamten and a moderate to strong CYP3A4 inducer, reduce the dose of aficamten when discontinuing the inducer as follows: -If the current dose is 20 mg daily, reduce to 10 mg daily. -If the current dose is 15 mg daily, reduce to 5 mg daily. -If the current dose is 10 mg daily, reduce to 5 mg daily. -If the current dose is 5 mg daily, maintain 5 mg daily. Assess LVEF 2 to 8 weeks after discontinuation of such inducers and adjust the dose of aficamten accordingly.(1)

DISCUSSION: In a study, carbamazepine (moderate to strong CYP3A4 inducer, weak CYP2C9 inducer) decreased aficamten's area-under-curve (AUC) 51%.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Crinecerfont

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of crinecerfont.(1)

CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may reduce the clinical effectiveness of crinecerfont.(1)

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

PATIENT MANAGEMENT: The US manufacturer of crinecerfont states that concurrent use of moderate CYP3A4 inducers requires a dose adjustment of crinecerfont. Increase the evening dose of crinecerfont by 2-fold. Do not increase the morning dose. In adults, increase the dosage of crinecerfont to 100 mg in the morning and 200 mg in the evening. In pediatric patients 4 years and older weighing: - 10 kg to <20 kg: increase the crinecerfont dosage to 25 mg in the morning and 50 mg in the evening, - 20 kg to <55 kg: increase the crinecerfont dosage to 50 mg in the morning and 100 mg in the evening, - >=55 kg: increase the crinecerfont dosage to 100 mg in the morning and 200 mg in the evening.(1)

DISCUSSION: In a study, concomitant use of rifampin (strong CYP3A4 inducer) decreased crinecerfont maximum concentration (Cmax) by 23% and area-under-curve (AUC) by 62%.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Daclatasvir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of daclatasvir.(1)

CLINICAL EFFECTS: Concurrent use of a moderate inducer of CYP3A4 without a dosage adjustment of daclatasvir is expected to reduce levels and effectiveness of daclatasvir.(1)

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

PATIENT MANAGEMENT: The dose of daclatasvir should be increased to 90 mg once daily in patients receiving moderate inducers of CYP3A4.(1)

DISCUSSION: Efavirenz (600 mg daily) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of daclatasvir by 17%, 32%, and 59%, respectively.(1) Moderate inducers of CYP3A4 include belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(1-3)

Moderate Cyp3a4 Inducers/Daraxonrasib (>= 400 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Daraxonrasib is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of daraxonrasib.(1)

CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of daraxonrasib.(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 daraxonrasib states that concomitant use of moderate CYP3A4 inducers requires a dose increase of daraxonrasib to 400 mg once daily.(1)

DISCUSSION: In a clinical study, daraxonrasib area-under-curve (AUC) is predicted to decrease by 50-84% with concomitant use of efavirenz 600 mg once daily and modafinil 400 mg once daily (moderate CYP3A4 inducers).(1) Moderate CYP3A4 inducers linked to this monograph include: asunaprevir, belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lopinavir, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Lenacapavir (Prep)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Agents that induce the CYP3A4 isoenzyme may accelerate the metabolism of lenacapavir.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inducers may decrease the levels and effectiveness of lenacapavir.(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 lenacapavir for PrEP states that concurrent use of moderate CYP3A inducers requires supplemental doses of lenacapavir. Moderate CYP3A inducers may be initiated anytime after the first dose of lenacapavir. Recommendations for supplemental doses of lenacapavir state: -On the day moderate CYP3A inducer is initiated: Supplement with 463.5 mg subcutaneously. -If the moderate CYP3A inducer is coadministered longer than 6 months: Every 6 months after CYP3A inducer is initiated, supplement lenacapavir as above. After a moderate CYP3A inducer is stopped, continue the scheduled continuation doses of lenacapavir every 6 months.(1)

DISCUSSION: In a study, efavirenz 600 mg once daily (inducer of CYP3A4 [moderate] and P-glycoprotein) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of lenacapavir by 36% and 56%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: barbiturates, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad, lorlatinib, modafinil, nafcillin, nevirapine, oxcarbazepine, phenobarbital, primidone, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Paltusotine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate CYP3A4 inducers may induce the metabolism of paltusotine.(1)

CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may alter the clinical effectiveness of paltusotine.(1)

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

PATIENT MANAGEMENT: Patients taking moderate CYP3A4 inducers may require an increased dosage of paltusotine.(1) The manufacturer of paltusotine states do not exceed two-fold the paltusotine dosage prior to concomitant use or 120 mg daily, whichever is less.(1) Monitor patients receiving concurrent therapy for reduced efficacy.

DISCUSSION: Paltusotine is metabolized by CYP3A4.(1) Moderate CYP3A4 inducers such as efavirenz are predicted to decrease concentration maximum (Cmax) and area-under-curve (AUC) of paltusotine approximately 5% and 30%, respectively.(1) In an interaction study, paltusotine concentration maximum (Cmax) and area-under-curve (AUC) decreased by 44% and 70%, respectively, following concomitant administration of carbamazepine (strong CYP3A inducer).(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Rolapitant

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Rolapitant is metabolized primarily by CYP3A4. Moderate inducers of CYP3A4 may increase the metabolism and clearance of rolapitant via CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use with moderate inducers of CYP3A4 may result in significantly decreased levels and effectiveness of rolapitant.(1)

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

PATIENT MANAGEMENT: The UK manufacturer of rolapitant states that rolapitant is not recommended in patients already taking moderate CYP3A4 inducers.(1) If concomitant use is warranted, monitor the patient for decreased antiemetic efficacy. When possible and clinically appropriate, consider use of an alternative antiemetic or alternatives to the moderate CYP3A4 inducer.

DISCUSSION: The effect of moderate CYP3A4 inducers on rolapitant has not been studied. The UK manufacturer of rolapitant does not recommend the concurrent use of rolapitant with moderate CYP3A4 inducers. Rifampin (600 mg daily for 14 days), a strong CYP3A4 inducer, decreased the Cmax and AUC of a single dose of rolapitant (180 mg on Day 7) by 30% and 85%, respectively. The half-life of rolapitant decreased from 176 hours to 41 hours.(3) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Moderate Cyp3a4 Inducers/Tavapadon

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of tavapadon.(1)

CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of tavapadon.(1)

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

PATIENT MANAGEMENT: For patients initiating tavapadon who are already taking a moderate CYP3A4 inducer, the following tavapadon titration regimen is recommended: - Days 1 to 4: 0.25 mg twice daily - Days 5 to 8: 0.5 mg twice daily - Days 9 to 12: 0.75 mg twice daily - Days 13 to 16: 1 mg twice daily - Days 17 to 20: 1.5 mg twice daily - Days 21 to 24: 2.25 mg twice daily - Days 25 to 40: 3 mg twice daily - Days 41 and after: 5 mg twice daily If needed, based on clinical response and tolerability, the maintenance dosage may be increased to 5 mg three times a day. If further escalation is needed, the dose may be increased by 5 mg every 15 days administered in divided doses (either twice a day or three times a day), to the maximum recommended daily dosage of 45 mg daily (15 mg three times daily). For patients on tavapadon maintenance dosage who are initiating a moderate CYP3A4 inducer, the following dose modifications are recommended: - Days 1 to 7 of concomitant use: continue the current maintenance dosage of tavapadon (5 mg, 10 mg, or 15 mg once daily) - Day 8 and thereafter during concomitant use: increase the frequency of the maintenance dosage of tavapadon to twice daily. If needed, based on clinical response and tolerability, the maintenance dosage can be increased to three times daily. Upon discontinuation of moderate CYP3A4 inducers, gradually reduce the tavapadon dosage to once daily. Monitor patients for clinical response and tolerability.(1)

DISCUSSION: Concurrent administration of efavirenz (600 mg), a moderate CYP3A4 inducer, with 15 mg tavapadon is predicted to decrease the area-under-the-curve (AUC) and maximum concentration (Cmax) by 70% and 58%.(1) When a moderate CYP3A4 inducer is initiated during maintenance therapy (5, 10, or 15 mg doses) of tavapadon, with increased dosing frequency from once daily to three times daily, steady state AUC and Cmax are not predicted to differ significantly relative to once daily dosing without an inducer.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Omepraz(<20Mg);Lansopraz(<20 Mg);Pantopraz(<40Mg)/Pritelivir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The aqueous solubility of pritelivir is pH dependent. Higher gastric pH leads to lower solubility which may reduce pritelivir absorption.(1)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) may reduce the bioavailability of pritelivir leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant use of omeprazole or lansoprazole at daily doses above 20 mg with pritelivir.(1) Avoid concomitant use of pantoprazole at daily doses above 40 mg with pritelivir.(1)

DISCUSSION: Coadministration of a single oral dose of 100 mg pritelivir (on Day 1) with esomeprazole 40 mg once daily (from day -3 to Day 1; 4 days total) decreased pritelivir's maximum concentration (Cmax) by 76% and area-under-curve (AUC) by 59% compared to pritelivir administered alone.(1)

Omeprazole; Pantoprazole/Voriconazole

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Voriconazole is a strong CYP3A4 inhibitor and a moderate inhibitor of CYP2C19. Omeprazole and pantoprazole are predominantly metabolized by CYP2C19 but are also a substrate of CYP3A4. Voriconazole may inhibit the metabolism of omeprazole and pantoprazole by CYP2C19 and CYP3A4.(1-3)

CLINICAL EFFECTS: The concurrent use of voriconazole and either omeprazole or pantoprazole may result in elevated levels of omeprazole and pantoprazole, and increase the risk of proton pump inhibitor (PPI) related side effects including gastroenteritis, Clostridioides difficile associated diarrhea, fractures, hypomagnesemia and vitamin B12 deficiency.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of voriconazole states that when voriconazole is initiated in patients receiving dosages of omeprazole of 40 mg/day or greater, the dosage of omeprazole should be reduced by one-half.(1) The manufacturer of voriconazole states concurrent use of other proton pump inhibitors (PPIs) that are CYP2C19 substrates such as pantoprazole may also require a dose adjustment.(1)

DISCUSSION: In healthy subjects, concurrent voriconazole (400 mg every 12 hours Day 1, 200 mg Days 2-7) with omeprazole (40 mg daily for Days 1-7) increased the maximum concentration (Cmax) and area-under-curve (AUC) of omeprazole by 2-fold and 4-fold, respectively. Therefore, the manufacturer of voriconazole recommends that when voriconazole is initiated in patients receiving dosages of omeprazole of 40 mg/day or greater, the dosage of omeprazole should be reduced by one-half.(1) In healthy subjects, concurrent voriconazole (400 mg every 12 hours Day 1, 200 mg Days 2-10) with omeprazole (40 mg once daily) increased the Cmax and AUC of voriconazole by 15% and 40%, respectively. The manufacturer of voriconazole does not recommend a dosage adjustment of voriconazole when administered with omeprazole.(1)

P-Glycoprotein (P-Gp) Inducers; Phenobarbital/Afatinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Afatinib is a substrate of the intestinal efflux transporter P-glycoprotein (P-gp). Apalutamide, carbamazepine, efavirenz, lorlatinib, phenytoin, rifabutin, rifampin, rifapentine, and St. John's wort induce production of P-gp which may lead to decreased exposure to afatinib.(1,2) Phenobarbital may also induce the metabolism of afatinib.(1) Primidone is metabolized to phenobarbital.

CLINICAL EFFECTS: Concurrent or recent use of P-glycoprotein inducers (apalutamide, carbamazepine, efavirenz, lorlatinib, phenytoin, rifabutin, rifampin, rifapentine, or St. John's wort), phenobarbital, or primidone may result in decreased levels and effectiveness of afatinib.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of afatinib recommends an increase of afatinib dose by 10 mg per day as tolerated in patients receiving chronic therapy with a P-gp inducer or phenobarbital.(1) Onset of induction is gradual and maximal induction may be delayed for many days or longer, depending upon the inducing agent and dose. If the P-gp inducer, phenobarbital, or primidone is stopped, the manufacturer of afatinib recommends resumption of previous afatinib dose 2 to 3 days after discontinuation of the inducing agent.(1)

DISCUSSION: In a drug interaction study, co-administration of rifampin 600 mg once daily for 7 days decreased afatinib exposure 34%.(1) P-gp inducers include apalutamide, carbamazepine, efavirenz, lorlatinib, phenytoin, rifabutin, rifampin, rifapentine, and St. John's wort.(1,2) Based on 2 case reports(3,4) and in vitro studies,(5,6) the manufacturer of afatinib also includes phenobarbital as a P-gp inducer.(1)

Penicillins/Oral Contraceptives

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Estrogens and progesterones are extensively excreted in bile, principally as glycuronide conjugates. Subsequently, they undergo enterohepatic circulation where bacterial hydrolysis occurs, allowing for reabsorption of the oral contraceptives through the bowel wall and eventual urinary excretion. Treatment with antibiotics destroys the gut flora and prevents steroid reabsorption, resulting in lower than normal concentrations of the contraceptive and excretion via the feces rather than the urine.

CLINICAL EFFECTS: May observe reduced pharmacologic effects of oral contraceptives with resultant breakthrough bleeding and pregnancy. Reduced effects may be seen for several days after discontinuation of antibiotic therapy.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Current guidelines suggest that additional precautions are not necessary when non-enzyme inducing antibiotics are used concurrently with hormonal contraceptives; however, some patients may still prefer to use an additional method of contraception.

DISCUSSION: Evidence for this interaction is limited and conflicting; however, the CDC and the Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness Unit no longer recommend use of a backup contraceptive method during use of a non-enzyme inducing antibiotic. Reports of breakthrough bleeding and loss of contraceptive protection leading to unwanted pregnancies have occurred in women taking oral contraceptive agents who received concurrent ampicillin, amoxicillin, penicillin G, or oxacillin. Several studies have shown that the administration of ampicillin or penicillin to pregnant and nonpregnant women resulted in lowered urinary estrogen excretion, in some women as soon as three days after ampicillin therapy began. However in one small prospective study, plasma ethinyl estradiol concentrations showed a tendency to decrease during ampicillin administration on the third, fourth, and fifth morning of ampicillin administration, but were never lower than pretreatment values. In another small prospective study of women taking low dose combination contraceptives, concurrent ampicillin therapy neither altered the plasma levels nor the AUC of norethisterone and ethinyl estradiol. In addition, progesterone levels were in an anovulatory range. In another prospective study of 13 women taking long term oral contraceptive steroids, concurrent ampicillin was not associated with any significant changes in plasma concentrations of ethinyl estradiol, levonorgestrel, follicle stimulating hormone or progesterone, although lower concentrations of ethinyl estradiol were noted in two women.

Proton Pump Inhibitors/Belumosudil

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Belumosudil is best absorbed in an acidic environment. Proton pump inhibitors (PPIs) decrease gastric acidity and may decrease belumosudil absorption and systemic concentrations.(1)

CLINICAL EFFECTS: Coadministration of PPIs with belumosudil decreases systemic concentrations of belumosudil, which may decrease the efficacy of belumosudil.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Increase the dosage of belumosudil to 200 mg twice daily when coadministered with PPIs.(1)

DISCUSSION: Coadministration of rabeprazole decreased belumosudil maximum concentration (Cmax) by 87% and area-under-curve (AUC) by 80%, and omeprazole decreased belumosudil Cmax by 68% and AUC by 47% in healthy subjects.(1)

Proton Pump Inhibitors/Belumosudil (400 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Belumosudil is best absorbed in an acidic environment. Proton pump inhibitors (PPIs) decrease gastric acidity and may decrease belumosudil absorption and systemic concentrations.(1)

CLINICAL EFFECTS: Coadministration of PPIs with belumosudil decreases systemic concentrations of belumosudil, which may decrease the efficacy of belumosudil.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Increase the dosage of belumosudil to 200 mg twice daily when coadministered with PPIs.(1)

DISCUSSION: Coadministration of rabeprazole decreased belumosudil maximum concentration (Cmax) by 87% and area-under-curve (AUC) by 80%, and omeprazole decreased belumosudil Cmax by 68% and AUC by 47% in healthy subjects.(1)

Proton Pump Inhibitors/Immune Checkpoint Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of this interaction has not been fully investigated. Proposed mechanisms include: 1. Proton pump inhibitor (PPI)-induced changes of the microbiota (dysbiosis) causing resistance to immune checkpoint inhibitors, 2. Co-administration of PPIs with corticosteroids or non steroidal anti-inflammatory drugs (NSAIDs) and immune checkpoint inhibitors resulting in poorer prognosis.(1)

CLINICAL EFFECTS: PPIs may decrease the therapeutic effects of immune checkpoint inhibitors. Several observational studies have shown a reduction in progression free survival (PFS), overall survival (OS), and tumor response in patients on concurrent treatment with immune checkpoint inhibitors and PPIs.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of immune checkpoint inhibitors and PPIs should be approached with caution. Manufacturers of immune checkpoint inhibitors do not provide recommendations on the concurrent use of PPIs. Primary literature on the concurrent use of these agents include recommendations to evaluate the risks and benefits of PPI use and consideration of alternative therapy when possible such as histamine H2-receptor antagonists (H2RAs) or antacids.(1-3)

DISCUSSION: A meta analysis of 23 studies evaluating the impact of acid suppressing therapy on the efficacy of immune checkpoint inhibitors found coadministration of a PPI decreased PFS (HR 1.34 [95% confidence interval (CI), 1.13 to 1.58]) and OS (HR 1.43 [95% CI, 1.21 to 1.69]) compared with patients not treated with PPIs. Furthermore, the meta analysis identified that H2RAs did not affect OS. These results were consistent across cancer types.(1) In another meta analysis of 22 studies (5 prospective and 17 retrospective, n=16,072) evaluating the impact of concomitant medications on survival outcomes in patients treated with systemic therapy for advanced unresectable or metastatic renal cell carcinoma, concomitant use of PPIs (n=3959) was significantly associated with worse OS in patients treated with immune checkpoint inhibitors (HR 1.22, P=0.01).(4) A retrospective analysis of 635 patients treated with immune checkpoint inhibitors found PPI use was associated with significantly decreased OS (9 vs 26.5 months), PFS (3.5 vs. 8 months), and tumor response (61% vs. 72%).(5) Analysis of retrospective data from clinical trials of atezolizumab for urothelial carcinoma and non-small-cell lung cancer, among patients using a PPI within 30 days before or after therapy initiation, OS was significantly worse for patients randomized to treatment with atezolizumab than for patients randomized to chemotherapy.(6,7) A retrospective study of 381 patients treated with immune checkpoint inhibitors found use of acid-suppression therapy (n=168 PPIs, n=37 potassium competitive acid blocker, n=13 H2RAs) was associated with significantly shorter PFS and OS (2.9 vs. 6.2 months and 12.3 vs. 24 months, respectively) compared with patients who did not use acid-suppression therapy. However, when stratified by concomitant use of corticosteroids or NSAIDs, use of acid-suppression therapy was not associated with worse progression-free or overall survival.(8) In a retrospective cohort study of patients with advanced non-small-cell lung cancer treated with pembrolizumab, exposure to PPIs was associated with worse OS (HR, 1.13; 95% CI, 1.10-1.17).(9) Analysis of US and Japanese adverse drug event reporting system databases found administration of immune checkpoint inhibitors and PPIs was associated with an increased risk of adverse events including acute kidney injury (10) and congenital, familial and genetic disorders.(11) In a meta analysis of 14 observational studies, the risk of immune checkpoint inhibitor related AKI (ICI-AKI) in cancer patients concurrently using PPIs was found to be significantly higher (pooled OR of 1.84 [95% CI 1.16-2.90]) in comparison to the overall incidence of AKI from all-causes (1.57 [95% CI 1.02-2.40]).(12) In contrast to these findings, other studies have not found a negative effect on PFS or OS when patients are co-administered PPIs and immune checkpoint inhibitors. In a retrospective study of 159 patients treated with ipilimumab, coadministration of PPIs was associated with increased odds of experiencing a partial or complete response to ipilimumab (OR 3.73 [95% CI, 1.26 to 11.04]).(13) In another retrospective study of 233 patients who received nivolumab or pembrolizumab, use of PPI had no effect on OS (HR 1.2 [95% CI, 0.8-1.9]) or PFS (HR 1.1 [95% CI, 0.8 to 1.5]).(14) A nested case-control study of patients (n=38,930) with cancer who were new PPI or immune checkpoint inhibitor users and had no history of AKI before cohort entry, found the risk of AKI in patients treated with both PPIs and immune checkpoint inhibitors was not higher than then additional or multiplication of the risks in those who were treated with PPIs or immune checkpoint inhibitors alone. The study reinforces the association between PPIs and immune checkpoint inhibitors use and the increased risk of AKI and the need for careful monitoring and evaluation of kidney function when treated with both medicines.(15)

Proton Pump Inhibitors/Methotrexate(Low Strength Inj, Oral)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Proton pump inhibitors(PPIs) may inhibit the active secretion of methotrexate from the kidney via inhibition of the hydrogen-potassium ATPase(1) and may reduce uptake of methotrexate into breast cancer resistance protein via competitive inhibition.(2,3)

CLINICAL EFFECTS: The concurrent use of methotrexate and proton pump inhibitors may result in elevated levels of methotrexate and increased methotrexate-related adverse effects and toxicities, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia.(1-7,9)

PREDISPOSING FACTORS: High dose methotrexate therapy appears to increase the risk for and severity of this interaction.(4,9)

PATIENT MANAGEMENT: Patients receiving concurrent use of methotrexate and proton pump inhibitors should be monitored closely for elevated methotrexate levels and methotrexate toxicity. The US manufacturer of omeprazole states that secretory ability returns gradually over three to five days following discontinuation.(4) This interaction has best described in patients receiving high dose methotrexate for cancer treatment. Therefore, it would seem prudent to discontinue proton pump inhibitors several days prior to high dose methotrexate therapy. The magnitude and frequency of this interaction in patients receiving less than or equal to 15 mg weekly is less clear. While a small study suggested lansoprazole was safe in rheumatoid arthritis patients taking 7.5 - 15 mg weekly(8), at least one case report of PPI associated methotrexate toxicity at a low dose (15 mg IM weekly) has been described.(7)

DISCUSSION: In a clinical trial in 74 patients on high dose (1-5 G/m2) methotrexate therapy, data was examined to determine if proton pump inhibitor (omeprazole, pantoprazole, rabeprazole) use affects methotrexate elimination. Delayed elimination was found to be more frequent in those with co-administration of a proton pump inhibitor (31.7% vs. 13.8%), resulting in higher plasma methotrexate concentrations at 24, 48, and 74 hours. The effect was seen with lansoprazole, omeprazole, pantoprazole, and rabeprazole.(2) There are three case reports(1,5,6) of elevated methotrexate levels or delayed methotrexate elimination resulting from concurrent administration of high dose methotrexate and omeprazole, including one patient(6) that developed severe mucositis. In each case, omeprazole was discontinued and normal methotrexate kinetics were observed on subsequent cycles with no further adverse effects noted. In a case report of a 59 year-old male on low dose (15 mg weekly) methotrexate, administration of pantoprazole (20 mg daily) was found to increase the AUC of the metabolite 7-hydroxymethotrexate by 70%.(7) In a manufacturer sponsored clinical trial, 28 adults with rheumatoid arthritis on low dose (7.5-15 mg weekly) methotrexate were assigned to receive lansoprazole (30 mg daily) and naproxen (500 mg twice daily) on Days 1-7 of therapy. The half life of the metabolite 7-hydroxymethotrexate was prolonged with concurrent administration, but no other statistically significant differences were found in regards to the plasma concentration profiles of methotrexate or 7-hydroxymethotrexate.(8)

Proton Pump Inhibitors/Mycophenolate Mofetil

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown. One theory is that proton pump inhibitors may prevent mycophenolate mofetil from being converted to mycophenolic acid in the gastrointestinal tract.(1-5)

CLINICAL EFFECTS: Concurrent use of proton pump inhibitors (PPIs) may result in decreased mycophenolic acid levels and effects, including increased risk of transplant rejection.

PREDISPOSING FACTORS: Other factors which may affect systemic mycophenolate exposure include renal function, serum albumin, gender, race, the choice of calcineurin inhibitor (CNI), and use of other drugs which inhibit absorption or enterohepatic recirculation of mycophenolate.

PATIENT MANAGEMENT: If concurrent treatment of mycophenolate mofetil and a PPI is needed, evaluate predisposing risk factors (e.g. renal function, gender, race, and presence of other interacting drugs) which may increase or decrease mycophenolate exposure. If a patient is at risk for low mycophenolic acid levels, options may include converting to delayed release mycophenolic acid (mycophenolate sodium) which is not susceptible to this interaction (4,8,9), or monitoring mycophenolic acid levels to assure therapeutic concentrations are attained.

DISCUSSION: A study compared 21 heart transplant patients maintained on mycophenolate mofetil and pantoprazole (40 mg daily) to 12 patients maintained on mycophenolate without pantoprazole. There was no significant difference in mycophenolate dose between the groups. However, mycophenolic acid levels at 30 minutes, 1 hour, 2 hours, and 12 hours were significantly lower in patients who received pantoprazole (63%, 44%, 34%, 52%, respectively). Mycophenolic acid area-under-curve (AUC) and maximum concentration (Cmax) were also significantly lower in patients who received pantoprazole (30% and 78%, respectively). There was a trend for more acute rejection episodes and transplant vasculopathy in patients receiving pantoprazole.(1) A study compared 23 patients with autoimmune diseases maintained on mycophenolate mofetil and pantoprazole (40 mg daily) to 13 patients maintained on mycophenolate without pantoprazole. There was no significant difference in mycophenolate dose between the groups. The AUC and Cmax of mycophenolic acid decreased by 37% and 60%, respectively, in patients treated with pantoprazole. The activity of mycophenolic acid decreased by 42% in patients receiving pantoprazole.(2) In a study in 22 heart transplant patients receiving mycophenolate mofetil (1000 mg twice daily), mycophenolic acid levels at 30 and 60 minutes post-dose were 55% and 37% lower, respectively, when patients were receiving pantoprazole (40 mg daily). The AUC and Cmax of mycophenolic acid were both 41% when patients were receiving pantoprazole. The time to reach Cmax (Tmax) was 29% longer.(3) A study in 12 healthy subjects compared the effects of pantoprazole (40 mg twice daily) on single doses of mycophenolate mofetil (1000 mg) and enteric-coated mycophenolate sodium (720 mg). Pantoprazole decreased the Cmax and AUC of mycophenolic acid following mycophenolate mofetil administration by 57% and 27%, respectively. There were no effects on mycophenolate acid following mycophenolate sodium administration.(4) A study in renal transplant patients, patients receiving mycophenolate mofetil and tacrolimus without PPI therapy (n=22) were compared to patients receiving concurrent mycophenolate mofetil, tacrolimus, and lansoprazole (30 mg, n=22) and patients receiving concurrent mycophenolate mofetil, tacrolimus, and rabeprazole (10 mg, n=17). Mycophenolic acid Cmax, dose-adjusted Cmax, and AUC(0-6h) were significantly lower in patients receiving lansoprazole when compared to patients not receiving PPI therapy. There were no significant differences between patients receiving rabeprazole and those not receiving PPI therapy; however, rabeprazole acid lowering effects are lower than lansoprazole.(5) A cross-sectional, retrospective analysis of renal transplant patients on omeprazole, mycophenolate, and a calcineurin inhibitor found that in the first week post-transplant the mycophenolate active moiety levels were reduced to a point of clinical significance. However, after that first week, the effect seemed to be less clinically significant.(6) In a study of heart transplant patients, use of pantoprazole (20 mg to 80 mg daily) significantly reduced the AUC of mycophenolic acid produced from a mean daily dose of 2.2+/-0.8 mycophenolate mofetil (p=0.02). However, mycophenolic acid minimum concentration (Cmin) was not significantly different.(7) In a study in healthy subjects, the Cmax and AUC of mycophenolic acid were decreased when mycophenolate mofetil was administered with omeprazole (20 mg BID); however, there was no effect on the Cmax or AUC of mycophenolic acid when enteric-coated mycophenolate mofetil was administered with omeprazole.(8) In a study in heart or lung transplant patients, concurrent pantoprazole had no effect on the Cmax, Tmax, or AUC of mycophenolic acid following administration of enteric-coated mycophenolate sodium. Additionally no significant difference of inosine 5?-monophosphate dehydrogenase (IMPDH) activity was seen with EC-mycophenolate given alone or with pantoprazole.(9) In a subanalysis of the CLEAR Study, there were no significant effects of omeprazole or pantoprazole on mycophenolic acid levels in the study group randomized to received intensified dosing with mycophenolate mofetil (1.5 g BID for 5 days, then 1 g BID).(10)

Proton Pump Inhibitors/Palbociclib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of this interaction is not fully understood and may involve dysbiosis or gastric pH changes resulting from proton pump inhibitors (PPIs).(1,2) The aqueous solubility of palbociclib is pH-dependent. Higher gastric pH leads to lower solubility which may reduce palbociclib absorption.(1)

CLINICAL EFFECTS: Coadministration of PPIs may reduce the bioavailability of palbociclib, leading to decreased systemic levels and effectiveness.(1) Although administration of palbociclib with food minimizes the decrease in absorption,(1) retrospective studies and a meta-analysis have found lower survival rates among patients on concurrent PPIs.(2-7)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of palbociclib capsules states that palbociclib should be taken with food, whereas palbociclib tablets may be taken with or without food. There are no constraints on concurrent use of proton pump inhibitors.(1) Given the decreased survival rates observed in patients who received PPIs with palbociclib, the authors of some studies on concurrent use of these agents have made various recommendations, including avoiding PPIs with palbociclib, using ribociclib instead of palbociclib, using low strengths of PPIs, or using H2-antagonists or antacids.(2-7)

DISCUSSION: Palbociclib solubility decreases significantly above pH 4.(1) In a study with healthy volunteers, rabeprazole decreased the maximum concentration (Cmax) and area-under-curve (AUC) of single-dose palbociclib without food by 80% and 62%, respectively. In another study of healthy volunteers in a fed state, rabeprazole decreased Cmax and AUC of single-dose palbociclib by 41% and 13%, respectively.(1) A systematic review and meta-analysis examined studies of HER2-negative, hormone receptor-positive patients with metastatic breast cancer treated with palbociclib or ribociclib with or without concomitant PPIs that reported on survival outcomes. Eight studies consisting of 2,584 patients (830 on PPIs, 1754 not on PPIs) were included. Patients on concurrent PPIs had a significantly higher risk of all-cause mortality (HR, 2.03; 95% CI, 1.49 to 2.77) and disease progression (HR, 1.75; 95% CI, 1.26 to 2.43) compared to patients not on PPIs, though there was a high degree of heterogeneity in disease progression.(2) A retrospective cohort of patients with advanced or metastatic breast cancer treated with palbociclib capsules (344 patients on PPIs, 966 patients not on PPIs) revealed that patients on PPIs had shorter progression-free survival (PFS) (HR 1.76 (95% CI, 1.46-2.13) and lower overall survival (HR, 2.71 [95% CI, 2.07-3.53]).(3) A post-hoc analysis of the phase 2 PARSIFAL trial evaluated PFS in patients on palbociclib capsules. 326 patients were PPI-naive, 64 patients were early users of PPIs (started on PPIs since starting palbociclib), and 91 patients were long-term users of PPIs. PPI use was associated with a shorter PFS (HR in early PPI users 1.5; 95% CI 1.1-2.2; HR in long-term PPI users 1.4; 95% CI 1.1-1.9).(4) A retrospective study of 50 patients with metastatic breast cancer on palbociclib found that concurrent PPI use was associated with a shorter PFS.(5) In an observational study of patients with metastatic breast cancer on palbociclib capsules, PFS was compared between 65 patients on PPIs and 40 patients not on PPIs. On multivariate analysis, PPI usage was an independent predictor of shorter PFS (HR 5.60; 95% confidence interval: 1.98-15.85).(6) A retrospective observational cohort of metastatic breast cancer patients on palbociclib found that patients on concurrent PPIs had a shorter PFS than those not on PPIs (14.0 versus 37.9 months, p < 0.0001).(7) In contrast to these findings, other studies have not found a detrimental effect of PPIs on palbociclib efficacy. A retrospective observational study focused on 112 patients with endocrine-resistant metastatic breast cancer on palbociclib capsules (n=58) and tablets (n=20). There was no difference in PFS in patients on concurrent PPIs compared to those not on PPIs.(8) A study looking at 82 patients with metastatic breast cancer treat 1st line with palbociclib tablets(9) and a retrospective observational study on metastatic breast cancer patients on palbociclib capsules(10) also did not find a significantly different PFS between patients with and without concurrent PPIs.

Proton Pump Inhibitors/Paltusotine (< 60 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The aqueous solubility of paltusotine is pH dependent. Higher gastric pH leads to lower solubility which may reduce paltusotine absorption.(1)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) may reduce the bioavailability of paltusotine, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of paltusotine states that concomitant use of paltusotine with PPIs may require an increased dosage of paltusotine. Patients who are already on paltusotine 60 mg daily should avoid concomitant use with PPIs.(1)

DISCUSSION: In an interaction study, paltusotine area-under-the-curve (AUC) was decreased by 21% with 20 mg dose and 42% with 60 mg dose levels.(1)

Proton Pump Inhibitors/Saquinavir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of this interaction is not clear. Saquinavir is a poorly soluble drug with a low bioavailability. It is possible that proton pump inhibitors (PPIs) induced elevation of gastric pH increases systemic absorption of saquinavir.(1)

CLINICAL EFFECTS: Concurrent use of proton pump inhibitors may lead to elevated saquinavir concentrations and an increased risk for toxicities including gastrointestinal symptoms, hypertriglyceridemia, deep vein thrombosis (DVT) and QT prolongation.(1)

PREDISPOSING FACTORS: The risk of QT prolongation may be increased in patients with congenital long QT syndrome, cardiovascular disease (e.g. heart failure, myocardial infarction), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female sex, advanced age, concurrent use of more than one agent known to cause QT prolongation, and with higher blood concentrations of saquinavir.(2)

PATIENT MANAGEMENT: The manufacturer of saquinavir recommends monitoring for saquinavir toxicities including gastrointestinal symptoms, hypertriglyceridemia, DVT and QT prolongation in patients receiving saquinavir and a PPI. No specific saquinavir dose adjustments are recommended.(1) If a PPI is newly added to existing saquinavir therapy it would be prudent to assure the patient has been evaluated for QT prolongation risk factors and that laboratory tests (e.g. potassium, magnesium, calcium) are normal.

DISCUSSION: A study performed in 19 subjects of concurrent omeprazole 40 mg daily with saquinavir/ritonavir (1000/100 mg twice daily) increased area-under-curve (AUC) and maximum-concentration (Cmax) by 82% and 75%, respectively.(1) Concurrent use of omeprazole 40 mg with saquinavir/ritonavir increased saquinavir AUC, minimum concentration (Cmin), and Cmax by 54%, 73%, and 55%, respectively. Staggered administration of omeprazole 40 mg with saquinavir/ritonavir by 2 hours increased AUC, Cmin, and Cmax by 67%, 97%, and 65%, respectively.(3)

Rifabutin/Clarithromycin; Erythromycin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Clarithromycin and erythromycin inhibit CYP3A4 isoenzymes and may inhibit the CYP3A4 mediated metabolism of rifabutin.(1-5) Rifabutin has been shown to induce CYP3A4 isoenzymes and therefore may accelerate the metabolism of clarithromycin and erythromycin and may decrease the plasma concentrations of both agents.(2,3)

CLINICAL EFFECTS: The clinical effects of clarithromycin or erythromycin may be decreased. Rifabutin plasma levels may be increased possibly leading to toxicity.

PREDISPOSING FACTORS: In patients with hepatic impairment or severe renal impairment, increased rifabutin levels from this interaction may have an even greater impact.

PATIENT MANAGEMENT: The US manufacturer of rifabutin recommends using caution and monitoring for adverse events when rifabutin is given with CYP3A4 inhibitors. Reduce the dose or suspend use of rifabutin if toxicity is suspected.(1) The Australian manufacturer of rifabutin recommends reducing the dose of rifabutin to 300 mg daily when given concomitantly with clarithromycin.(2) The US manufacturer of clarithromycin states the concomitant use of clarithromycin and rifabutin should be approached with caution.(5)

DISCUSSION: Concurrent use of clarithromycin and rifabutin in 12 HIV-infected patients resulted in the rifabutin area-under-curve (AUC) increasing by 75% and the clarithromycin AUC decreasing by 50%.(1) In a study in 34 subjects, rifabutin (300 mg daily) decreased clarithromycin area-under-curve (AUC) by 44%. The AUC of 14-hydroxyclarithromycin was 57% higher.(6) The Australian and U.K. manufacturers of rifabutin have stated that rifabutin has been shown to induce CYP3A4 isoenzymes and may decrease the plasma concentrations of erythromycin.(2,3) The Australian manufacturer of erythromycin has stated that erythromycin is an inhibitor of CYP3A4 isoenzymes and there have been published reports and spontaneous reports of CYP3A4 based interactions with erythromycin and rifabutin.(2)

Rifabutin/Doravirine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Rifabutin may induce the metabolism of doravirine by CYP3A4.(1-3)

CLINICAL EFFECTS: Concurrent or recent use of rifabutin may result in decreased levels and effectiveness of doravirine.(1-3)

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

PATIENT MANAGEMENT: If concurrent therapy is necessary, increase doravirine dosage to one tablet twice daily for the duration of coadministration with rifabutin.(1) Patients on the fixed-dose combination of doravirine-lamivudine-tenofovir should take 1 tablet (100 mg) of doravirine about 12 hours after their dose of doravirine-lamivudine-tenofovir for the duration of rifabutin co-administration.(2) Patients on the fixed-dose combination of doravirine-islatravir should take 1 tablet (100 mg) of doravirine about 12 hours after their dose of doravirine-islatravir for the duration of rifabutin co-administration.(3)

DISCUSSION: Doravirine is metabolized by CYP3A4. Moderate inducers of CYP3A4 such as rifabutin are expected to reduce doravirine levels, which may lead to loss of response.(1) In a study in 12 subjects, rifabutin (300 mg daily), a moderate inducer of CYP3A4, decreased the area-under-curve (AUC) and 24 hour concentration (C24) of a single dose of doravirine (100 mg) by 50% and 68%, respectively.(1) In a study of 15 patients, doravirine 100 mg twice daily given concurrently with rifabutin 300 mg once daily resulted in similar doravirine levels and exposure as doravirine 100 mg once daily alone.(3)

Rifabutin/Efavirenz

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Efavirenz may induce the metabolism of rifabutin via CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent use of efavirenz may result in decreased levels and therapeutic failure of rifabutin.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of efavirenz recommends increasing the dose of rifabutin by 50% in patients receiving concurrent efavirenz. In regimens when rifabutin is only given 2 or 3 times per week, the manufacturer of efavirenz recommends doubling the dose of rifabutin.(1,2)

DISCUSSION: In a study in 9 subjects, concurrent efavirenz (600 mg daily) and rifabutin (300 mg daily) decreased the rifabutin maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) by 32%, 38%, and by 45%, respectively. The efavirenz Cmin decreased by 12%.(1,2) In a study in 21 patients with tuberculosis and HIV infection, administration of twice weekly rifabutin (600 mg) with isoniazid (15 mg/kg) with efavirenz produced levels that adequately compensated for the efavirenz interaction. Efavirenz levels were 10% higher than in historical controls.(3) In a case report, a patient receiving efavirenz (600 mg daily, increased to 800 mg daily) had subtherapeutic efavirenz levels during concomitant use of rifabutin (450 mg daily). Expected clinical outcomes of efavirenz were seen 12 days after discontinuation of rifabutin.(4) In another case report, a patient receiving efavirenz experienced treatment failure with rifabutin.(5)

Rifabutin/Maribavir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Rifabutin, a moderate CYP3A4 inducer, may accelerate the metabolism of maribavir.(1)

CLINICAL EFFECTS: The concurrent administration of rifabutin may result in decreased levels and effectiveness of maribavir.(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 maribavir states that concurrent use with rifabutin requires a dose adjustment of maribavir. Increase the dosage of maribavir to 800 mg (four 200 mg tablets) twice daily.(1) If concurrent use is necessary, closely monitor for treatment response.(1)

DISCUSSION: Maribavir is metabolized by CYP3A4. A PBPK model predicted that the area-under-curve (AUC) and maximum concentration (Cmax) of maribavir was comparable when maribavir 800 mg twice daily was coadministered with rifabutin 300 mg daily versus maribavir 400 mg twice daily given alone (AUC ratio 1.38, Cmax ratio 1.52).(1)

Rifamycins/Beta-Blockers, Oral

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Rifampin is a well recognized enzyme inducer that increases the clearance of many drugs that are metabolized.(1) Beta-blockers that are extensively metabolized may be affected by rifampin.

CLINICAL EFFECTS: Decreased pharmacologic effects of certain beta-blockers.

PREDISPOSING FACTORS: Dose ranging of rifampin did not suggest a dose proportional interaction.(2)

PATIENT MANAGEMENT: Monitor the patient's response to beta-blocker therapy when starting or stopping treatment with rifampin and adjust the dose accordingly.

DISCUSSION: Controlled studies involving healthy volunteers have demonstrated rifampin to increase the clearance of metoprolol and propranolol by more than two fold.(2),(3),(4) Steady state plasma concentrations of propranolol were also reduced. The elimination half-life and protein binding of propranolol were not altered by rifampin. In a study in eight subjects, the concurrent administration of rifampin and carvedilol decreased carvedilol concentrations by 70%.(5)

Rifamycins/Digitalis Glycosides

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Rifamycins may inhibit the absorption of digitalis glycosides by inducing P-glycoprotein.(1-2)

CLINICAL EFFECTS: Concurrent or recent use of rifamycins may result in decreased levels and effectiveness of digitalis glycosides.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor digoxin levels if a rifamycin is initiated or discontinued. The dosage of digoxin may need to be increased by 20% to 40%.(2)

DISCUSSION: In a study in 18 healthy volunteers, rifampin (300 mg BID for 7 days) decreased the maximum concentration (Cmax), 3-hour area-under-curve (AUC), and 24-hour AUC by 38.5%, 30.4%, and 24.6%, respectively.(1) Case reports also document decreased digoxin(3-5) and digitoxin(6-7) levels with rifampin.

Rifamycins/Disopyramide; Mexiletine; Propafenone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Rifampin and other rifamycins may increase the hepatic metabolism of disopyramide,(1-2) mexiletine(3) and propafenone(4-6).

CLINICAL EFFECTS: Concurrent use of rifampin may result in decreased levels and effectiveness of disopyramide,(2) mexiletine(3) and propafenone(4-6).

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor patient's cardiac function and serum disopyramide, mexiletine or propafenone levels. Adjust the dosage accordingly.

DISCUSSION: Coadministration of mexiletine and rifampin have been reported to decrease the elimination half-life and increase the nonrenal clearance of mexiletine.(3) In a study in six elderly subjects, pretreatment with rifampin (600 mg daily for 9 days) decreased the bioavailability of a single dose of oral propafenone (300 mg) by 86%. Maximum QRS prolongation after oral propafenone was decreased by 50%. There were no significant effects on intravenous propafenone.(5) In a study in six extensive CYP2D6 metabolizers and six poor CYP2D6 metabolizers, pretreatment with rifampin (600 mg daily for 9 days) decreased the bioavailability of a single dose of oral propafenone by 67% and by 41% in extensive and poor metabolizers, respectively. Maximum QRS prolongation after oral propafenone decreased by 38% and by 40% in extensive and poor metabolizers, respectively. There were no effects on intravenous propafenone.(6) During concomitant administration of disopyramide and rifampin to patients with tuberculosis, serum disopyramide concentrations decreased by approximately 50% while the concentration of an active metabolite of disopyramide increased.(1) Concurrent administration of disopyramide and rifampin to a 62-year-old patient produced subtherapeutic disopyramide levels and a failure in correcting the patient's arrhythmia. Five days after stopping rifampin, disopyramide levels increased and the arrhythmia was abolished.(2) Rifamycins linked to this monograph are rifabutin, rifampin and rifapentine.

Rifamycins/Estrogen Replacement Therapy

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Rifamycins (rifampin, rifabutin and rifapentine) induce the the CYP3A4 mediated metabolism of estrogens and progestins.

CLINICAL EFFECTS: Concurrent use of rifampin, rifabutin, or rifapentine may result in reduced levels and clinical effectiveness of hormone replacement therapy. Effects may be seen for several weeks after discontinuation of the rifamycin.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving rifamycins should be alerted to the risk for decreased effectiveness of their hormone replacement therapy. The patient should be asked to report any spotting or bleeding.

DISCUSSION: In an open-label, randomized crossover study, 22 healthy females received oral contraceptives for 21 days, then were randomized to receive rifampin or rifabutin (300 mg/d for 10 days). Rifampin and rifabutin decreased the area-under-curve (AUC) of ethinyl estradiol by 64% and 35%, respectively, and maximum concentration (Cmax) by 42% and 20%, respectively. Rifampin and rifabutin decreased the AUC of norethindrone by 60% and 20%, respectively. Incidences of spotting were much greater in the rifampin co-administration group. In a study, a single dose of oral contraceptive (ethinyl estradiol 50 mcg and norethindrone acetate 1 mg) was administered to 7 female patients with tuberculosis, both during TB treatment and one month after stopping rifampin (450-600 mg/d). Upon cessation of rifampin therapy, the AUC for ethinyl estradiol significantly increased by 70%, and terminal plasma half-life more than doubled. A similar study design analyzed the pharmacokinetics of norethisterone (1 mg) in 8 women receiving rifampin (450-600 mg/d). Upon termination of TB treatment, it was found that rifampin reduced the AUC of a single dose of norethisterone (1 mg) by approximately 40%, with a half-life reduction of 50%. In a study, male volunteers received 50 mcg iv of ethinyl estradiol, followed by rifampin (600 mg for 6 days). Ethinyl estradiol half-life decreased by approximately 55%. The upward titration of ethinyl estradiol to 100 mcg resulted in a more than 2-fold increase in ethinyl estradiol metabolism caused by rifampicin treatment. An analytical trial evaluated liver biopsies from four patients treated with rifampin 600 mg for a period of 6-10 days. Hepatic microsomes from the biopsies were incubated with hormone substrates, including oestradiol and ethinyloestradiol. Rifampin resulted in a fourfold increase in hydroxylation. Not only did rifampin increase the rate of hydroxylation through enzyme induction, it also caused an increase in cytochrome P-450. There are reports of breakthrough bleeding and unintended pregnancy during concurrent use.

Selected Cephalosporins & Penicillins/Probenecid

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Probenecid impairs the clearance of some cephalosporins and penicillins via inhibition of renal anion transporters in the proximal tubule.(49) It has also been hypothesized that probenecid may affect tissue distribution of cephalosporins.(1-5)

CLINICAL EFFECTS: The concurrent administration of probenecid may result in increased maximum concentration (Cmax), area-under-curve (AUC), and half-life of the cephalosporin or penicillin.(49) While this may improve antibiotic efficacy,(46-48) increased levels may also increase the risk for antibiotic-associated nephrotoxicity.(4)

PREDISPOSING FACTORS: Underlying renal dysfunction may increase the risk for nephrotoxicity.

PATIENT MANAGEMENT: In patients receiving the combination to improve antibiotic efficacy, monitor for antibiotic adverse effects and consider monitoring renal function. In patients receiving probenecid therapy to prevent or treat hyperuricemia, exposure to the antibiotic will be increased. A decrease in antibiotic dose or frequency may be required. The US manufacturer of piperacillin-tazobactam states probenecid should not be coadministered with piperacillin-tazobactam unless the benefit outweighs the risk.(50)

DISCUSSION: Concurrent use of probenecid with a cephalosporin or penicillin may cause an increase in the Cmax, AUC, and an increased elimination half life of the antibiotic.(6-8,49) This may be beneficial or necessary in difficult to treat infections,(46-48) but an increased risk for adverse effects should be expected. Antibiotics not dose adjusted for concurrent use with probenecid may be associated with an increased risk for adverse effects, such as nephrotoxicity. Probenecid administered concurrently with piperacillin-tazobactam prolongs the half-life of piperacillin by 21% and tazobactam by 71%. In a study in 8 healthy males, concurrent administration of probenecid (1 g) with piperacillin (1 g IM) increased piperacillin's Cmax and AUC by 30% and 60%. Renal clearance was reduced by 40%.(51) The cephalosporins affected by probenecid include cefazolin,(9-11) cephacetrile,(12,13) cephaloglycin,(14,15) cephalexin,(16-21) cephradine, (22-23) cefoxitin,(24-28) cefadroxil(29), cefaclor,(23) cefamandole,(30) ceftizoxime,(31,32) cefuroxime,(33,34) cefprozil,(35) cefonicid,(36) cefmetazole,(37) cefmenoxime,(38) and cefditoren.(39) Probenecid has been shown not to affect moxalactam,(4,40,41) ceforanide, (4,42), cefoperazone, ceftazidime(4,34,43) or ceftriaxone.(4)

Selected Cyp2c19 Inhibitors/Citalopram (<= 20 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Citalopram is primarily metabolized by the CYP2C19 isoenzyme.(1)

CLINICAL EFFECTS: Concurrent use of an agent that inhibits CYP2C19 may result in elevated levels of and toxicity from citalopram, including including risks for serotonin syndrome or prolongation of the QTc interval.(1-5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(5)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age, poor metabolizer status at CYP2C19, or higher blood concentrations of citalopram.(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) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,5) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

PATIENT MANAGEMENT: The dose of citalopram should be limited to 20 mg in patients receiving concurrent therapy with an inhibitor of CYP2C19.(1,4) Evaluate the patient for other drugs, diseases and conditions which increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, hypocalcemia, hypomagnesemia, discontinue other QT prolonging drugs) when possible.(1,2) Weigh the specific benefits versus risks for each patient. The US manufacturer recommends ECG monitoring for citalopram patients with congestive heart failure, bradyarrhythmias, taking concomitant QT prolonging medications or receiving concurrent therapy.(4) Citalopram should be discontinued in patients with persistent QTc measurements greater than 500 ms.(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. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: Concurrent use of citalopram (40 mg daily) and cimetidine (400 mg twice daily) for 8 days increased the maximum concentration (Cmax) and area-under-curve (AUC) of citalopram by 39% and 43%, respectively.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), armodafinil, asciminib, berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, elagolix, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, tecovirimat, treosulfan, and vonoprazan.(7,8)

Selected Cyp2c19 Inhibitors/Escitalopram (<= 15 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: At lower systemic concentrations, escitalopram is primarily metabolized by CYP2C19; at higher concentrations is also metabolized by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of an agent which significantly inhibits CYP2C19, or which inhibits both CYP2C19 and CYP3A4 may result in elevated concentrations and toxicity from escitalopram, including risks for serotonin syndrome or prolongation of the QTc interval.(1,5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3)

PREDISPOSING FACTORS: The risk of QT prolongation may be increased in patients with congenital long QT syndrome, cardiovascular disease (e.g. heart failure, myocardial infarction), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female sex, advanced age, poor metabolizer status at CYP2C19, concurrent use of more than one agent known to cause QT prolongation, or with higher blood concentrations of escitalopram.(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) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,3) 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.

PATIENT MANAGEMENT: Evaluate patient for other drugs, diseases and conditions which may further increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, discontinue other QT prolonging drugs) when possible.(2,3) It would be prudent to limit the escitalopram dose to 10 mg daily in patients with QT prolonging risk factors who also receive concurrent therapy with selected CYP2C19 inhibitors.(5) Weigh the specific benefits versus risks for each patient. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: A thorough QT study evaluating escitalopram 10 mg or 30 mg once daily was conducted; a change of 10 msec for upper bound of the 95% confidence level is the threshold for regulatory concern. In this study, changes to the upper bound of the 95% confidence interval were 6.4 msec and 12.6 msec for the 10 mg and supratherapeutic 30 mg dose respectively. The Cmax for 30 mg was 1.7-fold higher than the Cmax for the maximum recommended escitalopram dose of 20 mg. Systemic exposure at the 30 mg dose was similar to expected steady state concentrations in 2C19 poor metabolizers following a 20 mg escitalopram dose.(1) In an interaction study, 30 mg of omeprazole, an irreversible inhibitor of CYP2C19 was administered daily for 6 days. On day 5 a single dose of escitalopram 20 mg was also administered; the area-under-curve (AUC) of escitalopram was increased by 50%. Manufacturer prescribing information recommends a maximum citalopram dose of 20mg daily in patients receiving CYP2C19 inhibitors.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), armodafinil, asciminib, berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, elagolix, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, tecovirimat, treosulfan, and vonoprazan.(4)

Selected Cyp2c19 Inhibitors/Escitalopram (> 15 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: At lower systemic concentrations, escitalopram is primarily metabolized by CYP2C19; at higher concentrations is also metabolized by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of an agent which significantly inhibits CYP2C19, or which inhibits both CYP2C19 and CYP3A4 may result in elevated concentrations and toxicity from escitalopram, including risks for serotonin syndrome or prolongation of the QTc interval.(1,5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3)

PREDISPOSING FACTORS: The risk of QT prolongation may be increased in patients with congenital long QT syndrome, cardiovascular disease (e.g. heart failure, myocardial infarction), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female sex, advanced age, poor metabolizer status at CYP2C19, concurrent use of more than one agent known to cause QT prolongation, or with higher blood concentrations of escitalopram.(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) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,3) 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.

PATIENT MANAGEMENT: Evaluate patient for other drugs, diseases and conditions which may further increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, discontinue other QT prolonging drugs) when possible.(2,3) It would be prudent to limit the escitalopram dose to 10 mg daily in patients with QT prolonging risk factors who also receive concurrent therapy with selected CYP2C19 inhibitors.(5) Weigh the specific benefits versus risks for each patient. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: A thorough QT study evaluating escitalopram 10 mg or 30 mg once daily was conducted; a change of 10 msec for upper bound of the 95% confidence level is the threshold for regulatory concern. In this study, changes to the upper bound of the 95% confidence interval were 6.4 msec and 12.6 msec for the 10 mg and supratherapeutic 30 mg dose respectively. The Cmax for 30 mg was 1.7-fold higher than the Cmax for the maximum recommended escitalopram dose of 20 mg. Systemic exposure at the 30 mg dose was similar to expected steady state concentrations in 2C19 poor metabolizers following a 20 mg escitalopram dose.(1) In an interaction study, 30 mg of omeprazole, an irreversible inhibitor of CYP2C19 was administered daily for 6 days. On day 5 a single dose of escitalopram 20 mg was also administered; the area-under-curve (AUC) of escitalopram was increased by 50%. Manufacturer prescribing information recommends a maximum citalopram dose of 20mg daily in patients receiving CYP2C19 inhibitors.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), armodafinil, asciminib, berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, elagolix, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, tecovirimat, treosulfan, and vonoprazan.(4)

Selected Cyp3a4 Inducers/Selected Benzodiazepines

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: CYP3A4 inducers may induce the metabolism of some benzodiazepines.

CLINICAL EFFECTS: Concurrent or recent use of CYP3A4 inducers may result in decreased levels and loss of effectiveness of some benzodiazepines.

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

PATIENT MANAGEMENT: Monitor patients receiving CYP3A4 inducers or who have received these agents in the previous 2 weeks for decreased benzodiazepine effectiveness. The dose of the benzodiazepine may need to be adjusted or an alternative agent used. If the CYP3A4 inducer is discontinued, benzodiazepine levels will gradually rise as induction effects diminish. Monitor for increased benzodiazepine effects and adjust the dose accordingly.

DISCUSSION: In a study in 95 healthy subjects, rifampin (450 mg daily for 5 days) decreased the plasma concentrations of a single oral dose of alprazolam (1 mg) by 79%.(1) In another study in 4 healthy subjects, rifampin (given for 4 days) decreased the area-under-curve (AUC) of a single oral dose of alprazolam (1 mg) by 88%.(2) In a double-blind, randomized, cross-over trial in 13 healthy subjects, rifampin (450 mg daily for 7 days) decreased the maximum concentration (Cmax), AUC, and half-life of a single oral dose of brotizolam (0.5 mg) by 69%, 90%, and 69%, respectively. Concurrent rifampin increased scores on the Digit Symbol Substitution Test (DSST) and decreased scores on the Stanford Sleepiness Scale.(3) In a study in 21 healthy subjects, rifampin (600 mg or 1200 mg daily for 7 days) increased total body clearance of diazepam by 300%.(4) An in vitro study in human hepatocytes found that rifampin increased the biotransformation of diazepam and midazolam by 1.9-fold.(5) In a study in 24 healthy subjects, rifampin (600 mg daily for 10 days) increased the clearance of a single intravenous dose of lorazepam by 140%.(6) In an open-label cross-over study in 19 healthy subjects, rifampin (600 mg daily for 9 days) increased the clearance of a single oral dose of midazolam (0.075 mg/kg) by 7-fold.(7) In a study in 57 healthy subjects, rifampin increased the systemic and oral clearance of midazolam by 2-fold and 16-fold, respectively.(8) In a study in 8 healthy subjects, rifampin (given for 6 days) significantly increased the clearance of midazolam.(9) In a study in 9 healthy subjects, received a single oral dose of midazolam (15 mg) before, one day after the administration of rifampin (600 mg daily for 5 days), and 4 days after the last dose of rifampin. One day after rifampin, the AUC of midazolam was decreased by 97.7% when compared to the administration of midazolam prior to rifampin. Four days after the completion of rifampin, the AUC of midazolam was decreased by 87% when compared to the administration of midazolam prior to rifampin.(10) In a double-blind, randomized, cross-over study in 10 healthy subjects, rifampin (600 mg daily for 5 days) decreased the Cmax, AUC, and half-life of a single oral dose of midazolam (15 mg) by 94%, 96%, and 58%, respectively. The pharmacodynamic effects of midazolam were also significantly decreased during rifampin therapy.(11) In a study in 16 healthy subjects, rifampin (600 mg daily for 7 days) increased the clearance of nitrazepam by 83%. There were no significant effects on the pharmacokinetics of temazepam.(12) In a randomized, double-blind, cross-over study in 10 healthy subjects, rifampin (600 mg daily for 5 days) decreased the Cmax, AUC, and half-life of a single dose of triazolam (0.5 mg) by 87.6%, 94.9%, and 54%, respectively. The pharmacodynamic effects of triazolam were also significantly decreased during rifampin therapy.(13) In an open-label, randomized, cross-over study in 27 healthy subjects, rifaximin (200 mg three times daily for 7 days) had no effect on the pharmacokinetics of single doses of oral or intravenous midazolam.(14) In a study in 98 patients with schizophrenia or bipolar disorder, the expression of CYP3A4 was found to be the major determinant of clonazepam plasma concentrations normalized by the dose and bodyweight (1263 +/- 482.9 and 558.5 +/- 202.4 ng/mL per mg/kg bodyweight in low and normal expressers, respectively, p<0.0001).(18) Selected CYP3A4 inducers linked to this monograph include: apalutamide, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenytoin, rifabutin, rifampin, rifapentine, and St. John's wort.

Selected Moderate And Strong Cyp3a4 Inducers/Siponimod

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Drugs that are moderate or strong inducers of CYP3A4 may increase the metabolism of siponimod.(1) Patients with a CYP2C9*1/*3 or *2/*3 genotype who are more dependent on CYP3A4 for the metabolism of siponimod would experience a greater effect of CYP3A4 induction.

CLINICAL EFFECTS: Concurrent use of a siponimod with a moderate or strong CYP3A4 inducer in patients with a CYP2C9*1/*3 or *2/*3 genotype may result in decreased levels and effectiveness of siponimod.(1)

PREDISPOSING FACTORS: Patients with a CYP2C9*1/*3 or *2/*3 genotype who are more dependent on CYP3A4 for the metabolism of siponimod would experience a greater effect of CYP3A4 induction. Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Monitor the combination of siponimod with a moderate or strong CYP3A4 inducer in patients with a CYP2C9*1/*3 or *2/*3 genotype for loss of efficacy.(1) Agents that are both moderate CYP3A4 inducers and moderate CYP2C9 inducers (e.g., lorlatinib) should be used with caution regardless of the patient's CYP2C9 genotype.(1)

DISCUSSION: In a study, efavirenz (a moderate CYP3A4 inducer) decreased the area-under-curve (AUC) of siponimod by up to 52% across CYP2C9 genotypes. Drugs that are moderate or strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, belzutifan, bosentan, cenobamate, dabrafenib, elagolix, etravirine, fosphenytoin, lesinurad, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, modafinil, nafcillin, pexidartinib, phenobarbital, phenytoin, primidone, rifabutin, rifapentine, St John's Wort, sotorasib, telotristat ethyl, and tovorafenib.(2-3)

Selected Moderate-Weak Cyp3a4 Inducers/Exemestane

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: CYP3A4 inducers may induce the metabolism of exemestane.(1)

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

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

PATIENT MANAGEMENT: The US manufacturer of exemestane recommends that patients receiving concurrent therapy with a strong CYP3A4 inducer receive 50 mg of exemestane daily after a meal.(1) It may be prudent to consider a dosage increase for patients receiving weaker CYP3A4 inducers.

DISCUSSION: In a study in 10 healthy postmenopausal subjects, pretreatment with rifampin (a strong CYP3A4 inducer, 600 mg daily for 14 days) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of exemestane (25 mg) by 54% and 41%, respectively.(1) Strong inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 80% or more and include: carbamazepine, enzalutamide, mitotane, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's wort.(1-3) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, elafibranor, enasidenib, eslicarbazepine, floxacillin, garlic, gingko, ginseng, glycyrrhizin, lorlatinib, meropenem-vaborbactam, methylprednisolone, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)

Selected P-Gp Inducers; Phenobarbital/Tenofovir Alafenamide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Tenofovir alafenamide (TAF) is a substrate of the intestinal efflux transporter P-glycoprotein (P-gp). Inducers of P-gp may decrease systemic absorption of TAF.(1-4) Phenobarbital may also induce the metabolism of tenofovir alafenamide.(1-4) Primidone is metabolized to phenobarbital.

CLINICAL EFFECTS: Concurrent or recent use of P-gp inducers, phenobarbital, or primidone may result in decreased systemic levels and effectiveness of tenofovir alafenamide.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Recommendations regarding concurrent use of tenofovir alafenamide and P-gp inducers vary depending on the region and drug formulation. The European manufacturer of tenofovir alafenamide (DESCOVY for HIV infection and VEMLIDY for hepatitis B) states that concurrent use is not recommended with carbamazepine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, or St. John's wort.(1,2) The US manufacturer of DESCOVY states that rifabutin, rifampin, rifapentine, and St. John's wort are not recommended. Alternatives should be considered for carbamazepine, phenobarbital, phenytoin, and primidone.(3) The Australian and US manufacturers of tenofovir alafenamide (VEMLIDY for hepatitis B) states that concurrent use with phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, or St. John's wort is not recommended. If concurrent therapy with carbamazepine is indicated during treatment for Hepatitis B, the manufacturer recommends increasing the dose of tenofovir alafenamide to two tablets (50 mg) once daily.(4-5)

DISCUSSION: When tenofovir alafenamide (TAF) was coadministered with carbamazepine, the maximum concentration (Cmax) and area-under-curve (AUC) were decreased 57% and 55%, respectively.(1-4) A subsequent study suggests that this interaction may not have clinically significant effects on intracellular levels of tenofovir diphosphate, the active metabolite of tenofovir alafenamide. In a study of 23 healthy volunteers, the intracellular Cmax and AUC of tenofovir diphosphate were 38% and 36% lower, respectively, when tenofovir alafenamide was coadministered with rifampin than without rifampin. However, these levels of tenofovir diphosphate were 4.4- and 4.21-fold higher, respectively, than levels obtained from tenofovir disoproxil 300 mg daily without rifampin.(6) Selected P-gp inducers linked to this monograph include: apalutamide, carbamazepine, fosphenytoin, lorlatinib, phenytoin, rifabutin, rifampin, rifapentine, or St. John's wort.(1-7) The manufacturer of tenofovir alafenamide also classifies phenobarbital as a P-gp inducer.(1-4)

Selected Penicillins/Selected Anticoagulants (Vit K Antag)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown.

CLINICAL EFFECTS: Large doses of parenterally administered penicillins and oral amoxicillin appear to increase the risk of bleeding during concurrent administration of anticoagulants.

PREDISPOSING FACTORS: Renal failure may predispose patients to penicillin-induced coagulation abnormalities. A study suggests that various inflammatory syndromes or the nature of the infection can affect INR levels. The risk for bleeding episodes may be greater in patients with additional 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: Monitor patient INR for an increase in the hypoprothrombinemic response to anticoagulants during concomitant administration of penicillins. Adjust the dose of warfarin accordingly. When concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: High dose parenteral administration of penicillins and oral amoxicillin have been reported to cause an increase in the hypoprothrombinemic effects of warfarin producing bleeding. Significant clinical effects have been reported with combined administration of warfarin and either carbenicillin or penicillin G. There have been several case reports and retrospective reviews documenting increased acenocoumarol and warfarin effects, including bleeding, following the addition of amoxicillin, with and without clavulanic acid, to therapy. In a randomized controlled trial, adult ambulatory patients that had no recent and ongoing infectious or inflammatory conditions received warfarin to a target INR between 2 and 3 with amoxicillin-clavulanic acid (1 gram twice daily for seven days) or placebo. The results showed the mean maximum INR increase from baseline to day 10 did not differ between amoxicillin/clavulanic acid (0.22 +/- 0.3) and the placebo period (0.24 +/- 0.6, p = 0.94). No patient experienced an INR of greater than 3.5. No bleeding events were reported during the entire study. A prospective cross-sectional observational study in 120 patients evaluated warfarin drug interactions, particularly with high-dose amoxicillin/clavulanate. The study found that patients on amoxicillin/clavulanate had a relative risk of having an INR >=4 of 4.8 compared to patients not on amoxicillin/clavulanate (95% CI 2.1-11.3, p < 0.001). This risk was primarily driven by patients on high-dose amoxicillin/clavulanate, who were 5.8 times more likely to have INR >=4 (95% CI 3.5-9.6, p<0.001). Significantly more patients on high-dose than normal dose amoxicillin/clavulanate had an INR value >= 4 (87.5% v. 28.9%, respectively). Nine out of ten patients who experienced bleeding during hospitalization were prescribed amoxicillin/clavulanate. A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 11 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and antimicrobials (OR=1.63; 95% CI 1.45-1.83). Increased bleeding risk was also seen in subgroup analyses with penicillins (OR=1.59; 95% CI 1.14-2.20) and amoxicillin (OR=1.78; 95% CI 1.14-2.79). A case-control nested cohort study of Medicare beneficiaries with warfarin prescriptions was evaluated for antibiotic use and warfarin toxicity in older adults. An increased risk of bleeding was associated with penicillins with an adjusted odds ratio of 1.92. Parenteral penicillins linked to this monograph include: almecillin, amdinocillin, amoxicillin, ampicillin, azlocillin, bacampicillin, carbenicillin, cyclacillin, hetacillin, mezlocillin, penicillin, penicillin G, penicillin V, phenethicillin, piperacillin, and ticarcillin. Oral penicillins linked to this monograph include: amoxicillin and penicillin.

Selected Proton Pump Inhibitors/Tacrolimus

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Some proton-pump inhibitors (PPIs) may inhibit the metabolism of tacrolimus by CYP3A4 and intestinal CYP3A5.

CLINICAL EFFECTS: Concurrent use may increase tacrolimus levels in some patients and result in toxic effects, including nephrotoxicity, neurotoxicity, and prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.

PREDISPOSING FACTORS: This interaction may be is more severe in patients who are poor metabolizers of CYP2C19. 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.(17) 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).(17)

PATIENT MANAGEMENT: Consider monitoring tacrolimus levels when initiating or discontinuing a PPI other than pantoprazole in patients who are poor metabolizers of CYP2C19 or whose genotype is unknown. The dosage of tacrolimus may need to be adjusted. Pantoprazole may be an alternative to other PPIs in patients maintained on tacrolimus. When concurrent therapy of selected proton pump inhibitors and tacrolimus 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 vitro studies have shown that omeprazole inhibits the metabolism of tacrolimus.(1,2) In a case report, tacrolimus levels increased 1.8-fold in a pediatric live-transplant patient following the initiation of omeprazole.(3) In another report, the tacrolimus concentration/dose ratio was higher during omeprazole therapy when compared to rabeprazole therapy.(4) In a study in 48 renal transplant patients, the dose/weight normalized trough levels of tacrolimus decreased 15% following the switch of cimetidine to omeprazole.(5) In contrast, in a study in 51 renal transplant patients found no difference in tacrolimus level/dose ratio following the discontinuation of omeprazole.(6) In a study in 12 renal transplant patients who were CYP3A5-nonexpressors, there was no effect by omeprazole on tacrolimus pharmacokinetics.(7) A study in 89 liver transplant patients showed that the interaction between omeprazole and tacrolimus was more severe in patients that are either poor or intermediate metabolizers of CYP2C19.(8) There are three reports of elevated tacrolimus levels during the use of lansoprazole.(9,10,11,12) In a study in 73 renal transplant patients, lansoprazole and rabeprazole had significant effects on tacrolimus levels only in patients who were poor or intermediate metabolizers of CYP2C19.(13) In a study in 19 healthy subjects, lansoprazole increased tacrolimus levels in extensive and poor CYP2C19 metabolizers by 81% and 20%, respectively.(14) In contrast, a study in 55 liver-transplant patients, rabeprazole had no effect on tacrolimus concentrations regardless of CYP3A5 or CYP2C19 genotype.(15) In a study in 12 transplant recipients, pantoprazole had no effect on tacrolimus levels.(16)

Selected Strong Cyp3a4 Inducers/Corticosteroids

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of corticosteroids. Corticosteroids may affect the metabolism of phenytoin.

CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers may result in decreased levels and effectiveness of corticosteroids. Dexamethasone has been shown to increase and decrease phenytoin levels.

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

PATIENT MANAGEMENT: Patients receiving concurrent therapy with a strong CYP3A4 inducer should be monitored for decreased effectiveness of their corticosteroid. Increased dosage of corticosteroid may be required during concurrent therapy and for several weeks after completing concurrent therapy. If concurrent therapy is discontinued, the dosage of the corticosteroid may need to be adjusted. Phenytoin levels should be closely monitored in patients receiving corticosteroids. The dosage of phenytoin may need to be adjusted if corticosteroids are initiated or discontinued.

DISCUSSION: Carbamazepine has been shown to increase the metabolism of methylprednisolone, prednisolone, and prednisone, resulting in decreased levels and effectiveness of these agents. Phenobarbital has been shown to increase the metabolism of dexamethasone, methylprednisolone, and prednisolone. Primidone is metabolized to phenobarbital. Phenytoin has been shown to increase the metabolism of dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone, resulting in decreased levels and effectiveness of these agents Rifampin has been shown to increase the metabolism of cortisol, dexamethasone, methylprednisolone, prednisolone, and prednisone. Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifapentine, rifampin, and St. John's wort.

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 2C19 Inhibitor/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 CYP2C19 may inhibit the metabolism of cilostazol.(1-4)

CLINICAL EFFECTS: Concurrent use of strong or moderate inhibitors of CYP2C19 may result in elevated levels of 3,4-dehydro-cilostazol, a metabolite of cilostazol that is 4-7 times as active as cilostazol.(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 CYP2C19.(1) The Australian manufacturer of esomeprazole states concomitant use with cilostazol is contraindicated.(5)

DISCUSSION: In a study in 20 subjects examined the effects of omeprazole (40 mg daily) on a single dose of cilostazol (100 mg). Concurrent omeprazole increased the cilostazol maximum concentration (Cmax) and area-under-curve (AUC) by 18% and 26%, respectively. The Cmax and AUC of the 3,4-dehydro-cilostazol metabolite of cilostazol increased 29% and 69%, respectively. The Cmax and AUC of the OPC-13213 metabolite of cilostazol decreased by 22% and 31%, respectively.(4)

Strong & Moderate Cyp3a4 Inducers/Apixaban; Rivaroxaban

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Apixaban and rivaroxaban are both substrates of CYP3A4 and P-glycoprotein (P-gp). Apixaban is about 20% metabolized and rivaroxaban is about 18% metabolized, mainly by CYP3A4.(1-8) Strong and moderate CYP3A4 inducers may induce the metabolism of apixaban and rivaroxaban by CYP3A4.

CLINICAL EFFECTS: Concurrent or recent use of a CYP3A4 inducer may result in decreased levels and effectiveness of apixaban(1-4) or rivaroxaban,(5-8) especially in the setting of concurrent therapy with an agent that induces P-gp.

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. Drug-associated risk factors include concurrent use of P-gp inducers.

PATIENT MANAGEMENT: The US, Australian, Canadian, and UK manufacturers of apixaban provide recommendations regarding concurrent use with strong inducers of both CYP3A4 and P-gp, but do not provide guidance for concurrent use with agents that induce CYP3A4 alone.(1) The US manufacturer of rivaroxaban provides recommendations regarding concurrent use with strong inducers of both CYP3A4 and P-gp, but does not provide guidance for concurrent use with agents that induce CYP3A4 alone.(5) The Australian manufacturer of rivaroxaban states that concurrent use of strong CYP3A4 inducers should be approached with caution.(6) The Canadian and UK labels for rivaroxaban state that concurrent use of strong CYP3A4 inducers should be avoided.(7-8) When considering concurrent therapy with a strong or moderate CYP3A4 inducer with either apixaban or rivaroxaban, evaluate the patient's other concurrent therapy for CYP3A4 and P-gp effects. In patients who are taking strong CYP3A4 inducers and are also on concurrent P-gp inducers, consider the manufacturer recommendations for use with dual CYP3A4 and P-gp inducers. The US manufacturers of apixaban and rivaroxaban both state to avoid the concurrent use of agents that are combined P-gp and strong CYP3A4 inducers in patients receiving apixaban or rivaroxaban.(1-8) In patients who are taking moderate CYP3A4 inducers and are also on concurrent P-gp inducers, it may be prudent to consider alternative therapy or monitor the patient closely. For patients taking efavirenz or etravirine, the US and European HIV guidelines recommend considering alternative therapies or performing additional monitoring.(9-10)

DISCUSSION: The concurrent use of apixaban or rivaroxaban with strong CYP3A4 inducers that are not also P-gp inducers has not been studied. Apixaban and rivaroxaban are metabolized primarily by CYP3A4. Strong CYP3A4 inducers may decrease the levels and effectiveness of apixaban and rivaroxaban. 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%.(11) 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.(12) Strong CYP3A4 inducers linked to this monograph include: barbiturates, encorafenib, ivosidenib, lumacaftor, and mitotane.(13,14) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(13,14)

Strong And Moderate Cyp3a4 Inducers/Perampanel

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong and moderate CYP3A4 inducers may induce the metabolism of perampanel by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of strong and moderate CYP3A4 inducers and perampanel may result in decreased levels and clinical effectiveness of perampanel.(1)

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

PATIENT MANAGEMENT: Patients receiving concurrent therapy with strong and moderate CYP3A4 inducers and perampanel should be observed for decreased anticonvulsant levels and clinical effectiveness. The manufacturer of perampanel recommends a starting dose of 4 mg once daily at bedtime in patients receiving concurrent therapy with CYP3A4 inducers. Dose increases are recommended by 2 mg increments once daily based on clinical response and tolerability, no more frequently than at weekly intervals. The highest studied dose with concurrent enzyme-inducing antiepileptic drugs was 12 mg once daily.(1) The dose of the anticonvulsant may need to be adjusted if a strong or moderate CYP3A4 inducer is added to or removed from therapy.(1)

DISCUSSION: In a study in healthy subjects, carbamazepine 300 mg BID decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single 2 mg tablet dose of perampanel by 26% and 67%, respectively. The half-life (t1/2) of perampanel was shortened from 56.8 hours to 25 hours. In clinical studies examining partial-onset and primary generalized tonic-clonic seizures, a population pharmacokinetic analysis showed that perampanel AUC was reduced by 64% in patients on carbamazepine compared to the AUC in patients not on enzyme-inducing antiepileptic drugs.(1) In a study in partial-onset and primary generalized tonic-clonic seizures, a population pharmacokinetic analysis showed that perampanel AUC was reduced by 48% in patients on oxcarbazepine compared to patients not on enzyme-inducing antiepileptic drugs.(1) In a study in partial-onset and primary generalized tonic-clonic seizures, a population pharmacokinetic analysis showed that perampanel AUC was reduced by 43% in patients on phenytoin compared to patients not on enzyme-inducing antiepileptic drugs.(1) In a study in partial-onset and primary generalized tonic-clonic seizures in clinical trials (40 patients co-administered phenobarbital and 9 patients co-administered primidone), no significant effect on perampanel AUC was found. A modest effect of phenobarbital and primidone on perampanel concentrations cannot be excluded.(1) In a study in 76 patients, concentration-to-dose (CD) ratio of perampanel was assessed with and without concurrent antiepileptic agents. In patients only on perampanel the mean CD ratio was 3963 ng/mL/mg/kg (range: 1793-13,299) compared to the mean CD ratio in patients using enzyme-inducing AEDs [1760 (range: 892-3090), 2256 (range: 700-4703), and 1120 (range: 473-1853) ng/mL/mg/kg in patients taking phenytoin, phenobarbital, and carbamazepine, respectively], and carbamazepine had a significantly greater reduction in the CD ratio compared with phenytoin or phenobarbital (P < 0.001).(3) Strong and moderate CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, bosentan, carbamazepine, cenobamate, dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, eslicarbazepine, etravirine, fexinidazole, fosphenytoin, ivosidenib, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, modafinil, nafcillin, oxcarbazepine, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(1,2)

Strong And Moderate Cyp3a4 Inducers/Sildenafil (Pah)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Sildenafil is metabolized by CYP3A4. Strong and moderate inducers of CYP3A4 may increase the metabolism of sildenafil.(1)

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

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

PATIENT MANAGEMENT: Concomitant use of sildenafil with strong or moderate CYP3A4 inducers should be monitored closely. An increased dosage of sildenafil may be needed. Reduce sildenafil dose to 20 mg three times daily when discontinuing treatment with strong and moderate CYP3A4 inducers.(1)

DISCUSSION: Population pharmacokinetic analysis of data from patients in clinical trials found that sildenafil clearance increased about 3-fold when coadministered with mild CYP3A4 inducers.(1) A randomized, double-blind, placebo-controlled, parallel-group study of 55 healthy volunteers found that 10 days of bosentan (125 mg twice daily), a moderate CYP3A4 inducer, decreased the maximum concentration (Cmax) and area-under-curve (AUC) of sildenafil by 55.4% and 62.6%, respectively. Sildenafil increased bosentan Cmax and AUC by 42% and 49.8%, respectively. The combination was well tolerated without serious adverse events.(2) In a study of 15 HIV-negative subjects, etravirine (800 mg twice daily for 14 days), a moderate CYP3A4 inducer, decreased the Cmax and AUC of sildenafil by 45% and 57%, respectively.(3) The authors of a review article on drug interactions in pulmonary arterial hypertension therapy state that phenytoin and rifampin (strong CYP3A4 inducers) are not recommended with sildenafil due to an expected near-complete clearance of sildenafil.(4) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(5,6) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(5,6)

*Known hypersensitivity reactions (including anaphylaxis) to omeprazole, esomeprazole, or other substituted benzimidazoles (e.g., lansoprazole, pantoprazole, rabeprazole), or any ingredient in the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria.

*Concomitant use of proton-pump inhibitors (PPIs), including omeprazole, and rilpivirine is contraindicated.

There are no contraindication contraindications for this drug.

• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Clostridioides difficile infection
• Infectious mononucleosis
• Interstitial nephritis
• Subacute cutaneous lupus erythematosus
• Systemic lupus erythematosus

• CYp2c19 poor metabolizer
• Disease of liver
• Fracture
• Hypomagnesemia
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Neutropenic disorder
• Osteoporosis
• Thrombocytopenic disorder
• Vitamin b12 deficiency

Adverse effects reported in >=2% of adults receiving omeprazole in clinical trials include headache, abdominal pain, nausea, diarrhea, vomiting, and flatulence.

Adverse effects reported in pediatric patients 2--16 years of age receiving omeprazole were similar to those reported in adults, except for more frequently reported respiratory system events and fever.

More Frequent

• Skin rash

Less Frequent

• Anaphylaxis
• Exfoliative dermatitis
• Leukopenia
• Urticaria

Rare or Very Rare

• Abnormal hepatic function tests
• Abnormal hepatic function tests
• Acute generalized exanthematous pustulosis
• Acute generalized exanthematous pustulosis
• Acute generalized exanthematous pustulosis
• Agranulocytosis
• Agranulocytosis
• Agranulocytosis
• Anaphylaxis
• Anaphylaxis
• Anemia
• Angioedema
• Angioedema
• Anterior ischemic optic neuropathy
• Arthralgia
• Atrophic gastritis
• Autoimmune hemolytic anemia
• Bradycardia
• Bronchospastic pulmonary disease
• Bronchospastic pulmonary disease
• Cardiac arrhythmia
• Cholestatic hepatitis
• Clostridioides difficile infection
• Clostridioides difficile infection
• Clostridioides difficile infection
• Conjunctivitis
• Crystalluria
• DRESS syndrome
• DRESS syndrome
• DRESS syndrome
• Drug-induced hepatitis
• Dysgeusia
• Enterocolitis
• Eosinophilia
• Erythema multiforme
• Erythema multiforme
• Esophageal candidiasis
• Fracture
• Furred tongue
• Hematuria
• Hemolysis
• Hepatic failure
• Hepatitis
• Hepatitis
• Hyperbilirubinemia
• Hypersensitivity angiitis
• Hypersensitivity drug reaction
• Hypertension
• Hypocalcemia
• Hypoglycemic disorder
• Hypokalemia
• Hyponatremia
• Hypotension
• Idiopathic thrombocytopenic purpura
• Increased alanine transaminase
• Increased aspartate transaminase
• Interstitial nephritis
• Interstitial nephritis
• Jaundice
• Laryngeal edema
• Leukocytosis
• Leukopenia
• Leukopenia
• Lymphopenia
• Maculopapular rash
• Myalgia
• Myositis
• Neutropenic disorder
• Neutropenic disorder
• Obstructive hyperbilirubinemia
• Optic neuritis
• Pancreatitis
• Pancytopenia
• Pancytopenia
• Proteinuria
• Seizure disorder
• Seizure disorder
• Serum sickness
• Stevens-johnson syndrome
• Stevens-johnson syndrome
• Stevens-johnson syndrome
• Subacute cutaneous lupus erythematosus
• Systemic lupus erythematosus
• Thrombocytopenic disorder
• Thrombocytopenic disorder
• Thrombocytopenic disorder
• Toxic epidermal necrolysis
• Toxic epidermal necrolysis
• Toxic epidermal necrolysis
• Urticaria
• Urticaria
• Uveitis

More Frequent

• Acute abdominal pain
• Diarrhea
• Diarrhea
• Discoloration of sweat
• Discolored feces
• Dyschromia
• Flatulence
• Headache disorder
• Nausea
• Nausea
• Saliva discoloration
• Skin rash
• Sputum discoloration
• Tear discoloration
• Urine discoloration
• Vomiting
• Vomiting
• Vomiting
• Vulvovaginal candidiasis

Less Frequent

• Abdominal pain with cramps
• Back pain
• Chest pain
• Constipation
• Cough
• Dizziness
• Dyspepsia
• Dyspnea
• Fever
• Flatulence
• General weakness
• Insomnia
• Nausea
• Pruritus of skin
• Pruritus of skin
• Sore throat
• Upper respiratory infection

Rare or Very Rare

• Abdominal distension
• Acute abdominal pain
• Acute cognitive impairment
• Agitation
• Alopecia
• Anemia
• Anorexia
• Arthralgia
• Behavioral disorders
• Benign fundic gland polyposis of stomach
• Blurred vision
• Chest pain
• Cramps
• Dental discoloration
• Diarrhea
• Diplopia
• Discolored feces
• Dizziness
• Dry eye
• Dry skin
• Dysgeusia
• Eosinophilia
• Epistaxis
• Erectile dysfunction
• Eructation
• Fatigue
• Fever
• Flu-like symptoms
• Glycosuria
• Gynecomastia
• Hyperhidrosis
• Hypomagnesemia
• Insomnia
• Irritable bowel syndrome
• Leg pain
• Malaise
• Mucocutaneous candidiasis
• Muscle weakness
• Myalgia
• Ocular irritation
• Pain
• Palpitations
• Paresthesia
• Peripheral edema
• Petechiae
• Purpura
• Skin inflammation
• Skin photosensitivity
• Skin rash
• Sleep disorder
• Stomatitis
• Symptoms of anxiety
• Tachycardia
• Testicular pain
• Tinnitus
• Tremor
• Urinary tract infection
• Vertigo
• Vitamin b12 deficiency
• Weight gain
• Xerostomia

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Safety and efficacy of omeprazole magnesium delayed-release oral suspension have been established for the treatment of erosive esophagitis due to acid-mediated gastroesophageal reflux disease (GERD) in pediatric patients >=1 month of age. Safety and efficacy of omeprazole magnesium delayed-release oral suspension have also been established for the treatment of symptomatic GERD and maintenance of healing of erosive esophagitis in pediatric patients 1-16 years of age. Safety and efficacy of omeprazole delayed-release capsules have been established for the treatment of symptomatic GERD and maintenance of healing of erosive esophagitis in pediatric patients 2-16 years of age. Use in pediatric patients is supported by adequate and well-controlled studies in adults and uncontrolled safety, efficacy, and pharmacokinetic studies in pediatric and adolescent patients.

Safety and efficacy of omeprazole magnesium delayed-release oral suspension are not established in pediatric patients <1 month of age or for other uses in pediatric patients. Safety and efficacy of omeprazole delayed-release capsules in pediatric patients <1 year of age for the treatment of symptomatic GERD or maintenance of healing of erosive esophagitis have not been established. Safety and efficacy of omeprazole delayed-release capsules have not been established in pediatric patients for the treatment of active duodenal ulcer, H. pylori eradication to reduce the risk of duodenal ulcer recurrence, treatment of active benign gastric ulcer, or pathological hypersecretory conditions. Safety and efficacy of omeprazole immediate-release capsules and oral suspension have not been established in pediatric patients.

Safety and efficacy of omeprazole and sodium bicarbonate powder kit for oral suspension (Konvomep(R)) have not been established in pediatric patients.

Safety and efficacy of co-packaged omeprazole delayed-release capsules, clarithromycin tablets, and amoxicillin capsules (Omeclamox-Pak(R)) have not been established in pediatric patients with H. pylori.

Respiratory adverse reactions and accidental injuries have been reported more frequently in pediatric patients of all ages than in adults. Otitis and fever have been reported more frequently in patients less than one year of age and patients from one month to less one year to less than 2 years of age, respectively, than in other pediatric and adult patients.

Safe use of amoxicillin during pregnancy has not been definitely established. There are no adequate or controlled studies using aminopenicillins in pregnant women, and amoxicillin should be used during pregnancy only when clearly needed. However, amoxicillin has been administered to pregnant women without evidence of adverse effects to the fetus. In addition, amoxicillin is included in the US Centers For Disease Control and Prevention (CDC) recommendations for the treatment of chlamydial infections+ during pregnancy and included in CDC recommendations for the treatment of cutaneous anthrax+ or for postexposure prophylaxis+ following exposure to Bacillus anthracis spores.

Reproduction studies in rats and rabbits using rifabutin dosages up to 200 mg/kg daily (40 times the recommended human daily dosage) did not reveal evidence of teratogenicity. In rats receiving 200 mg/kg daily, decreased fetal viability occurred. An increase in fetal skeletal variants was observed in rats receiving rifabutin dosages of 40 mg/kg daily (8 times the recommended human daily dosage). In rabbits receiving rifabutin dosages of 80 mg/kg daily (16 times the recommended human daily dosage), maternotoxicity and an increase in fetal skeletal anomalies occurred. There are no adequate and controlled studies to date using rifabutin in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus. The American Thoracic Society (ATS), US Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) state that data are insufficient to date to recommend use of rifabutin in pregnant women.

Reproductive studies in rats and rabbits using omeprazole dosages during organogenesis of up to 138 and 69.1 mg/kg daily (about 34 times the human dosage of 40 mg daily based on body surface area (BSA)), respectively, have not revealed evidence of teratogenicity. However, in rabbits given omeprazole dosages of 6.9-69.1 mg/kg daily during organogenesis (about 3.4-34 times the human dosage of 40 mg daily based on BSA), dose-related increases in embryolethality, fetal resorptions, and pregnancy loss occurred. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from administration of omeprazole in dosages of 13.8-138 mg/kg daily (about 3.4-34 times the human dosage of 40 mg daily based on BSA) prior to mating through the lactation period.

Reproductive studies of oral esomeprazole (an enantiomer of omeprazole) in rats and rabbits during organogenesis using dosages approximately 68 and 42 times the usual human dosage of 40 mg daily based on BSA, did not reveal evidence of embryo/fetal toxicity. When administered through most of pregnancy and lactation, effects on bone morphology were observed in rat offspring at dosages approximately 34 times the human dosage of 40 mg daily based on BSA of esomeprazole; however, when confined to administration during the gestational period only, no effects on bone morphology were observed in another study.

There are no adequate and well controlled studies using omeprazole in pregnant women. Available epidemiologic data have not demonstrated an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester exposure to omeprazole. Reproductive studies in rats and rabbits using omeprazole dosages approximately 3.4-34 times the human dosage of 40 mg daily (based on BSA) resulted in dose-dependent increases in embryolethality.

A population-based retrospective cohort epidemiologic study using data from the Swedish Medical Birth Registry reported on outcomes in infants whose mothers used omeprazole during pregnancy; most (about 86%) were exposed to omeprazole during the first trimester, 5% during and beyond the first trimester, and about 14% were exposed only after the first trimester of pregnancy. The number of infants exposed to omeprazole in utero with any malformation, low birth weight, low Apgar score, or hospitalization was similar to the number in this population. The number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole-exposed infants than the expected number in this population.

In a population-based retrospective cohort study in Denmark reporting on 1800 live births whose mothers received omeprazole during the first trimester and 837,317 live births whose mothers did not receive a PPI, the overall rate of birth defects was 2.9% in infants whose mothers received omeprazole during the first trimester and 2.6% in infants born to mothers not exposed to any PPI during the first trimester.

In a retrospective cohort study, the incidence of congenital malformations in 689 women who received omeprazole or histamine H2-antagonists in the first trimester of pregnancy was compared with a control group of women who were not exposed to acid-suppressant drugs. The malformation rate associated with histamine H2-antagonists exposure was 5.5%, the malformation rate for nonexposed women was 4.1%, and the malformation rate associated with omeprazole exposure was 3.6%.

A small prospective cohort study followed women exposed to omeprazole (89% during the first trimester) during pregnancy; major congenital malformations occurred in 4% of live births in omeprazole-exposed women, 2.8% of disease-paired controls, and 2% exposed to non-teratogenic agents. Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups.

The manufacturers state that several studies reported that adverse short-term effects were not observed in infants when a single oral or IV dose of omeprazole was administered to pregnant women as premedication for cesarean section under general anesthesia.

Available data on sodium bicarbonate administration during pregnancy have not identified a drug-associated risk of major fetal malformations or miscarriage.

Because amoxicillin is distributed into milk and may lead to sensitization of infants, the drug should be used with caution in nursing women. Because of its general safety in infants, CDC states that amoxicillin is an option for anti-infective prophylaxis in breast-feeding women when B. anthracis is known to be penicillin susceptible and there is no contraindication to maternal amoxicillin use.

It is not known whether rifabutin is distributed into human milk. Because of the potential for serious adverse reactions to rifabutin in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Limited data suggest omeprazole is distributed into human milk. The effects of omeprazole on milk production and on the breast-fed infant are unknown. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for the drug and any potential adverse effects on the breast-fed infant from omeprazole or from the underlying maternal condition.

Although the elimination rate of omeprazole is somewhat decreased in geriatric patients and the bioavailability increased, no adjustment of the usual recommended dosage is required in geriatric patients.

In US and European clinical trials, more than 2000 patients treated with omeprazole were >=65 years of age. Although no overall differences in efficacy or safety were observed between geriatric and younger patients, and other clinical experience revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.