Turalio (pexidartinib hydrochloride)

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

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)

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/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/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/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)

Pexidartinib/Hormonal Contraceptives

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: Pexidartinib is a moderate CYP3A4 inducer and may increase the CYP3A4-mediated metabolism of both estrogen and progestin components of hormonal contraceptives.(1)

CLINICAL EFFECTS: Coadministration of pexidartinib with hormonal contraceptives can result in decreased concentrations and reduced efficacy.(1) Breakthrough bleeding and contraceptive failure/pregnancy may result. Pexidartinib may cause fetal harm if administered to pregnant women.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of pexidartinib recommends that female patients of reproductive potential use effective non-hormonal contraception during treatment with pexidartinib and for 1 month after the final dose.(1) Patients should be alerted to the risk for decreased effectiveness(e.g. contraceptive failure) of their hormonal contraceptive therapy. 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 (i.e., a copper IUD).(2)

DISCUSSION: Coadministration of pexidartinib 400 mg twice daily with oral midazolam, a sensitive CYP3A4 substrate, in patients decreased midazolam area-under-curve (AUC) by 59% and maximum concentration (Cmax) by 28%.(1)

Pexidartinib/Strong Cyp3a4 Inducers

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

MECHANISM OF ACTION: Pexidartinib is a substrate of CYP3A4. Strong inducers of CYP3A4 may induce the metabolism of pexidartinib.(1)

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

DISCUSSION: Concomitant administration of rifampin (strong CYP3A4 inducer) decreased pexidartinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 33% and 65%.(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)

Selected Cyp3a4 Inducers/Docetaxel

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 accelerate the metabolism of docetaxel.(1) Mitapivat, pexidartinib, and sotorasib are moderate CYP3A4 inducers.(2-6)

CLINICAL EFFECTS: Concurrent or recent use of an inducer of CYP3A4 may result in decreased levels and effectiveness of docetaxel.(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 use of inducers of CYP3A4 with docetaxel.(1) Consider the use of agents with no or minimal induction potential if possible. Monitor patients for decreased response to therapy.

DISCUSSION: Docetaxel is metabolized by CYP3A4 and inducers of this isoenzyme are expected to decrease levels of docetaxel.(1) In a study in 10 cancer patients, St. John's wort, a strong CYP3A4 inducer, decreased the area-under-curve (AUC) of docetaxel by 11.6%. There were no significant decreases in docetaxel maximum concentration (Cmax) or half-life. Docetaxel-related toxicities were lower during coadministration of St. John's wort.(7) In an in vitro study, hyperforin, a constituent of St. John's wort, induced the metabolism of docetaxel in a dose-dependent fashion with induction ranging from 2.6-fold to 7-fold greater than controls. In this same experiment, rifampin induced docetaxel metabolism 6.8-fold to 32-fold.(8) Selected CYP3A4 inducers linked to this monograph include: aumolertinib, fexinidazole, mitapivat, pexidartinib, and sotorasib.(2-6)

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)

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.

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 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)

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

Cyp3a4 Inducers/Erlotinib

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 erlotinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of a CYP3A4 inducer may result in decreased levels and effectiveness of erlotinib.(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 CYP3A4 inducers in patients receiving therapy with erlotinib. Consider the use of alternative agents with less enzyme induction potential.(1) 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 the inducer is discontinued.(1)

DISCUSSION: Pretreatment and concurrent therapy with rifampin increased erlotinib clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by 66% to 80%. This is equivalent to a dose of about 30 mg to 50 mg in NSCLC.(1) 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.(1) 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).(2) In a study, concurrent use of sorafenib (400 mg twice daily) and erlotinib (150 mg daily) decreased the concentration minimum (Cmin), concentration maximum (Cmax), and AUC of erlotinib.(3) In an animal study, concurrent use of dexamethasone and erlotinib decreased the AUC of erlotinib by 0.6-fold.(4) Strong inducers of CYP3A4 include: barbiturates, encorafenib, enzalutamide, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(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, sotorasib, telotristat, thioridazine, and tovorafenib.(5,6) Weak inducers of CYP3A4 include: amprenavir, armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dicloxacillin, echinacea, eslicarbazepine, flucloxacillin, garlic, genistein, ginkgo, ginseng, glycyrrhizin, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(5,6)

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/Brigatinib

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

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

CLINICAL EFFECTS: Concurrent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of brigatinib.(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 brigatinib states to avoid concurrent administration with moderate CYP3A4 inducers. If concurrent use cannot be avoided, increase the daily dose of brigatinib in 30 mg increments every 7 days, as tolerated, to a maximum of twice the brigatinib dose that was tolerated prior to initiation of the moderate CYP3A4 inducer. After discontinuation of a moderate CYP3A4 inducer, resume the brigatinib dose that was tolerated prior to initiation of the inducer.(1)

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. Moderate CYP3A4 inducers are expected to decrease the AUC of brigatinib by 50%.(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, sotorasib, telotristat ethyl, thioridazine, tipranavir/ritonavir 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/Doravirine

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

MECHANISM OF ACTION: Moderate CYP3A4 inducers are expected to increase the metabolism of doravirine.(1-3)

CLINICAL EFFECTS: Concurrent or recent use of a moderate CYP3A4 inducer 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: Recommendations for concurrent use of moderate CYP3A4 inducers with doravirine vary depending on the reference. The manufacturer of the fixed dose combination of doravirine-islatravir states concurrent use with moderate CYP3A4 inducers is not recommended.(3) The DHHS HIV guidelines state when coadministering doravirine with bosentan, dexamethasone, and eslicarbazepine (moderate CYP3A4 inducers): consider an alternative antiretroviral or alternative drug to the moderate CYP3A4 inducer. It would be prudent to consider alternative drugs to other moderate CYP3A4 inducers. If co-administration is necessary monitor virologic response.(4) The University of Liverpool HIV Drug Interactions Database states concurrent use with moderate CYP3A4 inducers should be avoided. If concurrent use cannot be avoided, dose adjustment of doravirine to 100 mg twice daily is recommended and should be maintained for at least 2 weeks following cessation of the moderate CYP3A4 inducer. If a patient is on eslicarbazepine, doravirine should not be coadministered.(5) The manufacturer of single ingredient doravirine and the fixed dose combination of doravirine-lamivudine-tenofovir does not have a recommendation for concurrent use with moderate CYP3A4 inducers.(1,3)

DISCUSSION: Doravirine is metabolized by CYP3A4. Moderate CYP3A4 inducers 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 CYP3A4 inducer, 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) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dexamethasone, dipyrone, elagolix, eslicarbazepine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine and tovorafenib.(3-4)

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/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/Ranolazine

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 ranolazine.(1,2)

CLINICAL EFFECTS: Concurrent use of a moderate 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 such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John's wort is contraindicated. Concurrent use of moderate CYP3A4 inducers should be avoided.(1) The UK manufacturer of ranolazine states that ranolazine should not be used in patients receiving CYP3A4 inducers.(2)

DISCUSSION: Concurrent rifampin (600 mg daily), strong inducer of CYP3A4, decreased ranolazine plasma concentrations by 95%.(1,2) The effects of a moderate CYP3A4 inducer on ranolazine concentrations has not been studied. Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, lesinurad, lorlatinib, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, sotorasib, telotristat, and tovorafenib.(1-4)

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)

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Pexidartinib (125 Mg)/Duvelisib

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

MECHANISM OF ACTION: Duvelisib and pexidartinib are both metabolized by CYP3A4. Pexidartinib is a moderate CYP3A4 inducer while duvelisib is a moderate CYP3A4 inhibitor.(1-2)

CLINICAL EFFECTS: The net effect of coadministration of duvelisib and pexidartinib on CYP3A4 enzyme activity is unknown. Concurrent or recent use of pexidartinib may either decrease the clinical effectiveness of duvelisib(1) or increase the levels and toxicities of pexidartinib.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: There are no recommendations for concurrent use of duvelisib with pexidartinib. Concurrent therapy should be avoided. If use of this combination is necessary, the patient should be closely monitored for duvelisib efficacy and pexidartinib toxicity. The manufacturer of duvelisib makes the recommendations below for concurrent use with CYP3A4 inducers. 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. 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) The manufacturer of pexidartinib makes the recommendations below for concurrent use with CYP3A4 inhibitors. Coadministration with moderate inhibitors of CYP3A4 should be avoided.(2) If coadministration with a moderate CYP3A4 inhibitor cannot be avoided, reduce the pexidartinib dose according to the following recommendations. If the planned total daily dose is currently 500 mg, modify the total daily dose to 250 mg by administering 125 mg twice daily. If the planned total daily dose is currently 375 mg, modify the total daily dose to 250 mg by administering 125 mg twice daily. If the planned total daily dose is currently 250 mg, modify the total daily dose to 125 mg by administering 125 mg once daily. If concomitant use of a moderate CYP3A4 inhibitor is discontinued, increase the pexidartinib dose to the dose that was used before starting the inhibitor after three plasma half-lives of the moderate CYP3A4 inhibitor. Monitor liver tests, including AST, ALT, total bilirubin, direct bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the recommendations in the Turalio package insert. Advise patients to immediately report any symptoms of hepatotoxicity.

DISCUSSION: 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) Coadministration of fluconazole (a moderate CYP3A4 inhibitor) increased pexidartinib Cmax and AUC by 41% and 67%, respectively.(2)

Pexidartinib (125 Mg)/Lenacapavir

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

MECHANISM OF ACTION: Lenacapavir and pexidartinib are both metabolized by CYP3A4. Pexidartinib is a moderate CYP3A4 inducer while lenacapavir is a moderate CYP3A4 inhibitor.(1-4)

CLINICAL EFFECTS: The net effect of coadministration of lenacapavir and pexidartinib on CYP3A4 enzyme activity is unknown. Concurrent or recent use of pexidartinib may either decrease the clinical effectiveness of lenacapavir or increase the levels and toxicities of pexidartinib.(1-4

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: There are no recommendations for concurrent use of lenacapavir with pexidartinib. Concurrent therapy is not recommended. If use of this combination is necessary, the patient should be closely monitored for lenacapavir efficacy and pexidartinib toxicity. The manufacturer of lenacapavir states concurrent use with moderate CYP3A4 inducers is not recommended.(1-3) Lenacapavir has a long half-life and may increase the levels of CYP3A4 substrates initiated within 9 months after the last dose of subcutaneous lenacapavir.(1-3) The manufacturer of pexidartinib makes the recommendations below for concurrent use with CYP3A4 inhibitors. Coadministration with moderate inhibitors of CYP3A4 should be avoided.(4) If coadministration with a moderate CYP3A4 inhibitor cannot be avoided, reduce the pexidartinib dose according to the following recommendations. If the planned total daily dose is currently 500 mg, modify the total daily dose to 250 mg by administering 125 mg twice daily. If the planned total daily dose is currently 375 mg, modify the total daily dose to 250 mg by administering 125 mg twice daily. If the planned total daily dose is currently 250 mg, modify the total daily dose to 125 mg by administering 125 mg once daily. If concomitant use of a moderate CYP3A4 inhibitor is discontinued, increase the pexidartinib dose to the dose that was used before starting the inhibitor after three plasma half-lives of the moderate CYP3A4 inhibitor. Monitor liver tests, including AST, ALT, total bilirubin, direct bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the recommendations in the Turalio package insert. Advise patients to immediately report any symptoms of hepatotoxicity.

DISCUSSION: 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) Coadministration of fluconazole (a moderate CYP3A4 inhibitor) increased pexidartinib Cmax and AUC by 41% and 67%, respectively.(4)

Pexidartinib/Carbamazepine

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

MECHANISM OF ACTION: Carbamazepine is a strong CYP3A4 inducer and may increase the CYP3A4-mediated metabolism of pexidartinib. Pexidartinib is a moderate CYP3A4 inducer, which metabolizes carbamazepine.(1,2)

CLINICAL EFFECTS: Concurrent use of pexidartinib and carbamazepine may result in decreased levels and effectiveness of both drugs.(1,2)

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 carbamazepine with pexidartinib.(1)

DISCUSSION: Concomitant administration of rifampin (strong CYP3A4 inducer) decreased pexidartinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 33% and 65%.(1) Several studies have shown decreased carbamazepine serum concentrations when phenytoin (strong CYP3A4 inducer) was administered concurrently. In one study involving 22 patients, the carbamazepine serum concentration was shown to increase by 28% when the phenytoin dosage was reduced, indicating that phenytoin initially reduced carbamazepine levels.(3)

Pexidartinib/Crizotinib

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

MECHANISM OF ACTION: Crizotinib is a substrate and moderate inhibitor of CYP3A4.(1) Pexidartinib is a substrate and moderate inducer of CYP3A4.(2) Agents that induce the CYP3A4 isoenzyme may induce the metabolism of crizotinib.(1) Moderate CYP3A4 inhibitors may inhibit the CYP3A4 mediated metabolism of pexidartinib.(2)

CLINICAL EFFECTS: Concurrent use of crizotinib and pexidartinib may decrease the levels and effectiveness of crizotinib(1) while increasing levels and toxicity of pexidartinib, such as hepatotoxicity.(2) Symptoms can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the concurrent use of crizotinib and pexidartinib. Consider the use of alternative agents with less or no effect on the CYP3A4 enzyme.(1) There is currently no FDA-approved indication for the concurrent use of crizotinib and pexidartinib. The optimal doses of crizotinib and pexidartinib when used in combination is unknown. Combination therapy with crizotinib and pexidartinib would ideally be utilized within the context of a clinical trial.

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) Coadministration of fluconazole (a moderate CYP3A4 inhibitor) increased pexidartinib Cmax and AUC by 41% and 67%.(2)

Pexidartinib/Dronedarone

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

MECHANISM OF ACTION: Dronedarone may moderately inhibit the CYP3A4 metabolism of pexidartinib.(1,2) Pexidartinib is a moderate inducer of CYP3A4 and may increase the metabolism of dronedarone.(1)

CLINICAL EFFECTS: Concurrent use of dronedarone may result in elevated levels and increased effects of pexidartinib, such as hepatotoxicity.(1,2) Symptoms can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue. Concurrent use of dronedarone may also result in decreased serum levels and effectiveness of dronedarone.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of pexidartinib states that co-administration of CYP3A4 substrates with a narrow therapeutic window, like dronedarone, should be avoided. Pexidartinib coadministration with moderate inhibitors of CYP3A4 should also be avoided.(1) The optimal dosing of pexidartinib and dronedarone when used in combination is unknown. Manufacturers provide recommendations for dose modification of pexidartinib when used with a moderate CYP3A4 inhibitor, but the recommendations may not apply when there is a multi-directional interaction. Dose modifications mentioned below are informational only. If coadministration of pexidartinib with moderate CYP3A4 inhibitors cannot be avoided, reduce the pexidartinib dose according to the following recommendations. If the planned total daily dose is currently 500 mg, modify the total daily dose to 250 mg by administering 125 mg twice daily. If the planned total daily dose is currently 375 mg, modify the total daily dose to 250 mg by administering 125 mg twice daily. If the planned total daily dose is currently 250 mg, modify the total daily dose to 125 mg by administering 125 mg once daily. If concomitant use of a moderate CYP3A4 inhibitor is discontinued, increase the pexidartinib dose to the dose that was used before starting the inhibitor after three plasma half-lives of the moderate CYP3A4 inhibitor. Monitor liver tests, including AST, ALT, total bilirubin, direct bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the recommendations in the Turalio package insert. Advise patients to immediately report any symptoms of hepatotoxicity. There are no recommendations to guide dosing of dronedarone in the presence of a moderate CYP3A4 inducer.

DISCUSSION: Coadministration of fluconazole (a moderate CYP3A4 inhibitor) increased pexidartinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 41% and 67%.(1) Coadministration of pexidartinib 400 mg twice daily with oral midazolam, a sensitive CYP3A4 substrate, in patients decreased midazolam area-under-curve (AUC) by 59% and maximum concentration (Cmax) by 28%.(1)

Pexidartinib/Idelalisib

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

MECHANISM OF ACTION: Idelalisib is both a substrate and a strong inhibitor of the CYP3A4 isoenzyme.(1) Pexidartinib is both a substrate and a moderate inducer of CYP3A4.(2) Concurrent use of pexidartinib and idelalisib may alter exposure to one or both agents.

CLINICAL EFFECTS: Concurrent use of pexidartinib and idelalisib may result in elevated levels of and toxicity from pexidartinib(2) and decreased levels and efficacy of idelalisib.(1) The net effect and magnitude of the two-way interaction between pexidartinib and idelalisib is unknown.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the concurrent use of pexidartinib and idelalisib.(2,3) Consider alternatives with no or minimal effect on the CYP3A4 isoenzyme. The optimal dosing of pexidartinib and idelalisib when used in combination is unknown. Manufacturers provide recommendations for dose modification of pexidartinib when used with a strong CYP3A4 inhibitor, but the recommendations may not apply when there is a multi-directional interaction. Dose modifications mentioned below are informational only. If coadministration of pexidartinib with a strong CYP3A4 inhibitor cannot be avoided, reduce the pexidartinib dose according to the following recommendations. If the planned total daily dose is currently 500 mg, modify the total daily dose to 250 mg by administering 125 mg twice daily. If the planned total daily dose is currently 375 mg, modify the total daily dose to 250 mg by administering 125 mg twice daily. If the planned total daily dose is currently 250 mg, modify the total daily dose to 125 mg by administering 125 mg once daily. If concomitant use of a strong CYP3A4 inhibitor is discontinued, increase the pexidartinib dose to the dose that was used before starting the inhibitor after three plasma half-lives of the strong CYP3A4 inhibitor. Monitor liver tests, including AST, ALT, total bilirubin, direct bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the recommendations in the Turalio package insert. Advise patients to immediately report any symptoms of hepatotoxicity. Patients receiving concurrent therapy with pexidartinib and idelalisib should be monitored closely for efficacy and signs of toxicities.(1,2)

DISCUSSION: Coadministration of itraconazole, a strong CYP3A inhibitor, increased pexidartinib area-under curve (AUC) by 70% and maximum concentration (Cmax) by 48%.(2) In a study in healthy subjects, rifampin (600 mg daily for 8 days) decreased the Cmax and AUC of idelalisib (150 mg single dose) by 58% and 75%, respectively.(3)

Pexidartinib/Moderate Cyp3a4 Inhibitors

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

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

CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in elevated levels and increased effects of pexidartinib, such as hepatotoxicity.(1,2) Symptoms can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of pexidartinib states that pexidartinib coadministration with moderate inhibitors of CYP3A4 should be avoided.(1) If coadministration with a moderate CYP3A4 inhibitor cannot be avoided, reduce the pexidartinib dose according to the following recommendations. If the planned total daily dose is currently 500 mg, modify the total daily dose to 250 mg by administering 125 mg twice daily. If the planned total daily dose is currently 375 mg, modify the total daily dose to 250 mg by administering 125 mg twice daily. If the planned total daily dose is currently 250 mg, modify the total daily dose to 125 mg by administering 125 mg once daily. If concomitant use of a moderate CYP3A4 inhibitor is discontinued, increase the pexidartinib dose to the dose that was used before starting the inhibitor after three plasma half-lives of the moderate CYP3A4 inhibitor. Monitor liver tests, including AST, ALT, total bilirubin, direct bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the recommendations in the Turalio package insert. Advise patients to immediately report any symptoms of hepatotoxicity.

DISCUSSION: Coadministration of fluconazole (a moderate CYP3A4 inhibitor) increased pexidartinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 41% and 67%.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, erythromycin, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, letermovir, netupitant, nilotinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(1,3)

Pexidartinib/Moderate Cyp3a4 Inhibitors & Substrates

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

MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of pexidartinib.(1,2) Fedratinib,(2) oral lefamulin,(3) rilzabrutinib,(4)and voxelotor(5) are moderate CYP3A4 inhibitors. Moderate inducers of CYP3A4 may induce the metabolism of fedratinib,(2) lefamulin,(3) rilzabrutinib,(4) and voxelotor.(5) Pexidartinib is a moderate CYP3A4 inducer.(1)

CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in elevated levels and increased effects of pexidartinib, such as hepatotoxicity.(1,2) Symptoms can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue. The concurrent use of a moderate CYP3A4 inducer may result in decreased levels and effectiveness of fedratinib,(2) lefamulin,(3) rilzabrutinib,(4) and voxelotor.(5)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of pexidartinib states that pexidartinib coadministration with moderate inhibitors of CYP3A4 should be avoided.(1) The US manufacturers of fedratinib states that concurrent use with moderate CYP3A4 inducers should be avoided.(2) The US manufacturers of lefamulin states that concurrent use with moderate CYP3A4 inducers should be avoided.(3) The US manufacturer of rilzabrutinib states that concurrent use with moderate CYP3A4 inducers should be avoided.(4) The US manufacturers of voxelotor states that concurrent use with moderate CYP3A4 inducers should be avoided.(5)

DISCUSSION: Coadministration of fluconazole (a moderate CYP3A4 inhibitor) increased pexidartinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 41% and 67%.(1) The effect of CYP3A4 inducers has not been studied. Fedratinib is metabolized by CYP3A4.(2) In a study, concurrent administration of rifampin (a strong inducer) with lefamulin injection decreased lefamulin AUC and Cmax by 28% and 8%.(3) In a study, concurrent administration of rifampin (a strong inducer) with oral lefamulin (tablets) decreased lefamulin AUC and Cmax by 72% and 57%.(3) In a study, oral lefamulin tablets administered concomitantly with and at 2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the AUC and Cmax of midazolam by 200% and 100%, respectively. No clinically significant effect on midazolam pharmacokinetics was observed when co-administered with lefamulin injection.(3) Concomitant administration of rilzabrutinib with efavirenz or rifabutin (moderate CYP3A4 inducers) is predicted to decrease rilzabrutinib AUC and Cmax by up to 70% at steady state.(4) A pharmacokinetic model predicted that co-administration of rifampin, a strong CYP3A4 inducer, would decrease the area-under-curve (AUC) of voxelotor by 40%.(5) Co-administration of efavirenz, a moderate CYP3A4 inducer, is predicted to decrease the AUC of voxelotor by 24%.(5) Drugs that are both moderate inhibitors and substrates of CYP3A4 include: fedratinib, oral lefamulin, rilzabrutinib, and voxelotor.(2-7)

Pexidartinib/Selected Cyp3a4 Substrates

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

MECHANISM OF ACTION: Pexidartinib is a moderate inducer of CYP3A4 and may increase the metabolism of drugs metabolized by the CYP3A4 enzyme.

CLINICAL EFFECTS: Concurrent use of pexidartinib may lead to decreased serum levels and effectiveness of drugs metabolized by the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of pexidartinib states that co-administration of CYP3A4 substrates for which minimal concentration decreases may lead to serious therapeutic failure should be avoided. If concomitant use is unavoidable, increase the dose of the CYP3A4 substrate in accordance with approved product labeling.(1)

DISCUSSION: Coadministration of pexidartinib 400 mg twice daily with oral midazolam, a sensitive CYP3A4 substrate, in patients decreased midazolam area-under-curve (AUC) by 59% and maximum concentration (Cmax) by 28%.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: everolimus, felodipine, fentanyl, hydroquinidine, midazolam, nisoldipine, quinidine, sirolimus, tacrolimus, ticagrelor, and triazolam.(1-3)

Pexidartinib/Strong Cyp3a4 Inhibitors

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

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

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in elevated levels and increased effects of pexidartinib, such as hepatotoxicity.(1,2) Symptoms can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of pexidartinib states that pexidartinib coadministration with strong inhibitors of CYP3A4 should be avoided.(1) If coadministration with a strong CYP3A4 inhibitor cannot be avoided, reduce the pexidartinib dose according to the following recommendations. If the planned total daily dose is currently 500 mg, modify the total daily dose to 250 mg by administering 125 mg twice daily. If the planned total daily dose is currently 375 mg, modify the total daily dose to 250 mg by administering 125 mg twice daily. If the planned total daily dose is currently 250 mg, modify the total daily dose to 125 mg by administering 125 mg once daily. If concomitant use of a strong CYP3A4 inhibitor is discontinued, increase the pexidartinib dose to the dose that was used before starting the inhibitor after three plasma half-lives of the strong CYP3A4 inhibitor. Monitor liver tests, including AST, ALT, total bilirubin, direct bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the recommendations in the Turalio package insert. Advise patients to immediately report any symptoms of hepatotoxicity.

DISCUSSION: Coadministration of itraconazole (strong CYP3A4 inhibitor) increased pexidartinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 48% and 70%.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, indinavir, itraconazole, josamycin, ketoconazole, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, tucatinib, and voriconazole.(1,3)

Pexidartinib/Ugt1a4 Inhibitors

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

MECHANISM OF ACTION: Inhibitors of UGT1A4 may inhibit the metabolism of pexidartinib.(1)

CLINICAL EFFECTS: Concurrent use of a inhibitors of UGT1A4 may result in elevated levels and increased effects of pexidartinib, such as hepatotoxicity.(1,2) Symptoms can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of pexidartinib states that pexidartinib coadministration with inhibitors of UGT1A4 should be avoided.(1) If coadministration with a UGT1A4 inhibitor cannot be avoided, reduce the pexidartinib dose according to the following recommendations. If the planned total daily dose is currently 500 mg, modify the total daily dose to 250 mg by administering 125 mg twice daily. If the planned total daily dose is currently 375 mg, modify the total daily dose to 250 mg by administering 125 mg twice daily. If the planned total daily dose is currently 250 mg, modify the total daily dose to 125 mg by administering 125 mg once daily. If concomitant use of a UGT1A4 inhibitor is discontinued, increase the pexidartinib dose to the dose that was used before starting the inhibitor after three plasma half-lives of the UGT1A4 inhibitor. Monitor liver tests, including AST, ALT, total bilirubin, direct bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the recommendations in the Turalio package insert. Advise patients to immediately report any symptoms of hepatotoxicity.

DISCUSSION: Coadministration of probenecid (UGT1A4 inhibitor) increased pexidartinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 5% and 60%.(1) Inhibitors of UGT1A4 linked to this monograph include: probenecid.(1,2)

Pexidartinib/Vonoprazan

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

MECHANISM OF ACTION: Multiple mechanisms are involved in this interaction. With concurrent use of pexidartinib and vonoprazan: 1. The solubility of pexidartinib is pH dependent. Changes in gastric pH from proton pump inhibitors (PPIs) may decrease the absorption of pexidartinib.(1) Vonoprazan is a PPI.(2) 2. Pexidartinib is a moderate CYP3A4 inducer. If pexidartinib is absorbed, it may increase the CYP3A4-mediated metabolism of vonoprazan.(1,2) The triple pak formulation of vonoprazan-clarithromycin-amoxicillin is also affected by the mechanisms above when used with pexidartinib. In addition, if pexidartinib is absorbed, CYP3A4 induction by pexidartinib may increase the metabolism of clarithromycin, and clarithromycin, a strong CYP3A4 inhibitor, may decrease the metabolism of pexidartinib.(1,2)

CLINICAL EFFECTS: Use of proton pump inhibitors may result in decreased levels and effectiveness of pexidartinib.(1) If pexidartinib is absorbed, it may decrease the levels and effectiveness of vonoprazan and clarithromycin. In addition, concurrent use of a strong CYP3A4 inhibitor may increase the levels and toxicities of pexidartinib, such as hepatotoxicity.(1,2) Symptoms can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue. The net effect of vonoprazan-clarithromycin on pexidartinib levels is unknown.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of vonoprazan, vonoprazan-amoxicillin and vonoprazan-clarithromycin-amoxicillin in patients receiving treatment with pexidartinib.(1,2) Consider the use of short-acting antacids. If antacids are used, separate the administration times by at least 2 hours for pexidartinib.(1) If H2 antagonist therapy is required, pexidartinib must be given 10 hours after the H2 blocker and at least 2 hours before the next dose of the H2 blocker.(1)

DISCUSSION: Coadministration of esomeprazole decreased pexidartinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 55% and 50%.(1) Vonoprazan and clarithromycin are CYP3A4 substrates. Strong CYP3A4 inducers like rifampin are predicted to decrease the AUC of vonoprazan by 80%, and moderate CYP3A4 inducers like efavirenz are predicted to decrease vonoprazan AUC by 50%.(1) Pexidartinib is a moderate CYP3A4 inducer.(2-3) Coadministration of itraconazole (strong CYP3A4 inhibitor) increased pexidartinib Cmax and AUC by 48% and 70%.(1)

Selected Kinase Inhibitors/Proton Pump 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)

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 And Moderate Cyp3a4 Inducers/Velpatasvir

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

MECHANISM OF ACTION: Strong or moderate CYP3A4 inducers may induce the metabolism of velpatasvir via CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inducers may result in decreased levels and effectiveness of velpatasvir.(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 concurrent use of velpatasvir with strong or moderate CYP3A4 inducers is not recommended.(1,2)

DISCUSSION: In an interaction study, efavirenz 600 mg daily (in combination with emtricitabine-tenofovir DF) decreased velpatasvir concentration maximum (Cmax) and area-under-curve (AUC) by 47% and 53%, respectively.(1) In an interaction study, rifampin 600 mg daily decreased velpatasvir Cmax and AUC by 71% and 82%, respectively.(1) Strong and moderate CYP3A4 inducers include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, enzalutamide, fexinidazole, ivosidenib, lesinurad, lumacaftor, mavacamten, methimazole, mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib, sotorasib, telotristat, thioridazine, and tovorafenib.(3)

Strong Or Moderate Cyp3a4 Inducer And Substrates/Avacopan

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

MECHANISM OF ACTION: Avacopan is moderate inhibitor and substrate of CYP3A4. Strong or moderate inducers of CYP3A4 may induce the metabolism of avacopan.(1) Avacopan may inhibit the metabolism of CYP3A4 substrates.(1)

CLINICAL EFFECTS: The concurrent administration of strong or moderate CYP3A4 inducers may result in decreased levels and effectiveness of avacopan.(1) Concurrent administration of avacopan with CYP3A4 substrates may result in increased levels and side effects of the CYP3A4 substrate.(1) If the patient is on fexinidazole, concurrent administration of avacopan with fexinidazole may result in decreased levels of fexinidazole's active metabolite, resulting in decreased efficacy.(2)

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

PATIENT MANAGEMENT: The manufacturer of avacopan states that concurrent use with strong or moderate CYP3A4 inducers should be avoided.(1) Consider dose reduction of CYP3A4 substrates when coadministering avacopan with CYP3A4 substrates. Consult the concomitant CYP3A4 substrate product information when considering administration with avacopan.(1) The manufacturer of fexinidazole states that concurrent use with moderate CYP3A4 inhibitors should be avoided.(2)

DISCUSSION: Co-administration of rifampin 600 mg once daily for 11 days, a strong CYP3A4 inducer, decreased the avacopan maximum concentration (Cmax) by 79% and area-under-curve (AUC) by 93%.(1) In a study, avacopan 60 mg twice daily with food was administered for 7 days with simvastatin. Since it takes 13 weeks to reach steady state, this high dose of avacopan was used to achieve systemic levels similar to those achieved at steady state with a dose of 30 mg twice daily with food. Avacopan increased the AUC and Cmax of simvastatin by 3.53-fold and 3.20-fold, respectively.(1) Moderate inducers and substrates of CYP3A4 include: bosentan, encorafenib, fexinidazole, ivosidenib, mavacamten, pacritinib, pexidartinib, and repotrectinib.(3-4)

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)

Moderate Interaction: Assess the risk to the patient and take action as needed.

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/Larotrectinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

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

CLINICAL EFFECTS: Concurrent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of larotrectinib.(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 larotrectinib states that the concurrent use of moderate CYP3A4 inducers requires a dose modification. Double the dose of larotrectinib when coadministered with moderate CYP3A4 inducers. After the moderate CYP3A4 inducer has been discontinued for 3 to 5 elimination half-lives, resume the larotrectinib dose at the dose taken prior to initiating the CYP3A4 inducer.(1)

DISCUSSION: In a study, efavirenz (a moderate CYP3A4 inducer) was predicted to decrease area-under-curve (AUC) and maximum concentration (Cmax) by 72% and 60%, respectively, compared to larotrectinib administered alone.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(3-4)

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)

Pexidartinib/Selected H2 Antagonists

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The solubility of pexidartinib is pH dependent. Changes in gastric pH from H2 antagonists may decrease the absorption of pexidartinib.(1)

CLINICAL EFFECTS: Use of H2 antagonists may result in decreased levels and effectiveness of pexidartinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Consider the use of short-acting antacids in patients taking pexidartinib. If antacids are used, separate the administration times by at least 2 hours. If H2 antagonist therapy is required, the pexidartinib must be given 10 hours after the H2 blocker and at least 2 hours before the next dose of the H2 blocker. Avoid the use of proton pump inhibitors (PPIs).(1)

DISCUSSION: Coadministration of esomeprazole decreased pexidartinib maximum concentration (Cmax) and area-under-curve (AUC) by 55% and 50%, respectively.(1)

Select Moderate Cyp3a4 Inducer/Emtricitabine-Rilpivirine-Taf

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 rilpivirine.(1-2)

CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may result in decreased levels and effectiveness of rilpivirine, as well as the development of resistance.(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 DHHS HIV guidelines state that concurrent use of bosentan or mavacamten (moderate CYP3A4 inducers) with oral rilpivirine should be monitored closely. Consider alternative therapies that do not affect CYP3A4 or alternative antiretroviral agents. If concurrent use is necessary, virologic response should be monitored.(3) The US manufacturer of oral rilpivirine states that concurrent use of rifabutin (moderate CYP3A4 inducer) warrants dose adjustment. When administering moderate CYP3A4 inducers 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.(2)

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. (2) Selected moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, eslicarbazepine, fexinidazole, lesinurad, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine and tovorafenib.(3)

Selected Cyp3a4 Inducers/Alfentanil

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of alfentanil.(1)

CLINICAL EFFECTS: Concurrent use of a CYP3A4 inducer may result in decreased levels of alfentanil, which may result in decreased effectiveness and may precipitate withdrawal symptoms. In addition, discontinuation of the CYP3A4 inducer may result in an increased levels and toxicity of alfentanil, including serious respiratory depression.(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 alfentanil may require dosage adjustments if a CYP3A4 inducer is initiated or discontinued. Patients should be monitored closely. The effects of the interaction may last for several weeks after the discontinuation of the inducer.(1)

DISCUSSION: In a clinical study of 10 healthy volunteers, rifampin (a strong CYP3A4 inducer) decreased the area-under-curve (AUC) of oral alfentanil by 96% and of IV alfentanil by 42%.(5) Selected CYP3A4 inducers linked to this monograph include: aumolertinib, fexinidazole, mitapivat, pexidartinib, and sotorasib.

Selected Kinase Inhibitors/Antacids

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The solubility of bosutinib,(1) dasatinib,(2) erlotinib,(3) gefitinib,(4) neratinib,(5) nilotinib(6), pazopanib,(7) and pexidartinib(8) is pH dependent. Antacid-induced changes in gastric pH may decrease the absorption of these agents.(1-8)

CLINICAL EFFECTS: Simultaneous administration of antacids may result in decreased levels and effectiveness of bosutinib,(1) dasatinib,(2) erlotinib,(3) gefitinib,(4) neratinib,(5) nilotinib(6), pazopanib,(7) and pexidartinib.(8)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antacid use should be considered in place of H2 blockers or proton pump inhibitors in patients receiving bosutinib,(1) dasatinib,(2) erlotinib,(3) gefitinib,(4) neratinib,(5) nilotinib(6), pazopanib,(7) and pexidartinib;(8) however, separation of administration times is required. If antacids are used, separate the administration times by several hours(1-8) but at least 2 hours for bosutinib,(1) dasatinib,(2) nilotinib,(6) and pexidartinib(8), 6 hours for gefitinib,(4) and 3 hours for neratinib.(5) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.

DISCUSSION: In a study in 24 healthy subjects, lansoprazole (60 mg) decreased bosutinib (400 mg single dose) area-under-curve (AUC) and maximum concentration (Cmax) by 26% and 46%, respectively.(1) 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.(2) In a study in 24 healthy subjects, administration of a single dose of dasatinib (50 mg) 10 hours after famotidine decreased dasatinib AUC and Cmax by 61% and 63%, respectively.(2) In a study, concurrent omeprazole decreased the AUC and Cmax of erlotinib by 46% and 61%, respectively.3) In a study, concurrent esomeprazole decreased the AUC of nilotinib by 34%.(6) 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.(5) There were no significant changes in nilotinib pharmacokinetics when famotidine was administered 10 hours before or 2 hours after nilotinib.(6) There were no significant changes in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered 2 hours before or after nilotinib.(6) Coadministration of esomeprazole decreased pexidartinib Cmax and AUC by 55% and 50%, respectively.(8)

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 Cyp3a4 Inducers/Rilpivirine

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 rilpivirine.(1)

CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers 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 DHHS HIV guidelines state that concurrent use of bosentan or mavacamten (moderate CYP3A4 inducers) with oral or intramuscular rilpivirine should be monitored closely. Consider alternative therapies that do not affect CYP3A4 or alternative antiretroviral agents. If concurrent use is necessary, virologic response should be monitored.(2) The US manufacturer of oral rilpivirine states that concurrent use of rifabutin (moderate CYP3A4 inducer) warrants dose adjustment. When administering moderate CYP3A4 inducers 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) Selected moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, eslicarbazepine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine and tovorafenib.(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)

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)

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• Lactation

• Biliary tract disorder
• Child-pugh class B hepatic impairment
• Chronic kidney disease stage 2 (mild) GFR 60-89 ml/min
• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Disease of liver
• Hyperbilirubinemia
• Pregnancy

• Kidney disease with likely reduction in glomerular filtration rate (GFr)

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More Frequent

• Abnormal hepatic function tests
• Anemia
• Hypercholesterolemia
• Hypophosphatemia
• Increased alanine transaminase
• Increased aspartate transaminase
• Lymphopenia
• Neutropenic disorder

Less Frequent

• Cholangitis
• Hyperbilirubinemia
• Reduced visual acuity
• Thrombocytopenic disorder

Rare or Very Rare

• Cholestasis
• Hepatocellular damage
• Vanishing bile duct syndrome

More Frequent

• Dysgeusia
• Eyelid edema
• Fatigue
• Hair discoloration
• Skin rash

Less Frequent

• Acute abdominal pain
• Acute cognitive impairment
• Alopecia
• Anorexia
• Blurred vision
• Constipation
• Diplopia
• Disturbance of attention
• Dizziness
• Dyschromia
• Fever
• Hypertension
• Hypoesthesia
• Memory impairment
• Nausea
• Papilledema
• Paresthesia
• Peripheral edema
• Peripheral neuropathy
• Photophobia
• Pruritus of skin
• Skin hypopigmentation
• Skin pigmentation enhancement
• Stinging of skin
• Stomatitis
• Vomiting
• Xerostomia

Rare or Very Rare

• Increased creatine kinase level
• Skin photosensitivity

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No enhanced messaging available.