Tracleer (bosentan)
PAH Agents- Endothelin Receptor Antagonists Oral Tablet; Oral Tablet For Suspension
Last reviewed · Source: First Databank (FDB) drug data
Overview
Bosentan, an endothelin-receptor antagonist, is a vasodilator.
Bosentan, an endothelin receptor antagonist, improves exercise capacity and hemodynamics in patients with pulmonary arterial hypertension (PAH) by inhibiting the vasoconstricting effects of endothelin-1. Endothelin-1 (ET-1) concentrations have been shown to be elevated in plasma and lung tissue of patients with PAH, suggesting a pathogenic role for ET-1 in this disorder. Two ET-1 receptor subtypes, type A and type B, have been identified; activation of ET-1 type A receptors mediates vasoconstriction and smooth muscle cell proliferation, while activation of ET-1 type B receptors results in vasodilation and facilitates clearance of ET-1.
Bosentan exhibits specific and competitive antagonism of both endothelin type A and type B receptors in the endothelium and vascular smooth muscle, with slightly greater affinity for ET-1 type A receptors. The clinical importance of selective versus nonselective endothelin receptor blockade is not known.
After oral administration, maximum plasma concentrations of bosentan are attained within 3-5 hours and the terminal elimination half-life is about 5 hours in healthy subjects. Peak plasma concentrations achieved with the dispersible tablet are approximately 14% lower than those observed with the film-coated tablet, and AUC is approximately 11% lower. The absolute bioavailability of bosentan is approximately 50%.
Bosentan is 98% protein-bound. Bosentan is metabolized by cytochrome P-450 (CYP) isoenzymes 2C9 and 3A. The drug is eliminated principally by biliary excretion following metabolism in the liver; less than 3% of an orally administered dose is recovered in urine.
Bosentan has been shown to induce CYP2C9 and CYP3A and may possibly induce CYP2C19. Bosentan appears to induce its own metabolism following oral administration of multiple doses of the drug. Exposure to bosentan reaches a plateau at lower doses in pediatric patients than in adults, and doses higher than 2 mg/kg twice daily do not increase the exposure to bosentan in pediatric patients.
USES: Bosentan is used to treat high blood pressure in the lungs (pulmonary arterial hypertension). This condition is thought to be caused by increased levels of a certain natural substance (endothelin-1). This medication blocks the effects of endothelin-1, which helps lower blood pressure in the lungs, slow the worsening of symptoms from the disease, and improve your ability to exercise.
Generic name: bosentan
Pronunciation: (boe-SEN-tan)
Drug class: PAH Agents- Endothelin Receptor Antagonists
Therapeutic class: Cardiovascular Therapy Agents
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Tracleer
Indications
The following indications are listed for Tracleer:
- Pulmonary Arterial Hypertension
Also known as: Hypertensive Pulmonary Arterial Disease, Pulmonary Hypertensive Arterial Disease.
Dosing
No dosing information is available for this tab.
No dosing information is available for this tab.
| Drug label | Dosing type | Instructions |
|---|---|---|
| Tracleer 62.5 Mg Tablet | Maintenance | Take 2 tablets (125 mg) by oral route 2 times per day in the morning and evening. |
| Tracleer 125 Mg Tablet | Maintenance | Take 1 tablet (125 mg) by oral route 2 times per day in the morning and evening. |
| Drug label | Dosing type | Instructions |
|---|---|---|
| Bosentan 62.5 Mg Tablet | Maintenance | Take 2 tablets (125 mg) by oral route 2 times per day in the morning and evening. |
| Bosentan 125 Mg Tablet | Maintenance | Take 1 tablet (125 mg) by oral route 2 times per day in the morning and evening. |
Drug interactions
There is no enhanced messaging for this drug.
Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
Ace Inhibitors; Arbs; Eras; Aliskiren/Sparsentan
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Sparsentan is an antagonist of the endothelin type A receptor and the angiotensin II type 1 receptor which are thought to contribute to the pathogenesis of IgA nephropathy.(1) Coadministration with renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs) may result in additive inhibition of angiotensin. RAAS inhibitors include ACE inhibitors, angiotensin II receptor blockers (ARBs), and aliskiren.
CLINICAL EFFECTS: Concurrent use of sparsentan with renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs) may result in hypotension, syncope, hyperkalemia, and changes in renal function (including renal failure).(1)
PREDISPOSING FACTORS: Patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion may be at risk of developing acute kidney injury on sparsentan.(1) Patients with advanced kidney disease or taking concomitant potassium-increasing drugs (e.g., potassium supplements, potassium-sparing diuretics), or using potassium-containing salt substitutes are at increased risk for developing hyperkalemia.(1)
PATIENT MANAGEMENT: Do not coadminister sparsentan with renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs). Prior to initiating treatment with sparsentan, discontinue use of renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs).(1) RAAS inhibitors include ACE inhibitors, angiotensin II receptor blockers (ARBs), and aliskiren.
DISCUSSION: The US manufacturer of sparsentan states that concomitant use of sparsentan with renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs) is contraindicated.(1) RAAS inhibitors include ACE inhibitors, angiotensin II receptor blockers (ARBs), and aliskiren.
Bosentan/Fluconazole
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Bosentan is metabolized by CYP2C9 and CYP3A4. It is also an inducer of these enzymes. With regular dosing bosentan auto-induces its own metabolism.(1) Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 and may inhibit the metabolism of bosentan.(1,2)
CLINICAL EFFECTS: Concurrent use of bosentan with fluconazole may result in elevated levels of and toxicity from bosentan.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of bosentan states that coadministration of bosentan and fluconazole is not recommended due to possible large increases in bosentan plasma concentrations.(1) For patients stabilized on bosentan when fluconazole is initiated, monitor tolerance to concomitant therapy and adjust bosentan dose if needed.
DISCUSSION: The combination of bosentan and fluconazole has not been studied. In a study in healthy subjects, concurrent bosentan and ketoconazole (a strong CYP3A4 inhibitor) administration increased bosentan steady-state maximum concentrations (Cmax) and area-under-curve (AUC) by 2.1-fold and 2.3-fold, respectively.(1)
Bosentan/Glyburide
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: The mechanism behind the increased risk of elevated liver aminotransferases is unknown.
CLINICAL EFFECTS: Concurrent use of bosentan and glyburide may increase the risk of liver enzyme elevations.(1,2)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturers of bosentan and glyburide state that the concurrent use of these agents is contraindicated(1,2) and that alternative hypoglycemic agents should be considered.(1)
DISCUSSION: An increased risk of liver enzyme elevation was seen in patients receiving concurrent bosentan and glyburide.(1,2)
Bosentan; Sitaxsentan/Cyclosporine
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Bosentan may induce the metabolism of cyclosporine by CYP3A4.(1) The exact mechanisms behind the increased levels of bosentan is unknown, but may involve competitive inhibition for CYP3A4.(1) The exact mechanism behind the increased levels of sitaxsentan is unknown;(2,3) however, sitaxsentan may be a substrate of the OATP transporter system.(2)
CLINICAL EFFECTS: Concurrent use of bosentan and cyclosporine may result in elevated levels of and effects from bosentan, including severe headache, nausea, and vomiting, and may increase the risk of liver damage. Concurrent use may result in decreased levels and effectiveness of cyclosporine.(1) Concurrent use of sitaxsentan and cyclosporine may result in elevated levels of and effects from sitaxsentan, including severe headache, nausea, and vomiting, and may increase the risk of liver damage.(2)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of bosentan states that the concurrent use of bosentan and cyclosporine is contraindicated.(1) The Canadian(3) and UK(2) manufacturers of sitaxsentan state that the concurrent use of sitaxsentan and cyclosporine is contraindicated.
DISCUSSION: On the first day of concurrent bosentan (500 mg and 1000 mg twice daily) and cyclosporine therapy, bosentan trough concentrations (Cmin) increased 30-fold. Steady-state bosentan concentrations were 3- to 4-fold higher during concurrent cyclosporine. Side effects reported during concurrent therapy included severe headache, nausea, and vomiting. Mild decreases in blood pressure and heart rate were observed. Cyclosporine concentrations were decreased by 50%.(1) In a study in healthy subjects, administration of bosentan (250 mg to 1000 mg twice daily) and cyclosporine (300 mg twice daily, adjusted to achieve a Cmin of 200-250 ng/ml) increased dose-normalized bosentan Cmin on Day 1 and Day 8 by approximately 21-fold and 2-fold, respectively, when compared to bosentan administration alone. Cyclosporine mean dose-normalized maximum concentration (Cmax), area-under-curve (AUC), and Cmin decreased by 30%, 50%, and 60%, respectively, when compared to cyclosporine administration alone.(4,5) Concurrent use of sitaxsentan (100 mg daily) and cyclosporine (3.5 mg/kg twice daily) increased the minimum concentration (Cmin) of sitaxsentan by 6-fold. There were no effects on cyclosporine clearance.(2,3)
Cyp3a4 Inducers/Lumateperone
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Lumateperone is a substrate of CYP3A4. Inducers of CYP3A4 may induce the metabolism of lumateperone.(1)
CLINICAL EFFECTS: The concurrent administration of a CYP3A4 inducer may decrease the exposure to lumateperone.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of lumateperone states that concurrent use with CYP3A4 inducers should be avoided.(1)
DISCUSSION: Coadministration of lumateperone with rifampin, a strong CYP3A4 inducer, resulted in a 98% reduction in area-under-curve (AUC) and a 90% reduction in concentration maximum (Cmax).(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, repotrectinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 include: amprenavir, armodafinil, aumolertinib, bexarotene, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, garlic, genistein, gingko, ginseng, glycyrrhizin, nevirapine, omaveloxolone, oxcarbazepine, pioglitazone, quercetin, rufinamide, sotorasib, sulfinpyrazone, sunvozertinib, tecovirimat, terbinafine, ticlopidine, troglitazone, vemurafenib, and vinblastine.(2,3)
Cyp3a4 Inducers/Zuranolone
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of zuranolone.(1)
CLINICAL EFFECTS: Concurrent use of a CYP3A4 inducer may result in a loss of zuranolone efficacy.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Avoid the concurrent use of zuranolone with CYP3A4 inducers.(1)
DISCUSSION: Coadministration of zuranolone with rifampin decreased the maximum concentration (Cmax) by 0.31-fold and area-under-curve (AUC) by 0.15-fold.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib. Weak CYP3A4 inducers linked to this monograph include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, flucloxacillin, garlic, genistein, ginseng, glycyrrhizin, methylprednisolone, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)
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)
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-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/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)
Strong Or Moderate Cyp3a4 Inducers/Vonoprazan
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Vonoprazan is a substrate of CYP3A4. Strong or moderate inducers of CYP3A4 may increase the metabolism of vonoprazan.(1)
CLINICAL EFFECTS: The concurrent administration of strong or moderate CYP3A4 inducers may result in decreased levels and effectiveness of vonoprazan.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of vonoprazan states that concurrent use with strong or moderate CYP3A4 inducers should be avoided.(1)
DISCUSSION: Strong CYP3A4 inducers like rifampin are predicted to decrease the area-under-curve (AUC) of vonoprazan by 80%, and moderate CYP3A4 inducers like efavirenz are predicted to decrease vonoprazan AUC by 50%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2-3)
Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
Bosentan/Camizestrant
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Camizestrant is a CYP3A4 substrate and strong inhibitor of CYP2C9.(1) Bosentan is a CYP2C9 substrate and moderate inducer of CYP3A4.(2) Agents that induce the CYP3A4 isoenzyme may induce the metabolism of camizestrant.(1) Strong CYP2C9 inhibitors may inhibit the CYP2C9 mediated metabolism of bosentan.(2)
CLINICAL EFFECTS: Concurrent use of camizestrant and bosentan may decrease the levels and effectiveness of camizestrant(1) while increasing levels and toxicity of bosentan.(2)
PREDISPOSING FACTORS: Concurrent use of bosentan, camizestrant, and a strong or moderate CYP3A4 inhibitor could lead to blockade of both major metabolic pathways for bosentan, resulting in large increases in bosentan plasma concentrations.(2,3)
PATIENT MANAGEMENT: The effect of the two-way inhibition and induction of camizestrant and bosentan metabolism is unknown. The optimal doses of camizestrant and bosentan when used concurrently have not been determined. Concurrent use should be avoided. Dose modifications mentioned below are informational only. Review the patient's medication list to see if the patient is also receiving a CYP3A4 inhibitor. Concomitant use of both a CYP2C9 and CYP3A4 inhibitor with bosentan is not recommended as the combination may lead to large increases in bosentan plasma concentrations.(2) For patients stabilized on bosentan when a CYP2C9 inhibitor is initiated, monitor tolerance to concomitant therapy and adjust bosentan dose if needed. The US manufacturer of camizestrant states that dosage recommendations for concomitant use of moderate CYP3A4 inducers differ depending on the CDK4/6 inhibitor used in combination with camizestrant: - Avoid concomitant use of moderate CYP3A4 inducers for patients who are receiving camizestrant in combination with abemaciclib and palbociclib. If concomitant use cannot be avoided, increase the camizestrant dosage from 75 mg once daily to 150 mg once daily for patients who are receiving camizestrant in combination with abemaciclib or palbociclib. 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. - No camizestrant dosage modification is recommended for patients who are receiving camizestrant in combination with ribociclib concomitantly with a moderate CYP3A4 inducer.(1)
DISCUSSION: The combined use of camizestrant and bosentan has not been studied. Camizestrant area-under-curve (AUC) is predicted to decrease to 43% and maximum concentration (Cmax) to 58% following concomitant administration of phenobarbital (moderate CYP3A4 inducer) 100 mg once daily for 17 days. Phenobarbital and efavirenz (moderate CYP3A inducers) are predicted to have minimal effects on camizestrant AUC and Cmax when camizestrant is given in combination with 400 mg or 600 mg ribociclib.(1) Camizestrant is predicted to increase the AUC and Cmax of warfarin (sensitive CYP2C9 substrate) by 13-fold and 1.1-fold, respectively, and of siponimod (moderately sensitive CYP2C9 substrate) by 5.3-fold and 1.1-fold, respectively.(1)
Bosentan/Cobicistat
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Cobicistat may inhibit the metabolism of bosentan by CYP3A4 and by inhibiting its uptake into hepatocytes by OATP.(1)
CLINICAL EFFECTS: Concurrent use of cobicistat without adjusting the dose of bosentan may result in elevated levels of and toxicity from bosentan.(1)
PREDISPOSING FACTORS: Concurrent use of bosentan, a CYP3A4 inhibitor and a CYP2C9 inhibitor (e.g. amiodarone, fluconazole, oxandrolone, or sulfinpyrazone)(3) could lead to blockade of both major metabolic pathways for bosentan, resulting in large increases in bosentan plasma concentrations.(3)
PATIENT MANAGEMENT: Review medication list to see if patient is also receiving a CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone, sulfinpyrazone, or phenylbutazone). Concomitant use of both a CYP2C9 and CYP3A4 inhibitor is not recommended by the manufacturer as the combination may lead to large increases in bosentan plasma concentrations.(1) For patients stabilized on bosentan when a CYP3A4 inhibitor is initiated, monitor tolerance to concomitant therapy and adjust bosentan dose if needed. In patients who have been receiving a strong CYP3A4 inhibitor for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of a strong CYP3A4 inhibitor. After at least 10 days following the initiation of a strong CYP3A4 inhibitor, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.)
DISCUSSION: In a study in healthy subjects, concurrent lopinavir/ritonavir increased the initial and steady-state minimum concentrations (Cmin) of bosentan by 48-fold and 5-fold, respectively. There were no significant effects on lopinavir/ritonavir pharmacokinetics.(2) Cobicistat inhibits CYP3A4 to a similar extent that ritonavir does.(1)
Bosentan/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) Bosentan is a substrate and moderate inducer of CYP2C9 and 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 bosentan.(2)
CLINICAL EFFECTS: Concurrent use of crizotinib and bosentan may decrease the levels and effectiveness of crizotinib(1) while increasing levels and toxicity of bosentan(2).
PREDISPOSING FACTORS: Concurrent use of bosentan, crizotinib, and a CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone, sulfinpyrazone, or phenylbutazone)(3) could lead to blockade of both major metabolic pathways for bosentan, resulting in large increases in bosentan plasma concentrations.(1,3)
PATIENT MANAGEMENT: Avoid the concurrent use of crizotinib and bosentan. Consider the use of alternative agents with less or no effect on the CYP3A4 enzyme.(1) Review medication list to see if patient is also receiving a CYP2C9 inhibitor. Concomitant use of both a CYP2C9 and CYP3A4 inhibitor is not recommended by the manufacturer as the combination may lead to large increases in bosentan plasma concentrations.(2) For patients stabilized on bosentan when a CYP3A4 inhibitor is initiated, monitor tolerance to concomitant therapy and adjust bosentan dose if needed.(2)
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) In a study in healthy subjects, concurrent bosentan and ketoconazole (a strong CYP3A4 inhibitor) administration increased bosentan steady-state Cmax and AUC by 2.1-fold and 2.3-fold, respectively.(2)
Bosentan/Duvelisib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Duvelisib and bosentan are both metabolized by CYP3A4. Bosentan is a moderate CYP3A4 inducer while duvelisib is a moderate CYP3A4 inhibitor.(1-2)
CLINICAL EFFECTS: The net effect of coadministration of duvelisib and bosentan on CYP3A4 enzyme activity is unknown. Concurrent or recent use of bosentan may either decrease the clinical effectiveness of duvelisib(1) or increase the levels and toxicities of bosentan.(2)
PREDISPOSING FACTORS: Concurrent use of bosentan, duvelisib, and a CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone, sulfinpyrazone, or phenylbutazone)(4) could lead to blockade of both major metabolic pathways for bosentan, resulting in large increases in bosentan plasma concentrations.(2)
PATIENT MANAGEMENT: There are no recommendations for concurrent use of duvelisib with bosentan. Concurrent therapy should be avoided. If use of this combination is necessary, the patient should be closely monitored for duvelisib efficacy and bosentan 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 bosentan makes the recommendations below for concurrent use with CYP3A4 inhibitors. Review medication list to see if patient is also receiving a CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone, sulfinpyrazone, or phenylbutazone). Concomitant use of both a CYP2C9 and CYP3A4 inhibitor is not recommended by the manufacturer as the combination may lead to large increases in bosentan plasma concentrations.(2) For patients stabilized on bosentan when a CYP3A4 inhibitor is initiated, monitor tolerance to concomitant therapy and adjust bosentan dose if needed.
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) In a study in healthy subjects, concurrent bosentan and ketoconazole (a strong CYP3A4 inhibitor) administration increased bosentan steady-state Cmax and AUC by 2.1-fold and 2.3-fold, respectively.(2)
Bosentan/Fedratinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Bosentan is metabolized by CYP2C9 and CYP3A4. It is also an inducer of these enzymes. With regular dosing bosentan auto-induces its own metabolism.(1) Moderate CYP3A4 inhibitors such as fedratinib may inhibit the CYP3A4 mediated metabolism of bosentan.(1,2) Fedratinib is a substrate of CYP3A4. Moderate CYP3A4 inducers such as bosentan may induce the metabolism of fedratinib.(2)
CLINICAL EFFECTS: Concurrent use of bosentan with an inhibitor of CYP3A4 such as fedratinib may result in elevated levels of and toxicity from bosentan.(1) The concurrent use of fedratinib with a moderate CYP3A4 inducer such as bosentan may result in decreased levels and effectiveness of fedratinib.(2)
PREDISPOSING FACTORS: Concurrent use of bosentan, a CYP3A4 inhibitor and a CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone, sulfinpyrazone, or phenylbutazone)(3) could lead to blockade of both major metabolic pathways for bosentan, resulting in large increases in bosentan plasma concentrations.(1,3)
PATIENT MANAGEMENT: The effect of the two-way inhibition and induction of fedratinib and bosentan metabolism is unknown. The optimal doses of fedratinib and bosentan when used concurrently have not been determined. Concurrent use should be avoided. Dose modifications mentioned below are informational only. The manufacturer of fedratinib states that concurrent use with moderate CYP3A4 inducers should be avoided.(2) In patients receiving bosentan, review medication list to see if patient is also receiving a CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone, sulfinpyrazone, or phenylbutazone). Concomitant use of both a CYP2C9 and CYP3A4 inhibitor is not recommended by the manufacturer of bosentan as the combination may lead to large increases in bosentan plasma concentrations.(1) For patients stabilized on bosentan when a CYP3A4 inhibitor is initiated, monitor tolerance to concomitant therapy and adjust bosentan dose if needed. In patients who have been receiving a strong CYP3A4 inhibitor for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of a strong CYP3A4 inhibitor. After at least 10 days following the initiation of a strong CYP3A4 inhibitor, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
DISCUSSION: In a study in healthy subjects, concurrent bosentan and ketoconazole (a strong CYP3A4 inhibitor) administration increased bosentan steady-state maximum concentrations (Cmax) and area-under-curve (AUC) by 2.1-fold and 2.3-fold, respectively.(1) The effect of CYP3A4 inducers has not been studied. Fedratinib is metabolized by CYP3A4.(2)
Bosentan/Hormonal Contraceptive Agents
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Bosentan may induce the metabolism of hormonal contraceptive agents by CYP3A4.(1,2)
CLINICAL EFFECTS: Concurrent use of bosentan and hormonal contraceptive agents may decrease the effectiveness of the hormonal contraceptive agent, which may result in contraceptive failure.(1,2) Bosentan is likely to cause major birth defects if used by pregnant women.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Women receiving bosentan therapy should not rely solely on hormonal contraceptive agents (including oral, implantable, injectable, or transdermal agents) because they may not be effective. Consider consulting a gynecologist or similar expert for advice on adequate contraception.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.
DISCUSSION: Concurrent use of bosentan and Ortho-Novum (norethindrone and ethinyl estradiol) resulted in average decreases of norethindrone and ethinyl estradiol by 14% and 31%, respectively. However, individual subjects experienced decreases in norethindrone and ethinyl estradiol by as much as 56% and 66%, respectively. Therefore, hormonal contraceptive agents may not be reliable in patients taking bosentan.(1,2)
Bosentan/Idelalisib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Bosentan is metabolized by CYP2C9 and CYP3A4. It is also an inducer of these enzymes. With regular dosing bosentan auto-induces its own metabolism.(1) Strong and moderate CYP3A4 inhibitors may inhibit the CYP3A4 mediated metabolism of bosentan.(1,2) Idelalisib is a strong CYP3A4 inhibitor.(3,4) Idelalisib is a substrate of CYP3A4. Agents that induce the CYP3A4 isoenzyme may induce the metabolism of idelalisib.(3)
CLINICAL EFFECTS: Concurrent use of bosentan with an inhibitor of CYP3A4 may result in elevated levels of and toxicity from bosentan.(1) Concurrent use of moderate CYP3A4 inducers may decrease the levels and effectiveness of idelalisib.(2)
PREDISPOSING FACTORS: Concurrent use of bosentan, idelalisib, and a CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone, sulfinpyrazone, or phenylbutazone)(3) could lead to blockade of both major metabolic pathways for bosentan, resulting in large increases in bosentan plasma concentrations.(1,3)
PATIENT MANAGEMENT: Avoid the concurrent use of bosentan, a moderate CYP3A4 inducer, in patients receiving therapy with idelalisib. Consider the use of alternative agents with less enzyme induction potential.(3) Review medication list to see if patient is also receiving a CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone, sulfinpyrazone, or phenylbutazone). Concomitant use of both a CYP2C9 and CYP3A4 inhibitor is not recommended by the manufacturer as the combination may lead to large increases in bosentan plasma concentrations.(1) For patients stabilized on bosentan when a CYP3A4 inhibitor is initiated, monitor tolerance to concomitant therapy and adjust bosentan dose if needed. In patients who have been receiving a strong CYP3A4 inhibitor for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of a strong CYP3A4 inhibitor. After at least 10 days following the initiation of a strong CYP3A4 inhibitor, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.(1)
DISCUSSION: In a study in healthy subjects, concurrent bosentan and ketoconazole (a strong CYP3A4 inhibitor) administration increased bosentan steady-state maximum concentrations (Cmax) and area-under-curve (AUC) by 2.1-fold and 2.3-fold, respectively.(2) In a study in healthy subjects, rifampin (600 mg daily for 8 days) decreased the concentration maximum (Cmax) and area-under-curve (AUC) of idelalisib (150 mg single dose) by 58% and 75%, respectively.(3)
Bosentan/Lenacapavir
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Lenacapavir and bosentan are both metabolized by CYP3A4. Bosentan is a moderate CYP3A4 inducer while lenacapavir is a moderate CYP3A4 inhibitor.(1-4)
CLINICAL EFFECTS: The net effect of coadministration of lenacapavir and bosentan on CYP3A4 enzyme activity is unknown. Concurrent or recent use of lenacapavir may either decrease the clinical effectiveness of lenacapavir(1-3) or increase the levels and toxicities of bosentan.(4)
PREDISPOSING FACTORS: Concurrent use of bosentan, lenacapavir, and a CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone, sulfinpyrazone, or phenylbutazone)(6) could lead to blockade of both major metabolic pathways for bosentan, resulting in large increases in bosentan plasma concentrations.(4)
PATIENT MANAGEMENT: There are no recommendations for concurrent use of lenacapavir with bosentan. Concurrent therapy is not recommended. If use of this combination is necessary, the patient should be closely monitored for lenacapavir efficacy and bosentan toxicity. The manufacturer of lenacapavir states that 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 bosentan makes the recommendations below for concurrent use with CYP3A4 inhibitors. Review medication list to see if patient is also receiving a CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone, sulfinpyrazone, or phenylbutazone). Concomitant use of both a CYP2C9 and CYP3A4 inhibitor is not recommended by the manufacturer as the combination may lead to large increases in bosentan plasma concentrations.(4) For patients stabilized on bosentan when a CYP3A4 inhibitor is initiated, monitor tolerance to concomitant therapy and adjust bosentan dose if needed.
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.(1-3) In a study in healthy subjects, concurrent bosentan and ketoconazole (a strong CYP3A4 inhibitor) administration increased bosentan steady-state Cmax and AUC by 2.1-fold and 2.3-fold, respectively.(4)
Bosentan/Leniolisib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: OATP1B1 inhibitors such as leniolisib may decrease the hepatic uptake of bosentan.(1,2) Moderate CYP3A4 inducers such as bosentan may increase the metabolism of leniolisib.(1,2)
CLINICAL EFFECTS: Concurrent use of an inhibitor of OATP1B1 may result in elevated levels of and side effects from bosentan.(1) Concurrent use of a moderate CYP3A4 inducer may decrease the serum levels and effectiveness of leniolisib.(2)
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 leniolisib with substrates of BCRP, OATP1B1, and OATP1B3 such as bosentan should be avoided.(1) Avoid concomitant use of leniolisib with moderate CYP3A4 inducers.(2)
DISCUSSION: Bosentan is a substrate of OATP1B1.(4) 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)
Bosentan/Protease Inhibitors
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Protease inhibitors may inhibit the metabolism of bosentan by CYP3A4 and by inhibiting its uptake into hepatocytes by OATP.(1-11) Bosentan may induce the metabolism of atazanavir.(2)
CLINICAL EFFECTS: Concurrent use of protease inhibitors without adjusting the dose of bosentan may result in elevated levels of and toxicity from bosentan.(1) Administration of bosentan and atazanavir without ritonavir may result in decreased levels of atazanavir.(2)
PREDISPOSING FACTORS: Concurrent use of bosentan, a protease inhibitor that is a CYP3A4 inhibitor and a CYP2C9 inhibitor (e.g. amiodarone, fluconazole, oxandrolone, or sulfinpyrazone)(12) could lead to blockade of both major metabolic pathways for bosentan, resulting in large increases in bosentan plasma concentrations.(12)
PATIENT MANAGEMENT: In patients who have been receiving a protease inhibitor for at least 10 days, initiate bosentan at a dosage of 62.5 mg once daily or every other day based on tolerability.(1-11) In patients who have been receiving bosentan, discontinue bosentan for at least 36 hours prior to initiating atazanavir, darunavir, ensitrelvir, fosamprenavir, lopinavir/ritonavir, nirmatrelvir/ritonavir, ritonavir, saquinavir, or tipranavir. After 10 days of protease inhibitor therapy, bosentan may be resumed at a dosage of 62.5 mg once daily or every other day based on tolerability.(1-8,11) In patients who have been receiving bosentan, adjust the dosage of bosentan to 62.5 mg once daily or every other day based on tolerability in patients who have been receiving indinavir or nelfinavir.(9-10) Review medication list to see if patient is also receiving a CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone, sulfinpyrazone, or phenylbutazone). Concomitant use of both a CYP2C9 and CYP3A4 inhibitor is not recommended by the manufacturer as the combination may lead to large increases in bosentan plasma concentrations.(1)
DISCUSSION: In a study in healthy subjects, concurrent lopinavir/ritonavir increased the initial and steady-state minimum concentrations (Cmin) of bosentan by 48-fold and 5-fold, respectively. There were no significant effects on lopinavir/ritonavir pharmacokinetics.(1) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Bosentan/Rilzabrutinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Bosentan is metabolized by CYP2C9 and CYP3A4. It is also an inducer of these enzymes. With regular dosing bosentan auto-induces its own metabolism.(1) Moderate CYP3A4 inhibitors such as rilzabrutinib may inhibit the CYP3A4 mediated metabolism of bosentan.(1,2) Rilzabrutinib is a substrate of CYP3A4. Moderate CYP3A4 inducers such as bosentan may induce the metabolism of rilzabrutinib.(2)
CLINICAL EFFECTS: Concurrent use of bosentan with an inhibitor of CYP3A4 such as rilzabrutinib may result in elevated levels of and toxicity from bosentan.(1) The concurrent use of rilzabrutinib with a moderate CYP3A4 inducer such as bosentan may result in decreased levels and effectiveness of rilzabrutinib.(2)
PREDISPOSING FACTORS: Concurrent use of bosentan, a CYP3A4 inhibitor and a CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone, sulfinpyrazone, or phenylbutazone)(3) could lead to blockade of both major metabolic pathways for bosentan, resulting in large increases in bosentan plasma concentrations.(1,3)
PATIENT MANAGEMENT: The effect of the two-way inhibition and induction of rilzabrutinib and bosentan metabolism is unknown. The optimal doses of rilzabrutinib and bosentan when used concurrently have not been determined. Concurrent use should be avoided. Dose modifications mentioned below are informational only. The manufacturer of rilzabrutinib states that concurrent use with moderate CYP3A4 inducers should be avoided.(2) In patients receiving bosentan, review medication list to see if patient is also receiving a CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone, sulfinpyrazone, or phenylbutazone). Concomitant use of both a CYP2C9 and CYP3A4 inhibitor is not recommended by the manufacturer of bosentan as the combination may lead to large increases in bosentan plasma concentrations.(1) For patients stabilized on bosentan when a CYP3A4 inhibitor is initiated, monitor tolerance to concomitant therapy and adjust bosentan dose if needed.
DISCUSSION: In a study in healthy subjects, concurrent bosentan and ketoconazole (a strong CYP3A4 inhibitor) administration increased bosentan steady-state maximum concentrations (Cmax) and area-under-curve (AUC) by 2.1-fold and 2.3-fold, respectively.(1) 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.(2)
Bosentan/Strong And Moderate Cyp2c9 Inhibitors
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Bosentan is metabolized by CYP2C9 and CYP3A4. It is also an inducer of these enzymes. With regular dosing bosentan auto-induces its own metabolism.(1) Strong and moderate CYP2C9 inhibitors may inhibit the CYP2C9 mediated metabolism of bosentan.(1-2)
CLINICAL EFFECTS: Concurrent use of bosentan with an inhibitor of CYP2C9 may result in elevated levels of and toxicity from bosentan.(1)
PREDISPOSING FACTORS: Concurrent use of bosentan, a CYP2C9 inhibitor and a CYP3A4 inhibitor could lead to blockade of both major metabolic pathways for bosentan, resulting in large increases in bosentan plasma concentrations.
PATIENT MANAGEMENT: Review medication list to see if patient is also receiving a CYP3A4 inhibitor (e.g. aprepitant, boceprevir, ceritinib, ciprofloxacin, clarithromycin, conivaptan, crizotinib, cyclosporine, darunavir, diltiazem, dronedarone, erythromycin, fluconazole, fosaprepitant, idelalisib, imatinib, isavuconazole, itraconazole, ketoconazole, letermovir, mibefradil, nefazodone, netupitant, nilotinib, posaconazole, ribociclib, telaprevir, telithromycin, troleandomycin, verapamil, and voriconazole). Concomitant use of both a CYP2C9 and CYP3A4 inhibitor is not recommended by the manufacturer as the combination may lead to large increases in bosentan plasma concentrations.(1) For patients stabilized on bosentan when a CYP2C9 inhibitor is initiated, monitor tolerance to concomitant therapy and adjust bosentan dose if needed. The manufacturer of nitisinone recommends reducing the dosage of a CYP2C9 substrate like bosentan by one-half.(3)
DISCUSSION: Concurrent use with CYP2C9 inhibitors has not been studied. In a study in healthy subjects, concurrent bosentan and ketoconazole (a strong CYP3A4 inhibitor) increased bosentan steady-state maximum concentrations (Cmax) and area-under-curve (AUC) by 2.1-fold and 2.3-fold, respectively.(2) Strong CYP2C9 inhibitors linked to this monograph include: miconazole.(4) Moderate CYP2C9 inhibitors linked to this monograph include: amiodarone, apazone, asciminib, benzbromarone, nitisinone, oxandrolone, piperine, sulfaphenazole, and phenylbutazone.(4)
Bosentan/Strong And Moderate Cyp3a4 Inhibitors
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Bosentan is metabolized by CYP2C9 and CYP3A4. It is also an inducer of these enzymes. With regular dosing bosentan auto-induces its own metabolism.(1) Strong and moderate CYP3A4 inhibitors may inhibit the CYP3A4 mediated metabolism of bosentan.(1,2)
CLINICAL EFFECTS: Concurrent use of bosentan with an inhibitor of CYP3A4 may result in elevated levels of and toxicity from bosentan.(1)
PREDISPOSING FACTORS: Concurrent use of bosentan, a CYP3A4 inhibitor and a CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone, sulfinpyrazone, or phenylbutazone)(3) could lead to blockade of both major metabolic pathways for bosentan, resulting in large increases in bosentan plasma concentrations.(1,3)
PATIENT MANAGEMENT: Review medication list to see if patient is also receiving a CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone, sulfinpyrazone, or phenylbutazone). Concomitant use of both a CYP2C9 and CYP3A4 inhibitor is not recommended by the manufacturer as the combination may lead to large increases in bosentan plasma concentrations.(1) For patients stabilized on bosentan when a CYP3A4 inhibitor is initiated, monitor tolerance to concomitant therapy and adjust bosentan dose if needed. In patients who have been receiving a strong CYP3A4 inhibitor for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of a strong CYP3A4 inhibitor. After at least 10 days following the initiation of a strong CYP3A4 inhibitor, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
DISCUSSION: In a study in healthy subjects, concurrent bosentan and ketoconazole (a strong CYP3A4 inhibitor) administration increased bosentan steady-state maximum concentrations (Cmax) and area-under-curve (AUC) by 2.1-fold and 2.3-fold, respectively.(2) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, itraconazole, josamycin, ketoconazole, levoketoconazole, mibefradil, mifepristone, nefazodone, posaconazole, relacorilant, ribociclib, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(3) Moderate CYP3A4 inhibitors linked to this monograph include: aprepitant, berotralstat, clofazimine, conivaptan, diltiazem, dronedarone, erythromycin, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, letermovir, netupitant, nilotinib, schisandra, stiripentol, treosulfan, and verapamil.(3)
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/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/Iv And Oral Lefamulin
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Lefamulin is a substrate of CYP3A4. Moderate inducers of CYP3A4 may induce the metabolism of lefamulin.(1) Oral lefamulin tablets may inhibit the metabolism of agents that are also sensitive CYP3A4 substrates.(1-3)
CLINICAL EFFECTS: The concurrent administration of a moderate CYP3A4 inducer may result in decreased levels and effectiveness of lefamulin.(1) Coadministration of oral lefamulin with agents that are also sensitive CYP3A4 substrates may result in elevated levels and toxicities of the sensitive CYP3A4 substrate.
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of lefamulin states that concurrent use with moderate CYP3A4 inducers should be avoided.(1) Concomitant use of lefamulin tablets with sensitive CYP3A4 substrates requires close monitoring for adverse effects of these drugs.(1)
DISCUSSION: In a study, concurrent administration of rifampin (a strong inducer) with lefamulin injection decreased lefamulin area-under-the-curve (AUC) and maximum concentration (Cmax) by 28% and 8%.(1) In a study, concurrent administration of rifampin (a strong inducer) with oral lefamulin (tablets) decreased lefamulin AUC and Cmax by 72% and 57%.(1) In a study, oral lefamulin tablets administered concomitantly with and at 2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200% and 100%, respectively. No clinically significant effect on midazolam pharmacokinetics was observed when co-administered with lefamulin injection.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, lesinurad, lorlatinib, modafinil, nafcillin, rifabutin, telotristat, and tovorafenib.(2-3)
Moderate Cyp3a4 Inducers/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)
Selected Strong Or Moderate Cyp3a4 Inducers/Voxelotor
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Voxelotor is a substrate of CYP3A4. Strong or moderate inducers of CYP3A4 may induce the metabolism of voxelotor.(1)
CLINICAL EFFECTS: The concurrent administration of strong or moderate CYP3A4 inducers may result in decreased levels and effectiveness of voxelotor.(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 voxelotor states that concurrent use with strong or moderate CYP3A4 inducers should be avoided. If concomitant use is unavoidable, increase the dose of voxelotor as follows: Patients 12 years and older on concurrent strong CYP3A4 inducers: increase voxelotor dose to 2,500 mg daily. Patients 12 years and older on concurrent moderate CYP3A4 inducers: increase voxelotor dose to 2,000 mg daily. Patients 4 years to less than 12 years on concurrent strong or moderate CYP3A4 inducers: refer to prescribing information for recommended weight-based dosage adjustments.(1)
DISCUSSION: A pharmacokinetic model predicted that co-administration of rifampin, a strong CYP3A4 inducer, would decrease the area-under-curve (AUC) of voxelotor by 40%. Co-administration of efavirenz, a moderate CYP3A4 inducer, is predicted to decrease the AUC of voxelotor by 24%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, lesinurad, lorlatinib, modafinil, nafcillin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2-3)
Str Or Mod 3A4 Inducer & Substrate/Vonoprazan-Clarithro-Amox
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Bosentan, carbamazepine, dabrafenib, elagolix, ivosidenib, lorlatinib, lumacaftor, and mitapivat are both moderate to strong inducers and substrates of CYP3A4.(1,2) Moderate and strong inducers of CYP3A4 may increase the CYP3A4-mediated metabolism of vonoprazan and clarithromycin.(3) Clarithromycin is a strong inhibitor of CYP3A4 and may decrease the metabolism of CYP3A4 substrates.(3)
CLINICAL EFFECTS: Concurrent use of moderate to strong CYP3A4 inducers may result in decreased levels and effectiveness of vonoprazan and clarithromycin.(3) Concurrent use of CYP3A4 substrates with clarithromycin may result in elevated levels of and toxicity from the substrate.(3)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of vonoprazan states that concurrent use with strong or moderate CYP3A4 inducers should be avoided.(3)
DISCUSSION: Vonoprazan and clarithromycin are CYP3A4 substrates. Strong CYP3A4 inducers like rifampin are predicted to decrease the area-under-curve (AUC) of vonoprazan by 80%, and moderate CYP3A4 inducers like efavirenz are predicted to decrease vonoprazan AUC by 50%.(1) Strong inducers of CYP3A4 that are CYP3A4 substrates include: carbamazepine, ivosidenib, and lumacaftor. Moderate inducers of CYP3A4 that are CYP3A4 substrates include: bosentan, dabrafenib, elagolix, lorlatinib, mitapivat, and rifabutin.(2-3)
Strong & Moderate Cyp3a4 Inducers/Guanfacine
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Strong or moderate inducers of CYP3A4 may induce the metabolism of guanfacine.(1)
CLINICAL EFFECTS: The concurrent administration of a strong or moderate CYP3A4 inducer may result in decreased levels and effectiveness of guanfacine.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Patients maintained on guanfacine may need dosage adjustments if strong or moderate inducers of CYP3A4 are initiated or discontinued. The manufacturer of extended-release guanfacine recommends a starting dose of extended-release guanfacine initiated at up to double the recommended level of the weight based dosing in patients receiving strong or moderate inducers of CYP3A4. If a patient has been maintained on extended-release guanfacine and is started on a strong or moderate CYP3A4 inducer, the dose of extended-release guanfacine should be increased up to double the recommended weight based dose over 1 to 2 weeks. If a patient has been maintained on extended-release guanfacine and a strong or moderate CYP3A4 inducer, and the strong or moderate CYP3A4 inducer is discontinued, the dose of extended-release guanfacine may need to be decreased to the recommended weight based dose over 1 to 2 weeks. Extended-release guanfacine target dose range for attention deficit hyperactivity disorder is 0.05-0.12 mg/kg/day. Doses above 4 mg/day have not been evaluated in children ages 6-12 years and doses above 7 mg/day have not been evaluated in adolescents ages 13-17 years.(1)
DISCUSSION: Rifampin (dosage not stated), a strong inducer of CYP3A4, decreased the maximum concentration (Cmax) and area-under-curve (AUC) of guanfacine (dosage not stated) by approximately 50%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(1-3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine, and tovorafenib.(1-3)
Strong & Moderate Cyp3a4 Inducers/Olaparib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Agents that induce the CYP3A4 isoenzyme may induce the metabolism of olaparib.(1)
CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inducers may decrease the levels and effectiveness of olaparib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Avoid the concurrent use of strong or moderate CYP3A4 inducers in patients receiving therapy with olaparib.(1) Consider the use of alternatives with little to no induction potential.
DISCUSSION: In a drug interaction trial, olaparib area-under-curve (AUC) and maximum concentration (Cmax) decreased 87% and 71% respectively when olaparib was administered with rifampin. Based upon simulated models, a moderate CYP3A4 inducer is predicted to decrease olaparib AUC by 50-60% and Cmax by 20-30%.(1-3) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate inducers of CYP3A4 include: bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(4-5)
Strong And Moderate Cyp3a4 Inducers/Cariprazine
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Cariprazine and its major active metabolite DDCAR are metabolized by CYP3A4. Strong and moderate inducers of CYP3A4 may accelerate the metabolism of cariprazine.(1-4)
CLINICAL EFFECTS: Concurrent use of a strong or moderate inducer of CYP3A4 may result in decreased levels and effectiveness of cariprazine.(1-4)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The US manufacturer of cariprazine does not recommend concurrent use of strong CYP3A4 inducers.(1) The Australian, Canadian, and UK manufacturers of cariprazine state that concurrent use of strong and moderate CYP3A4 inducers is contraindicated.(2-4)
DISCUSSION: Cariprazine and its active metabolites are primarily metabolized by CYP3A4. Coadministration with CYP3A4 inducers has not been studied and the net effect is unclear. Due to the long half life of the active metabolites, it takes several weeks for cariprazine to reach steady state after dosage changes.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(5-6) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(5-6)
Strong And Moderate Cyp3a4 Inducers/Pimavanserin
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Strong or moderate inducers of CYP3A4 may induce the metabolism of pimavanserin.(1)
CLINICAL EFFECTS: Concurrent use of a strong or moderate inducer of CYP3A4 may result in decreased levels and effectiveness of pimavanserin.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The US manufacturer of pimavanserin recommends avoiding concomitant use of strong or moderate CYP3A4 inducers.(1)
DISCUSSION: Pimavanserin is primarily metabolized by CYP3A4 while other metabolic enzymes CYP2J2, CYP2D6 and FMO play a lesser role.(1) In a study of subjects pretreated with 7 days of rifampin (600 mg daily, a strong CYP3A4 inducer), a single dose of pimavanserin (34 mg) produced an area-under-curve (AUC) and maximum concentration (Cmax) that was 91 % and 71 % lower, respectively, than when pimavanserin is given without rifampin.(1) A physiology-based pharmacokinetic model predicted that efavirenz (a moderate CYP3A4 inducer) would decrease pimavanserin AUC and Cmax by 70 % and 60 %, respectively.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(3-4) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, and tovorafenib.(3-4)
Strong And Moderate Cyp3a4 Inducers/Pretomanid
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Strong and moderate CYP3A4 inducers may induce the metabolism of pretomanid by CYP3A4.(1)
CLINICAL EFFECTS: The concurrent use of strong and moderate CYP3A4 inducers and pretomanid may result in decreased levels and clinical effectiveness of pretomanid.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of pretomanid recommends avoiding concurrent use with strong or moderate CYP3A4 inducers during pretomanid therapy.(1) Patients receiving concurrent therapy with strong and moderate CYP3A4 inducers and pretomanid should be observed for decreased levels and clinical effectiveness.
DISCUSSION: In a clinical study, concurrent use of pretomanid 200 mg with efavirenz 600 mg for 7 days resulted in decreased mean area-under-curve (AUC) by 35% and maximum concentration (Cmax) by 28%.(1) In a clinical study, concurrent use of pretomanid 200 mg with rifampin 600 mg for 7 days resulted in decreased mean AUC by 66% and Cmax by 53%.(1) Strong and moderate CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate, dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, etravirine, fexinidazole, fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin, rifapentine, St. John's wort, sotorasib, telotristat, thioridazine, and tovorafenib.(1,2)
Strong 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.
Bcrp Or Oatp1b1 Substrates/Eltrombopag
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Eltrombopag has been shown to inhibit BCRP and OATP1B1.(1-3) Inhibition of BCRP may increase absorption and/or decrease biliary excretion of substrates, while inhibition of OATP1B1 may decrease hepatic uptake of substrates.
CLINICAL EFFECTS: Simultaneous use of eltrombopag with BCRP or OATP1B1 substrates may result in increased levels and side effects from the substrates.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of eltrombopag states that concomitant BCRP or OATP1B1 substrates should be used cautiously. Patients on concurrent therapy should be closely monitored for adverse effects, and dose reduction of the substrate should be considered.(1)
DISCUSSION: In a clinical trial in 39 healthy subjects, administration of eltrombopag (75 mg daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of rosuvastatin (10 mg, a BCRP and OATP1B1 substrate) by 55% and 103%, respectively.(1,4) In a physiologically-based pharmacokinetic (PBPK) model, eltrombopag 75 mg was predicted to increase the AUC and Cmax of pitavastatin 1 mg by approximately 2-fold.(5) BCRP substrates linked to this monograph include: imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, and topotecan.(1) OATP1B1 substrates linked to this monograph include: atorvastatin, bosentan, fluvastatin, glyburide, irinotecan, letermovir, pitavastatin, pravastatin, repaglinide, and simvastatin.(1)
Moderate And Weak Cyp3a4 Inducers/Tacrolimus
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 accelerate the metabolism of tacrolimus.(1)
CLINICAL EFFECTS: Concurrent use of a moderate or weak CYP3A4 inducer may result in decreased levels and effectiveness of tacrolimus.(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 tacrolimus recommends monitoring tacrolimus whole blood trough concentrations and adjusting tacrolimus dose if needed. Monitor clinical response closely.(1)
DISCUSSION: A 13-year-old cystic fibrosis patient with a history of liver transplant on stable doses of tacrolimus underwent 2 separate courses of nafcillin therapy (a moderate CYP3A4 inducer). During the 1st course of nafcillin, his tacrolimus levels started to fall 3 days after starting nafcillin, became undetectable at day 8, and recovered to therapeutic levels without a change in tacrolimus dose 5 days after discontinuation of nafcillin. During the 2nd course of nafcillin, tacrolimus level became undetectable 4 days after starting nafcillin and recovered 3 days after stopping nafcillin.(2) 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, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, modafinil, nafcillin, repotrectinib, telotristat, and tovorafenib.(3,4) 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, darolutamide, dexamethasone, dicloxacillin, echinacea, elafibranor, enasidenib, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, meropenem-vaborbactam, nevirapine, oritavancin, omaveloxolone, oxcarbazepine, pioglitazone, relugolix, rufinamide, sulfinpyrazone, sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vinblastine, and zanubrutinib.(3,4)
Moderate And Weak Cyp3a4 Inducers/Ubrogepant
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate or weak CYP3A4 inducers may induce the metabolism of ubrogepant.(1)
CLINICAL EFFECTS: Concurrent use of a moderate or weak CYP3A4 inducer may result in decreased levels and effectiveness of ubrogepant.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when coadministered with moderate or weak CYP3A4 inducers. Initial dose of ubrogepant should be 100 mg. If a second dose is needed, the dose of ubrogepant should be 100 mg.(1)
DISCUSSION: Coadministration of ubrogepant with rifampin, a strong CYP3A4 inducer, resulted in an 80% reduction in ubrogepant exposure. No dedicated drug interaction studies were conducted to assess concomitant use with moderate or weak CYP3A4 inducers. Dose adjustment for concomitant use of ubrogepant with moderate or weak CYP3A4 inducers is recommended based on a conservative prediction of 50% reduction in exposure of ubrogepant.(1) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, dexamethasone, dicloxacillin, echinacea, elafibranor, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, meropenem-vaborbactam, methylprednisolone, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, relugolix, repotrectinib, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)
Moderate Cyp3a4 Inducers/Aficamten
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Aficamten is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of aficamten.(1)
CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may decrease the levels and effectiveness of aficamten and increase the risk of developing heart failure due to systolic dysfunction.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: In patients who are on stable concurrent therapy with aficamten and a moderate to strong CYP3A4 inducer, reduce the dose of aficamten when discontinuing the inducer as follows: -If the current dose is 20 mg daily, reduce to 10 mg daily. -If the current dose is 15 mg daily, reduce to 5 mg daily. -If the current dose is 10 mg daily, reduce to 5 mg daily. -If the current dose is 5 mg daily, maintain 5 mg daily. Assess LVEF 2 to 8 weeks after discontinuation of such inducers and adjust the dose of aficamten accordingly.(1)
DISCUSSION: In a study, carbamazepine (moderate to strong CYP3A4 inducer, weak CYP2C9 inducer) decreased aficamten's area-under-curve (AUC) 51%.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Crinecerfont
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of crinecerfont.(1)
CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may reduce the clinical effectiveness of crinecerfont.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The US manufacturer of crinecerfont states that concurrent use of moderate CYP3A4 inducers requires a dose adjustment of crinecerfont. Increase the evening dose of crinecerfont by 2-fold. Do not increase the morning dose. In adults, increase the dosage of crinecerfont to 100 mg in the morning and 200 mg in the evening. In pediatric patients 4 years and older weighing: - 10 kg to <20 kg: increase the crinecerfont dosage to 25 mg in the morning and 50 mg in the evening, - 20 kg to <55 kg: increase the crinecerfont dosage to 50 mg in the morning and 100 mg in the evening, - >=55 kg: increase the crinecerfont dosage to 100 mg in the morning and 200 mg in the evening.(1)
DISCUSSION: In a study, concomitant use of rifampin (strong CYP3A4 inducer) decreased crinecerfont maximum concentration (Cmax) by 23% and area-under-curve (AUC) by 62%.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Daclatasvir
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of daclatasvir.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inducer of CYP3A4 without a dosage adjustment of daclatasvir is expected to reduce levels and effectiveness of daclatasvir.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The dose of daclatasvir should be increased to 90 mg once daily in patients receiving moderate inducers of CYP3A4.(1)
DISCUSSION: Efavirenz (600 mg daily) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of daclatasvir by 17%, 32%, and 59%, respectively.(1) Moderate inducers of CYP3A4 include belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(1-3)
Moderate Cyp3a4 Inducers/Daraxonrasib (>= 400 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Daraxonrasib is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of daraxonrasib.(1)
CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of daraxonrasib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of daraxonrasib states that concomitant use of moderate CYP3A4 inducers requires a dose increase of daraxonrasib to 400 mg once daily.(1)
DISCUSSION: In a clinical study, daraxonrasib area-under-curve (AUC) is predicted to decrease by 50-84% with concomitant use of efavirenz 600 mg once daily and modafinil 400 mg once daily (moderate CYP3A4 inducers).(1) Moderate CYP3A4 inducers linked to this monograph include: asunaprevir, belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lopinavir, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/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)
Oatp1b1 Substrates/Midostaurin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Midostaurin has been shown to inhibit OATP1B1.(1) Inhibition of OATP1B1 may decrease hepatic uptake of substrates.
CLINICAL EFFECTS: Simultaneous use of midostaurin with OATP1B1 substrates may result in increased levels and side effects from the substrates.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of midostaurin states that concomitant OATP1B1 substrates should be used cautiously. Patients on concurrent therapy should be closely monitored for adverse effects as dose adjustments of the substrate may be necessary.(1)
DISCUSSION: In a study, single dose midostaurin 100 mg increased the area-under-curve (AUC) of single dose rosuvastatin by 48%. With a 50 mg twice daily dose, midostaurin is predicted to increase the AUC of an OATP1B1 substrate by up to 2-fold.(1) OATP1B1 substrates linked to this monograph include: atorvastatin, bosentan, fluvastatin, glyburide, irinotecan, letermovir, pitavastatin, pravastatin, repaglinide, rosuvastatin and simvastatin.
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 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)
Contraindications
*Known pregnancy.
*Concomitant therapy with cyclosporine or glyburide.
*Known hypersensitivity to bosentan or any ingredient in the formulation.
- Pregnancy
- Pulmonary veno-occlusive disease
- Acute decompensated heart failure
- Disease of liver
- Pulmonary edema
- Anemia
- Edema
- Thrombocytopenic disorder
Adverse reactions
Common adverse effects (>=3%) reported with bosentan tablets in clinical studies include respiratory tract infection and anemia. Adverse effects occurring in >=15% of patients who received the dispersible tablet include upper respiratory tract infection and pyrexia.
More Frequent
- Anemia
Less Frequent
- Abnormal hepatic function tests
- Edema
- Increased alanine transaminase
- Increased aspartate transaminase
- Palpitations
- Worsening of chronic heart failure
Rare or Very Rare
- Angioedema
- DRESS syndrome
- Eosinophilia
- Hepatic cirrhosis
- Hepatic failure
- Hepatocellular damage
- Hyperbilirubinemia
- Hypersensitivity drug reaction
- Jaundice
- Leukopenia
- Neutropenic disorder
- Skin rash
- Thrombocytopenic disorder
More Frequent
- Fever
- Flushing
- Headache disorder
- Upper respiratory infection
Less Frequent
- Arthralgia
- Body fluid retention
- Chest pain
- Hypotension
- Peripheral edema
- Sinusitis
- Syncope
Rare or Very Rare
- Autoimmune hepatitis
- Nasal congestion
- Oligospermia
Precautions
No enhanced messaging available.
The efficacy of bosentan in patients <18 years of age is supported by an uncontrolled trial in which 19 pediatric patients were treated with the drug. In this study, hemodynamic improvements were similar to those seen in adults treated with bosentan. The safety of bosentan in pediatric patients is supported by data from 100 pediatric patients treated with bosentan for a median of 17 months.
Based on data from animal reproduction studies, bosentan may cause fetal harm, including birth defects and fetal death; bosentan is contraindicated during pregnancy. Limited data from postmarketing reports and published literature in humans involving endothelin receptor antagonists have not identified an increased risk of major birth defects. Studies in pregnant rats found that bosentan at 2 times the maximum recommended human dose caused teratogenic effects, including malformations of the head, mouth, face, and large blood vessels.
A single case report describes the presence of bosentan in human milk. Insufficient information exists to determine the effects of bosentan on the breastfeeding infant or on milk production. Because of the potential for serious adverse reactions to bosentan in breastfed infants (e.g., fluid retention, hepatotoxicity), advise patients not to breastfeed during treatment with bosentan.
The manufacturer makes no specific dosage recommendations for geriatric patients.
Experience with bosentan in patients 65 years of age and older is insufficient to determine whether they respond differently than younger adults.
ICD codes
| Code | Type | Description |
|---|---|---|
| Pulmonary arterial hypertension | ||
| I27.0 | ICD10CM | Primary pulmonary hypertension |
| I27.21 | ICD10CM | Secondary pulmonary arterial hypertension |
ICD code information from First Databank (FDB).
Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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