Please wait while the formulary information is being retrieved.
Drug overview for XTANDI (enzalutamide):
Generic name: ENZALUTAMIDE (EN-za-LOO-ta-mide)
Drug class: Antiandrogen
Therapeutic class: Antineoplastics
Enzalutamide, a nonsteroidal antiandrogen, is an antineoplastic agent.
No enhanced Uses information available for this drug.
Generic name: ENZALUTAMIDE (EN-za-LOO-ta-mide)
Drug class: Antiandrogen
Therapeutic class: Antineoplastics
Enzalutamide, a nonsteroidal antiandrogen, is an antineoplastic agent.
No enhanced Uses information available for this drug.
DRUG IMAGES
XTANDI 40 MG CAPSULE
XTANDI 40 MG TABLET
XTANDI 80 MG TABLET
The following indications for XTANDI (enzalutamide) have been approved by the FDA:
Indications:
Castration-resistant prostate cancer
Metastatic castration-sensitive prostate cancer
Non-metastatic castration-sensitive prostate cancer with biochem recurrence at high risk for mets
Professional Synonyms:
Hormone-refractory prostate cancer
Metastatic hormone sensitive prostate cancer
Indications:
Castration-resistant prostate cancer
Metastatic castration-sensitive prostate cancer
Non-metastatic castration-sensitive prostate cancer with biochem recurrence at high risk for mets
Professional Synonyms:
Hormone-refractory prostate cancer
Metastatic hormone sensitive prostate cancer
The following dosing information is available for XTANDI (enzalutamide):
Enzalutamide is commercially available in capsule and tablet formulations; these formulations are equivalent on a mg-per-mg basis.
Enzalutamide is administered orally without regard to meals. Enzalutamide is commercially available in capsule and tablet formulations. The capsules should be swallowed whole and should not be chewed, dissolved, or opened. The tablets should be swallowed whole and should not be cut, crushed, or chewed.
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| XTANDI 40 MG CAPSULE | Maintenance | Adults take 4 capsules (160 mg) by oral route once daily at the same time each day swallowing whole. Do not chew, open, dissolve and/or crush. |
| XTANDI 40 MG TABLET | Maintenance | Adults take 4 tablets (160 mg) by oral route once daily |
| XTANDI 80 MG TABLET | Maintenance | Adults take 2 tablets (160 mg) by oral route once daily |
No generic dosing information available.
The following drug interaction information is available for XTANDI (enzalutamide):
There are 24 contraindications.
These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.
| Drug Interaction | Drug Names |
|---|---|
| Delavirdine; Etravirine/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of delavirdine(1) and etravirine(2) by CYP3A4. CLINICAL EFFECTS: Concurrent use of delavirdine(1) or etravirine(2) with strong CYP3A4 inducers may result in sub-therapeutic levels of the non-nucleoside reverse transcriptase inhibitor (NNRTI) and the development of resistance to antiretroviral agents. PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The US manufacturers of delavirdine(1) and etravirine (2) state that strong CYP3A4 inducers should not be used in combination with delavirdine and etravirine. DISCUSSION: In a study in 8 subjects, administration of various doses of barbiturates, carbamazepine, phenytoin, and phenobarbital with delavirdine (300-400 mg 3 times daily) decreased the minimum concentration (Cmin) of delavirdine by 90%.(1) In a study of 12 subjects, rifabutin (300 mg daily), a moderate CYP3A4 inducer, decreased both the area-under-curve (AUC) and maximum concentration (Cmax) of etravirine by 37%.(2) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, and primidone.(3) |
ETRAVIRINE, INTELENCE |
| Isavuconazonium; Voriconazole/Selected CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inducers of CYP3A4 and rifabutin may increase the metabolism of isavuconazonium(1,2) and voriconazole.(3) CLINICAL EFFECTS: The concurrent use of strong inducers of CYP3A4 or rifabutin with isavuconazonium(1,2) or voriconazole(3) may result in severely reduced levels of the azole antifungal and therapeutic failure. PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The concurrent use of isavuconazonium(1,2) or voriconazole(3) with strong inducers of CYP3A4 is contraindicated. The concurrent use of voriconazole with rifabutin is also contraindicated.(3,4) The UK manufacturer of voriconazole states that concurrent use with rifabutin should be avoided. If concurrent use is necessary, the maintenance dose of voriconazole may be increased from 200 mg to 350 mg orally twice daily. If the patient weighs less than 40 kg, the maintenance dose of voriconazole may be increased from 100 mg to 200 mg orally twice daily. If concurrent use is necessary, the maintenance dose of intravenous voriconazole can be increased to 5 mg/kg intravenously twice daily.(9) The US manufacturer of isavuconazonium does not make any recommendations for concurrent use with rifabutin,(1) but the UK manufacturer states that concurrent use of rifabutin is contraindicated.(2) DISCUSSION: The concurrent use of rifampin (600 mg) with isavuconazonium (multiple doses) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of voriconazole by 75% and 97%, respectively.(1) The concurrent use of rifampin (600 mg once daily) with voriconazole (200 mg every 12 hours for 7 days) decreased the Cmax and AUC of voriconazole by 93% and 96%, respectively. Doubling the dose of voriconazole did not restore adequate exposure to voriconazole during rifampin.(3) The concurrent use of rifabutin (300 mg once daily) with voriconazole (200 mg twice daily) decreased the Cmax and AUC of voriconazole by 67% and 79%, respectively. The concurrent use of rifabutin (300 mg once daily) with voriconazole (400 mg twice daily) increased the Cmax and AUC of voriconazole to twice that seen with voriconazole alone at 200 mg twice daily. However, the Cmax and AUC of rifabutin were 3-fold and 4-fold higher, respectively, when given with voriconazole at 400 mg twice daily.(3) In a study in 16 subjects, subjects received single doses of voriconazole (400 mg) alone, after one dose of St. John's wort (300 mg), and after 15 days of St. John's wort (300 mg daily). After 10 hours of St. John's wort, voriconazole area-under-curve (AUC) increased 22%. After 15 days of St. John's wort, voriconazole AUC decreased 59%.(5) Therapeutic failures have been reported with voriconazole in patients treated concurrently with carbamazepine,(6) phenobarbital,(7) and rifampin.(8) In a study in 12 healthy male subjects, voriconazole (400 mg twice daily for 7 days) with rifabutin (300 mg daily for 7 days) increased rifabutin's AUC and Cmax by 331% and 195%, respectively. The AUC and Cmax of voriconazole were increased by approximately 100%.(4) Selected CYP3A4 inducers linked to this monograph include apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, ivosidenib, lumacaftor, mitotane, phenobarbital, primidone, rifabutin, rifampin, rifapentine, and St. John's wort. |
CRESEMBA, VFEND, VFEND IV, VORICONAZOLE |
| Nimodipine/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Concurrent use of strong CYP3A4 inducers may induce the metabolism of nimodipine.(1,2) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may result in decreased levels and effectiveness of nimodipine.(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 UK manufacturer of nimodipine states that the concurrent use of strong CYP3A4 inducers is contraindicated.(1) The US manufacturer of nimodipine states that the concurrent use of strong CYP3A4 inducers should be avoided.(2) DISCUSSION: A study examined nimodipine pharmacokinetics in three groups: normal drug-free controls (n=8), epileptic patients taking enzyme-inducing anticonvulsants (phenobarbital alone, n=4; phenobarbital with carbamazepine, n=2, carbamazepine with clobazam, n=1, and carbamazepine with phenytoin, n=1). In patients taking enzyme-inducing anticonvulsants, nimodipine area-under-curve (AUC), maximum concentration (Cmax), and half-life (T1/2) were 86.2%, 89.2%, and 68.1%, respectively, lower than in controls.(2) Strong CYP3A4 inducers linked include: apalutamide, encorafenib, enzalutamide, ivosidenib, lumacaftor, mitotane, rifampin, rifapentine, and St. Johns wort.(3) |
NIMODIPINE, NYMALIZE |
| Ranolazine/Strong CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of ranolazine.(1,2) CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of ranolazine.(1,2) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The US manufacturer of ranolazine states that the concurrent use of CYP3A4 inducers is contraindicated.(1) The UK manufacturer of ranolazine states that ranolazine should not be used in patients receiving CYP3A4 inducers such as rifampin.(2) DISCUSSION: Concurrent rifampin (600 mg daily), strong inducer of CYP3A4, decreased ranolazine plasma concentrations by 95%.(1,2) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(1-4) |
ASPRUZYO SPRINKLE, RANOLAZINE ER |
| Nifedipine/Selected CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: CYP3A4 inducers may induce the hepatic metabolism of nifedipine.(1) CLINICAL EFFECTS: Concurrent use of an inducer of CYP3A4 may decrease levels and effectiveness of nifedipine.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The concurrent use of strong CYP3A4 inducers with nifedipine is contraindicated.(1) DISCUSSION: In a study in 12 healthy males, pretreatment with rifampin (600 mg daily for 14 days) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of nifedipine (20 mg) by 95% and 97%, respectively.(1) In a study of 6 healthy subjects, pretreatment with rifampin (600 mg daily for 7 days) increased the clearance of a single oral dose of nifedipine (20 mg) by 9.28-fold and decrease the nifedipine bioavailability by 87%. There were no significant effects on a single intravenous dose of nifedipine.(2) In a study in 6 healthy subjects, pretreatment with a single dose of rifampin (600 mg) 8 hours before a single oral dose of nifedipine decreased nifedipine bioavailability by 64.2%. Nifedipine half-life decreased by 60%. Nifedipine clearance increased by 1.89-fold.(3) There have been case reports of decreased effectiveness of nifedipine during concurrent rifampin therapy.(4-6) Enzalutamide is a strong inducer of CYP3A4.(7) Selected CYP3A4 inducers linked to this monograph include apalutamide, encorafenib, enzalutamide, ivosidenib, lumacaftor, mitotane, rifabutin, rifampin, and rifapentine. |
NIFEDIPINE, NIFEDIPINE ER, NIFEDIPINE MICRONIZED, PROCARDIA XL |
| Praziquantel/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of praziquantel by CYP3A4.(1) CLINICAL EFFECTS: Concurrent or recent use of a strong CYP3A4 inducer may decrease the levels and effectiveness of praziquantel. 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 praziquantel and strong inducers of CYP3A4 is contraindicated.(1) In patients receiving strong CYP3A4 inducers who need immediate treatment for schistosomiasis, alternative agents for schistosomiasis should be used. If praziquantel is required, increase monitoring for praziquantel efficacy. If schistosomiasis treatment can be delayed, discontinue strong CYP3A4 inducers at least 2 to 4 weeks before administration of praziquantel. The inducer may be resumed 1 day after completion of praziquantel therapy.(1) DISCUSSION: A study examined praziquantel levels in 10 healthy controls, 10 subjects maintained on phenytoin monotherapy, and 10 subjects maintained on carbamazepine monotherapy. Praziquantel area-under-curve (AUC) and maximum concentration (Cmax) were reduced by 90.3% and by 92.1%, respectively, in carbamazepine-treated subjects when compared to control subjects. Praziquantel AUC and Cmax were reduced by 74% and 76%, respectively, in phenytoin-treated subjects when compared to control subjects.(2) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, and St. John's Wort.(3) |
BILTRICIDE, PRAZIQUANTEL |
| Lurasidone/Strong CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of lurasidone.(1) CLINICAL EFFECTS: Concurrent or recent use of strong inducers of CYP3A4 may result in decreased levels and efficacy of lurasidone.(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 lurasidone states that concurrent use of strong CYP3A4 inducers is contraindicated.(1) DISCUSSION: Pretreatment with rifampin (600 mg daily for 8 days) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of lurasidone (40 mg) by 86%, and 80%, 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) |
LATUDA, LURASIDONE HCL |
| Ticagrelor; Vorapaxar/Strong CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of ticagrelor(1,2) and vorapaxar.(3) CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers may result in decreased levels and loss of efficacy of ticagrelor(1,2) and vorapaxar.(3) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturers of ticagrelor and vorapaxar state concurrent use with strong CYP3A4 inducers should be avoided due to the substantially reduced levels which may result in loss of ticagrelor and vorapaxar efficacy.(1,3) If therapy with a strong CYP3A4 inducer is needed, it would be prudent to select an alternative antiplatelet agent. If concurrent therapy cannot be avoided, consider performing platelet reactivity measurements to determine patient-specific risk for treatment failure. Monitor patients receiving concurrent therapy for signs of heart attack, stroke, or blood clots. DISCUSSION: Concurrent use of rifampin (600 mg once daily) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of ticagrelor by 73% and 86%, respectively. The AUC of ticagrelor's active metabolite decreased 46%.(1,4) A retrospective study of CArdiovascular Percutaneous Intervention TriAL (CAPITAL) registry participants was performed to determine the effects of antiepileptic (AED) CYP3A4 inducers on ticagrelor efficacy. Platelet reactivity in 8 patients receiving one or more AED CYP3A4 inducers were compared with 49 patients on identical doses of aspirin and ticagrelor who were not receiving CYP3A4 inducers. The mean P2Y12 reaction units (PRU) in AED patients was 194.6(+ or - 29.9) vs 26.3(+ or - 29.8) in control patients. Three of 8 AED patients had PRU = or > 208, the cut off for high platelet reactivity. One ticagrelor AED patient was changed to clopidogrel. PRU on ticagrelor was 220, and after conversion to clopidogrel was reduced to 110.(5) In a study in 12 healthy subjects, rifampin (600 mg daily for 28 days) decreased the exposure of vorapaxar (20 mg on Day 7, 2.5 mg on Days 8-28) by 50%.(6) Strong inducers of CYP3A4 include apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine and St. John's wort.(7,8) |
BRILINTA, TICAGRELOR, ZONTIVITY |
| Selected Protease Inhibitors; Cobicistat/CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inducers of CYP3A4 are expected to increase the metabolism of boceprevir,(1) cobicistat,(2,3) and telaprevir.(4) Inhibitors of CYP3A4 may inhibit the metabolism of carbamazepine.(5,6) Boceprevir, cobicistat, nirmatrelvir, and telaprevir are CYP3A4 inhibitors.(7,8) CLINICAL EFFECTS: Concurrent or recent use of strong inducers of CYP3A4 may result in decreased levels and effectiveness of boceprevir,(1) cobicistat,(2,3) and telaprevir.(4) Increased serum carbamazepine levels with subsequent increases in the pharmacological and toxic effects of carbamazepine, including dizziness, ataxia, blurred vision, or SIADH.(5) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Concurrent administration of strong inducers of CYP3A4 with boceprevir,(1) cobicistat,(2,3) and telaprevir(4) is contraindicated. DISCUSSION: Boceprevir is metabolized by CYP3A4. Strong inducers of CYP3A4 are expected to reduce boceprevir levels, which may lead to loss of response.(1) In a study in 16 subjects, rifampin (600 mg daily for 8 days), a strong inducer of CYP3A4, decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of telaprevir (750 mg) by 86% and 92%, respectively.(4) Carbamazepine is almost completely metabolized to carbamazepine-10,11-epoxide, with only 5% of the drug excreted unchanged. Pharmacokinetic studies have indicated the major pathway for carbamazepine metabolism is catalyzed by CYP3A4, with minor contributions from CYP2C8 and CYP3A5.(5,6) In a study of 12 healthy volunteers, carbamazepine was titrated to 300 mg every 12 hours and then coadministered with nirmatrelvir/ritonavir 300 mg/100 mg on day 15 of carbamazepine. Carbamazepine decreased nirmatrelvir AUC and Cmax by 55% and 43%, respectively, and decreased ritonavir AUC and Cmax both by about 74%.(7) Strong inducers of CYP3A4 include apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, primidone, rifampin, and St. John's wort.(8,9) |
PREZCOBIX, SYMTUZA, TYBOST |
| Rilpivirine/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Apalutamide, barbiturates, carbamazepine, dexamethasone, enzalutamide, eslicarbazepine, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, primidone, oxcarbazepine, rifampin, rifapentine, and St. John's wort may induce the metabolism of rilpivirine by CYP3A4.(1) CLINICAL EFFECTS: Concurrent or recent use of apalutamide, barbiturates, carbamazepine, dexamethasone, enzalutamide, eslicarbazepine, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, primidone, oxcarbazepine, rifampin, rifapentine, or St. John's wort may result in decreased levels and effectiveness of rilpivirine, as well as the development of resistance.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The US manufacturer of rilpivirine states that concurrent use of CYP3A4 inducers such as apalutamide, barbiturates, carbamazepine, dexamethasone, enzalutamide, eslicarbazepine, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, primidone, oxcarbazepine, rifampin, rifapentine, or St. John's wort is contraindicated.(1) It may take several weeks after the discontinuation of an enzyme inducer for enzyme activity to return to normal.(1) DISCUSSION: In a study in 16 subjects, rifampin (600 mg daily) decreased the Cmax, AUC, and Cmin of rilpivirine (150 mg daily) by 69%, 80%, and 89%, respectively. There were no significant effects on the Cmax or AUC of rifampin or 25-desacetylrifampin.(1) Strong CYP3A4 inducers linked include: apalutamide, barbiturates, carbamazepine, dexamethasone, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, primidone, oxcarbazepine, rifampin, rifapentine, or St. John's wort. |
COMPLERA, EDURANT, EDURANT PED, EMTRICITABINE-RILPIVIRNE-TENOF, JULUCA, ODEFSEY, RILPIVIRINE ER (CABENUVA) |
| Artemether; Lumefantrine/Strong CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of artemether and lumefantrine.(1) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers with artemether and lumefantrine may result in decreased levels and effectiveness of the antimalarial agents and treatment failure.(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 artemether-lumefantrine states that the concurrent use of artemether-lumefantrine with strong CYP3A4 inducers is contraindicated.(1) DISCUSSION: In a study in 6 subjects, administration of rifampin (600 mg daily, a strong inducer of CYP3A4) with artemether-lumefantrine (6 dose regimen over 3 days) decreased the area-under-curve (AUC) of artemether, dihydroartemisinin (DHA), and lumefantrine by 89%, 85%, and 68%, respectively.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2) |
COARTEM |
| Elbasvir-Grazoprevir/Strong CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of elbasvir and grazoprevir.(1,2) CLINICAL EFFECTS: Concurrent use of a strong 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 strong CYP3A4 inducers is contraindicated.(1,2) If concurrent use is deemed medically necessary, 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) Strong inducers of CYP3A4 include apalutamide, barbiturates, carbamazepine, efavirenz, encorafenib, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, primidone, phenytoin, and St. John's wort.(1-4) |
ZEPATIER |
| Atazanavir/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inducers of CYP3A4 are expected to increase the metabolism of atazanavir.(1) CLINICAL EFFECTS: Concurrent or recent use of strong inducers of CYP3A4 may result in decreased levels and effectiveness of atazanavir and development of drug resistance.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Concurrent administration of strong inducers of CYP3A4 with atazanavir is contraindicated.(1) DISCUSSION: Atazanavir is metabolized by CYP3A4. Strong inducers of CYP3A4 are expected to reduce atazanavir levels, which may lead to loss of response.(1) Strong inducers of CYP3A4 included on this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, and primidone.(2,3) |
ATAZANAVIR SULFATE, EVOTAZ, REYATAZ |
| Doravirine/Strong CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inducers of CYP3A4 are expected to increase the metabolism of doravirine.(1) CLINICAL EFFECTS: Concurrent or recent use of strong inducers of CYP3A4 may result in decreased levels and effectiveness of doravirine.(3) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Concurrent administration of strong inducers of CYP3A4 with doravirine is contraindicated. A washout period of 4 weeks for the CYP3A4 inducer is recommended prior to initiation of doravirine.(1) DISCUSSION: Doravirine is metabolized by CYP3A4. Strong inducers of CYP3A4 are expected to reduce doravirine levels, which may lead to loss of response.(1) In a study in 10 subjects, rifampin (600 mg daily), a strong inducer of CYP3A4, decreased the area-under-curve (AUC), maximum concentration (Cmax), and 24 hour concentration (C24) of a single dose of doravirine (100 mg) by 88%, 57%, and 97% respectively.(1) Strong inducers of CYP3A4 include apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, oxcarbazepine, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(1) |
DELSTRIGO, PIFELTRO |
| Lorlatinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inducers of CYP3A4 are expected to increase the metabolism of lorlatinib.(1) Concurrent use of lorlatinib and rifampin may result in hepatotoxicity through activation of the pregnane X receptor (PXR) by both drugs, which are PXR agonists.(1) CLINICAL EFFECTS: Concurrent or recent use of strong inducers of CYP3A4 may result in decreased levels and effectiveness of lorlatinib. Concurrent lorlatinib and strong CYP3A4 inducers may result in hepatotoxicity. Symptoms may include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue.(1) PREDISPOSING FACTORS: Underlying liver disease, concurrent therapy with agents associated with liver injury, and alcoholism may predispose patients to liver damage. Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Concurrent administration of strong inducers of CYP3A4 with lorlatinib is contraindicated due to the potential for serious hepatotoxicity. Discontinue strong CYP3A4 inducers for three plasma half-lives of the strong CYP3A inducer prior to initiation of lorlatinib.(1) DISCUSSION: Lorlatinib is metabolized by CYP3A4. Strong inducers of CYP3A4 are expected to reduce lorlatinib levels, which may lead to loss of response.(1) In a study in 12 healthy subjects, rifampin (600 mg daily for 8 days), a strong inducer of CYP3A4, decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of lorlatinib (100 mg) by 85% and 76%, respectively. Severe hepatotoxicity occurred in 10 of 12 subjects. Grade 4 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations occurred in 50% of subjects, Grade 3 ALT/AST elevations occurred in 33%, and Grade 2 ALT/AST elevations occurred in 8%.(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.(1) |
LORBRENA |
| Tamoxifen/Strong CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of tamoxifen.(1) CLINICAL EFFECTS: Concurrent or recent use of apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort may result in decreased levels and effectiveness of tamoxifen.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Strong inducers of CYP3A4 should not be used in patients receiving tamoxifen.(1) DISCUSSION: In a study in healthy males, rifampin (600 mg daily for 5 days) decreased maximum concentration (Cmax) and AUC of a single dose of tamoxifen (80 mg) by 86% and 55%, respectively. The AUC of N-demethyltoremifene decreased by 62%.(1,2) Strong inducers of CYP3A4 include apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(3,4) |
SOLTAMOX, TAMOXIFEN CITRATE |
| Fostemsavir/Strong CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of fostemsavir via this pathway.(1) CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers may result in reduced plasma levels of fostemsavir, resulting in loss of virologic response.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The concurrent use of fostemsavir with strong CYP3A4 inducers is contraindicated.(1) DISCUSSION: In an interaction study of rifampin 600 mg daily (a strong CYP3A4 inducer) and a single 1200 mg dose of fostemsavir, concurrent use decreased fostemsavir concentration maximum (Cmax) by 76% and area-under-curve (AUC) by 82%.(1) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine and St John's Wort.(2,3) |
RUKOBIA |
| Lonafarnib/Strong and Moderate CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: 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) |
ZOKINVY |
| Cabotegravir-Rilpivirine/Strong CYP3A4 & UGT1A1 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Apalutamide, barbiturates, carbamazepine, dexamethasone, efavirenz, encorafenib, enzalutamide, eslicarbazepine, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, oxcarbazepine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, ritonavir, or St. John's wort may induce the metabolism of cabotegravir-rilpivirine by CYP3A4 and uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1).(1) CLINICAL EFFECTS: Concurrent or recent use of apalutamide, barbiturates, carbamazepine, dexamethasone, efavirenz, encorafenib, enzalutamide, eslicarbazepine, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, oxcarbazepine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, ritonavir, or St. John's wort may result in decreased levels and effectiveness of cabotegravir-rilpivirine, as well as the development of resistance.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The US manufacturer of cabotegravir-rilpivirine states that concurrent use of CYP3A4 inducers and/or UGT1A1 inducers is contraindicated.(1) It may take several weeks after the discontinuation of an enzyme inducer for enzyme activity to return to normal.(1) DISCUSSION: In a study in 16 subjects, rifampin (600 mg daily) decreased the concentration maximum (Cmax), area-under-curve (AUC), and concentration minimum (Cmin) of rilpivirine (150 mg daily) by 69%, 80%, and 89%, respectively. There were no significant effects on the Cmax or AUC of rifampin or 25-desacetylrifampin.(1) In a study in 15 subjects, rifampin (600 mg daily) decreased the Cmax, AUC, and Cmin of cabotegravir by 6%, 59%, and 50%, respectively.(1) Strong CYP3A4 inducers linked include: apalutamide, barbiturates, carbamazepine, dexamethasone, encorafenib, enzalutamide, eslicarbazepine, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, oxcarbazepine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, or St. John's wort.(1,2) UGT1A1 inducers linked include: carbamazepine, efavirenz, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin, primidone, rifapentine, rifampin, and ritonavir.(1,2) |
CABENUVA |
| Pacritinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Agents that induce the CYP3A4 isoenzyme may induce the metabolism of pacritinib.(1) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may decrease the levels and effectiveness of pacritinib.(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 CYP3A4 inducers in patients receiving therapy with pacritinib is contraindicated.(1) Consider the use of alternative agents with less enzyme induction potential.(1) DISCUSSION: Rifampin (600 mg daily for 10 days), a strong CYP3A4 inducer, decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of pacritinib (400 mg) by 51% and 87%, respectively.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2) |
VONJO |
| Mavacamten/Dual Strong or Moderate CYP2C19 & CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong and moderate inducers of CYP2C19 or CYP3A4 may increase the metabolism of mavacamten.(1-3) CLINICAL EFFECTS: Concurrent use of strong or moderate CYP2C19 or CYP3A4 inducers with mavacamten may decrease the levels of 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 strong or moderate inducers of CYP2C19 or CYP3A4 is contraindicated.(1,2) The UK manufacturer of mavacamten states concomitant use with strong or moderate CYP2C19 or CYP3A4 inducers is dependent on CYP2C19 phenotype. Labeling recommends: -When initiating or increasing the dose of a strong CYP2C19 or CYP3A4 inducer in patients who are CYP2C19 poor metabolizers, monitor patients closely and adjust mavacamten dose based on clinical response. The maximum recommended dose of mavacamten is 5 mg daily. -When initiating or increasing the dose of a moderate CYP3A4 inducer in patients who are CYP2C19 poor metabolizers, monitor patients closely and adjust mavacamten dose based on clinical response. -When initiating or increasing the dose a strong or moderate CYP2C19 or strong CYP3A4 inducer in patients who are CYP2C19 intermediate, normal, rapid, or ultrarapid metabolizers, monitor patients closely and adjust mavacamten dose based on clinical response. -When discontinuing or decreasing the dose of a strong CYP2C19 or a strong or moderate CYP3A4 inducer in patients who are CYP2C19 poor metabolizers, decrease the dose of mavacamten from 5 mg to 2.5 mg, or pause therapy if dose is 2.5 mg. -When discontinuing or decreasing the dose of a strong CYP2C19 or CYP3A4 inducer in patients who are CYP2C19 intermediate, normal, rapid, or ultrarapid metabolizers, decrease the dose of mavacamten by one dose level when on doses of 5 mg or higher. Maintain mavacamten dose when on 2.5 mg. -When discontinuing or decreasing the dose of a moderate CYP2C19 inducer in patients who are CYP2C19 intermediate, normal, rapid, or ultrarapid metabolizers, no dose adjustment is warranted. Monitor patients closely and adjust mavacamten dose based on clinical response. -No dose adjustment is warranted with moderate CYP2C19 inducers in patients who are CYP2C19 poor metabolizers. -No dose adjustment is warranted with moderate CYP3A4 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. Drugs that induce both CYP2C19 and CYP3A4 linked to this monograph include: apalutamide, asunaprevir, dipyrone, enzalutamide, fosphenytoin, pacritinib, phenytoin, and rifampin.(4,5) |
CAMZYOS |
| Nirmatrelvir-Ritonavir/Strong CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Strong inducers of CYP3A4 are expected to increase the metabolism of nirmatrelvir.(1) CLINICAL EFFECTS: Concurrent or recent use of strong inducers of CYP3A4 may result in decreased levels and effectiveness of nirmatrelvir.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Concurrent administration of strong CYP3A4 inducers with nirmatrelvir is contraindicated.(1) DISCUSSION: In a study of 12 healthy volunteers, carbamazepine was titrated to 300 mg every 12 hours and then coadministered with nirmatrelvir/ritonavir 300 mg/100 mg on day 15 of carbamazepine. Carbamazepine decreased nirmatrelvir AUC and Cmax by 55% and 43%, respectively, and decreased ritonavir AUC and Cmax both by about 74%.(2) Strong inducers of CYP3A4 include apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(8,9) |
PAXLOVID |
| Lenacapavir/Strong CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Agents that induce the CYP3A4 isoenzyme may accelerate the metabolism of lenacapavir.(1-3) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may decrease the levels and effectiveness of lenacapavir.(1-3) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of lenacapavir states that concurrent use of strong CYP3A4 inducers is contraindicated.(1-3) DISCUSSION: In a study, rifampin 600 mg once daily (inducer of CYP3A4 [strong], P-glycoprotein, and UGT1A1) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of lenacapavir by 55% and 84%, respectively.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenytoin, rifampin, rifapentine, and St. John's wort.(4,5) |
SUNLENCA, YEZTUGO |
| Nisoldipine/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: CYP3A4 inducers may induce the hepatic metabolism of nisoldipine.(1) CLINICAL EFFECTS: Concurrent use of an inducer of CYP3A4 may decrease levels and effectiveness of nisoldipine.(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 nisoldipine states it should generally not be coadministered with CYP3A4 inducers.(1) DISCUSSION: Concurrent administration of phenytoin with nisoldipine (40 mg) decreased nisoldipine plasma concentrations below detectable levels.(1) In a study comparing patients receiving chronic phenytoin therapy to healthy controls, phenytoin decreased the AUC of a single dose of nisoldipine by 89%.(2) Selected CYP3A4 inducers linked to this monograph include apalutamide, encorafenib, enzalutamide, ivosidenib, lumacaftor, mitotane and St. John's Wort.(3,4) |
NISOLDIPINE, SULAR |
There are 177 severe interactions.
These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.
| Drug Interaction | Drug Names |
|---|---|
| Selected Antimalarials/Strong CYP3A4 Inducers; Selected Barbiturates, Hydantoin SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of mefloquine, quinidine, and quinine. CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may result in decreased levels and effectiveness of mefloquine, quinidine, or quinine. PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: In patients receiving concurrent strong CYP3A4 inducers, monitor mefloquine, quinidine, or quinine serum levels and observe the patient for symptoms of reduced efficacy. Adjust the dosage accordingly. The US manufacturer of quinine recommends avoiding the concurrent use of rifampin, a strong CYP3A4 inducer, because of the increased risk of malaria treatment failure. DISCUSSION: Several studies document the reduction in quinidine response in patients receiving concurrent rifampin. Decreased elimination half-life, reduced area-under-curve (AUC), and low serum quinidine level were observed. In healthy volunteers, quinine AUC and maximum concentration (Cmax) were reduced 85% and 55%, respectively, after a single dose of rifampin was added after two weeks of quinine therapy.(6) In a randomized control trial of 59 male patients with Plasmodium falciparum malaria, treatment with concomitant quinine and rifampin was associated with a cure rate of only 35% compared to 88% in those treated with quinine monotherapy. The AUC of quinine during treatment days 3 through 7 was significantly reduced in the quinine plus rifampin group compared to those treated with quinine alone (11.7 vs. 47.5 mcg/ml/day; p < 0.004).(7) In an open-label, cross-over study in 7 healthy subjects, concurrent rifampin (600 mg daily) decreased the AUC and Cmax of a single dose of mefloquine (500 mg) by 68% and 19%, respectively.(8,9) Agents linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, ethotoin, fosphenytoin, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(10) |
MEFLOQUINE HCL, NUEDEXTA, QUALAQUIN, QUINIDINE GLUCONATE, QUINIDINE SULFATE, QUININE HCL, QUININE SULFATE |
| Felodipine/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Felodipine is designated as a sensitive CYP3A4 substrate. Strong CYP3A4 inducers may induce the metabolism of felodipine and decrease exposure (area-under-curve, AUC) by 80% or more.(1-2) Primidone is metabolized to phenobarbital. CLINICAL EFFECTS: Serum levels and bioavailability of felodipine may be decreased resulting in a decrease or loss of antihypertensive or antianginal effects. 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 felodipine states that alternative antihypertensive agents should be considered in patients taking anticonvulsants that induce CYP3A4.(1) Although there are no specific recommendations for other strong CYP3A4 inducers, a clinically significant interaction can be expected and a similar approach is reasonable with concurrent use. Monitor antihypertensive response and adjust the dose of felodipine as needed. In patients already receiving felodipine when the CYP3A4 inducer is started, the onset of this interaction may be delayed, and maximal induction effects may not be seen for 2 or more weeks. Monitor antihypertensive response and adjust the dose of felodipine as needed. In patients stabilized on the CYP3A4 inducer therapy, the addition of felodipine may not be effective for treatment of hypertension or angina. DISCUSSION: A study in healthy subjects compared felodipine exposure in patients receiving felodipine alone or with another strong CYP3A4 inducer (phenytoin). Combination therapy reduced felodipine exposure (area-under-curve, AUC) by 94%.(3) Felodipine levels have been shown to be reduced by 90% in patients taking anticonvulsants such as carbamazepine. Strong CYP3A4 inducers linked to this monograph include: apalutamide, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin and primidone.(2,4) |
FELODIPINE ER |
| Rolapitant/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Rolapitant is metabolized primarily by CYP3A4. Strong inducers of CYP3A4 may increase the metabolism and clearance via CYP3A4.(1) CLINICAL EFFECTS: Concurrent use with strong 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 manufacturer of rolapitant states concurrent use with strong CYP3A4 inducers should be avoided.(1) Patients treated concurrently with a strong CYP3A4 inducer should be monitored for decreased antiemetic efficacy. When possible and clinically appropriate, consider use of an alternative antiemetic or alternatives to the strong CYP3A4 inducer.(1) DISCUSSION: Rifampin (600 mg daily for 14 days) 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.(1) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's Wort.(2,3) FDA defines a Strong CYP inducer as an agent which decreases the area-under-curve (AUC) of a Sensitive Substrate by > or = 80 per cent.(2) |
VARUBI |
| Selected Antipsychotics/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers may increase the metabolic clearance of aripiprazole(1), brexpiprazole(2), and risperidone.(3) CLINICAL EFFECTS: Strong CYP3A4 inducers may result in decreased levels and effectiveness of aripiprazole, brexpiprazole, and risperidone.(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 dose of immediate release aripiprazole should be doubled over 1-2 weeks if a CYP3A4 inducer is added to aripiprazole therapy. Additional dosage increases should be based on clinical observation of the patient. If the inducer is withdrawn from concurrent therapy, the dosage of aripiprazole should be gradually reduced to the original level over 1-2 weeks.(1) The dose of brexpiprazole should be doubled over 1-2 weeks in patients taking strong CYP3A4 inducers. If the inducer is discontinued, reduce the dosage of brexpiprazole to the original level over 1-2 weeks.(2) The US manufacturer of risperidone (Risperdal) recommends that patients increase the dose of risperidone up to double the patient's usual dose when taken concurrently with a CYP3A4 inducer. Do not exceed twice the patient's usual dose. It may be necessary to decrease the risperidone dose when the CYP3A4 inducer is discontinued.(3) DISCUSSION: The concurrent administration of carbamazepine (200 mg twice daily) with aripiprazole (30 mg daily) resulted in 70% decreases in the area-under-curve (AUC) and maximum concentration (Cmax) of both aripiprazole and dehydro-aripiprazole, its active metabolite.(1) Rifampin decreased the AUC of brexpiprazole by approximately 75%.(2) A study in 11 schizophrenic inpatients examined the effects of the addition of carbamazepine (200 mg twice daily) for one week to risperidone (3 mg twice daily). Concurrent carbamazepine decreased plasma concentrations of risperidone, 9-hydroxyrisperidone, and active moiety by 50%, 44%, and 45%, respectively.(4) A study compared 23 patients receiving risperidone alone to 11 patients receiving concurrent risperidone and carbamazepine. The groups were matched for sex, age, body weight, and risperidone dosage. Plasma concentrations of 9-hydroxyrisperidone and the sum of risperidone and 9-hydroxyrisperidone were significantly lower in patients receiving concurrent carbamazepine. Five subjects received risperidone with and without carbamazepine. In these patients, dose-normalized plasma risperidone and 9-hydroxyrisperidone concentrations were lower during concurrent carbamazepine.(5) In a case report, a patient developed an exacerbation of psychotic symptoms four weeks after the addition of carbamazepine (800 mg daily) to his regimen. Plasma levels of risperidone and 9-hydroxyrisperidone had decreased by 77% and 63%, respectively.(6) In an open, randomized cross-over study in 10 healthy males, pretreatment with rifampin (600 mg daily for 5 days) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single oral dose of risperidone (4 mg) by 72% and 50%, respectively.(7) In a study in 10 healthy males, pretreatment with rifampin (600 mg daily for 7 days) decreased the AUC and Cmax of a single oral dose of risperidone (1 mg) by 51% and 38%, respectively. The AUC of 9-hydroxyrisperidone and the active moieties (risperidone + 9-hydroxyrisperidone) decreased by 43% and 45%, respectively. The Cmax of 9-hydroxyrisperidone and the active moieties decreased by 46% and 41%, respectively.(8) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, natisedine, phenytoin, primidone, rifampin, rifapentine and St. John's Wort.(9,10) |
ABILIFY, ARIPIPRAZOLE, ARIPIPRAZOLE ODT, OPIPZA, REXULTI, RISPERDAL, RISPERIDONE, RISPERIDONE ODT |
| Exemestane/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of exemestane.(1) CLINICAL EFFECTS: Concurrent use of a strong 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) The dosage of exemestane may need to be adjusted if the inducer is discontinued. DISCUSSION: In a study in 10 healthy postmenopausal subjects, pretreatment with rifampin (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: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine 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: bosentan, efavirenz, etravirine, modafinil, nafcillin, rifabutin, and thioridazine.(2,3) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: aprepitant, armodafinil, bexarotene, boceprevir, clobazam, danshen, dexamethasone, echinacea, garlic, gingko, ginseng, glycyrrhizin, nevirapine, oxcarbazepine, pioglitazone, prednisone, quercetin, raltegravir, rufinamide, sorafenib, sulfinpyrazone, telaprevir, terbinafine, ticagrelor, ticlopidine, vemurafenib, and vinblastine.(2,3) |
AROMASIN, EXEMESTANE |
| Ivabradine/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of ivabradine.(1,2) CLINICAL EFFECTS: Concurrent use of strong inducers of CYP3A4 may result in decreased levels and effectiveness of ivabradine.(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 strong CYP3A4 inducers should be avoided during ivabradine therapy.(1,2) If concurrent use is necessary, monitor patients for signs and symptoms of worsening heart failure and heart rate greater than 60 bpm. DISCUSSION: Concurrent use of St. John's wort with ivabradine (10 mg twice daily) decreased ivabradine area-under-curve (AUC) by 50%.(1,2) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. |
CORLANOR, IVABRADINE HCL |
| Bosutinib/Strong CYP3A4 Inducers 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 bosutinib.(1) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may decrease the levels and effectiveness of bosutinib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP3A4 inducers in patients receiving therapy with bosutinib. Consider the use of alternative agents with less enzyme induction potential.(1) DISCUSSION: In a study in 24 healthy subjects, rifampin decreased bosutinib area-under-curve (AUC) and maximum concentration (Cmax) by 94% and 86%.(1) In a study, 24 healthy subjects received a single dose of bosutinib 500 mg (days 1 and 14) and rifampin 600 mg (days 8-17). Bosutinib Cmax and AUC decreased by 86% and 92%, respectively. Bosutinib clearance increased by 13-fold.(2) Strong inducers of CYP3A4 include: barbiturates, encorafenib, enzalutamide, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(3,4) |
BOSULIF |
| Irinotecan/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of irinotecan by CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may result in decreased levels of irinotecan, as well as its active metabolites, and decreased clinical effectiveness. PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer states do not administer strong CYP3A4 inducers with irinotecan unless there are no therapeutic alternatives. Consideration should be given to substituting non-enzyme inducing therapies at least 2 weeks prior to irinotecan therapy.(1) Levels of irinotecan and the active metabolites should be monitored in patients receiving concurrent use of strong CYP3A4 inducers. If strong CYP3A4 inducers are added to or discontinued from concurrent irinotecan, the dosage of irinotecan may need to be adjusted to ensure therapeutic effects or prevent toxicity. DISCUSSION: The manufactures states that irinotecan may interact with strong CYP3A4 inducers which may result in increased irinotecan metabolism.(1) In a clinical trial, irinotecan clearance values were 65.4% higher in patients receiving phenytoin when compared to patients who were not taking enzyme-inducing anticonvulsants.(2) In another clinical trial, irinotecan clearance was 117% higher in patients receiving anticonvulsants that included phenytoin.(5) Data from another clinical trial also suggested that phenytoin increases irinotecan clearance.(6) Case reports have also noted increased irinotecan clearance by 4-fold(3) and by 62.7%(4) in patients receiving concurrent phenytoin. Levels of irinotecan and its active metabolite, SN-38 were both decreased. Selected strong CYP3A4 inducers linked include: apalutamide, encorafenib, enzalutamide, ivosidenib, lumacaftor, mitotane, rifabutin, rifampin, and rifapentine. |
CAMPTOSAR, IRINOTECAN HCL, ONIVYDE |
| Macitentan/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of macitentan.(1) CYP3A4 is the primary metabolism pathway of macitentan to its less active metabolite.(1,2) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may decrease systemic levels and effectiveness of macitentan.(1,2) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of macitentan recommends avoiding concurrent use of macitentan and strong CYP3A4 inducers.(2) If concurrent therapy is warranted, monitor closely for loss of efficacy and adjust macitentan dose or dosing interval if needed. Note the onset of induction is gradual; maximal induction may not occur for 2 or more weeks. When concurrent treatment with rifampin is stopped, induction will gradually wane and systemic concentrations of macitentan will gradually increase over 2 or more weeks. Monitor for toxicity and adjust dose as required. DISCUSSION: An interaction study in 10 healthy male subjects evaluated the effect of rifampin on macitentan and active metabolite pharmacokinetics. Although less potent, the active metabolite was evaluated as its longer half-life leads to a 3-fold higher systemic exposure than macitentan. About 40% of macitentan pharmacologic activity is thought due to this metabolite.(2) Subjects received a 30 mg macitentan loading dose followed by 10 mg daily for four more days. Beginning on day 6, rifampin 600 mg and macitentan 10 mg were co-administered daily for 7 days. Macitentan area-under-curve (AUC) and concentration minimum (Cmin) were measured on days 5 and 12. Co-administration decreased macitentan AUC 79% and trough concentration 93%. The AUC and Cmin of the macitentan active metabolite was unchanged and decreased 17% respectively.(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.(3) |
OPSUMIT, OPSYNVI |
| Maraviroc/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers may increase the metabolism of maraviroc.(1) CLINICAL EFFECTS: Concurrent use of strong inducers of CYP3A4 in the absence of an inhibitor of CYP3A4 and without a dosage adjustment of maraviroc may result in decreased levels and effectiveness of maraviroc.(1) PREDISPOSING FACTORS: This interaction may be more severe in patients with renal impairment.(1) Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The US manufacturer of maraviroc states that adult patients receiving therapy with inducers of CYP3A4 who are not also receiving an inhibitor of CYP3A4 should receive a dose of 600 mg maraviroc twice daily.(1) The US manufacturer of maraviroc states that adult patients receiving therapy with inducers of CYP3A4 who are also receiving a strong inhibitor of CYP3A4 should receive a dose of 150 mg maraviroc twice daily.(1) In adults, maraviroc should not be used with a strong CYP3A4 inducer in patients with a creatinine clearance less than 30 ml/min or end-stage renal disease.(1) In children aged 2 years and older weighing at least 10 kg, patients receiving therapy with strong CYP3A4 inducers who are not also receiving an inhibitor of CYP3A4 is not recommended.(1) In children aged 2 years and older weighing at least 10 kg, patients receiving therapy with a strong CYP3A4 inducer and a strong CYP3A4 inhibitor should receive the following maraviroc dose based on tablet or oral solution (20 mg/ml): - 10 - <20 kg: 50 mg twice daily or 50 mg (2.5ml) twice daily - 20 - <30 kg: 75 mg twice daily or 80 mg (4 ml) twice daily - 30 - <40 kg: 100 mg twice daily or 100 mg (5 ml) twice daily - >= 40 kg: 150 mg twice daily or 150 mg (7.5 ml) twice daily In pediatric patients aged 2 years and older weighing at least 10 kg, no dose recommendations are available with mild to moderate renal impairment. Maraviroc is contraindicated in pediatric patients with severe renal impairment or end-stage renal disease who are on concurrent therapy with strong CYP3A4 inhibitors.(1) DISCUSSION: In a study in 12 subjects, concurrent efavirenz (600 mg daily) decreased the minimum concentration (Cmin), area-under-curve (AUC), and maximum concentration (Cmax) of maraviroc (100 mg twice daily) by 45%, 44.8%, and 51.4%, respectively.(1) In a study in 12 subjects, concurrent efavirenz (600 mg daily) increased the Cmin, AUC, and Cmax of maraviroc (200 mg twice daily) by 9%, 15%, and 16%, respectively, when compared to the administration of maraviroc (100 mg twice daily) alone.(1) In a study in 12 subjects, concurrent rifampin (600 mg daily) decreased the Cmin, AUC, and Cmax of maraviroc (100 mg twice daily) by 78%, 63%, and 66%, respectively.(1) In a study in 12 subjects, concurrent rifampin (600 mg daily) decreased the Cmin and Cmax of maraviroc (200 mg twice daily) by 34% and 4%, respectively, when compared to the administration of maraviroc (100 mg twice daily) alone. The AUC of maraviroc increased by 3%.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, efavirenz, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, primidone, rifampin, and rifapentine. |
MARAVIROC, SELZENTRY |
| Tolvaptan/Strong CYP3A4 Inducers 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 tolvaptan.(1) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may result in decreased levels and effectiveness of tolvaptan.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Concurrent administration with strong CYP3A4 inducers should be avoided. If concurrent use is required, the dosage of tolvaptan may need to be increased.(1) DISCUSSION: Concurrent administration of rifampin, a strong inducer of CYP3A4, decreased tolvaptan exposure by 85%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(1,2) |
JYNARQUE, SAMSCA, TOLVAPTAN |
| Amiodarone/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of amiodarone by CYP3A4.(1) Amiodarone may inhibit the metabolism of phenytoin.(1) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may result in decreased levels and effectiveness of amiodarone.(1) Concurrent use of amiodarone and phenytoin may also result in elevated levels of and toxicity from phenytoin.(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 amiodarone states concurrent use with CYP3A4 inducers may decrease amiodarone serum concentrations. Consider monitoring amiodarone serum concentrations during concurrent use.(1) Monitor phenytoin levels when initiating or discontinuing amiodarone in patients maintained on phenytoin. DISCUSSION: In a study in cardiac patients, amiodarone had no effect on carbamazepine levels.(2) In a study in 5 healthy subjects, phenytoin (2-4 mg/kg/day) decreased amiodarone levels (200 mg daily) by 32% to 49%.(3) In a study in 7 healthy subject, amiodarone (200 mg daily for three weeks) increased phenytoin (5 mg/kg) area-under-curve (AUC) by 40%.(6) In a separate study in 7 healthy subjects, amiodarone (200 mg daily for 6 weeks) increased phenytoin (2-4 mg/kg/day) by 40%.(5) Concurrent use of rifampin, another potent inducer of CYP3A4, and amiodarone has been shown to decrease levels of amiodarone and desethylamiodarone.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, lumacaftor, mitotane, phenobarbital, phenytoin and primidone.(6) |
AMIODARONE HCL, AMIODARONE HCL-D5W, NEXTERONE, PACERONE |
| Ulipristal/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of ulipristal by CYP3A4.(1) CLINICAL EFFECTS: Concurrent use or use of strong CYP3A4 inducers within the previous 2-3 weeks may result in decreased levels and effectiveness of ulipristal.(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 and UK manufacturers of ulipristal states that concurrent use with CYP3A4 inducers such as barbiturates, carbamazepine, phenobarbital, phenytoin or primidone is not recommended. Decreased effectiveness of ulipristal may occur even 2-3 weeks after discontinuation of these agents.(1,2) DISCUSSION: CYP3A4 inducers may decrease levels and effectiveness of ulipristal. Enzyme induction may take 2-3 weeks to wear off. Plasma levels of ulipristal may be reduced even if the CYP3A4 inducer was discontinued in the previous 2-3 weeks.(1) Concurrent administration of ulipristal 30 mg and rifampin 600 mg, another CYP3A4 inducer, for 9 days decreased the maximum concentration (Cmax) and area-under-the-curve (AUC) by 90% and 93%, respectively. The Cmax and AUC of monodemethyl-ulipristal decreased by 84% and 90%, respectively.(2) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, and primidone.(3) |
ELLA |
| Romidepsin/Strong CYP3A4 Inducers; Rifabutin SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 and rifabutin may increase the metabolism of romidepsin.(1,2) CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inducer or rifabutin may result in decreased levels and effectiveness of romidepsin.(1,2) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of romidepsin recommends avoiding the use of strong inducers of CYP3A4 in patients receiving romidepsin.(1,2) The Canadian manufacturer includes rifabutin on its list of CYP3A4 inducers that should be avoided.(2) DISCUSSION: In a study in advanced cancer patients, rifampin, a strong inducer of CYP3A4 and an inhibitor and inducer of other CYP enzymes and transporters, unexpectedly increased the maximum concentration (Cmax) and area-under-curve (AUC) of romidepsin (14 mg/m2) by 60% and 80%, respectively. Romidepsin clearance and volume of distribution decreased by 44% and 52%, respectively. This is likely due to inhibition of an undetermined hepatic uptake process responsible for the disposition of romidepsin.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, dexamethasone, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifapentine and St. John's wort.(1-3) |
ISTODAX, ROMIDEPSIN |
| Ixabepilone/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of ixabepilone by CYP3A4.(1) CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers may result in decreased levels and effectiveness of ixabepilone.(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 ixabepilone states that concurrent use of strong inducers of CYP3A4 should be avoided. If concurrent therapy is required, the dose of ixabepilone may be gradually increased from 40 mg/m2 to 60 mg/m2, depending on tolerance. If the dose is increased, ixabepilone should be given as a 4 hour infusion. Monitor patients closely for toxicity. If the inducer is discontinued, the dose of ixabepilone should be returned to the dose used prior to concurrent therapy.(1) DISCUSSION: Concurrent use of rifampin, another strong inducer of CYP3A4, increased ixabepilone area-under-curve (AUC) by 43%, compared to treatment with ixabepilone alone.(1) Adjustment of the ixabepilone dose in the presence of a strong CYP3A4 inducer to 60 mg/m2 given over 4 hours is predicted to adjust the ixabepilone AUC to the range observed without inducers; however, there is no clinical data with this dose.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, and primidone.(2) |
IXEMPRA |
| Apremilast; Roflumilast/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: CYP3A4 inducers may induce the metabolism of apremilast(1) and roflumilast(2,3) by CYP3A4. CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers may reduce the clinical effectiveness of apremilast(1) and roflumilast.(2,3) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Monitor patients receiving concurrent CYP3A4 inducers for decreased apremilast(1) and roflumilast(2,3) efficacy. Concurrent use is not recommended.(1,2) The dosage of roflumilast may need to be adjusted or additional COPD therapy may need to be adjusted during and for up to two weeks after therapy with a CYP3A4 inducer has been completed. DISCUSSION: Pretreatment with rifampin (600 mg daily for 15 days) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of apremilast by 43% and 72%, respectively.(1) In an open-label study in 16 healthy males, rifampin (600 mg daily) decreased AUC and Cmax of a single dose of roflumilast (500 mcg) by 80% and 68%, respectively. The AUC and Cmax of roflumilast N-oxide decreased by 56% and 30%, respectively.(2) The total PDE4 inhibitory activity of roflumilast decreased by 60%.(2-4) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, primidone, rifampin, rifapentine and St. John's wort. |
DALIRESP, OTEZLA, ROFLUMILAST |
| Linagliptin/Strong P-gp or CYP3A4 Inducer SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong P-gp or CYP3A4 inducers may increase the metabolism of linagliptin.(1) CLINICAL EFFECTS: Concurrent or recent use of strong P-gp or CYP3A4 inducers may result in decreased levels and effectiveness of linagliptin.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: If possible, use an alternative agent to strong P-gp or CYP3A4 inducers in patients maintained on linagliptin. If concurrent therapy is required, patients may need adjustment to their diabetes therapy, including replacement of linagliptin.(1) DISCUSSION: Concurrent rifampin (600 mg daily) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of linagliptin (5 mg daily) by 40% and 44%, respectively.(1) Strong P-gp or CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, efavirenz, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lorlatinib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(2) |
GLYXAMBI, JENTADUETO, JENTADUETO XR, TRADJENTA, TRIJARDY XR |
| Toremifene/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of toremifene.(1) Toremifene may inhibit the metabolism of phenytoin.(1) CLINICAL EFFECTS: Concurrent or recent use of apalutamide, barbiturates, carbamazepine, dexamethasone, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort may result in decreased levels and effectiveness of toremifene.(1) Concurrent use of toremifene may decrease phenytoin levels.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the use of strong inducers of CYP3A4 in patients receiving toremifene. If concurrent toremifene and phenytoin are required, monitor phenytoin levels. The dosage of phenytoin may need to be adjusted.(1) DISCUSSION: In clinical trials, ten patients on anticonvulsants which included carbamazepine, phenobarbital, and phenytoin experienced a 2-fold increase in clearance and a decrease in the elimination half-life of toremifene.(1,2) The area-under-curve (AUC) and half-life of N-demethyltoremifene, an active metabolite of toremifene, decreased by 61% and 78%, respectively.(2) In a study in healthy males, rifampin (600 mg daily for 5 days) decreased maximum concentration (Cmax) and AUC of a single dose of toremifene (120 mg) by 55% and 87%, respectively. The Cmax of N-demethyltoremifene increased 48% and the AUC of N-demethyltoremifene decreased by 80%.(3) Strong inducers of CYP3A4 include apalutamide, barbiturates, carbamazepine, dexamethasone, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(4,5) |
FARESTON, TOREMIFENE CITRATE |
| Cobimetinib/Strong & Moderate CYP3A4 Inducers 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 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, lesinurad, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(1-3) |
COTELLIC |
| Ivacaftor/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of elexacaftor, tezacaftor, and ivacaftor.(1-3) CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of elexacaftor, tezacaftor, and ivacaftor.(1-3) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inducers in patients maintained on ivacaftor or the combination of elexacaftor-tezacaftor-ivacaftor, tezacaftor-ivacaftor.(1-3) Enzyme induction may last for several weeks after discontinuation a CYP3A4 inducer. DISCUSSION: Concurrent administration with rifampin (a strong inducer of CYP3A4) decreased ivacaftor area-under-curve (AUC) by 9-fold.(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.(1-4) |
KALYDECO, SYMDEKO, TRIKAFTA |
| Bortezomib/Selected Strong CYP3A4 Inducers 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 antineoplastic systemic enzyme inhibitors, including bortezomib(1). CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may decrease the levels and effectiveness of bortezomib. PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP3A4 inducers in patients receiving bortezomib therapy. Consider the use of alternative agents with less enzyme induction potential.(1-2) DISCUSSION: Rifampin (600 mg daily), a CYP3A4 inducer, decreased bortezomib area-under-curve (AUC) by 45%.(1,2) Strong inducers of CYP3A4 include apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(1,3) |
BORTEZOMIB, BORUZU, VELCADE |
| Cobicistat-Elvitegravir/Selected CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Cobicistat may inhibit rifabutin and rifapentine metabolism by CYP3A4. Apalutamide, encorafenib, enzalutamide, lumacaftor, mitotane, oxcarbazepine, rifabutin, and rifapentine may induce the metabolism of cobicistat and elvitegravir.(1) CLINICAL EFFECTS: Concurrent use of cobicistat-elvitegravir with apalutamide, encorafenib, enzalutamide, lumacaftor, mitotane, oxcarbazepine, rifabutin, or rifapentine may result decreased levels of elvitegravir and development of resistance.(1) Concurrent use of cobicistat-elvitegravir may result in elevated levels of apalutamide, oxcarbazepine, rifabutin, or rifapentine, as well as ivacaftor (which is coformulated with lumacaftor).(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Concurrent use of combination product containing cobicistat-elvitegravir-emtricitabine-tenofovir and rifabutin or rifapentine is not recommended.(1) Consider the use of alternative anticonvulsants to oxcarbazepine.(1) Concurrent use with carbamazepine, phenobarbital, or phenytoin is contraindicated.(1) DISCUSSION: Concurrent cobicistat-elvitegravir (150 mg each daily) increased the maximum concentration (Cmax) of rifabutin (150 mg every other day) by 1.09-fold. The area-under-curve (AUC) and minimum concentration (Cmin) of rifabutin decreased by 8% and 6%, respectively, when compared to the administration of 300 mg daily of rifabutin. The Cmax, AUC, and Cmin of 25-O-desacetyl-rifabutin increased by 4.84-fold, 6.25-fold, and 4.94-fold, respectively, when compared to the administration of 300 mg daily of rifabutin. The Cmax, AUC, and Cmin of elvitegravir decreased by 9%, 21%, and 67%, respectively.(1) Concurrent cobicistat-elvitegravir (150 mg each daily) with carbamazepine (200 mg twice daily) decreased the Cmax, AUC, and Cmin of elvitegravir by 45%, 69%, and 97%, respectively. Concurrent cobicistat-elvitegravir (150 mg each daily) with carbamazepine (200 mg twice daily) increased the Cmax, AUC, and Cmin of carbamazepine by 40%, 43%, and 51%, respectively. The Cmax, AUC, and Cmin was decreased for carbamazepine-10,11-epoxide by 29%, 35%, and 41%, respectively. (2) |
GENVOYA, STRIBILD |
| Enzalutamide/Strong CYP2C8 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inhibitors of CYP2C8 may inhibit the metabolism of enzalutamide.(1) CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP2C8 may result in elevated levels of and toxicity from enzalutamide.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid concurrent use of strong inhibitors of CYP2C8 with enzalutamide. If concurrent use is required, reduce the dosage of enzalutamide to 80 mg once daily. If the strong CYP2C8 inhibitor is discontinued, return the dosage of enzalutamide to the dosage used prior to initiation of the strong CYP2C8 inhibitor.(1) DISCUSSION: In a clinical trial in healthy subjects, administration of gemfibrozil (a strong inhibitor of CYP2C8, 600 mg BID) increased the area-under-curve (AUC of enzalutamide by 2.2-fold. There was no significant effect on enzalutamide maximum concentration (Cmax).(1) Strong inhibitors of CYP2C8 include gemfibrozil.(2,3) |
GEMFIBROZIL, LOPID |
| Enzalutamide/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may increase the metabolism of enzalutamide.(1) CLINICAL EFFECTS: Concurrent use of strong inducers of CYP3A4 may result in decreased levels and effectiveness of enzalutamide.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid concurrent use of strong inducers of CYP3A4 with enzalutamide. Consider the use of agents with no or minimal induction potential if possible.(1) If concurrent therapy with a strong CYP3A4 inducer is necessary, increase the enzalutamide dose from 160 mg to 240 mg once daily. If concurrent therapy with a strong CYP3A4 inducer is discontinued, the enzalutamide dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer.(1) DISCUSSION: Enzalutamide is primarily metabolized by CYP2C8 and CYP3A4. CYP2C8 is responsible for metabolism of enzalutamide to the active metabolite.(1) Coadministration of rifampin (strong CYP3A4 inducer and moderate CYP2C8 inducer) decreased the composite area-under-curve (AUC) of enzalutamide and its active metabolite by 37% with no effect on concentration maximum (Cmax).(1) Strong CYP3A4 inducers linked to this monograph include: barbiturates, carbamazepine, lumacaftor, mitotane, phenobarbital, primidone, rifampin, rifapentine, and St. John's wort.(2) |
ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTALBITAL, BUTALBITAL-ACETAMINOPHEN, BUTALBITAL-ACETAMINOPHEN-CAFFE, BUTALBITAL-ASPIRIN-CAFFEINE, CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, DONNATAL, EPITOL, EQUETRO, FIORICET, FIORICET WITH CODEINE, LYSODREN, MITOTANE, MYSOLINE, ORKAMBI, PENTOBARBITAL SODIUM, PHENOBARBITAL, PHENOBARBITAL SODIUM, PHENOBARBITAL-BELLADONNA, PHENOBARBITAL-HYOSC-ATROP-SCOP, PHENOHYTRO, PRIFTIN, PRIMIDONE, RIFADIN, RIFAMPIN, SEZABY, TEGRETOL, TEGRETOL XR, TENCON |
| Sensitive CYP3A4; CYP2C9; CYP2C19 Substrates/Enzalutamide SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Enzalutamide may induce the metabolism of agents metabolized by CYP3A4, CYP2C9, and CYP2C19.(1) CLINICAL EFFECTS: Concurrent use of enzalutamide with agents metabolized by CYP3A4, CYP2C9, and CYP2C19 may result in decreased levels and effectiveness of these agents.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid concurrent use of agents metabolized by CYP3A4, CYP2C9, or CYP2C19 that have a narrow therapeutic index with enzalutamide. If concurrent use is required, consider increased monitoring of the affected agent.(1) Dosage adjustments may be required. DISCUSSION: In a clinical trial in healthy subjects, enzalutamide was shown to reduce the area-under-curve (AUC) of midazolam (a sensitive CYP3A4 substrate), warfarin (a sensitive CYP2C9 substrate), and omeprazole (a sensitive CYP2C19 substrate.(1) A case report in a 77-year-old Caucasian male was initiated on 160 mg of enzalutamide after being stable on warfarin with an INR of 3.5. The INR dropped to 1.4 after approximately 20 days on enzalutamide therapy. Due to the drop in INR, the warfarin dose was increased by 50% which lead to a therapeutic INR. When enzalutamide was discontinued, the warfarin dose was decreased by 33% to remain at a therapeutic level. Upon reinitiation, the warfarin dose was increased once by 50% to achieve a therapeutic INR.(2) Sensitive CYP3A4 substrates with narrow therapeutic indexes include: abemaciclib, astemizole, cisapride, clarithromycin, cyclosporine, dihydroergotamine, ergonovine, ergotamine, hydroquinidine, pimozide, sirolimus, tacrolimus, temsirolimus, and terfenadine.(1,3,4) Sensitive CYP2C9 substrates with narrow therapeutic indexes include: warfarin.(1,3) Sensitive CYP2C19 substrates with narrow therapeutic indexes include: S-mephenytoin.(1,3) |
ASTAGRAF XL, CLARITHROMYCIN, CLARITHROMYCIN ER, CYCLOSPORINE, CYCLOSPORINE MODIFIED, DIHYDROERGOTAMINE MESYLATE, ENVARSUS XR, ERGOMAR, ERGOTAMINE TARTRATE, ERGOTAMINE-CAFFEINE, FYARRO, GENGRAF, JANTOVEN, LANSOPRAZOL-AMOXICIL-CLARITHRO, MIGERGOT, MIGRANAL, NEORAL, OMECLAMOX-PAK, PIMOZIDE, PROGRAF, SANDIMMUNE, SIROLIMUS, TACROLIMUS, TACROLIMUS XL, TEMSIROLIMUS, TORISEL, TRUDHESA, WARFARIN SODIUM |
| Ponatinib/Strong CYP3A4 Inducers; Rifabutin SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 and rifabutin may induce the metabolism of ponatinib via this pathway.(1-3) CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers or rifabutin may reduce the clinical effectiveness of ponatinib.(1-3) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the concurrent use of ponatinib with strong CYP3A4 inducers.(1-3) The Canadian and UK manufacturers of ponatinib include rifabutin in their list of CYP3A4 inducers that should be avoided.(2-3) When possible, select alternative agents in place of the strong CYP3A4 inducer. Monitor patients receiving concurrent therapy for reduced efficacy. DISCUSSION: Coadministration of a single ponatinib 45 mg dose with rifampin 600 mg daily in 19 healthy volunteers resulted in a decrease in ponatinib area-under-the-curve (AUC) and maximum concentration (Cmax) by 62% and 42%, respectively. (1) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine and St John's Wort.(4,5) |
ICLUSIG |
| Bedaquiline/Strong & Moderate CYP3A4 Inducers 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 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) |
SIRTURO |
| Dolutegravir/Selected UGT1A & CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Dolutegravir is metabolized by UGT1A1 and to a smaller extent by CYP3A4. Inducers of UGT1A1 and CYP3A4 may induce the metabolism of dolutegravir.(1-6) CLINICAL EFFECTS: Concurrent use of UGT1A1 and CYP3A4 inducers may result in decreased levels of and clinical effectiveness of dolutegravir.(1-6) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: When used with carbamazepine, fosamprenavir/ritonavir, rifampin, or tipranavir/ritonavir, the dosage of dolutegravir should be 50 mg twice daily. When using the combination abacavir-dolutegravir-lamivudine or dolutegravir-lamivudine product, an additional 50 mg dolutegravir table should be taken 12 hours apart from the combination product. In pediatric patients, increase the weight-based dose to twice daily. Refer to the current labeling for the specific dosing recommendation. Alternative combinations that do not induce metabolic inducers should be considered when possible for INSTI-experience patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.(1,4-6) Recommendations for other UGT1A1 and CYP3A4 inducers differ by region. The US manufacturer of dolutegravir states that concurrent use should be avoided due to insufficient data to make dosing recommendations for concomitant use.(1,4) The Canadian and UK manufacturers of dolutegravir state that the dosage of dolutegravir should be 50 mg twice daily when used concurrently with other UGT1A1 and CYP3A4 inducers. When using the combination abacavir-dolutegravir-lamivudine product, an additional 50 mg dolutegravir table should be taken 12 hours apart from the combination product. In pediatric patients, increase the weight-based dose to twice daily. Refer to the current labeling for the specific dosing recommendation. Alternative combinations that do not induce metabolic inducers should be considered when possible for patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.(5,6) DISCUSSION: In a study in 12 subjects, the administration of fosamprenavir/ritonavir (700/100 mg BID) with dolutegravir (50 mg daily) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of dolutegravir by 24%, 35%, and 49%, respectively.(1) In a study in 11 subjects, the administration of rifampin (600 mg daily) with dolutegravir (50 mg BID) decreased the Cmax, AUC, and Cmin of dolutegravir by 43%, 54%, and 32%, respectively, when compared to the administration of dolutegravir (50 mg BID) alone.(1) In a study in 11 subjects, the administration of rifampin (600 mg daily) with dolutegravir (50 mg BID) increased the Cmax, AUC, and Cmin of dolutegravir by 18%, 33%, and 22%, respectively, when compared to the administration of dolutegravir (50 mg daily) alone.(1) In a study in 14 subjects, the administration of tipranavir/ritonavir (500/200 mg BID) with dolutegravir (50 mg daily) decreased the Cmax, AUC, and Cmin of dolutegravir by 46%, 59%, and 76%, respectively.(1) In a study in 16 subjects, the administration of carbamazepine (300 mg twice daily) with dolutegravir (50 mg daily) decreased the Cmax, AUC, and Cmin of dolutegravir by 33%, 49%, and 73%, respectively. (1) UGT1A1 and CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosamprenavir/ritonavir, fosphenytoin, ivosidenib, lorlatinib, lumacaftor, mitotane, oxcarbazepine, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and tipranavir/ritonavir.(1,7) |
DOVATO, JULUCA, TIVICAY, TIVICAY PD, TRIUMEQ, TRIUMEQ PD |
| Guanfacine/Strong & Moderate CYP3A4 Inducers 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, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine, and tovorafenib.(1-3) |
GUANFACINE HCL, GUANFACINE HCL ER, INTUNIV |
| Quetiapine (Greater Than 150 mg)/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Quetiapine and its active metabolite are metabolized by CYP3A4.(1) In addition, FDA describes quetiapine as a sensitive CYP3A4 substrate: a drug which can have large changes in systemic exposure due to induction (or inhibition) of the CYP3A4 pathway.(2) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers and quetiapine will result in decreased systemic concentrations of quetiapine and may lead to therapeutic failure.(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 on quetiapine receiving chronic treatment (i.e., greater than 7-14 days) of inducers of CYP3A4, titrate the dose of quetiapine based on the patient's clinical response and tolerance, up to 5-fold of the original dose. The onset of induction is gradual but may begin within one week for potent agents (e.g. rifampin). The time to maximal induction may be 2 or more weeks depending upon the half-life and dose of the inducer. If the CYP3A4 inducer is discontinued, the dose of quetiapine should be reduced to the original level within 7-14 days.(1) DISCUSSION: In an interaction study, 18 stable patients with schizophrenia, schizoaffective or bipolar disorder started treatment with quetiapine, achieving the target dose of 300 mg twice daily on day five. On day 9 carbamazepine was started, gradually increasing to the target dose of 200 mg three times a day on day 13. Patients continued on the combination through day 33 to assure maximal enzyme induction was achieved. Carbamazepine decreased quetiapine AUC 87%, decreased steady-state maximum concentration (Cmax) by 80%, and increased clearance approximately 7-fold.(3) In a review of 2111 quetiapine levels from 1179 patients, quetiapine levels were 86% lower in patients receiving concurrent carbamazepine.(4) In a review of 62 psychiatric patients, patients receiving carbamazepine had significantly lower quetiapine concentration-to-dose ratios.(5) A case report described a newly hospitalized patient admitted on carbamazepine 600 mg daily and risperidone 8 mg daily for schizoaffective disorder. She was then converted from risperidone to quetiapine. After 7 days of treatment at the target quetiapine dose of 700 mg daily, serum quetiapine concentrations were undetectable. A repeat level 7 days later was also undetectable. The decision was then made to discontinue carbamazepine and continue quetiapine without dose adjustment. Quetiapine concentrations increased over the following days to weeks and were accompanied by clinical improvement sufficient for discharge. The authors also briefly described 2 additional patients, each receiving carbamazepine for a seizure disorder who were subsequently treated with quetiapine 600 mg or 700 mg daily for more than two weeks. As with the first case, quetiapine serum concentrations with concurrent carbamazepine therapy were below the limit of detection for each patient (lower limit of detection was 25 mcg/mL).(6) Concurrent use of phenytoin (100 mg three times daily), a strong CYP3A4 inducer, and quetiapine increased oral clearance of quetiapine by 5-fold.(7) FDA defines strong CYP inducers as agents which cause at least an 80% decrease in systemic exposure (area-under-curve or AUC) of a drug metabolized by a specific CYP enzyme.(2) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, natisedine, phenytoin, primidone, rifampin, rifapentine and St. John's Wort.(8) |
QUETIAPINE FUMARATE, QUETIAPINE FUMARATE ER, SEROQUEL, SEROQUEL XR |
| Ramelteon; Suvorexant; Tasimelteon/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of ramelteon, suvorexant or tasimelteon.(1-3) CLINICAL EFFECTS: Concurrent use with strong inducers of CYP3A4 may result in substantially lower systemic concentrations and decreased efficacy of ramelteon, suvorexant or tasimelteon.(1-3) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Ramelteon: The manufacturer notes that ramelteon efficacy may be reduced when used in combination with a strong CYP3A4 inducer.(1) Suvorexant: If possible, use alternatives to strong CYP3A4 inducers in patients who require suvorexant therapy. Patients requiring concurrent therapy may need larger doses of suvorexant; however, the maximum daily dose of 20 mg should not be exceeded.(2) Tasimelteon: The manufacturer of tasimelteon recommends avoiding concurrent use with strong CYP3A4 inducers due to the potentially large decrease in tasimelteon exposure and reduced efficacy.(3) DISCUSSION: Rifampin (600 mg daily for 11 days) decreased both maximum concentration (Cmax) and total exposure (area-under-curve or AUC) to ramelteon by 80%.(1) In an interaction study, rifampin substantially decreased levels of suvorexant. Suvorexant AUC and Cmax decreased by approximately 90% and 70%, respectively.(2) Rifampin (600 mg daily for 11 days) decreased exposure to tasimelteon by 90%.(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.(4-5) |
BELSOMRA, HETLIOZ, HETLIOZ LQ, RAMELTEON, ROZEREM, TASIMELTEON |
| Eliglustat/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may significantly increase the metabolism of eliglustat.(1) CLINICAL EFFECTS: Coadministration of eliglustat with a strong CYP3A4 inducer may increase the risk for treatment failure. PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The concurrent use of eliglustat with strong CYP3A4 inducers should be avoided.(1) Due to the risk for treatment failure, if treatment with a strong CYP3A4 inducer is required consider conversion to an alternate treatment for Gaucher disease. DISCUSSION: In CYP2D6 extensive metabolizers (EMs) and intermediate metabolizers (IMs) the concurrent use of eliglustat 127 mg twice daily (higher than approved dose) with rifampin 600mg PO daily decreased eliglustat maximum concentration (Cmax) and area-under-curve (AUC) by approximately 90%.(1) In CYP2D6 poor metabolizers (PMs), concurrent use of eliglustat 84 mg twice daily (twice the recommended dose for CYP2D6 PMs) with rifampin 600 mg PO daily decreased systemic eliglustat exposures approximately 95%.(1) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine and St. John's wort.(2,3) |
CERDELGA |
| Naloxegol/Strong CYP3A4 Inducers 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 naloxegol.(1) CLINICAL EFFECTS: Concurrent use of a strong inducers of CYP3A4 may result in decreased levels and effectiveness of naloxegol.(1) PREDISPOSING FACTORS: Patients taking methadone may be more likely to experience gastrointestinal side effects such as abdominal pain and diarrhea as a result of opioid withdrawal.(1) Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Concurrent use of a strong inducer of CYP3A4 with naloxegol is not recommended.(1) If concurrent use is warranted, monitor patients for signs of decreased naloxegol effectiveness, such as constipation. Patients may require additional laxative therapy. DISCUSSION: Rifampin (600 mg daily for 13 days), a strong inducer of CYP3A4, decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of naloxegol by 75% and 89%, respectively.(2) Strong inducers of CYP3A4 include apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(1,3,4) |
MOVANTIK |
| Abiraterone/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of abiraterone.(1) CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of abiraterone.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid concurrent use of strong inducers of CYP3A4 with abiraterone.(1) Consider the use of agents with no or minimal induction potential if possible. Monitor patients for decreased response to therapy. If concurrent administration of abiraterone and a strong CYP3A4 inducers is required, increase the dosing frequency of abiraterone from once daily to twice daily during the co-administration period. If the strong inducer is discontinued, reduce the dose of abiraterone back to the previous dose and frequency.(1) DISCUSSION: In a drug interaction trial, concurrent administration of rifampin, a strong CYP3A4 inducer, decreased abiraterone levels by 55%.(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) |
ABIRATERONE ACETATE, ABIRTEGA, AKEEGA, YONSA, ZYTIGA |
| Esomeprazole; Omeprazole/Select CYP2C19 and CYP3A4 Inducer SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Proton pump inhibitors are primarily metabolized by CYP2C19, while CYP3A4 also plays a role in metabolism.(1,2) Enzalutamide, rifampin, and St. John's wort are moderate inducers of CYP2C19 and strong inducers of CYP3A4.(3,4) Apalutamide is a strong inducer of CYP2C19 and CYP3A4.(5) Efavirenz and pacritinib are moderate inducers of CYP2C19 and CYP3A4.(3,6) CLINICAL EFFECTS: Concurrent use of agents which induce both CYP2C19 and CYP3A4 decrease systemic exposure and may result in decreased effectiveness of proton pump inhibitors.(1-7) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid concurrent use of esomeprazole or omeprazole with CYP2C19 or CYP3A4 inducers.(1,2) Monitor patients receiving concurrent therapy for reduced proton pump inhibitor (PPI) effectiveness. Although specific dosing recommendations are not available, a higher dose of the proton pump inhibitor may be considered to maintain PPI efficacy. DISCUSSION: In an interaction study, subjects with prostate cancer received omeprazole before and after enzalutamide 160 mg daily for at least 55 days. Enzalutamide decreased omeprazole area-under-curve (AUC) by 70.5%.(3,4) In an interaction study, rifampin 600 mg daily for 7 days decreased omeprazole AUC by 89.5%.(3,7) In an interaction study, pacritinib 200 mg twice daily at steady state decreased the maximum concentration (Cmax) and AUC of a single dose of omeprazole (20 mg) by 27% and 51%, respectively. In an interaction study, St. John's wort decreased the maximum concentration (Cmax) and AUC of omeprazole by 37.5% and 49.6%, respectively. The Cmax and AUC of omeprazole sulfone (via CYP2C19) increased by 160.3% and 136.6%, respectively. The Cmax and AUC of 5-hydroxyomeprazole (via CYP3A4) increased by 38.1% and 37.2%, respectively.(8,9) |
ESOMEPRAZOLE MAGNESIUM, ESOMEPRAZOLE SODIUM, KONVOMEP, NAPROXEN-ESOMEPRAZOLE MAG, NEXIUM, OMECLAMOX-PAK, OMEPRAZOLE, OMEPRAZOLE-SODIUM BICARBONATE, PRILOSEC, TALICIA, VIMOVO, YOSPRALA |
| Flibanserin/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Flibanserin is primarily metabolized by CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers and flibanserin will result in decreased systemic concentrations of flibanserin and may lead to therapeutic failure.(1,6) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of flibanserin states that concomitant use with CYP3A4 inducers is not recommended. In an interaction study, rifampin decreased flibanserin exposure(AUC) 95%.(1) The onset of induction is gradual but may begin within one week for potent agents (e.g. rifampin). The time to maximal induction may be 2 or more weeks depending upon the half-life and dose of the inducer. DISCUSSION: In an interaction study described in prescribing information, rifampin decreased flibanserin exposure (AUC) 95%.(1) FDA defines strong CYP inducers as agents which cause a > or = to 80% decrease in systemic exposure (area-under-curve or AUC) of a drug metabolized by a specific CYP enzyme.(2) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenytoin, primidone, rifabutin, rifampin, rifapentine and St. John's Wort.(3) |
ADDYI, FLIBANSERIN |
| Trabectedin/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Trabectedin is primarily metabolized by CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers will result in decreased systemic concentrations of trabectedin.(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 trabectedin states that concomitant use with CYP3A4 inducers should be avoided.(1) The onset of induction is gradual but may begin within one week for potent agents (e.g. rifampin). The time to maximal induction may be 2 or more weeks depending upon the half-life and dose of the inducer. DISCUSSION: In an interaction study, coadministration of multiple doses of rifampin (600 mg daily for 6 days) with a single dose of trabectedin on day 6 lowered trabectedin AUC by 31% compared to a single dose of trabectedin alone.(1) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenytoin, primidone, rifampin, rifapentine and St. John's Wort.(2) |
YONDELIS |
| Osimertinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of osimertinib via this pathway.(1) CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers may reduce the clinical effectiveness of osimertinib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Whenever possible, it would be prudent to use an alternative agent in place of the strong CYP3A4 inducer. After discontinuation of a strong CYP3A4 inducer, osimertinib systemic concentrations will gradually increase due to the relatively long half-life of osimertinib.(1) The US manufacturer of osimertinib states that concurrent use of CYP3A4 inducers should be avoided.(1) If concurrent therapy cannot be avoided increase the osimertinib dose to 160 mg daily. Resume osimertinib at 80 mg three weeks after the discontinuation of the strong CYP3A4 inducer. DISCUSSION: Osimertinib is itself an inducer of CYP3A4. The magnitude of induction and whether osimertinib auto-induces its own metabolism has not yet been described.(1) In a clinical pharmacokinetic study, the AUC of osimertinib was reduced by 78% in patients when coadministered with rifampin (600 mg daily for 21 days).(1) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine and St. John's Wort.(4,5) |
TAGRISSO |
| Ixazomib/Slt Moderate and Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ixazomib is primarily metabolized by CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of strong or selected moderate CYP3A4 inducers will result in decreased systemic concentrations of ixazomib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of ixazomib states that concomitant use with CYP3A4 inducers should be avoided. In an interaction study, rifampin decreased ixazomib exposure(AUC) by 74%.(1) Use an alternative to the inducing agent when possible. The onset of induction is gradual but may begin within one week for potent agents (e.g. rifampin). The time to maximal induction may be 2 or more weeks depending upon the half-life and dose of the inducer. DISCUSSION: In an interaction study, coadministration with rifampin decreased ixazomib AUC 74% and maximum concentration (Cmax) by 54%(1) Selected moderate and strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, belzutifan, carbamazepine, cenobamate, dabrafenib, elagolix, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin, rifapentine, St. John's Wort, sotorasib telotristat, and tovorafenib.(2) |
NINLARO |
| Tofacitinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of tofacitinib.(1) CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of tofacitinib(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 tofacitinib states that the concurrent use of CYP3A4 inducers is not recommended and may result in loss of or reduced clinical response of tofacitinib(1) DISCUSSION: A study of 12 subjects received tofacitinib (30 mg) with concurrent rifampin (600 mg daily), a strong inducer of CYP3A4, with a decreased tofacitinib area-under-curve (AUC) by 84% and maximum concentration (Cmax) by 74%.(4) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(1-3) |
TOFACITINIB CITRATE, XELJANZ, XELJANZ XR |
| Vemurafenib/Strong CYP3A4 Inducers; Rifabutin SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Vemurafenib is a substrate of CYP3A4. Strong inducers of CYP3A4 and rifabutin may increase the metabolism of vemurafenib.(1-3) CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 or rifabutin may result in decreased levels and effectiveness of vemurafenib.(1-3) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of vemurafenib states to avoid concurrent use with strong CYP3A4 inducers and replace these drugs with alternative drugs when possible.(1-3) The Canadian and UK manufacturers include rifabutin on their lists of CYP3A4 inducers that are to be avoided.(2,3) If concurrent administration with a strong CYP3A4 inducer is unavoidable, increase the dose of vemurafenib by 240 mg (one tablet) as tolerated.(1) If concurrent use of a strong CYP3A4 inducer is discontinued, allow a 2 week period to lapse and then resume the dose of vemurafenib that was taken prior to initiation of the strong CYP3A4 inducer.(1) DISCUSSION: In a study in healthy subjects, coadministration of single dose vemurafenib 960 mg with rifampin (600 mg daily, a strong CYP3A inducer) decreased vemurafenib area-under-curve (AUC) by 40% (90% CI: 24%, 53%) with no effect on maximum concentration (Cmax), when compared to vemurafenib alone.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(4-5) |
ZELBORAF |
| Venetoclax/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of venetoclax.(1) CLINICAL EFFECTS: Concurrent use of a strong 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) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2-4) |
VENCLEXTA, VENCLEXTA STARTING PACK |
| Pimavanserin/Strong and Moderate CYP3A4 Inducers 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) |
NUPLAZID |
| Ribociclib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of ribociclib.(1) CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of ribociclib.(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 ribociclib 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 healthy subjects, co-administration of rifampin(600 mg daily for 14 days), decreased ribociclib area-under-curve (AUC) by 89% and maximum concentration (Cmax) by 81%.(1) A pharmacokinetic simulation suggests that a moderate CYP3A4 inducer, efavirenz, may decrease ribociclib's Cmax and AUC by 51% and 70%.(4) Strong inducers of CYP3A4 include: apalutamide, barbiturates, enzalutamide, fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2-4) |
KISQALI |
| Naldemedine/Strong CYP3A4 Inducers 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 naldemedine.(1) CLINICAL EFFECTS: Concurrent use of strong inducers of CYP3A4 may result in decreased levels and effectiveness of naldemedine.(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 recommends avoid concurrent use of a strong inducer of CYP3A4 with naldemedine.(1) The UK manufacturer states concurrent use of a strong inducer of CYP3A4 is not recommended.(2) If concurrent use is warranted, monitor patients for signs of decreased naldemedine effectiveness, such as constipation. Patients may require additional laxative therapy. DISCUSSION: Rifampin (600 mg daily), a strong inducer of CYP3A4, decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of naldemedine by 38% and 83%, 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.(1-4) |
SYMPROIC |
| Valbenazine/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of valbenazine.(1) CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of valbenazine.(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 valbenazine states that the concurrent use of CYP3A4 inducers is not recommended, and that alternative treatments with less CYP3A4 induction should be considered.(1) DISCUSSION: In a study, co-administration of rifampin, approximately decreased valbenazine area-under-curve (AUC) by 70% and maximum concentration (Cmax) by 25%. The active metabolite of valbenazine (alpha-HTBZ) AUC and Cmax was decreased by 50% and 75%, 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) |
INGREZZA, INGREZZA INITIATION PK(TARDIV), INGREZZA SPRINKLE |
| Midostaurin/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Midostaurin is a substrate of CYP3A4. Strong inducers of CYP3A4 may induce the metabolism of midostaurin.(1) CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of midostaurin.(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 midostaurin states to avoid concurrent use with strong CYP3A4 inducers.(1) DISCUSSION: Midostaurin is a substrate of CYP3A4.(1) Concurrent administration of rifampicin (600 mg daily for 14 days, a strong CYP3A4 inducer) with a single 50 mg dose of midostaurin on day 9 decreased the area-under-curve (AUC) of midostaurin and CGP62221, the active metabolite, by 96% and 92%, respectively. The AUC over time to last measurable concentration of CGP62221 decreased by 59%.(1) Strong CYP3A4 inducers linked to this monograph include: barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2-3) |
RYDAPT |
| Brigatinib/Strong CYP3A4 Inducers; Rifabutin SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Brigatinib is a substrate of CYP3A4. Strong inducers of CYP3A4 and rifabutin may induce the metabolism of brigatinib.(1,2) CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 or rifabutin may result in decreased levels and effectiveness of brigatinib.(1,2) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of brigatinib states to avoid concurrent administration with strong CYP3A4 inducers.(1,2) The UK manufacturer of brigatinib includes rifabutin on its list of strong CYP3A4 inducers that should be avoided.(2) DISCUSSION: Brigatinib is a substrate of CYP3A4.(1) Concurrent administration of rifampin (600 mg daily, a strong CYP3A4 inducer) with a single 180 mg dose of brigatinib decreased the brigatinib maximum concentration (Cmax) by 60% and area-under-curve (AUC) by 80% compared to brigatinib alone.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(3-4) |
ALUNBRIG |
| Neratinib/Strong and Moderate CYP3A4 Inducers 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 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, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine, and tovorafenib.(1,2) |
NERLYNX |
| Copanlisib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Copanlisib is a substrate of CYP3A4. Strong inducers of CYP3A4 may induce the metabolism of copanlisib.(1) CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of copanlisib.(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 copanlisib states to avoid concurrent administration with strong CYP3A4 inducers.(1) DISCUSSION: Copanlisib is a substrate of CYP3A4.(1) Concurrent administration of rifampin (600 mg once daily for 12 days, a strong CYP3A4 inducer) with a single 60 mg dose of copanlisib decreased the copanlisib area-under-curve (AUC) by 63% and maximum concentration (Cmax) by 15% compared to copanlisib alone.(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.(2-3) |
ALIQOPA |
| Abemaciclib/Strong CYP3A4 Inducers 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. Strong inducers of CYP3A4 may induce the metabolism of abemaciclib.(1) CLINICAL EFFECTS: Concurrent use of a strong 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 strong 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 67% in healthy subjects.(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.(2-3) |
VERZENIO |
| Acalabrutinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Acalabrutinib is a substrate of CYP3A4. Strong inducers of CYP3A4 may induce the metabolism of acalabrutinib.(1) CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of acalabrutinib.(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, UK, and Australian manufacturers of acalabrutinib states to avoid concurrent administration with strong CYP3A4 inducers and consider alternative agents.(1-3) The US manufacturer of acalabrutinib states if concomitant use with a strong 3A4 inducer cannot be avoided, increase the acalabrutinib dose to 200 mg twice daily.(1) DISCUSSION: Concurrent administration of rifampin (600 mg once daily for 9 days, a strong CYP3A4 inducer) with acalabrutinib decreased the maximum concentration (Cmax) and area-under-curve (AUC) of acalabrutinib by 68% and 77%, respectively, in healthy subjects.(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.(4,5) |
CALQUENCE |
| Slt Proton Pump Inhibitors/Strong 2C19 and 3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP2C19 and CYP3A4 inducers may induce the metabolism of dexlansoprazole, lansoprazole, or pantoprazole.(1-3) CLINICAL EFFECTS: Concurrent use of strong CYP2C19 and CYP3A4 inducers may decrease systemic levels and effectiveness of lansoprazole, dexlansoprazole, or pantoprazole.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturers of lansoprazole and dexlansoprazole recommend avoiding concurrent use of CYP2C19 or CYP3A4 inducers.(1,2) Although the manufacturer of pantoprazole does not mention an interaction with CYP2C19 inducers, pantoprazole is also a substrate of CYP2C19 and CYP3A4.(3) If concurrent therapy is warranted, monitor closely for loss of efficacy. Although specific dosing recommendations are not available, a higher dose of the proton pump inhibitor may be considered to maintain PPI efficacy. DISCUSSION: Decreased exposure of lansoprazole, dexlansoprazole, or pantoprazole is expected when used concomitantly with strong CYP2C19 and CYP3A4 inducers. Strong CYP2C19 and CYP3A4 inducers linked to this monograph include: apalutamide, efavirenz, enzalutamide, fosphenytoin, phenytoin, rifampin, and St. John's Wort.(4,5) |
DEXILANT, DEXLANSOPRAZOLE DR, LANSOPRAZOL-AMOXICIL-CLARITHRO, LANSOPRAZOLE, PANTOPRAZOLE SODIUM, PANTOPRAZOLE SODIUM-0.9% NACL, PREVACID, PROTONIX, PROTONIX IV |
| Fostamatinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of fostamatinib via this pathway.(1) CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers may reduce the clinical effectiveness of fostamatinib's metabolite, R406.(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 fostamatinib states that concurrent use of CYP3A4 inducers is not recommended.(1) DISCUSSION: In a clinical pharmacokinetic study, the AUC of R406 was reduced by 75% in patients when coadministered with rifampin (600 mg daily for 8 days).(1) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, enzalutamide, carbamazepine, fosphenytoin, encorafenib, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's Wort.(2,3) |
TAVALISSE |
| Selected Long-Acting Aripiprazole Injections/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers may increase the metabolic clearance of aripiprazole.(1,2) CLINICAL EFFECTS: Strong CYP3A4 inducers may result in decreased levels and effectiveness of aripiprazole.(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 the extended release injectable aripiprazole lauroxil, submicronized (Aristada Initio) recommends avoiding use of strong CYP3A4 inducers with Aristada Initio. Aristada Initio is only available in a single strength as a single-dose prefilled syringe.(1) For patients receiving aripiprazole extended-release injection (Abilify Maintena or Abilify Asimtuffi), dose adjustments are not recommended by the manufacturer if the duration of strong CYP3A4 inducer treatment is less than 14 days. Concurrent use of Abilify Maintena or Abilify Asimtuffi with strong CYP3A4 inducers for greater than 14 days should be avoided.(2-3) DISCUSSION: Drug interaction studies have not been conducted with Aristada Initio,(1) Abilify Maintena,(2) or Abilify Asimtuffi.(3) Aristada Initio has a long half-life (15-18 days).(1) Abilify Maintena has a half-life of 29.9 days and 46.5 days after multiple injections for every 4-week injection with the 300 mg and 400 mg dose, respectively.(2) The concurrent administration of carbamazepine (200 mg twice daily) with aripiprazole (30 mg daily) resulted in 70% decreases in the area-under-curve (AUC) and maximum concentration (Cmax) of both aripiprazole and dehydro-aripiprazole, its active metabolite.(1) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenytoin, primidone, rifampin, rifapentine and St. John's Wort.(4-5) |
ABILIFY ASIMTUFII, ABILIFY MAINTENA, ARISTADA INITIO |
| Hormonal Contraceptives/Selected Strong & Moderate CYP3A4 Inducers 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 increase the CYP3A4-mediated metabolism of hormonal contraceptives.(1-2) CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inducers may reduce the effectiveness of hormonal contraceptives.(1-2) Apalutamide, enzalutamide, ivosidenib, and mitotane may cause birth defects and/or miscarriage if used by pregnant women. PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Women should use a back-up method of birth control during therapy with a CYP3A4 inducer. Women of reproductive potential should use effective non-hormonal methods of contraception during therapy with a CYP3A4 inducer. Continuation of an effective non-hormonal contraceptive after discontinuation of the CYP3A4 inducer is also advised for the period of time indicated below.(1-3) There is no specific recommendation for contraception in women on apalutamide or enzalutamide. Male patients with female partners of reproductive age are advised to continue effective contraception for 3 months after discontinuation of apalutamide or enzalutamide.(4,5) The manufacturer of mitotane recommends continuing effective contraception after discontinuation of mitotane for as long as mitotane plasma levels are detectable. Mitotane half life ranges from 18 to 159 days (median 53 days).(3) 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.(6) DISCUSSION: Strong and moderate CYP3A4 inducers may increase the CYP3A4-mediated metabolism of hormonal contraceptives and decrease the effectiveness of hormonal contraceptives, including oral contraceptives, patches, implants, and/or IUDs. Women should use a back-up method of birth control during and after CYP3A4 inducer therapy.(1-3) An in vivo mechanism static model predicted strong interactions between ulipristal combined with enzalutamide or mitotane. Enzalutamide was predicted to lower ulipristal area-under-curve (AUC) by 85%, and mitotane was predicted to lower ulipristal AUC by 93%.(2) Strong and moderate CYP3A4 inducers linked include: apalutamide, enzalutamide, ivosidenib, mitotane, nafcillin, sotorasib, telotristat, and thioridazine.(7,8) |
2-METHOXYESTRADIOL, AFIRMELLE, ALTAVERA, ALYACEN, AMETHIA, AMETHYST, ANNOVERA, APRI, ARANELLE, ASHLYNA, AUBRA, AUBRA EQ, AUROVELA, AUROVELA 24 FE, AUROVELA FE, AVERI, AVIANE, AYUNA, AZURETTE, BALCOLTRA, BALZIVA, BEYAZ, BLISOVI 24 FE, BLISOVI FE, BRIELLYN, CAMILA, CAMRESE, CAMRESE LO, CAZIANT, CHARLOTTE 24 FE, CHATEAL EQ, CRYSELLE, CYRED, CYRED EQ, DASETTA, DAYSEE, DEBLITANE, DEPO-PROVERA, DEPO-SUBQ PROVERA 104, DESOGESTR-ETH ESTRAD ETH ESTRA, DIETHYLSTILBESTROL, DOLISHALE, DROSPIRENONE-ETH ESTRA-LEVOMEF, DROSPIRENONE-ETHINYL ESTRADIOL, ELINEST, ELURYNG, EMZAHH, ENILLORING, ENPRESSE, ENSKYCE, ERRIN, ESTARYLLA, ESTRADIOL, ESTRADIOL BENZOATE, ESTRADIOL CYPIONATE, ESTRADIOL HEMIHYDRATE, ESTRADIOL HEMIHYDRATE MICRO, ESTRADIOL MICRONIZED, ESTRADIOL VALERATE, ESTRIOL, ESTRIOL MICRONIZED, ESTRONE, ETHINYL ESTRADIOL, ETHYNODIOL-ETHINYL ESTRADIOL, ETONOGESTREL-ETHINYL ESTRADIOL, FALMINA, FEIRZA, FEMLYV, FINZALA, GALBRIELA, GEMMILY, HAILEY, HAILEY 24 FE, HAILEY FE, HALOETTE, HEATHER, ICLEVIA, INCASSIA, INTROVALE, ISIBLOOM, JAIMIESS, JASMIEL, JENCYCLA, JOLESSA, JOYEAUX, JULEBER, JUNEL, JUNEL FE, JUNEL FE 24, KAITLIB FE, KALLIGA, KARIVA, KELNOR 1-35, KELNOR 1-50, KURVELO, LARIN, LARIN 24 FE, LARIN FE, LEENA, LESSINA, LEVONEST, LEVONORG-ETH ESTRAD ETH ESTRAD, LEVONORG-ETH ESTRAD-FE BISGLYC, LEVONORGESTREL-ETH ESTRADIOL, LEVORA-28, LO LOESTRIN FE, LO-ZUMANDIMINE, LOESTRIN, LOESTRIN FE, LOJAIMIESS, LORYNA, LOW-OGESTREL, LUTERA, LYLEQ, LYZA, MARLISSA, MEDROXYPROGESTERONE ACETATE, MELEYA, MERZEE, MIBELAS 24 FE, MICROGESTIN, MICROGESTIN FE, MILI, MINZOYA, MONO-LINYAH, NATAZIA, NECON, NEXPLANON, NEXTSTELLIS, NIKKI, NORA-BE, NORELGESTROMIN-ETH ESTRADIOL, NORETHIN-ETH ESTRA-FERROUS FUM, NORETHINDRON-ETHINYL ESTRADIOL, NORETHINDRONE, NORETHINDRONE-E.ESTRADIOL-IRON, NORGESTIMATE-ETHINYL ESTRADIOL, NORTREL, NUVARING, NYLIA, OCELLA, ORTHO TRI-CYCLEN, ORTHO-NOVUM, PHILITH, PIMTREA, PORTIA, RECLIPSEN, RIVELSA, ROSYRAH, SAFYRAL, SETLAKIN, SHAROBEL, SIMLIYA, SIMPESSE, SLYND, SPRINTEC, SRONYX, SYEDA, TARINA 24 FE, TARINA FE, TARINA FE 1-20 EQ, TAYTULLA, TILIA FE, TRI-ESTARYLLA, TRI-LEGEST FE, TRI-LINYAH, TRI-LO-ESTARYLLA, TRI-LO-MARZIA, TRI-LO-MILI, TRI-LO-SPRINTEC, TRI-MILI, TRI-SPRINTEC, TRI-VYLIBRA, TRI-VYLIBRA LO, TULANA, TURQOZ, TWIRLA, TYBLUME, VALTYA, VELIVET, VESTURA, VIENVA, VIORELE, VOLNEA, VYFEMLA, VYLIBRA, WERA, WYMZYA FE, XARAH FE, XELRIA FE, XULANE, YASMIN 28, YAZ, ZAFEMY, ZARAH, ZOVIA 1-35, ZUMANDIMINE |
| Eravacycline/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of eravacycline.(1) CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 may result in decreased levels of eravacycline and may lead to decreased efficacy of eravacycline and increase the risk of treatment failure.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: For the treatment of complicated intra-abdominal infections, the US manufacturer of eravacycline recommends dose adjustment of eravacycline to 1.5 mg/kg every 12 hours for a total duration of 4 to 14 days with concurrent use of a strong CYP3A4 inducer. No dose adjustment is warranted with concurrent use of a weak or moderate CYP3A4 inducer.(1) Standard dosing of eravacycline is 1 mg/kg every 12 hours for 4 to 14 days for complicated intra-abdominal infections.(1) DISCUSSION: Concurrent use of rifampin (a strong inducer of CYP3A4) decreased eravacycline area-under-curve (AUC) by 35% and increased eravacycline clearance by 54%.(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.(2-4) |
XERAVA |
| Duvelisib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of duvelisib.(1) CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 inducer may result in decreased levels and effectiveness of duvelisib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of duvelisib states that concurrent use with strong CYP3A4 inducers should be avoided. (1) DISCUSSION: Concurrent administration of rifampin 600 mg once daily for 7 days, a strong inducer of CYP3A4, decreased duvelisib concentration maximum (Cmax) and area-under-curve (AUC) by 66% and 82%, respectively.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2-3) |
COPIKTRA |
| Glasdegib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of glasdegib.(1) CLINICAL EFFECTS: Concurrent use of a strong 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 US manufacturer of glasdegib states that the concurrent use of CYP3A4 inducers should be avoided.(1) DISCUSSION: In a study with healthy subjects, co-administration of rifampin (strong 3A4 inducer), decreased glasdegib area-under-curve (AUC) by 70% and maximum concentration (Cmax) by 35%.(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) |
DAURISMO |
| Larotrectinib/Strong CYP3A4 Inducers; Rifabutin SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 and rifabutin may increase the metabolism of larotrectinib.(1,2) CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 or rifabutin may result in decreased levels and effectiveness of larotrectinib.(1,2) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of larotrectinib states that the concurrent use of strong CYP3A4 inducers should be avoided, and that alternative treatments with less CYP3A4 induction should be considered.(1,2) The Canadian manufacturer includes rifabutin on its list of CYP3A4 inducers that should be avoided.(2) If coadministration of a strong 3A4 inducer cannot be avoided, double the larotrectinib dose. After the strong 3A4 inducer has been discontinued for 3 to 5 elimination half-lives, resume the larotrectinib dose at the dose taken prior to initiating the 3A4 inducer.(1,2) DISCUSSION: In a study with healthy subjects, co-administration of rifampin (strong 3A4 inducer) with a single dose of larotrectinib (100 mg), decreased larotrectinib area-under-curve (AUC) by 81% and maximum concentration (Cmax) by 71%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(3-4) |
VITRAKVI |
| Siponimod/Dual Inducers of CYP2C9 and CYP3A4 SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Drugs that are both moderate inducers of CYP2C9 and strong inducers of CYP3A4 may increase the metabolism of siponimod.(1) CLINICAL EFFECTS: Concurrent use of a siponimod with a moderate CYP2C9/strong CYP3A4 dual inducer may result in decreased levels and effectiveness of siponimod.(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 siponimod says that the combination of siponimod with a moderate CYP2C9/strong CYP3A4 dual inducer is not recommended.(1) DISCUSSION: In a study, rifampin (600 mg daily) decreased siponimod area-under-curve (AUC) and maximum concentration (Cmax) by 57 % and 45 %, respectively in CYP2C9 normal metabolizers. Across all CYP2C9 genotypes, rifampin decreased the AUC of siponimod by 78 % in an in silico evaluation.(1) Drugs that are both moderate CYP2C9 inducers and strong CYP3A4 inducers linked to this monograph include: carbamazepine, enzalutamide, and rifampin.(1-3) |
MAYZENT |
| Protease Inhibitors/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers are expected to increase the metabolism of protease inhibitors.(1-2) CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers may result in decreased levels and effectiveness of protease inhibitors.(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 manufacturers of darunavir and lopinavir/ritonavir advise caution with concurrent use of drugs that induce CYP3A4 as they would be expected to decrease the plasma concentrations of the protease inhibitor.(1,2) The manufacturers of enzalutamide and mitotane (strong CYP3A4 inducers) advise avoiding concomitant use with narrow therapeutic drugs that are metabolized by CYP3A4.(3-5) If enzalutamide is discontinued, the effects of enzyme induction may persist for one month or longer.(4) DISCUSSION: In a study using rifampin 600 mg once daily with lopinavir/ritonavir 400 mg/100 mg twice daily, lopinavir area-under-curve (AUC) and maximum concentration (Cmax) were decreased by 75% and 55%, respectively, compared to lopinavir/ritonavir given alone.(2) Protease inhibitors linked to this monograph include: amprenavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, and tipranavir.(3,4) Strong CYP3A4 inducers linked to this monograph include: enzalutamide and mitotane.(6,7) |
APTIVUS, DARUNAVIR, FOSAMPRENAVIR CALCIUM, KALETRA, LOPINAVIR-RITONAVIR, PREZISTA, VIRACEPT |
| Erdafitinib/Strong CYP3A4 Inducers 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. Strong inducers of CYP2C9 or CYP3A4 may induce the metabolism of erdafitinib.(1) CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 inducer 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 concurrent use with strong CYP3A4 inducers should be avoided. (1) DISCUSSION: Simulations suggested that rifampin (a strong CYP3A4 and moderate CYP2C9 inducer) may significantly decrease the Cmax and AUC of erdafitinib.(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) |
BALVERSA |
| Tivozanib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of tivozanib by CYP3A4.(1,2) CLINICAL EFFECTS: The concurrent use of strong CYP3A4 inducers and tivozanib may result in decreased levels of tivozanib, which may lead to treatment failure.(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 tivozanib recommends avoiding concomitant use of strong CYP3A4 inducers.(1) The UK manufacturer of tivozanib states that concurrent use with strong CYP3A4 inducers should be undertaken with caution.(2) DISCUSSION: Concomitant use of multiple doses of rifampin (a strong CYP3A inducer) did not change tivozanib maximum concentration (Cmax) but decreased tivozanib area-under-curve (AUC) by 52%.(1) In a study in health volunteers, concurrent administration of single dose tivozanib (1340 mcg) with rifampin 600 mg once daily (a strong CYP3A4 inducer) decreased the half-life of tivozanib from 121 to 54 hours and decreased single dose AUC by 48%. The clinical effects of strong CYP3A4 inducers on repeated daily dosing has not been studied.(2) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, dexamethasone, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(3,4) |
FOTIVDA |
| Bictegravir-Emtricitabine-Tenofovir Alafenamide/Selected Strong CYP3A4 Inducers; Oxcarbazepine SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers and oxcarbazepine may induce the metabolism of bictegravir.(1,2) CLINICAL EFFECTS: Concurrent use of bictegravir with strong CYP3A4 inducers or oxcarbazepine may result in decreased levels of bictegravir, virologic failure, and 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 manufacturer of bictegravir recommends considering alternatives to oxcarbazepine.(1) The National Institute of Health HIV guidelines do not recommend coadministration of oxcarbazepine with bictegravir.(2) Other CYP3A4 inducers should not be coadministered with bictegravir.(1,2) DISCUSSION: Coadministration of rifampin (600 mg daily, a strong CYP3A4 inducer) decreased bictegravir area-under-curve (AUC) by 75% and maximum concentration (Cmax) by 28%.(1) Although the other CYP3A4 inducers linked to this monograph have not been studied with bictegravir, a similar effect is expected. Coadministration of rifabutin (300 mg daily) with bictegravir decreased bictegravir AUC and Cmax by 38% and 20%, respectively.(1) CYP3A4 inducers linked to this monograph include: barbiturates, encorafenib, enzalutamide, ivosidenib, mitotane, or oxcarbazepine.(1-3) |
BIKTARVY |
| Avatrombopag/Dual Inducers of CYP2C9 and CYP3A4 SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Agents that are both moderate or strong inducers of CYP2C9 and CYP3A4 may increase the metabolism of avatrombopag.(1-2) CLINICAL EFFECTS: Concurrent use of a dual inducer of CYP2C9 and CYP3A4 may result in decreased levels of and clinical effects of avatrombopag.(1-2) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of avatrombopag recommends dose adjustment of avatrombopag when used with drugs that are dual inducers of CYP2C9 and CYP3A4 in patients with chronic immune thrombocytopenia (ITP). When starting avatrombopag in a patient with chronic ITP already taking a dual CYP2C9 and CYP3A4 inducer, increase the dose of avatrombopag to 40 mg once daily.(1) When starting a dual CYP2C9 and CYP3A4 inducer in a chronic ITP patient already taking avatrombopag, monitor platelet counts and adjust the dose of avatrombopag as needed, according to the prescribing information for avatrombopag.(1) No dose adjustments are required for patients with chronic liver disease.(1) DISCUSSION: A study of 16 healthy subjects found that coadministration of rifampin (a moderate CYP2C9 and strong CYP3A4 inducer) and avatrombopag led to a 43 % decrease in the area-under-curve (AUC) of avatrombopag compared to avatrombopag administered alone and an approximately 5-fold reduction in the area-under-effect-curve (AUEC). There was no difference in the maximum concentration (Cmax) of avatrombopag or the maximum platelet count (Emax) with or without rifampin.(1-2) Drugs that are both moderate CYP2C9 inducers and strong CYP3A4 inducers linked to this monograph include: carbamazepine, enzalutamide, mavacamten, and rifampin.(1,3-4) |
DOPTELET |
| Darolutamide/P-gp and Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Apalutamide, carbamazepine, enzalutamide, fosphenytoin, phenytoin, rifampin, rifapentine, and St. John's wort may induce the metabolism of darolutamide by both P-gp and CYP3A4. CLINICAL EFFECTS: Concurrent or recent use of apalutamide, carbamazepine, enzalutamide, fosphenytoin, phenytoin, rifampin, rifapentine, or St. John's wort may result in decreased levels and effectiveness of darolutamide. PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: If possible, avoid the concurrent use of agents that are combined P-gp and strong CYP3A4 inducers, such as apalutamide, carbamazepine, enzalutamide, fosphenytoin, phenytoin, rifampin, rifapentine, and St. John's wort, in patients receiving darolutamide. DISCUSSION: Concurrent rifampin (combined P-gp and strong CYP3A4 inducer) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of darolutamide by 72% and 52%, respectively.(1) |
NUBEQA |
| Pexidartinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Pexidartinib is a substrate of CYP3A4. Strong inducers of CYP3A4 may induce the metabolism of pexidartinib.(1) CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 inducer may result in decreased levels and effectiveness of pexidartinib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of pexidartinib states that concurrent use with strong CYP3A4 inducers should be avoided. (1) DISCUSSION: Concomitant administration of rifampin (strong CYP3A4 inducer) decreased pexidartinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 33% and 65%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2-3) |
TURALIO |
| Pretomanid/Strong and Moderate CYP3A4 Inducers 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, 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) |
PRETOMANID |
| Entrectinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Entrectinib is a substrate of CYP3A4. Strong inducers of CYP3A4 may induce the metabolism of entrectinib.(1) CLINICAL EFFECTS: The concurrent administration of a strong 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 strong 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) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2-3) |
ROZLYTREK |
| Upadacitinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Upadacitinib is a substrate of CYP3A4. Strong inducers of CYP3A4 may induce the metabolism of upadacitinib. (1) CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 inducer may result in decreased levels and effectiveness of upadacitinib.(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 upadacitinib states that concurrent use with strong CYP3A4 inducers is not recommended. (1) DISCUSSION: Concomitant administration of rifampin (600 mg once daily for 9 days, strong CYP3A4 inducer) with upadacitinib decreased upadacitinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 51% and 61%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2-3) |
RINVOQ, RINVOQ LQ |
| Fedratinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Fedratinib is a substrate of CYP3A4. Strong inducers of CYP3A4 may induce the metabolism of fedratinib.(1) CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 inducer may result in decreased levels and effectiveness of fedratinib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of fedratinib states that concurrent use with strong CYP3A4 inducers should be avoided.(1) DISCUSSION: Coadministration with rifampin (a strong CYP3A4 inducer) resulted in a 70% decrease in fedratinib maximum concentration (Cmax) and an 81% decrease in fedratinib area-under-curve (AUC).(2) Strong inducers of CYP3A4 include: apalutamide, barbiturates, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(3-4) |
INREBIC |
| Intravenous and Oral Lefamulin/Strong CYP3A4 or P-glycoprotein (P-gp) Inducer 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 and of intestinal efflux transporter P-glycoprotein (P-gp). Strong inducers of CYP3A4 may induce the metabolism of lefamulin. P-gp inducers may decrease absorption of and exposure to lefamulin.(1) CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 or P-gp inducer may result in decreased levels and effectiveness of lefamulin.(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 lefamulin states that concurrent use with strong CYP3A4 or P-gp inducers should be avoided. (1) DISCUSSION: In a study, concurrent administration of rifampin (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 (strong inducer) with oral lefamulin (tablets) decreased lefamulin AUC and Cmax by 72% and 57%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2-3) |
XENLETA |
| Istradefylline/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Istradefylline is a substrate of CYP3A4. Strong inducers of CYP3A4 may induce the metabolism of istradefylline.(1) CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 inducer may result in decreased levels and effectiveness of istradefylline.(1) PREDISPOSING FACTORS: Tobacco smokers who smoke more than 20 cigarettes per day may have lower exposure to istradefylline and be more susceptible to the effects of a strong CYP3A4 inducer.(1) Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of istradefylline states that concurrent use with strong CYP3A4 inducers should be avoided.(1) DISCUSSION: Concomitant administration of rifampin (600 mg once daily for 20 days, strong CYP3A4 inducer) with istradefylline (40 mg) decreased istradefylline maximum concentration (Cmax) and area-under-the-curve (AUC) by 45% and 81%, respectively, compared to istradefylline administered alone.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2-3) |
NOURIANZ |
| Zanubrutinib/Strong CYP3A4 Inducers 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. Strong inducers of CYP3A4 may induce the metabolism of zanubrutinib.(1) CLINICAL EFFECTS: The concurrent administration of strong 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 strong CYP3A4 inducers should be avoided.(1) DISCUSSION: Co-administration of multiple doses of rifampin, a strong CYP3A4 inducer, decreased the zanubrutinib concentration maximum (Cmax) by 92% and area-under-curve (AUC) by 93%. Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2-3) |
BRUKINSA |
| Ubrogepant/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of ubrogepant.(1) CLINICAL EFFECTS: The concurrent administration of a strong 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 of ubrogepant states that concurrent use with strong CYP3A4 inducers should be avoided.(1) DISCUSSION: Coadministration of ubrogepant with rifampin, a strong CYP3A4 inducer, resulted in an 80% reduction in ubrogepant exposure.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2-3) |
UBRELVY |
| Daridorexant/Strong or Moderate CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3) |
QUVIVIQ |
| Lumateperone/CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, repotrectinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 include: amprenavir, armodafinil, bexarotene, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, garlic, genistein, gingko, ginseng, glycyrrhizin, nevirapine, omaveloxolone, oxcarbazepine, pioglitazone, quercetin, rufinamide, sotorasib, sulfinpyrazone, tecovirimat, terbinafine, ticlopidine, troglitazone, vemurafenib, and vinblastine.(2,3) |
CAPLYTA |
| Avapritinib/Strong or Moderate CYP3A4 Inducers 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 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, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine and tovorafenib.(2,3) |
AYVAKIT |
| Regorafenib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of regorafenib via this pathway. Regorafenib and active M2 and M5 metabolites contribute to anticancer activity.(1,2) Although interpatient variability is high, with repeated dosing the systemic exposure to each component (regorafenib, M2 and M5) is similar. CYP3A4 converts regorafenib to the active M2 metabolite. M2 is subsequently converted, via an unknown pathway, to the active M5 metabolite.(2) CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers may alter the clinical effectiveness of regorafenib.(1,2) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the concurrent use of regorafenib with strong CYP3A4 inducers.(1) When possible, select alternative agents in place of the strong CYP3A4 inducer. Monitor patients receiving concurrent therapy for reduced efficacy. DISCUSSION: In an interaction study of rifampin and regorafenib, rifampin was associated with a 50% decrease in exposure to regorafenib and no change in exposure to M2. However, the mean exposure to M5 increased 264%. Due to this large increase in M5, overall exposure to the combination of regorafenib, M2 and M5 was increased by 68%.(2) Regorafenib was approved for use prior to completion of an exposure-response analysis or a population pharmacokinetic study.(2) The outcomes of these studies will increase understanding and improve prediction of regorafenib interaction risks. Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine and St John's Wort.(3,4) |
STIVARGA |
| Tazemetostat/Strong or Moderate CYP3A4 Inducers 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 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, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3) |
TAZVERIK |
| Rimegepant/Strong and Moderate CYP3A4 Inducers 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 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, 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) |
NURTEC ODT |
| Selumetinib/Strong and Moderate CYP3A4 Inducers 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 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, 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) |
KOSELUGO |
| Pemigatinib/Strong and Moderate CYP3A4 Inducers 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 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, 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) |
PEMAZYRE |
| Tucatinib/Strong CYP3A4 Inducers; Moderate CYP2C8 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Tucatinib is a substrate of CYP3A4 and CYP2C8. Strong inducers of CYP3A4 or moderate inducers of CYP2C8 may induce the metabolism of tucatinib.(1) CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 or a moderate inducer of CYP2C8 may result in decreased levels and effectiveness of tucatinib.(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 tucatinib states to avoid concurrent administration with strong CYP3A4 inducers or moderate CYP2C8 inducers.(1) DISCUSSION: Coadministration of rifampin (a strong CYP3A4 and moderate CYP2C8 inducer- 600 mg once daily) decreased the area-under-the-curve (AUC) and maximum concentration (Cmax) of tucatinib (300 mg single dose) by 50% and 40%, respectively.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, enzalutamide, fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2-3) Moderate CYP2C8 inducers linked to this monograph include: rifampin.(2-3) |
TUKYSA |
| Capmatinib/Strong and Moderate CYP3A4 Inducers 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 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, 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) |
TABRECTA |
| Selpercatinib/Strong and Moderate CYP3A4 Inducers 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 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) |
RETEVMO |
| Ripretinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of ripretinib via this pathway. 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 strong 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 strong CYP3A4 inducers.(1) When possible, select alternative agents in place of the strong CYP3A4 inducer. Monitor patients receiving concurrent therapy for reduced efficacy. 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 an interaction study of efavirenz (a moderate CYP3A inducer), concurrent use was predicted to decrease ripretinib Cmax by 24% and decrease AUC by 56%.(1) 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) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine and St John's Wort.(2,3) |
QINLOCK |
| Lurbinectedin/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers may increase the metabolism of lurbinectedin.(1) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may decrease the serum levels and effectiveness of lurbinectedin.(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 lurbinectedin states that the concurrent use of lurbinectedin with strong CYP3A4 inducers should be avoided.(1) DISCUSSION: Pharmacokinetic studies have not been conducted with extended doses of CYP3A4 inducers with concurrent lurbinectedin therapy.(1) Bosentan (a moderate CYP3A4 inducer) decreased the area-under-curve (AUC) of total lurbinectedin by 20% and unbound lurbinectedin by 19%. This change was not considered to be clinically significant.(1) Strong CYP3A4 inducers would be expected to have a larger impact on lurbinectedin levels and may affect therapeutic effects. In a study including data from 443 patients with solid and hematologic malignancies treated in six phase I and three phase II trials with lurbinectedin as a single agent or combined with other agents, CYP3A inducers were coadministered in 52.2% of the patients but no changes in lurbinectedin pharmacokinetics were observed in in these patients. This is likely due to the CYP3A inducers mostly consisting of single-dose corticosteroids given as per-protocol antiemetic prophylaxis, minutes before lurbinectedin infusion.(2) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(3,4) |
ZEPZELCA |
| Fenfluramine/Strong CYP1A2, CYP2B6 or CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP1A2, CYP2B6, or CYP3A4 may increase the metabolism of fenfluramine.(1) Over 75% of fenfluramine is metabolized to norfenfluramine prior to elimination, primarily by CYP1A2, CYP2B6, and CYP2D6. CYP2C9, CYP2C19, and CYP3A4 play a minor role in fenfluramine metabolism.(1) CLINICAL EFFECTS: Concurrent use of agents that are strong inducers of CYP1A2, CYP2B6, or CYP3A4 may result in decreased levels and effectiveness of fenfluramine.(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 fenfluramine recommends avoiding coadministration with strong CYP1A2, CYP2B6, or CYP3A4 inducers. Patients who must receive concurrent therapy should be monitored for decreased efficacy and may require increased dosages of fenfluramine, not to exceed the maximum fenfluramine dosages below.(1) The maximum daily dose for patients with concomitant stiripentol and clobazam is 17 mg.(1) The maximum daily dose for patients without concomitant stiripentol is 26 mg.(1) If a strong CYP1A2, CYP2B6, or CYP3A4 inducer is discontinued, gradually lower the fenfluramine dosage to the dose administered before initiation of the inducer.(1) DISCUSSION: In a study with healthy volunteers, steady-state rifampin (a CYP1A2, CYP2B6, and CYP3A4 inducer) 600 mg daily decreased the area-under curve (AUC) and maximum concentration (Cmax) of single-dose fenfluramine 0.4 mg/kg by 58% and 40%, respectively, and increased the AUC and Cmax of norfenfluramine by 50% and 13%, respectively.(1) Strong inducers of CYP1A2, CYP2B6, or CYP3A4 linked to this monograph include apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(1-3) |
FINTEPLA |
| Pralsetinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of pralsetinib.(1) CLINICAL EFFECTS: Concurrent use of a strong 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 strong CYP3A4 inducers.(1) If coadministration cannot be avoided, increase the starting dose of pralsetinib to double the current dose on day 7 of coadministration with a strong CYP3A4 inducer. After discontinuation of a strong CYP3A4 inducer for at least 14 days, resume the previous pralsetinib dose prior to initiating the strong CYP3A4 inducer.(1) Monitor patients receiving concurrent therapy for reduced efficacy. DISCUSSION: Coadministration of rifampin 600 mg once daily with a single pralsetinib 400 mg dose decreased pralsetinib concentration maximum (Cmax) by 30% and area-under-curve (AUC) by 68%.(1) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine and St John's Wort.(2,3) |
GAVRETO |
| Lumacaftor-Ivacaftor/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of lumacaftor-ivacaftor.(1) CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of lumacaftor-ivacaftor.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inducers in patients maintained on lumacaftor-ivacaftor.(1) Enzyme induction may last for several weeks after discontinuation a CYP3A4 inducer. DISCUSSION: Concurrent administration of the combination of lumacaftor-ivacaftor with rifampin decreased ivacaftor area-under-curve (AUC) 57%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine and St. John's wort.(1-2) |
ORKAMBI |
| Voclosporin/Strong and Moderate CYP3A4 Inducers 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 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, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3) |
LUPKYNIS |
| Aprepitant; Netupitant/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Aprepitant and netupitant are metabolized primarily by CYP3A4. Strong inducers of CYP3A4 may increase their metabolism and clearance via CYP3A4.(1,2) CLINICAL EFFECTS: Concurrent use with strong inducers of CYP3A4 may result in significantly decreased levels and effectiveness of aprepitant and netupitant.(1,2) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of aprepitant recommends avoiding concurrent use with strong CYP3A4 inducers.(1) The manufacturer of netupitant recommends avoiding use of netupitant in patients who are chronically using strong CYP3A4 inducers.(2) Patients treated concurrently with a strong CYP3A4 inducer should be monitored for decreased antiemetic efficacy. When possible and clinically appropriate, consider use of an alternative antiemetic or alternatives to the strong CYP3A4 inducer. DISCUSSION: Rifampin (600 mg daily) decreased the area-under-curve (AUC) and half-life of aprepitant (375 mg single dose) by 11-fold and 3-fold, respectively.(1) Rifampin (600 mg daily for 17 days) decreased the mean maximum concentration (Cmax) and AUC of netupitant by 62% and 82% respectively.(2) Strong CYP3A4 inducers linked to this monograph are: apalutamide, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's Wort.(3,4) FDA defines a Strong CYP inducer as an agent which decreases the area-under-curve (AUC) of a Sensitive Substrate by > or = 80 per cent.(3) |
AKYNZEO, APONVIE, APREPITANT, CINVANTI, EMEND, FOCINVEZ, FOSAPREPITANT DIMEGLUMINE |
| Enzalutamide/Clopidogrel SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Clopidogrel metabolism to its active metabolite occurs primarily through CYP2C19, with contributions from other CYP enzymes including CYP3A4.(1) Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer and may increase the conversion of clopidogrel to its active form.(2) CLINICAL EFFECTS: Concurrent use of enzalutamide with clopidogrel may increase the effects and toxicity of clopidogrel, including bleeding.(1,2) PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patient with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Avoid concurrent use of clopidogrel with enzalutamide. Monitor patients for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue clopidogrel in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: In a study of 12 healthy volunteers, rifampin (a strong CYP3A4 inducer, 300 mg twice daily for 7 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of the active metabolite of clopidogrel by approximately 4-fold. In conjunction with this, there was a higher level of P2Y12 receptor blockade by clopidogrel after rifampin pre-treatment. Clopidogrel 600 mg alone decreased the number of unblocked receptors at 4 hours from 248 +/- 40 to 48 +/- 24 per platelet. After rifampin pre-treatment, clopidogrel decreased the number of unblocked receptors from 266 +/- 63 to 4 +/- 2 (p < 0.0001).(3) A study of 10 healthy volunteers found that rifampin 300 mg twice daily for 4 days then combined with clopidogrel 75 mg daily for 6 days led to a significantly greater inhibition of platelet aggregation compared to clopidogrel alone (56% versus 33%, respectively). Three subjects who were initially clopidogrel nonresponders and 1 subject who was a low responder all became responders after treatment with rifampin.(4) |
CLOPIDOGREL, CLOPIDOGREL BISULFATE, PLAVIX |
| Enzalutamide/Fosphenytoin; Phenytoin SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Phenytoin is a strong inducer of CYP3A4 and may increase the metabolism of enzalutamide.(1) Fosphenytoin is a prodrug of phenytoin. Enzalutamide is a moderate inducer of CYP2C9 and CYP2C19 and may increase the metabolism of fosphenytoin and phenytoin.(2) CLINICAL EFFECTS: Concurrent use of fosphenytoin or phenytoin with enzalutamide may decrease the levels and effectiveness of both agents.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid concurrent use of fosphenytoin or phenytoin with enzalutamide. Consider the use of agents with no or minimal induction potential if possible.(2) If concurrent therapy with fosphenytoin or phenytoin is necessary, increase the enzalutamide dose from 160 mg to 240 mg once daily. If concurrent therapy with fosphenytoin or phenytoin is discontinued, the enzalutamide dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer.(2) Phenytoin plasma levels and seizure frequency should be monitored closely when enzalutamide is added to or discontinued from therapy. The phenytoin dose should be adjusted as needed based on phenytoin levels and symptoms of seizure activity. DISCUSSION: In vitro data indicates that enzalutamide is primarily metabolized by CYP2C8 and CYP3A4. Inhibitors of these isoenzymes have been shown to increase enzalutamide levels and inducers of these isoenzymes are expected to decrease enzalutamide levels.(2) Coadministration of rifampin (strong CYP3A4 inducer and moderate CYP2C8 inducer) decreased the composite AUC of enzalutamide and its active metabolite by 37%.(2) In a clinical trial in healthy subjects, enzalutamide was shown to reduce the area-under-curve (AUC) of midazolam (a sensitive CYP3A4 substrate), warfarin (a sensitive CYP2C9 substrate), and omeprazole (a sensitive CYP2C19 substrate.(2) A case report in a 77-year-old Caucasian male was initiated on 160 mg of enzalutamide after being stable on warfarin with an INR of 3.5. The INR dropped to 1.4 after approximately 20 days on enzalutamide therapy. Due to the drop in INR, the warfarin dose was increased by 50% which lead to a therapeutic INR. When enzalutamide was discontinued, the warfarin dose was decreased by 33% to remain at a therapeutic level. Upon reinitiation, the warfarin dose was increased once by 50% to achieve a therapeutic INR.(3) |
CEREBYX, DILANTIN, DILANTIN-125, FOSPHENYTOIN SODIUM, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED |
| Sotorasib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of sotorasib.(1) CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inducer may result in a loss of sotorasib 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 sotorasib with strong CYP3A4 inducers.(1) DISCUSSION: Coadministration of repeat doses of rifampin (a strong CYP3A4 inducer) with a single dose of sotorasib decreased sotorasib area-under-curve (AUC) and maximum concentration (Cmax) by 51% and 35%, respectively.(1) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine and St John's Wort.(2,3) |
LUMAKRAS |
| Samidorphan/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Samidorphan is a substrate of CYP3A4. Strong inducers of CYP3A4 may increase the metabolism of samidorphan.(1) For co-formulations of samidorphan with olanzapine, strong CYP3A4 inducers that also induce CYP1A2 (e.g., carbamazepine, phenytoin, rifampin), may increase olanzapine metabolism.(1,2) CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 inducer may result in decreased levels and effectiveness of samidorphan.(1) In co-formulations of samidorphan with olanzapine, dual inducers of CYP1A2 and CYP3A4 (e.g., carbamazepine, phenytoin, rifampin) may decrease the levels and effectiveness of olanzapine.(1,2) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of olanzapine-samidorphan states that concurrent use with strong CYP3A4 inducers is not recommended. (1) DISCUSSION: In a clinical study of healthy subjects, rifampin (600 mg daily for 7 days, a strong CYP3A4 inducer and moderate CYP1A2 inducer) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose samidorphan 10 mg by 73% and 44%, respectively, and the AUC and Cmax of single-dose olanzapine 10 mg by 48% and 11%.(1,3) Concurrent use of carbamazepine increased olanzapine clearance by 50%, probably due to CYP1A2 induction by carbamazepine.(1,4) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,5) |
LYBALVI |
| Ibrexafungerp/Strong and Moderate CYP3A4 Inducers 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 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, 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) |
BREXAFEMME |
| Finerenone/Strong and Moderate CYP3A4 Inducers 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 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, 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) |
KERENDIA |
| Atogepant/CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong, moderate, and weak CYP3A4 inducers may increase the metabolism of atogepant by CYP3A4.(1) CLINICAL EFFECTS: The concurrent use of strong, moderate, or weak 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 strong, moderate, or weak CYP3A4 inducers receive atogepant 30 mg or 60 mg once daily for prevention of episodic migraines and avoid use of atogepant 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) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, 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, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine and tovorafenib. Weak CYP3A4 inducers linked to this monograph include: armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, methylprednisolone, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(1,2) |
QULIPTA |
| Avacopan/Strong or Moderate CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Avacopan is a substrate of CYP3A4. Strong or moderate inducers of CYP3A4 may induce the metabolism of avacopan.(1) CLINICAL EFFECTS: The concurrent administration of strong or moderate CYP3A4 inducers may result in decreased levels and effectiveness of avacopan.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of avacopan states that concurrent use with strong or moderate CYP3A4 inducers should be avoided.(1) The Australian manufacturer of avacopan states that patients anticipated to require long-term administration of a CYP3A4 inducer should not be treated with avacopan. If short term co-administration cannot be avoided in a patient already on avacopan, closely monitor for reoccurrence of disease activity.(4) DISCUSSION: Co-administration of rifampin 600 mg once daily for 11 days, a strong CYP3A4 inducer, decreased the avacopan concentration maximum (Cmax) by 79% and area-under-curve (AUC) by 93%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate inducers of CYP3A4 include: belzutifan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, lesinurad, lorlatinib, modafinil, nafcillin, rifabutin, sotorasib, telotristat ethyl, thioridazine and tovorafenib.(2-3) |
TAVNEOS |
| Maribavir/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may accelerate the metabolism of maribavir.(1) CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 inducer may result in decreased levels and effectiveness of maribavir.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of maribavir states that concurrent use with strong CYP3A4 inducers is not recommended. If concurrent use is necessary, closely monitor for treatment response.(1) DISCUSSION: In vitro data shows that maribavir is metabolized by CYP3A4. A study in 14 subjects with concurrent maribavir 400 mg twice daily and rifampin 600 mg daily resulted in a decrease in maribavir area-under-curve (AUC) and maximum concentration (Cmax) by 60% and 39%, respectively.(1) Strong inducers of CYP3A4 include: apalutamide, encorafenib, enzalutamide, ivosidenib, lumacaftor, mitotane, rifampin, rifapentine, and St. John's wort.(2-3) |
LIVTENCITY |
| Tadalafil (BPH, PAH)/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may accelerate the metabolism of tadalafil.(1-3) CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 inducer may result in decreased levels and effectiveness of tadalafil.(1-3) 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 strong CYP3A4 inducers with tadalafil is not recommended. If concurrent use is necessary, closely monitor for treatment response.(1-3) DISCUSSION: Rifampin (600 mg daily), a strong CYP3A4 inducer, reduced tadalafil 10 mg single-dose exposure AUC by 88% and Cmax by 46%, respectively, compared to tadalafil alone.(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.(4,5) |
ADCIRCA, ALYQ, ENTADFI, OPSYNVI, TADALAFIL, TADLIQ |
| Levoketoconazole/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of levoketoconazole.(1) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may reduce the clinical effectiveness of levoketoconazole.(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 levoketoconazole states that concurrent use with strong CYP3A4 inducers is not recommended. Avoid use during and two weeks before treatment with levoketoconazole.(1) DISCUSSION: The US manufacturer of levoketoconazole states that levoketoconazole is a substrate of CYP3A4.(1) Strong CYP3A4 inducers linked to this monograph are: barbiturates, carbamazepine, enzalutamide, fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine and St. John's Wort.(3,4) |
RECORLEV |
| Mitapivat/Enzalutamide SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Both mitapivat and enzalutamide are CYP3A4 substrates and inducers. Strong inducers of CYP3A4 may increase the metabolism of mitapivat.(1) Enzalutamide is a strong CYP3A4 inducer. Moderate inducers of CYP3A4 may increase the metabolism of enzalutamide.(2) Mitapivat is a moderate CYP3A4 inducer. CLINICAL EFFECTS: Concurrent use may result in decreased levels and effectiveness of both mitapivat and enzalutamide.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid the concurrent use of mitapivat with enzalutamide.(1,2) DISCUSSION: Mitapivat is a CYP3A4 substrate. In a pharmacokinetic study with a single 50 mg dose of mitapivat, rifampin decreased area-under-curve (AUC) and concentration maximum (Cmax) by 91% and 77%, respectively. After mitapivat doses of 5, 20, or 50 mg twice daily, rifampin decreased AUC and Cmax by 95% and 85%, respectively.(1) Coadministration of rifampin (strong CYP3A4 inducer and moderate CYP2C8 inducer) decreased the composite AUC of enzalutamide and its active metabolite by 37%.(2) |
PYRUKYND |
| Ganaxolone/Strong or Moderate CYP3A4 Inducers 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, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2-3) |
ZTALMY |
| Alpelisib/Strong CYP3A4 Inducers 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 alpelisib.(1,2) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may decrease the levels and effectiveness of alpelisib.(1,2) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of alpelisib states the use of strong CYP3A4 inducers in patients receiving therapy with alpelisib should be avoided. Consider the use of alternative agents with less enzyme induction potential.(1,2) DISCUSSION: In a study, rifampin, a strong CYP3A4 inducer, decreased the maximum concentration (Cmax) and area-under-curve (AUC) of single-dose alpelisib (300 mg) by 38% and 57%, respectively, and of multiple doses of alpelisib (300 mg) by 59% and 74%, respectively.(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.(3,4) |
PIQRAY, VIJOICE |
| Vonoprazan/Strong or Moderate CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2-3) |
VOQUEZNA, VOQUEZNA DUAL PAK |
| Vonoprazan-Clarithromycin-Amoxicillin/Strong or Moderate CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Vonoprazan and clarithromycin are substrates of CYP3A4. Strong or moderate inducers of CYP3A4 may increase the metabolism of vonoprazan and clarithromycin.(1) CLINICAL EFFECTS: The concurrent administration of strong or moderate CYP3A4 inducers may result in decreased levels and effectiveness of vonoprazan and clarithromycin.(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: 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 include: apalutamide, barbiturates, enzalutamide, fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate inducers of CYP3A4 include: belzutifan, cenobamate, dipyrone, etravirine, lesinurad, modafinil, nafcillin, telotristat ethyl, and tovorafenib.(2-3) |
VOQUEZNA TRIPLE PAK |
| Dronedarone/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of dronedarone by CYP3A4.(1) Dronedarone may inhibit the metabolism of carbamazepine.(2) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may result in decreased levels and effectiveness of dronedarone.(1) Concurrent use of dronedarone and carbamazepine may also result in elevated levels of and toxicity from carbamazepine.(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 dronedarone states that concurrent use of strong CYP3A4 inducers should be avoided.(1) The US manufacturer of carbamazepine states CYP3A4 inhibitors may increase plasma carbamazepine levels. If concurrent use is warranted, closely monitor carbamazepine levels and observe the patient for signs of toxicity (dizziness, ataxia, blurred vision, or SIADH). The dosage of carbamazepine may need to be adjusted or carbamazepine may need to be discontinued.(2) DISCUSSION: Concurrent use of rifampin and dronedarone (exact dosages not stated) decreased dronedarone exposure by 80%.(1) Carbamazepine is almost completely metabolized to carbamazepine-10,11-epoxide, with only 5% of the drug excreted unchanged. Pharmacokinetic studies have indicated the major pathway for carbamazepine metabolism is catalyzed by CYP3A4, with minor contributions from CYP2C8 and CYP3A5.(2,3) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, lumacaftor, mitotane, phenobarbital, phenytoin or primidone.(4) |
MULTAQ |
| Thiotepa/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Thiotepa is a prodrug and is converted to its active metabolite via CYP3A4. Strong CYP3A4 inducers may increase the conversion of thiotepa to its active metabolite, TEPA.(1-3) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may increase the levels of the active metabolite TEPA and increase the risk of toxicity, including bone marrow suppression, CNS effects (including headache, apathy, confusion, or seizures), and exfoliative dermatitis.(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 thiotepa states concurrent use of strong CYP3A4 inducers in patients receiving therapy with thiotepa should be avoided. Consider the use of alternative agents with less enzyme induction potential.(1) If concomitant use of strong CYP3A4 inducer cannot be avoided, closely monitor for signs of toxicity. A dose reduction of thiotepa may be required based on plasma levels of TEPA.(1) DISCUSSION: Thiotepa is converted to its active metabolite primarily through the CYP3A4 and CYP2B6 enzymes.(2) A case report demonstrated the effects of phenytoin on thiotepa metabolism. When phenytoin was co-administered with thiotepa, the area-under-the curve (AUC) of TEPA increased 115%.(3) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(1,4-5) |
TEPADINA, TEPYLUTE, THIOTEPA |
| Verapamil/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concurrent use of strong CYP3A4 inducers may accelerate the CYP3A4-mediated metabolism of verapamil.(1,2) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may decrease levels and effectiveness of verapamil.(1,2) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of verapamil states concurrent use of CYP3A4 inducers may result in significantly decreased verapamil levels.(1) Observe the patient for a decrease in the therapeutic effects of verapamil if a strong CYP3A4 inducer is initiated. The dose of verapamil may need to be adjusted if a strong CYP3A4 inducer is initiated or discontinued.(1) DISCUSSION: In healthy subjects, verapamil concentrations were evaluated after 21 days of phenobarbital treatment. After a single dose of verapamil, mean total apparent oral clearance was increased after phenobarbital treatment (75.1 vs. 376.2 ml/min/kg). Clearance of verapamil free drug was also increased. Mean total verapamil systemic clearance was increased (9.95 vs. 18.9 ml/min/kg). After multiple oral administration, total verapamil apparent oral clearance was increased after phenobarbital pretreatment (21.2 vs. 91.2 ml/min/kg). Free drug clearance was also increased.(2) A study in six subjects examined the effects of pretreatment with rifampin (600 mg daily for 15 days), a CYP3A4 inducer, on single doses of verapamil (10 mg intravenously or 120 mg orally). Rifampin significantly decreased the maximum concentration (Cmax) and area-under-curve (AUC) of oral verapamil and resulted in no changes in the P-R interval. There were small decreases in the AUC of intravenous verapamil.(3) In a study in 8 male subjects, pretreatment with rifampin (600 mg daily for 15 days) increased the systemic clearance of S-verapamil by 1.3-fold and the apparent oral-clearance of S-verapamil by 32-fold. The bioavailability of S-verapamil decreased 25-fold. The effect of oral verapamil on AV conduction was almost abolished. No significant changes were noted for intravenous administration of verapamil.(4) There have been case reports of decreased effectiveness of verapamil during concurrent rifampin therapy.(5,6) Strong CYP3A4 inducers linked to this monograph include: apalutamide, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, and primidone.(7,8) |
TRANDOLAPRIL-VERAPAMIL ER, VERAPAMIL ER, VERAPAMIL ER PM, VERAPAMIL HCL, VERAPAMIL SR |
| Olutasidenib/Strong and Moderate CYP3A4 Inducers 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 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, 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) |
REZLIDHIA |
| Adagrasib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may increase the metabolism of adagrasib.(1) CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of adagrasib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of adagrasib states that the concurrent use of strong CYP3A4 inducers should be avoided, and that alternative treatments with less CYP3A4 induction should be considered.(1) DISCUSSION: In a study with healthy subjects, co-administration of rifampin (strong 3A4 inducer) with a single dose of adagrasib (600 mg), decreased adagrasib area-under-curve (AUC) by 95% and maximum concentration (Cmax) by 88%.(1) Co-administration of rifampin (strong 3A4 inducer) with multiple doses of adagrasib (600 mg) is predicted to decrease adagrasib AUC by greater than 61% and Cmax by greater than 66%. Strong inducers of CYP3A4 linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(3-4) |
KRAZATI |
| Cariprazine/Strong and Moderate CYP3A4 Inducers 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, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(5-6) |
VRAYLAR |
| Pirtobrutinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Pirtobrutinib is metabolized by CYP3A4. Strong inducers of CYP3A4 may increase the metabolism of pirtobrutinib.(1) CLINICAL EFFECTS: Concurrent use of a strong 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 strong CYP3A4 inducers.(1) DISCUSSION: Coadministration of a single 200 mg dose of pirtobrutinib with rifampin (a strong CYP3A inducer) decreased the area-under-curve (AUC) of pirtobrutinib by 71%.(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) |
JAYPIRCA |
| Elacestrant/Strong and Moderate CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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: Avoid concomitant use of elacestrant with strong or moderate CYP3A4 inducers.(1) 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.(2,3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(2,3) |
ORSERDU |
| Sparsentan/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Sparsentan is metabolized by CYP3A4. Strong inducers of CYP3A4 may increase the metabolism of sparsentan.(1) CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of sparsentan.(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 sparsentan with strong CYP3A4 inducers.(1) DISCUSSION: Coadministration of a single dose of sparsentan with rifampin (a strong CYP3A inducer) is predicted to decrease the concentration maximum (Cmax) and area-under-curve (AUC) of sparsentan by 23% and 47%, 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) |
FILSPARI |
| Omaveloxolone/Strong and Moderate CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(2,3) |
SKYCLARYS |
| Leniolisib/Strong and Moderate CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Leniolisib is metabolized by CYP3A4. Strong and moderate inducers of CYP3A4 may increase the metabolism of leniolisib.(1) CLINICAL EFFECTS: Concurrent use of a strong or moderate inducer of CYP3A4 may result in decreased levels and effectiveness of leniolisib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid concomitant use of leniolisib with strong or moderate CYP3A4 inducers.(1) DISCUSSION: PBPK model-based simulations predicted a maximum decrease of 78% and 58% in leniolisib area-under-curve (AUC) with rifampin (strong CYP3A4 inducer) and efavirenz (moderate CYP3A4 inducer), respectively.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3) Moderate inducers of CYP3A4 include: belzutifan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(2,3) |
JOENJA |
| Tretinoin/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Tretinoin is metabolized by CYP3A4. Strong inducers of CYP3A4 may increase the metabolism of tretinoin.(1) CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of tretinoin.(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 tretinoin with strong CYP3A4 inducers.(1) DISCUSSION: The coadministration of tretinoin with strong CYP3A4 inducers has not been studied. Tretinoin is metabolized by CYP3A4, CYP2C8, and CYP2E, and undergoes glucuronidation.(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) |
RETINOIC ACID, TRETINOIN, TRETINOIN ACID |
| Imatinib/Strong CYP3A4 Inducers 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 imatinib.(1) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may decrease the levels and effectiveness of imatinib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP3A4 inducers in patients receiving therapy with antineoplastic enzyme inhibitors. Consider the use of alternative agents with less enzyme induction potential.(1) The dose of imatinib should be increased by at least 50% and clinical response should be carefully monitored. Dosages up to 1,200 mg daily (600 mg twice daily) have been used in patients receiving concurrent therapy with strong CYP3A4 inducers.(1) DISCUSSION: Pretreatment of 14 healthy subjects with rifampin (600 mg daily for 10 days) increased the clearance of a single dose of imatinib (400 mg) by 3.8-fold. The area-under-curve (AUC) and maximum concentration (Cmax) decreased by 74% and 54%, respectively.(1,2) The Cmax of the CGP74588 metabolite increased by 88.6%, but the AUC of CGP74588 decreased by 11%.(2) Strong inducers of CYP3A4 include: barbiturates, dexamethasone, enzalutamide, fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(3,4) |
GLEEVEC, IMATINIB MESYLATE, IMKELDI |
| Lapatinib/Strong CYP3A4 Inducers 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 lapatinib.(1) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may decrease the levels and effectiveness of lapatinib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP3A4 inducers in patients receiving therapy with lapatinib. Consider the use of alternative agents with less enzyme induction potential.(1) The dose of lapatinib should be gradually titrated from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer indication) or from 1,500 mg/day up to 5,500 mg/day (hormone receptor positive, HER2 positive breast cancer indication) based on patient tolerability. If the inducer is discontinued, the dose of lapatinib should be adjusted to the normal dose.(1) DISCUSSION: In healthy subjects, carbamazepine (100 mg twice daily for 3 days and 200 mg twice daily for 17 days), another CYP3A4 inducer, decreased the area-under-curve (AUC) of lapatinib by 72%. The dose adjustment recommendations are based on pharmacokinetic studies and are predicted to adjust lapatinib AUC to the range observed without concurrent CYP3A4 inducers; however, there are no clinical data with these doses in patients receiving strong CYP3A4 inducers.(1) Strong inducers of CYP3A4 include: barbiturates, dexamethasone, enzalutamide, fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(2,3) |
LAPATINIB, TYKERB |
| Axitinib/Strong & Moderate CYP3A4 Inducers 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 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, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat ethyl, thioridazine and tovorafenib.(1-3) |
INLYTA |
| Ritlecitinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ritlecitinib is a substrate of CYP3A4. Strong inducers of CYP3A4 may induce the metabolism of ritlecitinib.(1) CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of ritlecitinib.(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 ritlecitinib states concurrent administration with strong CYP3A4 inducers is not recommended.(1) DISCUSSION: Ritlecitinib is a substrate of CYP3A4.(1) Concurrent administration of rifampin (600 mg once daily for 8 days, a strong CYP3A4 inducer) with a single 50 mg dose of ritlecitinib decreased the area-under-curve (AUC) and maximum concentration (Cmax) of ritlecitinib by 44% and 25%, respectively, in healthy subjects.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2-3) |
LITFULO |
| Palovarotene/Strong and Moderate CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2) |
SOHONOS |
| Cabozantinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of cabozantinib.(1,2) CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of cabozantinib.(1,2) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP3A4 inducers in patients receiving therapy with cabozantinib. Consider the use of alternative agents with less enzyme induction potential.(1,2) If concurrent use of a 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 strong inducer.(1) Increase the daily dose of cabozantinib CAPsules by 40 mg (from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. The daily dose of cabozantinib should not exceed 180 mg. If the CYP3A4 inducer is discontinued, reduce the dosage of cabozantinib to the dose used prior to initiation of the inducer 2 to 3 days after discontinuation of the strong inducer.(2) DISCUSSION: In a study in healthy subjects, rifampin (600 mg daily for 31 days) decreased the AUC of a single dose of cabozantinib by 77%.(1,2) Strong inducers of CYP3A4 include: barbiturates, encorafenib, enzalutamide, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(3,4) |
CABOMETYX, COMETRIQ |
| Ceritinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of ceritinib.(1) CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of ceritinib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP3A4 inducers in patients receiving therapy with ceritinib. Consider the use of alternative agents with less enzyme induction potential.(1) DISCUSSION: In a study in 19 healthy subjects, rifampin (600 mg daily for 14 days) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of ceritinib by 44% and 70%, respectively.(1) Strong inducers of CYP3A4 include: barbiturates, enzalutamide, fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(2,3) |
ZYKADIA |
| Crizotinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of crizotinib.(1) CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of crizotinib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP3A4 inducers in patients receiving therapy with crizotinib. Consider the use of alternative agents with less enzyme induction potential.(1) DISCUSSION: Rifampin (600 mg daily) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of crizotinib (250 mg) by 69% and 82%, respectively.(1) Strong inducers of CYP3A4 include: barbiturates, enzalutamide, fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(2,3) |
XALKORI |
| Dasatinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of dasatinib.(1) CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of dasatinib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP3A4 inducers in patients receiving therapy with dasatinib. Consider the use of alternative agents with less enzyme induction potential.(1) If concurrent use is necessary, consider increasing the dose of dasatinib.(1) DISCUSSION: In a study in healthy subjects, concurrent rifampin (600 mg daily) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of dasatinib by 81% and 82%, respectively.(1) Strong inducers of CYP3A4 include: barbiturates, enzalutamide, fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(2,3) |
DASATINIB, SPRYCEL |
| Erlotinib/CYP3A4 Inducers 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, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine, and tovorafenib.(5,6) Weak inducers of CYP3A4 include: amprenavir, armodafinil, 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, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(5,6) |
ERLOTINIB HCL |
| Gefitinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of gefitinib.(1) CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of gefitinib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP3A4 inducers in patients receiving therapy with gefitinib. Consider the use of alternative agents with less enzyme induction potential.(1) If concurrent use of a CYP3A4 inducer cannot be avoided, consider a dose increase to 500 mg daily of gefitinib in the absence of severe adverse drug reaction. Clinical response and adverse events should be closely monitored.(1) DISCUSSION: In a study in healthy male volunteers, rifampicin decreased area-under-curve (AUC) of gefitinib by 85%.(1) Strong inducers of CYP3A4 include: barbiturates, encorafenib, enzalutamide, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(2,3) |
GEFITINIB, IRESSA |
| Ibrutinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of ibrutinib.(1) CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased 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 strong CYP3A4 inducers in patients receiving therapy with ibrutinib. 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) Strong inducers of CYP3A4 include: barbiturates, encorafenib, enzalutamide, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(2,3) |
IMBRUVICA |
| Idelalisib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of idelalisib.(1) CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of idelalisib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP3A4 inducers in patients receiving therapy with idelalisib. Consider the use of alternative agents with less enzyme induction potential.(1) DISCUSSION: In a study in healthy subjects, rifampin (600 mg daily for 8 days) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of idelalisib (150 mg single dose) by 58% and 75%, respectively.(1) Strong inducers of CYP3A4 include: barbiturates, enzalutamide, fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(2,3) |
ZYDELIG |
| Nilotinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of nilotinib.(1) CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of nilotinib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP3A4 inducers in patients receiving therapy with nilotinib. Consider the use of alternative agents with less enzyme induction potential.(1) Because of the nonlinear pharmacokinetic profile of nilotinib, increasing its dose is unlikely to compensate for enzyme induction.(1) DISCUSSION: In a study in healthy subjects, concurrent rifampin (600 mg daily for 12 days) decreased nilotinib area-under-curve (AUC) by 80%.(1) Strong inducers of CYP3A4 include: barbiturates, enzalutamide, fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(2,3) |
DANZITEN, NILOTINIB HCL, NILOTINIB TARTRATE, TASIGNA |
| Pazopanib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of pazopanib.(1) CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of pazopanib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP3A4 inducers in patients receiving therapy with pazopanib. Consider the use of alternative agents with less enzyme induction potential.(1) Pazopanib should not be administered to patients who cannot avoid chronic use of strong CYP3A4 inducers.(1) DISCUSSION: Pazopanib is primarily metabolized by CYP3A4.(1) Strong inducers of CYP3A4 include: barbiturates, enzalutamide, fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(2,3) |
PAZOPANIB HCL, VOTRIENT |
| Sorafenib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of sorafenib.(1) CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of sorafenib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP3A4 inducers in patients receiving therapy with sorafenib. Consider the use of alternative agents with less enzyme induction potential.(1) DISCUSSION: Concurrent rifampin (600 mg daily for 5 days) decreased the area-under-curve (AUC) of a single dose of sorafenib (400 mg) by 37%.(1) Strong inducers of CYP3A4 include: barbiturates, enzalutamide, fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(2,3) |
NEXAVAR, SORAFENIB |
| Sunitinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of sunitinib.(1) CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of sunitinib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP3A4 inducers in patients receiving therapy with sunitinib. Consider the use of alternative agents with less enzyme induction potential.(1) A dosage increase of sunitinib to a maximum of 87.5 mg daily in patients with gastrointestinal stromal tumors (GIST) or advanced renal cell carcinoma (RCC) or to a maximum of 62.5 mg in patients with pancreatic neuroendocrine tumors (pNET) should be considered.(1) DISCUSSION: In a study with healthy subjects, concurrent rifampin decreased the combined sunitinib plus primary active metabolite maximum concentration (Cmax) and area-under-curve (AUC) by 23% and 46%, respectively, of a single dose of sunitinib.(1) Strong inducers of CYP3A4 include: barbiturates, enzalutamide, fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(2,3) |
SUNITINIB MALATE, SUTENT |
| Vandetanib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of vandetanib.(1) CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of vandetanib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP3A4 inducers in patients receiving therapy with vandetanib. Consider the use of alternative agents with less enzyme induction potential.(1) DISCUSSION: In healthy volunteers, rifampin 600 mg daily (a strong CYP3A4 inducer) for 31 days decreased the area-under-curve (AUC) of vandetanib by 40% on day 10. There was no change in vandetanib maximum concentration (Cmax). The AUC and Cmax of N-desmethylvandetanib increased by 266% and 414%, respectively.(1) Strong inducers of CYP3A4 include: barbiturates, enzalutamide, fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(2,3) |
CAPRELSA |
| Olaparib/Strong & Moderate CYP3A4 Inducers 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, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(4-5) |
LYNPARZA |
| Palbociclib/Strong & Moderate CYP3A4 Inducers 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 palbociclib.(1) CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inducers may decrease the levels and effectiveness of palbociclib.(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 palbociclib.(1) Consider the use of alternatives with little to no induction potential. DISCUSSION: In a study in 14 healthy subjects, rifampin (600 mg daily) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of palbociclib by 70% and 85%, 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: bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2-3) |
IBRANCE |
| Sonidegib/Strong & Moderate CYP3A4 Inducers 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 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, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2-3) |
ODOMZO |
| Cabazitaxel/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of cabazitaxel.(1-3) CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of cabazitaxel.(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 UK and Canadian prescribing information recommends avoiding concurrent use of strong inducers of CYP3A4 with cabazitaxel.(1,2) Consider the use of agents with no or minimal induction potential if possible. Monitor patients for decreased response to therapy. The US prescribing information does not make a recommendation for concurrent use of cabazitaxel with strong CYP3A4 inducers.(3) DISCUSSION: Cabazitaxel is metabolized by CYP3A4 and strong inducers of this isoenzyme are expected to decrease levels of cabazitaxel.(1-3) In a study in 21 advanced cancer patients, rifampin (600mg) decreased the exposure to cabazitaxel (15mg/m2) by 17%.(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.(4,5) |
JEVTANA |
| Docetaxel/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of docetaxel.(1) CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of docetaxel.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid concurrent use of strong inducers of CYP3A4 with docetaxel.(1) Consider the use of agents with no or minimal induction potential if possible. Monitor patients for decreased response to therapy. DISCUSSION: Docetaxel is metabolized by CYP3A4 and strong inducers of this isoenzyme are expected to decrease levels of docetaxel.(1) In a study in 10 cancer patients, St. John's wort decreased the area-under-curve (AUC) of docetaxel by 11.6%. There were no significant decreases in docetaxel maximum concentration (Cmax) or half-life. Docetaxel-related toxicities were lower during St. John's wort.(2) In an in vitro study, hyperforin, a constituent of St. John's wort, induced the metabolism of docetaxel in a dose-dependent fashion with induction ranged from 2.6-fold to 7-fold greater than controls. In this same experiment, rifampin induced docetaxel metabolism 6.8-fold to 32-fold.(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.(4-5) |
DOCETAXEL, DOCIVYX |
| Doxorubicin/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of doxorubicin.(1) CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of doxorubicin.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid concurrent use of strong inducers of CYP3A4 with doxorubicin.(1) Consider the use of agents with no or minimal induction potential if possible. Monitor patients for decreased response to therapy. DISCUSSION: Doxorubicin is metabolized by CYP3A4 and strong inducers of this isoenzyme are expected to decrease levels of doxorubicin.(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) |
ADRIAMYCIN, CAELYX, DOXIL, DOXORUBICIN HCL, DOXORUBICIN HCL LIPOSOME |
| Paclitaxel/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of paclitaxel.(1) CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of paclitaxel.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid concurrent use of strong inducers of CYP3A4 with paclitaxel.(1) Consider the use of agents with no or minimal induction potential if possible. Monitor patients for decreased response to therapy. DISCUSSION: Paclitaxel is metabolized by CYP3A4 and strong inducers of this isoenzyme are expected to decrease levels of paclitaxel.(1) In a Phase 2 study of paclitaxel, none of the subjects taking phenytoin experienced a partial or complete response to paclitaxel. Paclitaxel levels were 70% lower in these patients than in patients not receiving phenytoin.(2) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(3,4) |
ABRAXANE, PACLITAXEL, PACLITAXEL PROTEIN-BOUND |
| Panobinostat/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of panobinostat.(1) CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of panobinostat.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid concurrent use of strong inducers of CYP3A4 with panobinostat.(1) Consider the use of agents with no or minimal induction potential if possible. Monitor patients for decreased response to therapy. DISCUSSION: Panobinostat is metabolized by CYP3A4 and strong inducers of this isoenzyme are expected to decrease levels of panobinostat.(1) Physiologically-based pharmacokinetic (PBPK) models predict a 70% decrease in exposure of panobinostat with strong inducers of CYP3A4.(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) |
FARYDAK |
| Vincristine/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of vincristine.(1) CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of vincristine.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid concurrent use of strong inducers of CYP3A4 with vincristine.(1) Consider the use of agents with no or minimal induction potential if possible. Monitor patients for decreased response to therapy. DISCUSSION: Vincristine is metabolized by CYP3A4 and strong inducers of this isoenzyme are expected to decrease levels of vincristine.(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) |
VINCASAR PFS, VINCRISTINE SULFATE |
| Quizartinib/Strong & Moderate CYP3A4 Inducers 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 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) |
VANFLYTA |
| Zuranolone/CYP3A4 Inducers 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 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, 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, 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, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3) |
ZURZUVAE |
| Fruquintinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of fruquintinib.(1) CLINICAL EFFECTS: Concurrent or recent use of a strong 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: Avoid concurrent use of strong inducers of CYP3A4 with fruquintinib.(1) DISCUSSION: Concomitant use with rifampin (strong CYP3A4 inducer) decreased the fruquintinib maximum concentration (Cmax) by 12% and the area-under-curve (AUC) by 65%.(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) |
FRUZAQLA |
| Nevirapine/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers may accelerate the metabolism of nevirapine.(1) CLINICAL EFFECTS: Concurrent use of nevirapine with strong CYP3A4 inducers may result in sub-therapeutic levels of nevirapine and the development of resistance to non-nucleoside reverse transcriptase inhibitor (NNRTIs). PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The University of Liverpool's HIV Drug Interactions database advises not coadministering most strong CYP3A4 inducers with nevirapine, except for carbamazepine and phenytoin, which should be used with caution and monitored for virologic response and drug levels.(2) The US Department of Health and Human Services HIV guidelines recommend considering alternative therapies to carbamazepine, phenytoin, and phenobarbital for patients on nevirapine. If concurrent use is necessary, monitor nevirapine levels and virologic response.(3) The US manufacturer of nevirapine states that concurrent use of carbamazepine (a strong CYP3A4 inducer) should be approached with caution and monitored for virologic response and anticonvulsant levels.(1) DISCUSSION: In a study in 14 subjects, concurrent nevirapine and rifampin decreased nevirapine area-under-curve (AUC), maximum concentration (Cmax), and minimum concentration (Cmin) of nevirapine by 58%, 50%, and 68%, respectively. There were no significant changes to rifampin Cmax or AUC.(1) In a study in 10 HIV-positive tuberculosis patients, concurrent rifampin and nevirapine decreased nevirapine AUC and Cmax by 31% and by 36%, respectively. There was a non-statistically significant decrease in nevirapine Cmin by 21%.(4) In an open label pharmacokinetic study of 36 healthy, HIV-negative women, the effects of several CYP3A4 inducers on plasma nevirapine levels after a single-dose of nevirapine 200 mg was determined. Phenobarbital 200 mg did not produce therapeutic levels and did not have an effect on nevirapine levels. Carbamazepine 400 mg and phenytoin 184 mg for 3 days and for 7 days lowered nevirapine half-life from 46.3 hours to 33.8 hours, 27.1 hours, and 34.5 hours, respectively. Time to undetectable nevirapine levels decreased from 14 days to 12 days with carbamazepine and 8.5 days with both phenytoin regimens.(5) A study in 158 HIV+ pregnant women examined the effect of single-dose carbamazepine 400 mg on plasma concentrations of nevirapine and development of nevirapine resistance mutations after single-dose nevirapine 200 mg administered at delivery. Nevirapine levels at 1 week post-partum were 36% lower in the patients who received carbamazepine, and there was a trend towards fewer nevirapine resistance mutations.(6) A pharmacokinetic study in 73 HIV+ pregnant women confirmed that phenytoin 184 mg for 7 days decreases the half-life of single-dose nevirapine. Nevirapine half-life was 25.5 hours in the phenytoin group and 63.2 hours in the control group.(7) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, and primidone.(8) |
NEVIRAPINE, NEVIRAPINE ER |
| Capivasertib/Strong and Moderate CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, and tovorafenib.(2,3) |
TRUQAP |
| Repotrectinib/Strong or Moderate CYP3A4 Inducers 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 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, carbamazepine, 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) |
AUGTYRO |
| Nirogacestat/Strong and Moderate CYP3A4 Inducers 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 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, 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, lesinurad, lorlatinib, mavacamten, modafinil, nafcillin, pacritinib, pexidartinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3) |
OGSIVEO |
| Itraconazole/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers may increase the metabolism of itraconazole via CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may result in decreased levels and effectiveness of itraconazole.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of itraconazole states that concurrent use with strong CYP3A4 inducers is not recommended two weeks before and during itraconazole treatment.(1) Consider alternatives to itraconazole in patients receiving strong CYP3A4 inducers unless the benefits of therapy outweigh the risks. If concurrent therapy is necessary, monitor patients closely for decreased therapeutic effects. DISCUSSION: Concurrent itraconazole (200 mg daily) with rifabutin (a CYP3A4 inducer) (300 mg daily) in six HIV-infected patients resulted in an increased effect on rifabutin and a decrease in itraconazole's area-under-curve (AUC) and concentration maximum (Cmax) by 70% and 75%, respectively.(1) In a study in 18 subjects, concurrent efavirenz (a CYP3A4 inducer) (600 mg daily) decreased the Cmax, AUC, and minimum concentration (Cmin) of itraconazole (200 mg twice daily) by 37%, 39%, and 44%, respectively. The Cmax, AUC, and Cmin of hydroxyitraconazole decreased by 35%, 37%, and 43%, respectively.(2-4) Strong inducers of CYP3A4 include: apalutamide, enzalutamide, mitotane, and St. John's wort.(5,6) |
ITRACONAZOLE, ITRACONAZOLE MICRONIZED, SPORANOX, TOLSURA |
| Lemborexant/Strong and Moderate CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3) |
DAYVIGO |
| Velpatasvir/Strong and Moderate CYP3A4 Inducers 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, ivosidenib, lesinurad, lumacaftor, mavacamten, methimazole, mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib, sotorasib, telotristat, thioridazine, and tovorafenib.(3) |
EPCLUSA, SOFOSBUVIR-VELPATASVIR, VOSEVI |
| Rivaroxaban/Enzalutamide SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Enzalutamide may induce the metabolism of rivaroxaban by CYP3A4, but increase rivaroxaban absorption by inhibiting P-glycoprotein (P-gp). The net result is an overall decrease in rivaroxaban levels.(1-4) CLINICAL EFFECTS: Concurrent or recent use of enzalutamide may result in decreased levels and effectiveness of rivaroxaban.(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 manufacturer of rivaroxaban states to avoid the concurrent use of agents that are combined P-gp and strong CYP3A4 inducers. It would be prudent to follow the same recommendations with enzalutamide.(1-4) Depending on indication and renal function, dabigatran, edoxaban, or warfarin may be alternatives. DISCUSSION: In a clinical trial, rifampin (600 mg daily) decreased the area-under-curve (AUC) and concentration maximum (Cmax) of a single dose of rivaroxaban (20 mg with food) by 50% and 22%, respectively. Similar decreases in pharmacodynamic effects were seen.(1) In a clinical trial, enzalutamide (160 mg daily) increased digoxin AUC by 33% and Cmax by 17%.(4) Enzalutamide is a strong inducer of CYP3A4 and an inhibitor of P-gp.(2) A PBPK model evaluated the effects of enzalutamide as a strong CYP3A4 inducer and P-gp inhibitor on rivaroxaban. The model predicted a decrease in rivaroxaban AUC by 45% with a 25% decrease in Cmax.(5) |
RIVAROXABAN, XARELTO |
| Enzalutamide/Strong CYP3A4 Inducers and Substrates SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ivosidenib and encorafenib are both strong inducers and substrates of CYP3A4.(1,2,4) Strong inducers of CYP3A4 may increase the metabolism of enzalutamide.(3) Enzalutamide is also a strong inducer of CYP3A4 and may increase the metabolism of encorafenib and ivosidenib.(3,4) CLINICAL EFFECTS: Concurrent use of strong inducers of CYP3A4 may result in decreased levels and effectiveness of enzalutamide.(1) Concurrent use of CYP3A4 substrates with enzalutamide may result in reduced levels and therapeutic effect of 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: Avoid concurrent use of strong inducers of CYP3A4 with enzalutamide. Consider the use of agents with no or minimal induction potential if possible.(3) DISCUSSION: Enzalutamide is primarily metabolized by CYP2C8 and CYP3A4. CYP2C8 is responsible for metabolism of enzalutamide to the active metabolite.(3) Coadministration of rifampin (strong CYP3A4 inducer and moderate CYP2C8 inducer) decreased the composite area-under-curve (AUC) of enzalutamide and its active metabolite by 37% with no effect on concentration maximum (Cmax).(3) Coadministration of enzalutamide with midazolam (sensitive CYP3A4 substrate) decreased the midazolam area-under-curve (AUC) by 86% and concentration maximum (Cmax) by 77%.(3) |
BRAFTOVI, TIBSOVO |
| Paliperidone Intramuscular Injection/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers may increase the metabolic clearance of paliperidone by CYP3A4.(1-3) CLINICAL EFFECTS: Strong CYP3A4 inducers may result in decreased levels and effectiveness of paliperidone.(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 manufacturer of extended release paliperidone injections recommends avoiding concurrent use of CYP3A4 inducers during the dosing interval. If concurrent therapy with a strong CYP3A4 inducer is necessary, consider managing the patient with paliperidone extended-release oral tablets.(1-3) DISCUSSION: In a study in 6 schizophrenic patients, carbamazepine at doses of 200 mg/day, 400 mg/day, and 600 mg/day decreased paliperidone concentrations by 55.7%, 36.1%, and 33.6%, respectively. Some patients experienced worsening of psychotic symptoms during concurrent therapy.(4) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, natisedine, phenytoin, primidone, rifampin, rifapentine and St. John's Wort.(5-6) |
ERZOFRI, INVEGA HAFYERA, INVEGA SUSTENNA, INVEGA TRINZA |
| Mavorixafor/Dual Strong CYP3A4 Inducers and P-gp Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Mavorixafor is a substrate of CYP3A4 and of the P-glycoprotein (P-gp) transporter.(1) Agents that are both strong CYP3A4 inducers and P-gp inhibitors such as enzalutamide, rifampin and St. John's Wort may induce the metabolism and increase the absorption of mavorixafor.(2,3) CLINICAL EFFECTS: The net effect of this interaction is unknown. Concurrent use of strong CYP3A4 inducers may result in decreased levels and effectiveness of mavorixafor. Concurrent use of P-gp inhibitors may result in elevated levels and toxicities of mavorixafor including QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1) PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(4) CYP3A4 induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Coadministration of mavorixafor with combined strong CYP3A4 inducers and P-gp inhibitors should be avoided. 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.(1) DISCUSSION: No interaction studies have been conducted between mavorixafor and dual strong CYP3A4 inducers and P-gp inhibitors. Mavorixafor is a CYP3A4 substrate. Concurrent use with strong CYP3A4 inducers is predicted to decrease the maximum concentration (Cmax) and area-under-curve (AUC) of mavorixafor.(1) Mavorixafor is also a P-gp substrate. In a study with healthy subjects, itraconazole 200 mg daily (a strong CYP3A4 and P-gp inhibitor) increased the exposure to single-dose mavorixafor 200 mg similar to that from single-dose mavorixafor 400 mg alone. This suggests that itraconazole increased mavorixafor exposure by about 2-fold.(1) A study in healthy volunteers found that ritonavir 100 mg twice daily (a strong CYP3A4 inhibitor and P-gp inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose mavorixafor 200 mg by 60% and 39%, respectively.(5) Combined strong CYP3A4 inducers and P-gp inhibitors linked to this monograph include: enzalutamide, rifampin and St. John's Wort.(2,3) |
XOLREMDI |
| Diltiazem/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concurrent use of strong CYP3A4 inducers may accelerate the CYP3A4-mediated metabolism of diltiazem.(1) Diltiazem is a CYP3A4 inhibitor and may inhibit the metabolism of phenytoin.(2) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may decrease the levels and effectiveness of diltiazem.(1) Concurrent use of diltiazem may also result in elevated levels of and toxicity from phenytoin.(2) PREDISPOSING FACTORS: Higher doses of diltiazem may increase the risk of elevated phenytoin levels. Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of diltiazem states that coadministration of CYP3A4 inducers should be avoided.(1) Observe the patient for a decrease in the therapeutic effects of diltiazem if a strong CYP3A4 inducer is initiated. The dose of diltiazem may need to be adjusted if an inducer is initiated or discontinued. Monitor phenytoin levels when initiating or discontinuing diltiazem in patients maintained on phenytoin.(2) DISCUSSION: Concurrent administration of rifampin, a strong CYP3A4 inducer, has been shown to lower diltiazem levels below detectable limits.(1) A study in six subjects examined the effects of pretreatment with rifampin (600 mg daily for 15 days) on single doses of verapamil (10 mg intravenously or 120 mg orally). Rifampin significantly decreased the maximum concentration (Cmax) and area-under-curve (AUC) of oral verapamil and resulted in no changes in the P-R interval. There were small decreases in the AUC of intravenous verapamil.(3) In a study in 8 male subjects, pretreatment with rifampin (600 mg daily for 15 days) increased the systemic clearance of S-verapamil by 1.3-fold and the apparent oral-clearance of S-verapamil by 32-fold. The bioavailability of S-verapamil decreased 25-fold. The effect of oral verapamil on AV conduction was almost abolished. No significant changes were noted with intravenous administration of verapamil.(4) In one case report, a patient established on phenytoin treatment (250 mg twice daily) experienced signs of phenytoin toxicity after initiating high-dose diltiazem (90 mg every 2 hours for a total of 4 doses, then 120 mg every 4 hours for a total of 4 doses and then 240 mg of sustained release formulation every 8 hours). Serum phenytoin concentration was raised at 41 mcg/ml and phenytoin was held and reloaded at a lower maintenance dose (150 mg twice daily), whilst the patient continued treatment on diltiazem. Subsequent serum phenytoin concentrations were within range (17.1 and 14.8 mcg/ml).(2) Strong CYP3A4 inducers linked to this monograph include: apalutamide, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, and primidone.(5,6) |
CARDIZEM, CARDIZEM CD, CARDIZEM LA, CARTIA XT, DILT-XR, DILTIAZEM 12HR ER, DILTIAZEM 24HR ER, DILTIAZEM 24HR ER (CD), DILTIAZEM 24HR ER (LA), DILTIAZEM 24HR ER (XR), DILTIAZEM HCL, DILTIAZEM HCL-0.7% NACL, DILTIAZEM HCL-0.9% NACL, DILTIAZEM HCL-NACL, DILTIAZEM-D5W, MATZIM LA, TIADYLT ER, TIAZAC |
| Stiripentol/Strong CYP3A4 or CYP2C19 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 or CYP2C19 may increase the metabolism of stiripentol.(1) CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 or CYP2C19 may result in decreased levels and effectiveness of stiripentol.(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 stiripentol with strong CYP3A4 or strong CYP2C19 inducers. If concurrent therapy cannot be avoided, consider a dose adjustment of stiripentol based on clinical monitoring and plasma levels.(1) DISCUSSION: Stiripentol is a substrate of CYP3A4 and CYP2C19.(1) Strong CYP3A4 or CYP2C19 inducers include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(1-3) |
DIACOMIT |
| Deuruxolitinib/Dual Inducers of CYP2C9 & CYP3A4 SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Drugs that are both strong CYP3A4 and strong or moderate inducers of CYP2C9 may increase the metabolism of deuruxolitinib.(1) CLINICAL EFFECTS: Concurrent use with a strong CYP3A4 and strong or moderate CYP2C9 dual inducer may result in decreased levels and effectiveness of deuruxolitinib.(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 deuruxolitinib states to avoid concomitant use with strong CYP3A4 and strong or moderate CYP2C9 inducers.(1) DISCUSSION: In a study with rifampin (a strong CYP3A4 and moderate CYP2C9 inducer), deuruxolitinib area-under-curve (AUC) decreased by 78% and maximum concentration (Cmax) by 41% following concomitant use of multiple doses of 600 mg rifampin and a single dose of 12mg deuruxolitinib (1.5 times the licensed 8 mg dose).(1) Drugs that are dual strong CYP3A4 and strong or moderate CYP2C9 inducers linked to this monograph include: enzalutamide, rifampin and ritonavir.(2-3) |
LEQSELVI |
| Mifepristone (Chronic)/Str 3A4 Inducer & 2C8;2C9 Substrates SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers such as enzalutamide, fosphenytoin, or phenytoin may accelerate the metabolism of mifepristone by CYP3A4.(1,2) Mifepristone is a moderate inhibitor of CYP2C8 and CYP2C9.(1) CLINICAL EFFECTS: The concurrent use of mifepristone and strong CYP3A4 inducers may result in decreased levels and effectiveness of mifepristone.(1,2) Decreased clearance of drugs primarily metabolized by CYP2C8 or CYP2C9 may increase systemic concentrations, leading to toxicity.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid co-administration of mifepristone with strong CYP3A4 inducers.(1-3) If mifepristone is used as a progestin antagonist and concurrent use cannot be avoided, conduct post-treatment assessment as detailed in the mifepristone prescribing information to verify treatment success.(1,3) If concurrent use cannot be avoided, closely monitor patients stable on CYP2C8/2C9 substrates for increased therapeutic effect or toxicity when chronic mifepristone therapy is started or adjusted. Adjust dosage of the 2C8/2C9 substrate drug accordingly. Because of the long half-life of mifepristone, the effect of changes in mifepristone therapy may not be seen for 2 weeks. For patients on chronic mifepristone and newly started on a CYP2C8/2C9 substrate, the smallest recommended dose of the CYP2C8/2C9 substrate is suggested by the manufacturer of mifepristone.(1) If chronic mifepristone therapy is discontinued, the manufacturer of mifepristone recommends waiting at least 2 weeks before increasing the dose of a concomitant interacting medication.(1) DISCUSSION: In a study, rifampin decreased mifepristone area-under-curve (AUC) by 6.3-fold. The AUC of mifepristone active metabolites 22-hydroxy-mifepristone and N-demethyl-mifepristone decreased by 20-fold and 5.9-fold, respectively.(4) Mifepristone 1200 mg was given daily for 7 days, followed by a single dose of fluvastatin (40 mg), a CYP 2C8/2C9. The area-under-curve (AUC) of fluvastatin was increased 3.57 fold. The manufacturer notes this result could be representative of other oral drugs with CYP2C8/2C9 metabolism.(1) Mifepristone has a long elimination half-life of approximately 85 hours and so full effects of a mifepristone dose change on CYP2C8/2C9 substrates may not be seen for two weeks. Extended monitoring for this interaction may be required when mifepristone is started, stopped or if dose is changed.(1) Medications linked to this interaction are enzalutamide, fosphenytoin, and phenytoin. These drugs have a narrow therapeutic range or are designated as CYP2C8 or CYP2C9 Sensitive Substrates(2,3), i.e. moderate CYP2C8 or 2C9 inhibitors are expected to increase exposure (AUC) to these agents by 2-fold to 5-fold. |
KORLYM, MIFEPRISTONE |
| Ketoconazole/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ketoconazole is mainly metabolized by CYP3A4. Concurrent use of strong CYP3A4 inducers may accelerate the metabolism of ketoconazole.(1) CLINICAL EFFECTS: Serum levels and bioavailability of ketoconazole may be decreased, resulting in decreased effectiveness of antifungal therapy.(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 ketoconazole states that coadministration of strong CYP3A4 inducers with ketoconazole is not recommended. These inducers should be avoided in the 2 weeks before and during ketoconazole therapy unless benefits outweigh the risk of potentially compromised ketoconazole efficacy. If coadministration cannot be avoided, monitor antifungal activity and increase ketoconazole dose as necessary.(1) DISCUSSION: In vitro studies have shown that CYP3A4 is the major enzyme responsible for ketoconazole metabolism.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, enzalutamide, mitotane, and St. John's wort.(2,4) |
KETOCONAZOLE |
| Lazertinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of lazertinib.(1) CLINICAL EFFECTS: Concurrent or recent use of strong 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 strong CYP3A4 inducers should be avoided. Consider an alternative concomitant medication with no potential to induce CYP3A4.(1) DISCUSSION: In a clinical pharmacokinetic study, concomitant use of rifampin (strong CYP3A4 inducer) decreased lazertinib concentration maximum (Cmax) by 72% and area-under-curve (AUC) by 83%.(1) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's Wort.(2,3) |
LAZCLUZE |
| Revumenib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of 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 strong 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 strong CYP3A4 inducers should be avoided.(1) DISCUSSION: Revumenib is primarily metabolized by CYP3A4. Concomitant use of a strong 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) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(3) |
REVUFORJ |
| Ensartinib/Dual Strong CYP3A4 Inducers & P-gp Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ensartinib is primarily metabolized by CYP3A4 and is transported by P-glycoprotein (P-gp).(1) Inducers of CYP3A4 may induce the metabolism of ensartinib while inhibitors of P-gp may increase the absorption of ensartinib.(1) CLINICAL EFFECTS: The net effect of this interaction is unknown. Concurrent use of ensartinib with CYP3A4 inducers may result in decreased levels and effectiveness of ensartinib while concurrent use of P-gp inhibitors may result in elevated systemic levels and toxicity from 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 manufacturer of ensartinib states concurrent use with both P-gp inhibitors and strong CYP3A4 inducers should be avoided.(1) DISCUSSION: Ensartinib is predominately metabolized by CYP3A4 and is a P-gp substrate.(1) Dual strong CYP3A4 inducers and P-gp inhibitors linked to this monograph include: enzalutamide, lumacaftor-ivacaftor, and St. John's wort.(2,3) |
ENSACOVE |
| Vanzacaftor-Tezacaftor-Deutivacaftor/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of vanzacaftor, tezacaftor, and deutivacaftor.(1) CLINICAL EFFECTS: Concurrent or recent use of a strong 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 strong CYP3A4 inducers in patients maintained on vanzacaftor- tezacaftor-deutivacaftor is not recommended.(1) DISCUSSION: Concurrent administration with rifampin (a strong inducer of CYP3A4) is predicted to decrease vanzacaftor and deutivacaftor area-under-curve (AUC) by 82% and 90%, respectively, and maximum concentration (Cmax) by 78% and 80%, respectively.(1) Carbamazepine (a strong CYP3A4 inducer) is predicted to decrease vanzacaftor and deutivacaftor AUC by 56% and 76%, respectively, and Cmax by 54% and 68%, 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) |
ALYFTREK |
| Suzetrigine/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of suzetrigine.(1) CLINICAL EFFECTS: Concurrent or recent use of strong 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 strong CYP3A4 inducers should be avoided.(1) DISCUSSION: In a study, concomitant use of rifampin (strong CYP3A4 inducer) decreased suzetrigine maximum concentration (Cmax) by 80% and area-under-curve (AUC) by 93%. Active metabolite M6-SUZ AUC decreased by 85% and Cmax was increased by 1.3-fold.(1) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's Wort.(2,3) |
JOURNAVX |
| Atrasentan/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of atrasentan.(1) CLINICAL EFFECTS: Concurrent or recent use of strong 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 strong 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) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifapentine, and St. John's Wort.(2,3) |
VANRAFIA |
| Defactinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers may accelerate the metabolism of defactinib by CYP3A4.(1) CLINICAL EFFECTS: The concurrent use of defactinib and strong CYP3A4 inducers 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 strong CYP3A4 inducers should be avoided.(1) DISCUSSION: 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) 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.(2) |
AVMAPKI-FAKZYNJA, FAKZYNJA |
| Taletrectinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of taletrectinib.(1) CLINICAL EFFECTS: Concurrent or recent use of a strong 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 strong CYP3A4 inducers should be avoided.(1) DISCUSSION: Taletrectinib is primarily metabolized by CYP3A4.(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) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, ethotoin, fosphenytoin, lumacaftor, mephenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2) |
IBTROZI |
| Sebetralstat/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers may accelerate the metabolism of sebetralstat by CYP3A4.(1) CLINICAL EFFECTS: The concurrent use of sebetralstat and strong CYP3A4 inducers 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 strong CYP3A4 inducers should be avoided.(1) DISCUSSION: Sebetralstat maximum concentration (Cmax) decreased by 66% and area-under-curve (AUC) decreased by 83% following concomitant administration with phenytoin (a strong CYP3A4 inducer) 100 mg three times daily for 15 days.(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.(2) |
EKTERLY |
There are 24 moderate interactions.
The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.
| Drug Interaction | Drug Names |
|---|---|
| Corticosteroids/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of corticosteroids. Corticosteroids may affect the metabolism of phenytoin. CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers may result in decreased levels and effectiveness of corticosteroids. Dexamethasone has been shown to increase and decrease phenytoin levels. PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Patients receiving concurrent therapy with a strong CYP3A4 inducer should be monitored for decreased effectiveness of their corticosteroid. Increased dosage of corticosteroid may be required during concurrent therapy and for several weeks after completing concurrent therapy. If concurrent therapy is discontinued, the dosage of the corticosteroid may need to be adjusted. Phenytoin levels should be closely monitored in patients receiving corticosteroids. The dosage of phenytoin may need to be adjusted if corticosteroids are initiated or discontinued. DISCUSSION: Carbamazepine has been shown to increase the metabolism of methylprednisolone, prednisolone, and prednisone, resulting in decreased levels and effectiveness of these agents. Phenobarbital has been shown to increase the metabolism of dexamethasone, methylprednisolone, and prednisolone. Primidone is metabolized to phenobarbital. Phenytoin has been shown to increase the metabolism of dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone, resulting in decreased levels and effectiveness of these agents Rifampin has been shown to increase the metabolism of cortisol, dexamethasone, methylprednisolone, prednisolone, and prednisone. Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifapentine, rifampin, and St. John's wort. |
ALDOSTERONE, ALKINDI SPRINKLE, ANUCORT-HC, ANUSOL-HC, BECLOMETHASONE DIPROPIONATE, BETA 1, BETALOAN SUIK, BETAMETHASONE ACETATE MICRO, BETAMETHASONE ACETATE-SOD PHOS, BETAMETHASONE DIPROPIONATE, BETAMETHASONE SOD PHOS-ACETATE, BETAMETHASONE SOD PHOS-WATER, BETAMETHASONE SODIUM PHOSPHATE, BETAMETHASONE VALERATE, BSP 0820, BUDESONIDE, BUDESONIDE DR, BUDESONIDE EC, BUDESONIDE ER, BUDESONIDE MICRONIZED, BUPIVACAINE-DEXAMETH-EPINEPHRN, CELESTONE, CLOBETASOL PROPIONATE MICRO, CORTEF, CORTENEMA, CORTIFOAM, CORTISONE ACETATE, DEFLAZACORT, DEPO-MEDROL, DESONIDE MICRONIZED, DESOXIMETASONE, DESOXYCORTICOSTERONE ACETATE, DEXABLISS, DEXAMETHASONE, DEXAMETHASONE ACETATE, DEXAMETHASONE ACETATE MICRO, DEXAMETHASONE INTENSOL, DEXAMETHASONE ISONICOTINATE, DEXAMETHASONE MICRONIZED, DEXAMETHASONE SOD PHOS-WATER, DEXAMETHASONE SODIUM PHOSPHATE, DEXAMETHASONE-0.9% NACL, DMT SUIK, DOUBLEDEX, EMFLAZA, EOHILIA, FLUDROCORTISONE ACETATE, FLUNISOLIDE, FLUOCINOLONE ACETONIDE, FLUOCINOLONE ACETONIDE MICRO, FLUOCINONIDE MICRONIZED, FLUTICASONE PROPIONATE, FLUTICASONE PROPIONATE MICRO, HEMADY, HEMMOREX-HC, HEXATRIONE, HYDROCORTISONE, HYDROCORTISONE ACETATE, HYDROCORTISONE SOD SUCCINATE, HYDROCORTISONE-PRAMOXINE, KENALOG-10, KENALOG-40, KENALOG-80, KHINDIVI, LIDOCIDEX-I, MAS CARE-PAK, MEDROL, MEDROLOAN II SUIK, MEDROLOAN SUIK, METHYLPREDNISOLONE, METHYLPREDNISOLONE AC MICRO, METHYLPREDNISOLONE ACETATE, METHYLPREDNISOLONE SODIUM SUCC, MILLIPRED, MILLIPRED DP, MOMETASONE FUROATE, ORAPRED ODT, ORTIKOS, PEDIAPRED, PREDNISOLONE, PREDNISOLONE ACETATE MICRONIZE, PREDNISOLONE MICRONIZED, PREDNISOLONE SODIUM PHOS ODT, PREDNISOLONE SODIUM PHOSPHATE, PREDNISONE, PREDNISONE INTENSOL, PREDNISONE MICRONIZED, PRO-C-DURE 5, PRO-C-DURE 6, PROCTOCORT, RAYOS, SOLU-CORTEF, SOLU-MEDROL, TAPERDEX, TARPEYO, TRIAMCINOLONE, TRIAMCINOLONE ACETONIDE, TRIAMCINOLONE DIACETATE, TRIAMCINOLONE DIACETATE MICRO, TRILOAN II SUIK, TRILOAN SUIK, UCERIS, VERIPRED 20, ZCORT, ZILRETTA |
| Doxycycline/CYP3A4 Inducers 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 doxycyline. CLINICAL EFFECTS: Concurrent or recent use of an inducer of CYP3A4 may result in decreased antimicrobial activity of doxycycline. PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: If both drugs are administered, monitor the response to doxycycline. Adjust the dose of the drug or consider administration of a non-interacting tetracycline analogue (e.g. tetracycline) if necessary. DISCUSSION: The effects of the interaction develop over approximately one to two weeks after starting the inducer and reverse over a period of several weeks after stopping the inducer. The elimination of demeclocycline, methacycline, oxytetracycline and tetracycline are not expected to be altered by CYP3A4 inducers as these tetracyclines are primarily excreted by the kidneys. Serum doxycycline concentrations may increase when the inducer is stopped. In a study, the half-life of doxycycline in 7 patients on long-term phenytoin therapy, 5 patients on long-term carbamazepine therapy, 4 patients on long-term combination phenytoin and carbamazepine therapy, and 9 control subjects was 7.2 hours, 8.4 hours, 7.4 hours, and 15.1 hours, respectively.(1) In a study, the half-life of doxycycline was significantly reduced in patients receiving barbiturate therapy.(2) In a study that compared healthy-controls with patients on long-term antiepileptic therapy, the half-life of doxycyline was significantly decreased in patients receiving barbiturates, phenytoin, or carbamazepine. The half-lives of chlortetracycline, demethylchlortetracycline, methacycline, oxytetracycline, and tetracycline were unaffected.(3) In a study in 7 patients, the half-life of doxycycline (200 mg/day) decreased from 17.9 hours to 9.2 hours following the addition of rifampin (10 mg/kg/day) to therapy.(4) CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenytoin, primidone, rifamycins, and St. John's Wort. |
AVIDOXY, AVIDOXY DK, BENZODOX 30, BENZODOX 60, DORYX, DORYX MPC, DOXY 100, DOXYCYCLINE HYCLATE, DOXYCYCLINE IR-DR, DOXYCYCLINE MONOHYDRATE, MONDOXYNE NL, MORGIDOX, ORACEA, TARGADOX |
| Selected Opioids/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of alfentanil, benzhydrocodone, buprenorphine,(1) fentanyl, hydrocodone, meperidine,(2-4) morphine,(5) oxycodone, papaveretum, and sufentanil.(6) CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inducer may result in decreased levels of alfentanil, benzhydrocodone, buprenorphine, fentanyl, hydrocodone, meperidine, morphine, oxycodone, papaveretum, and sufentanil, which may result in decreased effectiveness and may precipitate withdrawal symptoms.(1-6) Induction of meperidine metabolism may result in an increase in levels of normeperidine, the toxic metabolite of meperidine, resulting in a higher risk of excitatory effects, including hallucinations, tremors, and seizures.(2,3) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Patients maintained on alfentanil, benzhydrocodone, buprenorphine, fentanyl, hydrocodone, meperidine, morphine, oxycodone, papaveretum, and sufentanil may require dosage adjustments if a strong CYP3A4 inducer is initiated or discontinued. The effects of the interaction may last for several weeks after the discontinuation of the inducer. Patients who transfer to Sublocade (extended release subcutaneous syringe buprenorphine) from transmucosal buprenorphine used concomitantly with CYP3A4 inducers should be monitored to ensure that the plasma buprenorphine level produced by Sublocade is adequate. If patients already on Sublocade require newly-initiated treatment with CYP3A4 inducer, the patient should be monitored for withdrawal. If the dose of Sublocade is not adequate in the absence of the concomitant medication, and the concomitant medication cannot be reduced or discontinued, the patient should be transitioned back to a formulation of buprenorphine that permits dose adjustment. If a patient has been stabilized on Sublocade with a CYP3A4 inducer and the concomitant medication is discontinued, the patient should be monitored for signs and symptoms of over-medication. Within 2 weeks of Sublocade administration, if the dose provided by Sublocade is excessive in the absence of the concomitant inducer, it may be necessary to remove the Sublocade and treat the patient with a formulation of buprenorphine that permits dose adjustments.(15) The manufacturer of sufentanil sublingual tablets states that if concomitant use with CYP3A4 inducers is necessary, consider use of an alternate agent that allows dose adjustment.(6) DISCUSSION: In a study in 12 opoid-dependent patients, rifampin (600 mg daily) decreased the area-under-curve (AUC) of buprenorphine by 70%. Half of the subjects experienced withdrawal symptoms. When compared to historical values, there was no effect on rifampin levels.(1) In a study of four healthy volunteers, phenytoin increased meperidine clearance from 1017 +/- 225 ml/min (mean +/- SD) to 1280 +/- 130 ml/min and decreased half-life from 6.4 hours to 4.3 hours. Phenytoin also increased normeperidine AUC by 1.53-fold after IV meperidine and by 1.25-fold after oral meperidine.(3) In a study in 10 healthy subjects, pretreatment with rifampin (600 mg daily) for 13 days decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of morphine by 28% and 41%, respectively. The AUCs of morphine-3-glucuronide and morphine-6-glucuronide were proportionally decreased as well. Following rifampin pretreatment, no analgesic effects of morphine were seen.(5) In a randomized controlled trial of 12 healthy participants St. John's wort decreased the oxycodone AUC by 50%, shortened the oxycodone elimination half-life, and decreased the self-reported drug effect of oxycodone compared to placebo.(7) In a study in 12 healthy subjects, pretreatment with rifampin had no effect on fentanyl Cmax or time to Cmax (Tmax) after administration of oral transmucosal fentanyl. However, fentanyl AUC decreased 62%.(8) In a study in 9 healthy subjects, rifampin increased the clearance of alfentanil by 169%. Alfentanil half-life decreased 61%.(9) In a study of patients undergoing craniotomy, higher fentanyl maintenance doses were required in patients receiving carbamazepine and phenytoin compared to control subjects not receiving enzyme-inducing agents.(10) There are case reports of decreased levels and effectiveness of oxycodone with concurrent phenytoin(11) and rifampin(12) and with concurrent fentanyl and rifampin.(13-14) Selected strong CYP3A4 inducers linked to this monograph include: apalutamide, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenytoin, rifampin, rifapentine, and St. John's Wort. |
APADAZ, BELBUCA, BENZHYDROCODONE-ACETAMINOPHEN, BRIXADI, BUPRENORPHINE, BUPRENORPHINE HCL, BUPRENORPHINE-NALOXONE, BUTRANS, DEMEROL, DSUVIA, DURAMORPH, ENDOCET, FENTANYL, FENTANYL CITRATE, FENTANYL CITRATE-0.9% NACL, FENTANYL CITRATE-D5W, FENTANYL CITRATE-STERILE WATER, FENTANYL CITRATE-WATER, FENTANYL-BUPIVACAINE-0.9% NACL, FENTANYL-BUPIVACAINE-NACL, FENTANYL-ROPIVACAINE-0.9% NACL, FENTANYL-ROPIVACAINE-NACL, HYCODAN, HYDROCODONE BITARTRATE, HYDROCODONE BITARTRATE ER, HYDROCODONE-ACETAMINOPHEN, HYDROCODONE-CHLORPHENIRAMNE ER, HYDROCODONE-HOMATROPINE MBR, HYDROCODONE-IBUPROFEN, HYDROMET, HYSINGLA ER, INFUMORPH, MEPERIDINE HCL, MEPERIDINE HCL-0.9% NACL, MITIGO, MORPHINE SULFATE, MORPHINE SULFATE ER, MORPHINE SULFATE-0.9% NACL, MORPHINE SULFATE-NACL, MS CONTIN, NALOCET, OXYCODONE HCL, OXYCODONE HCL ER, OXYCODONE HYDROCHLORIDE, OXYCODONE-ACETAMINOPHEN, OXYCONTIN, PERCOCET, PRIMLEV, PROLATE, ROXICODONE, ROXYBOND, SUBLOCADE, SUBOXONE, SUFENTANIL CITRATE, XTAMPZA ER, ZUBSOLV |
| Select Sedative Hypnotics; Buspirone/Strong CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of buspirone,(1-3) eszopiclone,(4) zopiclone,(5) and zolpidem.(6) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may result in decreased levels and clinical effectiveness of buspirone,(1-3) eszopiclone,(4) zopiclone,(5) and zolpidem.(6) 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 buspirone may need adjusting to maintain anxiolytic effect.(1) Concurrent use of strong CYP3A4 inducers with zolpidem is not recommended.(6) If concomitant therapy is warranted, patients should be counseled about possible decreased buspirone or hypnotic effectiveness. DISCUSSION: In a randomized, placebo-controlled, cross-over study in 10 subjects, rifampin (600 mg daily) decreased buspirone (30 mg single dose) maximum concentration (Cmax), area-under-curve (AUC), and half-life by 89.6%, 83.7%, and 54%, respectively. During the placebo phase, all subjects had measurable plasma buspirone concentrations at 10 hours after administration; however, no subject had measurable plasma buspirone concentrations at 6 hours after administration during the rifampin phase.(2) The Cmax of the buspirone piperazine metabolite increased by 35%.(3) There were significant decreases in the effects of buspirone in the postural sway test with eyes closed, the visual analogue scale (VAS) test for subjective drowsiness, and the VAS test for overall drug effect during concurrent rifampin. Buspirone side effects were reported more often during the placebo phase.(2) In a study in 8 subjects, rifampin (600 mg daily for 6 days) decreased the area-under-curve (AUC) of a single dose of zopiclone (10 mg) by 82%. The maximum concentration (Cmax) and half-life of zopiclone were decreased by 71% and 15%, respectively. A significant reduction in zopiclone effects were seen in 3 of 5 psychomotor tests.(5) In a randomized cross-over study in 8 subjects, rifampin (600 mg daily for 6 days) decreased the AUC, Cmax, and half-life of a single dose of zolpidem (20 mg) by 73%, 58%, and 36%, respectively. A significant reduction in zolpidem effects were seen in all 6 psychomotor tests.(6,7) Similar effects are expected with eszopiclone.(4) |
AMBIEN, AMBIEN CR, BUCAPSOL, BUSPIRONE HCL, EDLUAR, ESZOPICLONE, LUNESTA, ZOLPIDEM TARTRATE, ZOLPIDEM TARTRATE ER |
| Selected Benzodiazepines/Selected CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: CYP3A4 inducers may induce the metabolism of some benzodiazepines. CLINICAL EFFECTS: Concurrent or recent use of CYP3A4 inducers may result in decreased levels and loss of effectiveness of some benzodiazepines. PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Monitor patients receiving CYP3A4 inducers or who have received these agents in the previous 2 weeks for decreased benzodiazepine effectiveness. The dose of the benzodiazepine may need to be adjusted or an alternative agent used. If the CYP3A4 inducer is discontinued, benzodiazepine levels will gradually rise as induction effects diminish. Monitor for increased benzodiazepine effects and adjust the dose accordingly. DISCUSSION: In a study in 95 healthy subjects, rifampin (450 mg daily for 5 days) decreased the plasma concentrations of a single oral dose of alprazolam (1 mg) by 79%.(1) In another study in 4 healthy subjects, rifampin (given for 4 days) decreased the area-under-curve (AUC) of a single oral dose of alprazolam (1 mg) by 88%.(2) In a double-blind, randomized, cross-over trial in 13 healthy subjects, rifampin (450 mg daily for 7 days) decreased the maximum concentration (Cmax), AUC, and half-life of a single oral dose of brotizolam (0.5 mg) by 69%, 90%, and 69%, respectively. Concurrent rifampin increased scores on the Digit Symbol Substitution Test (DSST) and decreased scores on the Stanford Sleepiness Scale.(3) In a study in 21 healthy subjects, rifampin (600 mg or 1200 mg daily for 7 days) increased total body clearance of diazepam by 300%.(4) An in vitro study in human hepatocytes found that rifampin increased the biotransformation of diazepam and midazolam by 1.9-fold.(5) In a study in 24 healthy subjects, rifampin (600 mg daily for 10 days) increased the clearance of a single intravenous dose of lorazepam by 140%.(6) In an open-label cross-over study in 19 healthy subjects, rifampin (600 mg daily for 9 days) increased the clearance of a single oral dose of midazolam (0.075 mg/kg) by 7-fold.(7) In a study in 57 healthy subjects, rifampin increased the systemic and oral clearance of midazolam by 2-fold and 16-fold, respectively.(8) In a study in 8 healthy subjects, rifampin (given for 6 days) significantly increased the clearance of midazolam.(9) In a study in 9 healthy subjects, received a single oral dose of midazolam (15 mg) before, one day after the administration of rifampin (600 mg daily for 5 days), and 4 days after the last dose of rifampin. One day after rifampin, the AUC of midazolam was decreased by 97.7% when compared to the administration of midazolam prior to rifampin. Four days after the completion of rifampin, the AUC of midazolam was decreased by 87% when compared to the administration of midazolam prior to rifampin.(10) In a double-blind, randomized, cross-over study in 10 healthy subjects, rifampin (600 mg daily for 5 days) decreased the Cmax, AUC, and half-life of a single oral dose of midazolam (15 mg) by 94%, 96%, and 58%, respectively. The pharmacodynamic effects of midazolam were also significantly decreased during rifampin therapy.(11) In a study in 16 healthy subjects, rifampin (600 mg daily for 7 days) increased the clearance of nitrazepam by 83%. There were no significant effects on the pharmacokinetics of temazepam.(12) In a randomized, double-blind, cross-over study in 10 healthy subjects, rifampin (600 mg daily for 5 days) decreased the Cmax, AUC, and half-life of a single dose of triazolam (0.5 mg) by 87.6%, 94.9%, and 54%, respectively. The pharmacodynamic effects of triazolam were also significantly decreased during rifampin therapy.(13) In an open-label, randomized, cross-over study in 27 healthy subjects, rifaximin (200 mg three times daily for 7 days) had no effect on the pharmacokinetics of single doses of oral or intravenous midazolam.(14) In a study in 98 patients with schizophrenia or bipolar disorder, the expression of CYP3A4 was found to be the major determinant of clonazepam plasma concentrations normalized by the dose and bodyweight (1263 +/- 482.9 and 558.5 +/- 202.4 ng/mL per mg/kg bodyweight in low and normal expressers, respectively, p<0.0001).(18) Selected CYP3A4 inducers linked to this monograph include: apalutamide, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenytoin, rifabutin, rifampin, rifapentine, and St. John's wort. |
ALPRAZOLAM, ALPRAZOLAM ER, ALPRAZOLAM INTENSOL, ALPRAZOLAM ODT, ALPRAZOLAM XR, ATIVAN, CLONAZEPAM, DIAZEPAM, HALCION, KLONOPIN, LORAZEPAM, LORAZEPAM INTENSOL, LOREEV XR, MIDAZOLAM, MIDAZOLAM HCL, MIDAZOLAM HCL-0.8% NACL, MIDAZOLAM HCL-0.9% NACL, MIDAZOLAM HCL-D5W, MIDAZOLAM HCL-NACL, MIDAZOLAM-0.9% NACL, MIDAZOLAM-NACL, MKO (MIDAZOLAM-KETAMINE-ONDAN), NAYZILAM, TRIAZOLAM, VALIUM, VALTOCO, XANAX, XANAX XR |
| Ospemifene/Selected CYP2C and CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Ospemifene is metabolized by CYP3A4, CYP2C9 and CYP2C19.(1) Agents linked to this monograph are strong inducers of CYP3A4, and moderate inducers of CYP2C9 and/or CYP2C19. CLINICAL EFFECTS: Concurrent or recent use of ospemifene with agents which induce both CYP3A4 and CYP2C enzyme pathways may lead to decreased levels and effectiveness of ospemifene.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Systemic levels of ospemifene are expected to decrease after starting an inducer, then stabilize at a new lower systemic concentration over approximately 2 to 4 weeks depending upon the dose and half-life of the inducing agent. The manufacturer of ospemifene notes that decreased systemic exposure may lead to a decrease in clinical effectiveness, but does not make recommendations for a dosage adjustment.(1) Instruct patient to contact their prescriber for a significant decrease in ospemifene effectiveness. To ensure maximal absorption, counsel patient to take ospemifene with a meal as food increases bioavailability 2-3 fold.(1) DISCUSSION: An interaction study included 12 postmenopausal women who received rifampin 600 mg daily for 5 days. On the 6th day, ospemifene 60mg was administered with food. Rifampin reduced maximum concentrations (Cmax) and area-under-curve (AUC) of ospemifene by 51% and 58% respectively.(1) Agents linked to this monograph are apalutamide, carbamazepine, dabrafenib, enzalutamide and rifampin. |
OSPHENA |
| Vilazodone/Strong CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of vilazodone.(1) CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 inducer may result in decreased levels and effectiveness of vilazodone.(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 vilazodone states that the vilazodone dosage may need to be increased 2-fold, up to a maximum of 80 mg daily in patients receiving strong inducers of CYP3A4 for 14 days or more. (1) If a patient has been maintained on concomitant treatment with vilazodone and a strong CYP3A4 inducer and the strong CYP3A4 inducer is subsequently discontinued, the dose of vilazodone should be decreased by 50% over 1-2 weeks based upon patient response.(1) DISCUSSION: Carbamazepine (dosage not stated), a strong inducer of CYP3A4, decreased vilazodone exposure approximately 45%.(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) |
VIIBRYD, VILAZODONE HCL |
| Perampanel/Strong and Moderate CYP3A4 Inducers 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, fosphenytoin, ivosidenib, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, modafinil, nafcillin, oxcarbazepine, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(1,2) |
FYCOMPA, PERAMPANEL |
| Apixaban/Enzalutamide SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Enzalutamide may induce the metabolism of apixaban by CYP3A4, but increase their absorption by inhibiting P-glycoprotein (P-gp).(1-7) CLINICAL EFFECTS: Concurrent or recent use of enzalutamide may have unpredictable effects on apixaban. If drug levels of apixaban are increased, concurrent use may increase the risk for bleeding.(1-7) If drug levels of apixaban decrease, loss of anticoagulant efficacy may result. PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: Consider the use of alternative agents for anticoagulation in patients requiring therapy with enzalutamide. Depending on indication and renal function, dabigatran, edoxaban, or warfarin may be alternatives.(6) If concurrent therapy is required, monitor patients for altered response to apixaban. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: Concurrent rifampin (a strong inducer of CYP3A4 and an inducer of P-gp) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of apixaban by 54% and 42%, respectively.(1-4) Concurrent ketoconazole (400 mg daily, a strong inhibitor of CYP3A4 and P-gp) increased the area-under-curve (AUC) and maximum concentration (Cmax) of apixaban by 2-fold and 1.6-fold, respectively.(1) Enzalutamide is a strong inducer of CYP3A4 and an inhibitor of P-gp.(5) A PKPB model study evaluated the effects of enzalutamide as a strong CYP3A4 inducer and P-gp inhibitor on apixaban. The model predicted a decrease in apixaban AUC by 31% with no change in Cmax.(7) |
ELIQUIS |
| Oxcarbazepine/Selected UGT and Strong CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Oxcarbazepine is metabolized by CYP3A4 to the active metabolite, eslicarbazepine, which is conjugated by UDP-glucuronosyltransferase (UGT) enzymes. Strong CYP3A4 inducers and UGT inducers decrease exposure to eslicarbazepine.(3) CLINICAL EFFECTS: Concurrent use of oxcarbazepine with UGT inducers and strong CYP3A4 inducers may lead to decreased levels and effectiveness of oxcarbazepine, e.g loss of seizure control.(3) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: For patients stabilized on UGT or strong CYP3A4 inducers, the US manufacturer of extended release oxcarbazepine recommends initiating extended release oxcarbazepine at 900 mg once daily in adults and 12-15 mg/kg once daily (not to exceed 900 mg per day in the first week) in pediatric patients.(3) If a strong CYP3A4 inducer or UGT inducer is added in a patient stabilized on oxcarbazepine, the dose of oxcarbazepine may need to be increased. Onset of induction is gradual and may not be maximal for days or weeks. If a strong CYP3A4 inducer or UGT inducer is discontinued in a patient stabilized on oxcarbazepine, the concentration of oxcarbazepine will increase over 1 to 4 weeks. Monitor serum levels and adjust dosages as needed. DISCUSSION: In interaction studies, phenytoin doses of 250 mg to 500 mg daily decreased the concentration of oxcarbazepine's active metabolite (eslicarbazepine) by approximately 30%.(3) Similarly, phenobarbital doses of 100 mg to 150 mg daily decreased the mean concentration of eslicarbazepine by 25%.(3) UGT and strong CYP3A inducers linked to this monograph include: apalutamide, carbamazepine, efavirenz, encorafenib, enzalutamide, etravirine, ivosidenib, lorlatinib, lumacaftor, mitotane, rifampin, rifapentine, and St. John's wort.(1-2) |
OXCARBAZEPINE, OXCARBAZEPINE ER, OXTELLAR XR, TRILEPTAL |
| Pitolisant/Strong CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of pitolisant via this pathway.(1) CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers may reduce the clinical effectiveness of pitolisant.(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 pitolisant states that concurrent use of strong CYP3A4 inducers requires a dose adjustment. For patients stable on pitolisant 8.9 mg or 17.8 mg, increase the dose of pitolisant to double the original daily dose (ex 17.8 mg or 35.6 mg, respectively) over 7 days. If concurrent use of a strong CYP3A4 inducer is discontinued, decrease the pitolisant dose by half.(1) The UK manufacturer of pitolisant states that concurrent use of strong CYP3A4 inducers should be done with caution and dose adjustment should be considered after during concurrent therapy and for one week after discontinuing the inducer.(2) DISCUSSION: In a clinical study, concurrent use of pitolisant with rifampin decreased the concentration maximum (Cmax) and area-under-curve (AUC) by approximately 0.75-fold and 0.5-fold change, respectively.(1) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine and St. John's Wort.(3,4) |
WAKIX |
| Cannabidiol; Tetrahydrocannabinol/Strong CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Cannabidiol (CBD) and tetrahydrocannabinol (THC) are substrates of CYP3A4. Strong inducers of CYP3A4 may induce the metabolism of CBD and THC.(1) CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 inducer may result in decreased levels and effectiveness of CBD and THC.(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 CBD solution recommends considering increasing cannabidiol dosage by up to 2-fold, based on the patient's clinical response and tolerance, when used concurrently with a strong CYP3A4 inducer.(1) The Canadian manufacturer of CBD-THC spray states that concurrent use with strong CYP3A4 inducers should be avoided. If concurrent therapy is necessary, careful dose adjustment is recommended. If the CYP3A4 inducer is discontinued, the dose of CBD and THC may need to be lowered within the two weeks following discontinuation of the CYP3A4 inducer.(2) DISCUSSION: In a study of 12 healthy volunteers, rifampin 600 mg (a strong CYP3A4 inducer) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of CBD by 52% and 58%, respectively, of THC by 39% and 24%, respectively, and of 11-hydroxy-THC (a primary metabolite of THC) by 86% and 87%, respectively.(3) In a study in 16 healthy volunteers, a single dose of cannabidiol with steady state rifampin decreased the Cmax and AUC of CBD by 34% and 32%, respectively, of 7-hydroxy-CBD by 67% and 63%, and 7-carboxy-CBD by 3% and 44%.(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) |
EPIDIOLEX |
| Haloperidol/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Strong CYP3A4 inducers may increase the metabolic clearance of haloperidol.(1) CLINICAL EFFECTS: Coadministration with a strong CYP3A4 inducer may result in decreased levels and effectiveness of haloperidol.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Monitor clinical response in patients maintained on haloperidol when initiating or discontinuing strong CYP3A4 inducers. The dosage of haloperidol may need to be adjusted.(1) DISCUSSION: In a study in 11 schizophrenic patients, the addition of carbamazepine resulted in a dose related decrease in haloperidol levels. Haloperidol levels were decreased by 2%, 61%, and 85%, respectively, from baseline following the addition and increase of carbamazepine at 100 mg/day, 300 mg/day, and 600 mg/day.(1,2) In a study in 27 patients with schizophrenia or schizoaffective disorder, the use of haloperidol with carbamazepine was associated with lower haloperidol levels and worse clinical outcomes than the use of haloperidol alone.(3) In a study in schizophrenic patients, haloperidol levels were significantly decreased in patients receiving concurrent carbamazepine.(4) In a study in 7 patients, haloperidol levels fell 60% following the addition of carbamazepine to therapy. Haloperidol levels were undetectable in 2 subjects, whose symptoms worsened.(5) In a study in 23 patients, the addition of carbamazepine to haloperidol resulted in improvement in symptoms.(6) In a retrospective review of 231 schizophrenic patients, patients receiving concurrent carbamazepine or phenobarbital had haloperidol levels that were 37% and 22% lower, respectively, than patients taking haloperidol without these agents.(7) In a study in 6 schizophrenic patients, switching carbamazepine to oxcarbazepine resulted in increased in haloperidol levels by 50% to 200% after 2-4 weeks of therapy.(8) In a study in schizophrenic patients, carbamazepine decreased haloperidol levels by 50%. One subject developed worsening of symptoms, while two improved.(9) There are also case reports documenting decreased haloperidol levels and effectiveness with concurrent carbamazepine.(10-14) In a study in schizophrenic patients, the addition of rifampin in 12 patients resulted in decreases in haloperidol levels by 37%, 58.7%, and 70% by Day 3, Day 7, and Day 28, respectively, of concurrent therapy. Mean scores on the Brief Psychiatric Rating Scale decreased from baseline. Discontinuation of rifampin from concurrent therapy in 5 patients increased haloperidol levels by 140.7%, 228.7%, and 329% of baseline by Day 3, Day 7, and Day 28, respectively, after rifampin discontinuation.(1,15) In a study in 7 schizophrenic patients, rifampin decreased the half-life of haloperidol by 48%.(16) Strong CYP3A4 inducers linked to this monograph are: carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenytoin, rifampin, rifapentine and St. John's Wort.(17,18) |
HALDOL DECANOATE 100, HALOPERIDOL, HALOPERIDOL DECANOATE, HALOPERIDOL DECANOATE 100, HALOPERIDOL LACTATE |
| Citalopram; Escitalopram/Slt Dual CYP2C19 & CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Dual CYP2C19 and CYP3A4 inducers may induce the metabolism of citalopram and escitalopram.(1,2) Citalopram and escitalopram are metabolized by CYP2C19 and CYP3A4.(1,2) CLINICAL EFFECTS: Concurrent use of dual CYP2C19 and CYP3A4 inducers may decrease systemic levels and effectiveness of citalopram and escitalopram.(1,2) PREDISPOSING FACTORS: The degree to which citalopram and escitalopram systemic levels are decreased may be related to higher doses of carbamazepine.(3) Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: When used concomitantly with dual CYP2C19 and CYP3A4 inducers, monitoring of concentrations or dosage adjustment of citalopram and escitalopram may be necessary.(1,2) DISCUSSION: Combined administration of racemic citalopram (40 mg/day for 14 days) and carbamazepine (a dual CYP3A4 and CYP2C19 inducer) titrated to 400 mg/day for 35 days did not affect citalopram plasma trough levels. Given the enzyme-inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of escitalopram should be considered if the two drugs are coadministered.(1,2) In an open pilot study of six patients who were nonresponders to a 4-week pretreatment with 40 to 60 mg/day of citalopram, carbamazepine (200-400 mg/day) augmentation therapy resulted in a decrease of plasma concentrations of S-citalopram and R-citalopram by 27% and 31%, respectively.(3) A case report of a 55-year-old man receiving citalopram 60 mg daily for panic disorder reported decreased therapeutic efficacy when rifampin 600 mg twice daily was started. His condition improved when rifampin was stopped.(4) In two case reports, patients on concomitant citalopram and carbamazepine experienced an increase in citalopram serum concentrations one month after carbamazepine therapy was changed to oxcarbazepine. A 31-year-old man taking citalopram 30 mg daily and carbamazepine 800 mg daily experienced an 8-fold increase in citalopram serum concentration after carbamazepine was discontinued, and a 42-year-old woman taking concomitant citalopram 80 mg daily and carbamazepine 400 mg daily experienced a 3.4-fold increase in citalopram serum concentration after carbamazepine was discontinued.(5) A case report of a 27-year-old female patient treated with citalopram 20 mg daily for two years describes a recurrence of panic attacks 5 days after starting rifampin 600 mg daily.(6) Dual CYP2C19 and CYP3A4 inducers linked to this monograph include: apalutamide, carbamazepine, enzalutamide, fosphenytoin, phenytoin, and rifampin.(7,8) |
CELEXA, CITALOPRAM HBR, ESCITALOPRAM OXALATE, LEXAPRO |
| Belumosudil/Strong CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Belumosudil is primarily metabolized by CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers and belumosudil may result in decreased systemic concentrations of belumosudil, which may decrease the efficacy of belumosudil.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Increase the dosage of belumosudil to 200 mg twice daily when coadministered with strong CYP3A inducers.(1) DISCUSSION: Coadministration of rifampin decreased belumosudil maximum concentration (Cmax) by 59% and area-under-curve (AUC) by 72% in healthy subjects. Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenytoin, primidone, rifampin, rifapentine and St. John's Wort.(2,3) |
REZUROCK |
| Cyclophosphamide/Strong CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of cyclophosphamide, resulting in increased formation of the active and toxic metabolites.(1) CLINICAL EFFECTS: The concurrent administration of cyclophosphamide and strong CYP3A4 inducers may result in increased levels and toxicity of cyclophosphamide metabolites.(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 both of these medications should be alerted to the possibility of increased toxicity from cyclophosphamide.(1) Monitor closely for signs of toxicity during concurrent therapy. The dosage of cyclophosphamide may need to be adjusted. DISCUSSION: A case report of a breast cancer patient who received three cycles of high-dose chemotherapy including cyclophosphamide (1,000 mg/m2) over 4 days with concomitant carbamazepine resulted in increased exposure to cyclophosphamide active metabolite 4-hydroxycyclophosphamide by 58% and decreased exposure to cyclophosphamide by 40%.(2) A case report of a 42-year-old patient with relapsing germ-cell cancer taking high-dose chemotherapy including cyclophosphamide (1,500 mg/m2) with concomitant phenytoin resulted in increased exposure to 4-hydroxycyclophosphamide by 51% and decreased exposure to cyclophosphamide by 67%.(3) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(4,5) |
CYCLOPHOSPHAMIDE, CYCLOPHOSPHAMIDE MONOHYDRATE, FRINDOVYX |
| Sildenafil (PAH)/Strong and Moderate CYP3A4 Inducers 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, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(5,6) |
REVATIO, SILDENAFIL CITRATE |
| Quetiapine (Less Than or Equal To 150 mg)/Strong CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Quetiapine and its active metabolite are metabolized by CYP3A4.(1) In addition, FDA describes quetiapine as a sensitive CYP3A4 substrate: a drug which can have large changes in systemic exposure due to induction (or inhibition) of the CYP3A4 pathway.(2) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers and quetiapine will result in decreased systemic concentrations of quetiapine and may lead to therapeutic failure.(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 on quetiapine receiving chronic treatment (i.e., greater than 7-14 days) of inducers of CYP3A4, titrate the dose of quetiapine based on the patient's clinical response and tolerance, up to 5-fold of the original dose. The onset of induction is gradual but may begin within one week for potent agents (e.g. rifampin). The time to maximal induction may be 2 or more weeks depending upon the half-life and dose of the inducer. If the CYP3A4 inducer is discontinued, the dose of quetiapine should be reduced to the original level within 7-14 days.(1) DISCUSSION: In an interaction study, 18 stable patients with schizophrenia, schizoaffective or bipolar disorder started treatment with quetiapine, achieving the target dose of 300 mg twice daily on day five. On day 9 carbamazepine was started, gradually increasing to the target dose of 200 mg three times a day on day 13. Patients continued on the combination through day 33 to assure maximal enzyme induction was achieved. Carbamazepine decreased quetiapine AUC 87%, decreased steady-state maximum concentration (Cmax) by 80%, and increased clearance approximately 7-fold.(3) In a review of 2111 quetiapine levels from 1179 patients, quetiapine levels were 86% lower in patients receiving concurrent carbamazepine.(4) In a review of 62 psychiatric patients, patients receiving carbamazepine had significantly lower quetiapine concentration-to-dose ratios.(5) A case report described a newly hospitalized patient admitted on carbamazepine 600 mg daily and risperidone 8 mg daily for schizoaffective disorder. She was then converted from risperidone to quetiapine. After 7 days of treatment at the target quetiapine dose of 700 mg daily, serum quetiapine concentrations were undetectable. A repeat level 7 days later was also undetectable. The decision was then made to discontinue carbamazepine and continue quetiapine without dose adjustment. Quetiapine concentrations increased over the following days to weeks and were accompanied by clinical improvement sufficient for discharge. The authors also briefly described 2 additional patients, each receiving carbamazepine for a seizure disorder who were subsequently treated with quetiapine 600 mg or 700 mg daily for more than two weeks. As with the first case, quetiapine serum concentrations with concurrent carbamazepine therapy were below the limit of detection for each patient (lower limit of detection was 25 mcg/mL).(6) Concurrent use of phenytoin (100 mg three times daily), a strong CYP3A4 inducer, and quetiapine increased oral clearance of quetiapine by 5-fold.(7) FDA defines strong CYP inducers as agents which cause at least an 80% decrease in systemic exposure (area-under-curve or AUC) of a drug metabolized by a specific CYP enzyme.(2) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, natisedine, phenytoin, primidone, rifampin, rifapentine and St. John's Wort.(8) |
QUETIAPINE FUMARATE, QUETIAPINE FUMARATE ER, SEROQUEL, SEROQUEL XR |
| Risperidone Intramuscular Every 2 Weeks (Consta)/Strong CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Strong CYP3A4 inducers may increase the metabolic clearance of risperidone by CYP3A4.(1) Risperidone may inhibit the metabolism of carbamazepine.(2) CLINICAL EFFECTS: Strong CYP3A4 inducers may result in decreased levels and effectiveness of risperidone.(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 extended release risperidone microspheres for injection (Risperdal Consta) recommends that patients maintained on this product be closely monitored during the first 4-8 weeks of concurrent therapy if an inducer of CYP3A4 is initiated. Patients may need a dosage increase of this product or additional oral risperidone. If the CYP3A4 inducer is discontinued, the manufacturer recommends that the dosage of risperidone should be re-evaluated and, if necessary, decreased. Patients may be placed on a lower dose between 2 to 4 weeks before the planned discontinuation of strong CYP3A4 inducers to adjust for the expected increase in risperidone concentrations. For patients treated with the recommended dose of 25 mg who are discontinuing from CYP3A4 inducers, it is recommended to continue treatment with the 25 mg dose unless clinical judgment necessitates lowering the dose to 12.5 mg or necessitates interruption of risperidone treatment. The efficacy of the 12.5 mg dose has not been investigated in clinical trials. Patients receiving carbamazepine should be closely monitored if risperidone is initiated or discontinued from concurrent therapy. The dosage of carbamazepine may need to be adjusted.(2) DISCUSSION: A study in 11 schizophrenic inpatients examined the effects of the addition of carbamazepine (200 mg twice daily) for one week to risperidone (3 mg twice daily). Concurrent carbamazepine decreased plasma concentrations of risperidone, 9-hydroxyrisperidone, and active moiety by 50%, 44%, and 45%, respectively.(3) A study compared 23 patients receiving risperidone alone to 11 patients receiving concurrent risperidone and carbamazepine. The groups were matched for sex, age, body weight, and risperidone dosage. Plasma concentrations of 9-hydroxyrisperidone and the sum of risperidone and 9-hydroxyrisperidone were significantly lower in patients receiving concurrent carbamazepine. Five subjects received risperidone with and without carbamazepine. In these patients, dose-normalized plasma risperidone and 9-hydroxyrisperidone concentrations were lower during concurrent carbamazepine.(4) A study in eight patients examined the effects of the addition of risperidone (1 mg daily) to carbamazepine (400 mg to 1200 mg daily). After two weeks of risperidone, carbamazepine levels increased 19%.(1) In a case report, a patient developed an exacerbation of psychotic symptoms four weeks after the addition of carbamazepine (800 mg daily) to his regimen. Plasma levels of risperidone and 9-hydroxyrisperidone had decreased by 77% and 63%, respectively.(5) In an open, randomized cross-over study in 10 healthy males, pretreatment with rifampin (600 mg daily for 5 days) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single oral dose of risperidone (4 mg) by 72% and 50%, respectively.(6) In a study in 10 healthy males, pretreatment with rifampin (600 mg daily for 7 days) decreased the AUC and Cmax of a single oral dose of risperidone (1 mg) by 51% and 38%, respectively. The AUC of 9-hydroxyrisperidone and the active moieties (risperidone + 9-hydroxyrisperidone) decreased by 43% and 45%, respectively. The Cmax of 9-hydroxyrisperidone and the active moieties decreased by 46% and 41%, respectively.(7) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, natisedine, phenytoin, primidone, rifampin, rifapentine and St. John's Wort.(8,9) |
RISPERDAL CONSTA, RISPERIDONE ER, RYKINDO |
| Risperidone Subcutaneous Every 1-2 Months (Uzedy)/Strong CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Strong CYP3A4 inducers may increase the metabolic clearance of risperidone by CYP3A4.(1) Risperidone may inhibit the metabolism of carbamazepine.(2) CLINICAL EFFECTS: Strong CYP3A4 inducers may result in decreased levels and effectiveness of risperidone.(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 extended release risperidone injectable suspension (Uzedy) recommends that patients maintained on this product be closely monitored during the first 4-8 weeks of concurrent therapy if an inducer of CYP3A4 is initiated. In patients receiving Uzedy at a specific dose, consider increasing the dose to the next highest dose. In patients receiving the 125 mg dose monthly or 250 mg once every 2 months, additional oral risperidone therapy may need to be considered. If the CYP3A4 inducer is discontinued, the dose of Uzedy or any additional risperidone therapy should be re-evaluated and, if necessary, decreased to adjust for the expected increase in plasma concentration of risperidone. For patients treated with Uzedy 50 mg once monthly or Uzedy 100 mg once every 2 months and discontinuing a strong CYP3A4 inducer, it is recommended to continue treatment with the same dose unless clinical judgment necessitates interruption of risperidone treatment.(1) Patients receiving carbamazepine should be closely monitored if risperidone is initiated or discontinued from concurrent therapy. The dosage of carbamazepine may need to be adjusted.(2) DISCUSSION: A study in 11 schizophrenic inpatients examined the effects of the addition of carbamazepine (200 mg twice daily) for one week to risperidone (3 mg twice daily). Concurrent carbamazepine decreased plasma concentrations of risperidone, 9-hydroxyrisperidone, and active moiety by 50%, 44%, and 45%, respectively.(3) A study compared 23 patients receiving risperidone alone to 11 patients receiving concurrent risperidone and carbamazepine. The groups were matched for sex, age, body weight, and risperidone dosage. Plasma concentrations of 9-hydroxyrisperidone and the sum of risperidone and 9-hydroxyrisperidone were significantly lower in patients receiving concurrent carbamazepine. Five subjects received risperidone with and without carbamazepine. In these patients, dose-normalized plasma risperidone and 9-hydroxyrisperidone concentrations were lower during concurrent carbamazepine.(4) A study in eight patients examined the effects of the addition of risperidone (1 mg daily) to carbamazepine (400 mg to 1200 mg daily). After two weeks of risperidone, carbamazepine levels increased 19%.(1) In a case report, a patient developed an exacerbation of psychotic symptoms four weeks after the addition of carbamazepine (800 mg daily) to his regimen. Plasma levels of risperidone and 9-hydroxyrisperidone had decreased by 77% and 63%, respectively.(5) In an open, randomized cross-over study in 10 healthy males, pretreatment with rifampin (600 mg daily for 5 days) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single oral dose of risperidone (4 mg) by 72% and 50%, respectively.(6) In a study in 10 healthy males, pretreatment with rifampin (600 mg daily for 7 days) decreased the AUC and Cmax of a single oral dose of risperidone (1 mg) by 51% and 38%, respectively. The AUC of 9-hydroxyrisperidone and the active moieties (risperidone + 9-hydroxyrisperidone) decreased by 43% and 45%, respectively. The Cmax of 9-hydroxyrisperidone and the active moieties decreased by 46% and 41%, respectively.(7) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, natisedine, phenytoin, primidone, rifampin, rifapentine and St. John's Wort.(8,9) |
UZEDY |
| Risperidone Subcutaneous Monthly (Perseris)/Strong CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Strong CYP3A4 inducers may increase the metabolic clearance of risperidone by CYP3A4.(1) Risperidone may inhibit the metabolism of carbamazepine.(2) CLINICAL EFFECTS: Strong CYP3A4 inducers may result in decreased levels and effectiveness of risperidone.(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 extended release risperidone injectable suspension (Perseris) recommends that patients maintained on this product be closely monitored during the first 4-8 weeks of concurrent therapy if an inducer of CYP3A4 is initiated. In patients receiving Perseris 90 mg, consider increasing the dose to 120 mg. In patients receiving the 120 mg dose, additional oral risperidone therapy may need to be considered. If the CYP3A4 inducer is discontinued, the dose of Perseris or any additional risperidone therapy should be re-evaluated and, if necessary, decreased to adjust for the expected increase in plasma concentration of risperidone. For patients treated with Perseris 90 mg and discontinuing a strong CYP3A4 inducer, it is recommended to continue treatment with the 90 mg dose unless clinical judgment necessitates interruption of risperidone treatment. Patients receiving carbamazepine should be closely monitored if risperidone is initiated or discontinued from concurrent therapy. The dosage of carbamazepine may need to be adjusted.(2) DISCUSSION: A study in 11 schizophrenic inpatients examined the effects of the addition of carbamazepine (200 mg twice daily) for one week to risperidone (3 mg twice daily). Concurrent carbamazepine decreased plasma concentrations of risperidone, 9-hydroxyrisperidone, and active moiety by 50%, 44%, and 45%, respectively.(3) A study compared 23 patients receiving risperidone alone to 11 patients receiving concurrent risperidone and carbamazepine. The groups were matched for sex, age, body weight, and risperidone dosage. Plasma concentrations of 9-hydroxyrisperidone and the sum of risperidone and 9-hydroxyrisperidone were significantly lower in patients receiving concurrent carbamazepine. Five subjects received risperidone with and without carbamazepine. In these patients, dose-normalized plasma risperidone and 9-hydroxyrisperidone concentrations were lower during concurrent carbamazepine.(4) A study in eight patients examined the effects of the addition of risperidone (1 mg daily) to carbamazepine (400 mg to 1200 mg daily). After two weeks of risperidone, carbamazepine levels increased 19%.(2) In a case report, a patient developed an exacerbation of psychotic symptoms four weeks after the addition of carbamazepine (800 mg daily) to his regimen. Plasma levels of risperidone and 9-hydroxyrisperidone had decreased by 77% and 63%, respectively.(5) In an open, randomized cross-over study in 10 healthy males, pretreatment with rifampin (600 mg daily for 5 days) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single oral dose of risperidone (4 mg) by 72% and 50%, respectively.(6) In a study in 10 healthy males, pretreatment with rifampin (600 mg daily for 7 days) decreased the AUC and Cmax of a single oral dose of risperidone (1 mg) by 51% and 38%, respectively. The AUC of 9-hydroxyrisperidone and the active moieties (risperidone + 9-hydroxyrisperidone) decreased by 43% and 45%, respectively. The Cmax of 9-hydroxyrisperidone and the active moieties decreased by 46% and 41%, respectively.(7) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, natisedine, phenytoin, primidone, rifampin, rifapentine and St. John's Wort.(8,9) |
PERSERIS |
| Aripiprazole Lauroxil (Aristada)/Strong 3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Strong CYP3A4 inducers may increase the metabolic clearance of aripiprazole.(1,2) CLINICAL EFFECTS: Strong CYP3A4 inducers may result in decreased levels and effectiveness of aripiprazole.(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 receiving the 441 mg dose of aripiprazole lauroxil extended-release injection and concomitant treatment with a CYP3A4 inducer for greater than 14 days, increase the aripiprazole lauroxil to 662 mg. No dose adjustment is needed for patients receiving the 662 mg, 882 mg, or 1,064 mg doses.(2) DISCUSSION: The concurrent administration of carbamazepine (200 mg twice daily) with aripiprazole (30 mg daily) resulted in 70% decreases in the area-under-curve (AUC) and maximum concentration (Cmax) of both aripiprazole and dehydro-aripiprazole, its active metabolite.(1) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, natisedine, phenytoin, primidone, rifampin, rifapentine and St. John's Wort.(3,4) |
ARISTADA |
| Crinecerfont/Strong CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of crinecerfont.(1) CLINICAL EFFECTS: Concurrent or recent use of strong 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 strong CYP3A4 inducers requires a dose adjustment of crinecerfont. Increase the morning and evening doses of crinecerfont by 2-fold. In adults, increase the dosage of crinecerfont to 200 mg twice daily. In pediatric patients 4 years and older weighing: - 10 kg to <20 kg: increase the crinecerfont dosage to 50 mg twice daily, - 20 kg to <55 kg: increase the crinecerfont dosage to 100 mg twice daily, - >=55 kg: increase the crinecerfont dosage to 200 mg twice daily.(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) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's Wort.(2,3) |
CRENESSITY |
| Clindamycin/Strong CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of clindamycin. CLINICAL EFFECTS: Concurrent or recent use of a strong CYP3A4 inducer may result in decreased antimicrobial activity of clindamycin. PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Monitor the response to clindamycin. Adjust the dose of clindamycin or consider administration of a non-interacting antimicrobial if necessary. DISCUSSION: The effects of the interaction develop over approximately one to two weeks after starting the inducer and reverse over a period of several weeks after stopping the inducer. Serum clindamycin concentrations may increase when the inducer is stopped. In an observational study, 6 patients treated concomitantly with clindamycin and rifampin showed significantly lower clindamycin trough concentrations. None of the patients reached the target clindamycin minimum concentration (Cmin) (1.7 mg/L).(2) A retrospective review of patients on concomitant clindamycin and rifampin showed a 82-93% decrease in the clindamycin median peak and trough concentrations.(3) Several other studies showed significant decreases in median peak and trough concentrations of clindamycin with concomitant rifampin.(4,6,7) In a study in patients on oral or intravenous clindamycin (600 mg three times daily), patients on concomitant rifampin showed a 43% increase in clindamycin clearance.(5) In another study, concomitant rifampin with intravenous or oral clindamycin led to a 2.7-fold and 7-fold increase in clindamycin clearance, respectively.(7) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, and St. John's Wort.(9) |
CLEOCIN HCL, CLEOCIN PEDIATRIC, CLEOCIN PHOSPHATE, CLINDAMYCIN (PEDIATRIC), CLINDAMYCIN HCL, CLINDAMYCIN PHOSPHATE, CLINDAMYCIN PHOSPHATE-D5W, CLINDAMYCIN-0.9% NACL |
The following contraindication information is available for XTANDI (enzalutamide):
Drug contraindication overview.
*None.
*None.
There are 2 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Lactation |
| Pregnancy |
There are 5 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Cerebral trauma |
| History of cerebrovascular accident |
| Lower seizure threshold |
| Seizure disorder |
| Transient cerebral ischemia |
There are 2 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Hypertension |
| Myocardial ischemia |
The following adverse reaction information is available for XTANDI (enzalutamide):
Adverse reaction overview.
Adverse effects reported in 10% or more of patients receiving enzalutamide for the treatment of prostate cancer and at an incidence that is at least 2% higher than that reported with placebo include musculoskeletal pain, fatigue, hot flush, constipation, decreased appetite, diarrhea, hypertension, hemorrhage, fall, fracture, and headache.
Adverse effects reported in 10% or more of patients receiving enzalutamide for the treatment of prostate cancer and at an incidence that is at least 2% higher than that reported with placebo include musculoskeletal pain, fatigue, hot flush, constipation, decreased appetite, diarrhea, hypertension, hemorrhage, fall, fracture, and headache.
There are 25 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Hypermagnesemia Hypertension Hyponatremia Lower respiratory infection |
Accidental fall Cauda equina syndrome Fracture Myocardial ischemia Spinal cord compression |
| Rare/Very Rare |
|---|
|
Acute generalized exanthematous pustulosis DRESS syndrome Erythema multiforme Facial edema Gastrointestinal hemorrhage Hypersensitivity drug reaction Infection Lip swelling Malignancy Neutropenic disorder Pharyngeal edema Posterior reversible encephalopathy syndrome Seizure disorder Stevens-johnson syndrome Tongue swelling Toxic epidermal necrolysis |
There are 44 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Anorexia Arthralgia Back pain Constipation Diarrhea Dizziness Drug-induced hot flash Dyspnea Fatigue General weakness Headache disorder Hematuria Hyperglycemia Insomnia Muscle weakness Myalgia Nausea Paresthesia Peripheral edema Symptoms of anxiety Upper respiratory infection Weight loss |
Acute cognitive impairment Anemia Disturbance of attention Dry skin Dysgeusia Epistaxis Gynecomastia Hypercalcemia Hypoesthesia Hypophosphatemia Increased urinary frequency Memory impairment Muscle rigidity Musculoskeletal pain Osteoarthritis Pruritus of skin Restless leg syndrome Syncope |
| Rare/Very Rare |
|---|
|
Dysphagia Hallucinations Skin rash Vomiting |
The following precautions are available for XTANDI (enzalutamide):
Safety and efficacy of enzalutamide have not been established in pediatric patients.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
Based on its mechanism of action and animal findings, enzalutamide can cause fetal harm and potential loss of pregnancy if administered to pregnant females.
Enzalutamide and/or its metabolites are distributed into milk in rats; peak concentrations in milk (achieved 4 hours following oral administration of the drug) are 4 times higher than plasma concentrations. It is not known whether the drug distributes into human milk or if the drug has any effect on milk production or on the nursing infant.
In clinical trials evaluating enzalutamide in men with prostate cancer, 78% of patients were 65 years of age or older and 33% were 75 years of age or older. No overall differences in safety and efficacy were observed between geriatric patients and younger adults. However, the possibility of increased sensitivity to the drug in some geriatric patients cannot be ruled out.
The following prioritized warning is available for XTANDI (enzalutamide):
No warning message for this drug.
No warning message for this drug.
The following icd codes are available for XTANDI (enzalutamide)'s list of indications:
| Castration-resistant prostate cancer | |
| C61 | Malignant neoplasm of prostate |
| Metastatic castration-sensitive prostate cancer | |
| C61 | Malignant neoplasm of prostate |
| Z19.1 | Hormone sensitive malignancy status |
| NmCSPC with biochem recurrence at high risk for mets | |
| C61 | Malignant neoplasm of prostate |
Formulary Reference Tool