Tegretol Xr (carbamazepine)

Dosage of carbamazepine must be carefully and slowly adjusted according to individual requirements and response. Therapy should be initiated with a low dosage and increased gradually. Once a therapeutic effect has been achieved, efforts should be made to reduce the dosage to the minimum effective dosage.

When transferring patients from conventional, immediate-release formulations to extended-release capsules or tablets, the same total daily dosage should be administered in 2 divided doses. Following the transition, patients should be closely monitored and dosage adjusted as necessary. Because a given dose of carbamazepine administered as the oral suspension will produce higher peak concentrations of the drug than when administered as tablets, therapy with the oral suspension should be initiated with low, frequent doses (e.g., 50 mg 4 times daily for children 6-12 years of age) and increased slowly to reduce the risk of adverse effects (e.g., sedation). When transferring patients from therapy with oral tablets to the oral suspension, the total daily dose administered as tablets should be divided into smaller, more frequent doses of the suspension (e.g., transfer from twice-daily divided dosing of tablets to thrice (3 times)-daily divided dosing of the suspension).

Carbamazepine is usually administered orally; however, an IV preparation is available for temporary (i.e., no longer than 7 days) use in the management of seizure disorders in adults when oral administration is not feasible.

Patients who are currently receiving or beginning therapy with carbamazepine and/or any other anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior. (See Cautions: Nervous System Effects and see Cautions: Precautions and Contraindications.)

There is no enhanced messaging for this drug.

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

Carbamazepine/Antineoplastic Systemic Enzyme Inhibitors

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

MECHANISM OF ACTION: Agents that induce the CYP3A4 isoenzyme, such as carbamazepine, may induce the metabolism of antineoplastic systemic enzyme inhibitors, including bosutinib,(1) cabozantinib,(2,3) dasatinib,(4) erlotinib,(5) gefitinib,(6) ibrutinib,(7) lapatinib,(8) pazopanib,(9) sorafenib,(10) sunitinib,(11) and vandetanib.(12)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may decrease the levels and effectiveness of antineoplastic systemic enzyme inhibitors, including bosutinib,(1) cabozantinib,(2,3) dasatinib,(4) erlotinib,(5) gefitinib,(6) ibrutinib,(7) lapatinib,(8) pazopanib,(9) sorafenib,(10) sunitinib,(11) and vandetanib.(12)

PREDISPOSING FACTORS: None determined.

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.(1-12) Pazopanib should not be administered to patients who cannot avoid chronic use of strong CYP3A4 inducers.(8) If concurrent use of a CYP3A4 inducer cannot be avoided with other antineoplastic enzyme inhibitors: 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.(2) 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.(3) Consider increasing the dose of dasatinib.(4) 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. If the inducer is dexamethasone, monitor the patient for sign of gastrointestinal perforation. Discontinue erlotinib in patients who develop gastrointestinal perforation.(5) 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.(6) 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.(8) 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.(11)

DISCUSSION: In a study in 24 healthy subjects, rifampin (a strong CYP3A4 inducer) decreased bosutinib area-under-curve (AUC) and maximum concentration (Cmax) by 94% and 86%. Bosutinib clearance increased by 13-fold.(1,14) In a study in healthy subjects, rifampin (600 mg daily for 31 days) decreased the AUC of a single dose of cabozantinib by 77%.(2) In a study in healthy subjects, concurrent rifampin (600 mg daily) decreased the Cmax and AUC of a single dose of dasatinib by 81% and 82%, respectively.(4) 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.(5) 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.(5) 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).(14) In a study in healthy male volunteers, rifampicin decreased AUC of gefitinib by 85%.(6) The coadministration of rifampin decreased the Cmax and AUC of ibrutinib by more than 13-fold and 10-fold.(7) In healthy subjects, carbamazepine (100 mg twice daily for 3 days and 200 mg twice daily for 17 days), another CYP3A4 inducer, decreased the AUC of lapatinib by 72%. The dose adjustment recommendations are based on pharmacokinetic studies and are predicted to adjust lapatinib AUC to the range observed without concurrent CYP3A4 inducers; however, there are no clinical data with these doses in patients receiving strong CYP3A4 inducers.(8) Pazopanib is primarily metabolized by CYP3A4.(9) Concurrent rifampin (600 mg daily for 5 days) decreased the AUC of a single dose of sorafenib (400 mg) by 37%.(10) In a study with healthy subjects, concurrent rifampin decreased the combined (sunitinib plus primary active metabolite) Cmax and AUC by 23% and 46%, respectively, of a single dose of sunitinib.(11) Strong CYP3A4 inducers are expected to alter vandetanib concentrations. The patient developed nystagmus, a sign of phenytoin toxicity.(12)

Carbamazepine/Istradefylline

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

MECHANISM OF ACTION: Istradefylline is a substrate of CYP3A4. Strong inducers of CYP3A4 may induce the metabolism of istradefylline.(1) Carbamazepine is a strong CYP3A4 inducer.(2) Inhibitors of CYP3A4 may inhibit the hepatic metabolism of carbamazepine.(2,3) Istradefylline is an inhibitor of CYP3A4.(1)

CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 inducer may result in decreased levels and effectiveness of istradefylline.(1) Increased serum carbamazepine levels with subsequent increases in the pharmacological and toxic effects of carbamazepine, including dizziness, ataxia, blurred vision, or SIADH.(2)

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)

PATIENT MANAGEMENT: The manufacturer of istradefylline states that concurrent use with strong CYP3A4 inducers should be avoided.(1) The manufacturer of carbamazepine states CYP3A4 inhibitors may increase plasma carbamazepine levels. If concurrent use is warranted, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required.(2) In patients receiving concurrent therapy with carbamazepine and a CYP3A4 inhibitor, carbamazepine levels should be monitored closely and the patient observed 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: 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) Carbamazepine is almost completely metabolized to carbamazepine-10,11-epoxide, with only 5% of the drug excreted unchanged. Pharmacokinetics studies have indicated the major pathway for carbamazepine is catalyzed by CYP3A4, with minor contributions from CYP2C8 and CYP3A5.(2,3)

Carbamazepine/Monoamine Oxidase Inhibitors

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

MECHANISM OF ACTION: Carbamazepine is structurally related to the tricyclic antidepressants, which may sensitize adrenergic receptors to amines that can accumulate extra neuronally as a result of MAO inhibition.

CLINICAL EFFECTS: Concurrent use of carbamazepine with a MAOI may result in serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(11) Possible increases in serum carbamazepine levels can be seen predisposing patients to carbamazepine toxicity. This may increase excitation, delirium, tremor, twitching, convulsions, coma, and circulatory collapse. It has also been suggested that the combination of carbamazepine and MAOIs may possibly lead to synergistic hepatotoxicity.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of carbamazepine states that MAOIs should be discontinued at least 14 days prior to initiation of carbamazepine therapy.(2) The US manufacturer of tranylcypromine states that concurrent use of dibenzazepine-related entities (such as carbamazepine) is contraindicated.(3) The US manufacturer of selegiline states that concurrent use of carbamazepine is contraindicated.(4) If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble coordination, or severe diarrhea.

DISCUSSION: Carbamazepine's chemical structure is similar to that of the tricyclic antidepressants (TCAs).(1,2) TCA serum levels have been elevated by coadministration of isoniazid, a monoamine oxidase inhibitor. Because of these similarities, it has been hypothesized that MAOIs could inhibit the metabolism of carbamazepine.(1,4) In a study(4) involving 10 patients, CBZ dosing, and subsequent serum levels, were compared to patients receiving phenelzine verses tranylcypromine. Results showed that the tranylcypromine group required a 2.3 times higher dose than the phenelzine group. In a related study,(1) 10 subjects were given a MAOI, with or without lithium, to examine changes in CBZ pharmacokinetics. Results showed no significant difference in CBZ level or dose when comparing the phenelzine and tranylcypromine group to baseline. There were also no differences in CBZ level or dose when comparing the phenelzine and tranylcypromine group to each other. In one case report,(5) a 52 year old woman on CBZ was started on tranylcypromine. Combination therapy was continued for 2 weeks, at which time the patient's mental state improved and tranylcypromine was discontinued. The patient experienced no adverse events. The same author reports another case(5) involving a 31 year-old woman on CBZ who was started on tranylcypromine. Subsequently, her serum CBZ level decreased 35% over following two weeks. In a related case,(6) a 24 year-old man on CBZ was started on tranylcypromine. CBZ levels were drawn on 15 separate occasions over 52 days, which resulted in no significant change in CBZ serum level from his baseline. This patient also experienced no adverse effects. Because these studies and case reports examined only a small group of patients and their results are conflicting, it is difficult to assess the clinical significance of this interaction. However, the manufacturer of carbamazepine states that MAOIs be discontinued for a minimum of 14 days before beginning carbamazepine therapy.(2) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A. Metaxalone is a weak inhibitor of MAO.

Carbamazepine/Nefazodone

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

MECHANISM OF ACTION: Carbamazepine may induce the metabolism of nefazodone.(1-3) Nefazodone may inhibit the metabolism of carbamazepine.(1,2)

CLINICAL EFFECTS: Concurrent administration of carbamazepine and nefazodone may result in decreased levels of nefazodone(1-3) and elevated levels of carbamazepine.(1,2) Nefazodone may be ineffective when administered to patients receiving carbamazepine.(1,3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of carbamazepine and nefazodone is contraindicated by their manufacturers.(1,2)

DISCUSSION: A study in 12 subjects examined the effects of concurrent administration of nefazodone (200 mg twice daily) and carbamazepine (200 mg twice daily). Concurrent use decreased the steady state nefazodone maximum concentration (Cmax) and area-under-curve (AUC) by 86% and 93%, respectively. The Cmax and AUC of hydroxynefazodone, an active metabolite of nefazodone, decreased 85% and 94%, respectively. The Cmax and AUC of two other nefazodone metabolites, meta-chlorophenylpiperazine and a triazole-dione metabolite, were also decreased, by 13%, 44%, 28%, and 57%, respectively. The Cmax and AUC of carbamazepine were each increased by 23%. The Cmax and AUC of the 10,11 epoxycarbamazepine metabolite decreased by 21% and 20%, respectively.(1) The concurrent administration of carbamazepine and nefazodone is expected to result in insufficient nefazodone levels to produce a clinical effect.(1,3) There are published case reports of carbamazepine toxicity in patient receiving concurrent nefazodone therapy, including somnolence and dizziness.(4,5)

Cyp1a2 Inducers/Florquinitau F-18

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Cyp3a4 Inducers/Lumateperone

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

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

CLINICAL EFFECTS: The concurrent administration of a CYP3A4 inducer may decrease the exposure to lumateperone.(1)

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

PATIENT MANAGEMENT: The manufacturer of lumateperone states that concurrent use with CYP3A4 inducers should be avoided.(1)

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

Cyp3a4 Inducers/Selected Protease Inhibitors; Cobicistat

SEVERITY LEVEL: 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, 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) Strong inducers of CYP3A4 include apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, primidone, rifampin, and St. John's wort.(7,8)

Cyp3a4 Inducers/Zuranolone

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

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

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

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

PATIENT MANAGEMENT: Avoid the concurrent use of zuranolone with CYP3A4 inducers.(1)

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

Moderate Cyp2c8 Inducers/Ozanimod

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

MECHANISM OF ACTION: Ozanimod is a substrate of CYP2C8. Moderate inducers of CYP2C8 may induce the metabolism of ozanimod.(1)

CLINICAL EFFECTS: Concurrent use of a moderate inducer of CYP2C8 may result in decreased levels and effectiveness of ozanimod and the active metabolites CC112273 and CC1084037.(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 ozanimod states to avoid concurrent administration with moderate CYP2C8 inducers.(1)

DISCUSSION: Coadministration of rifampin (a strong CYP3A4 and P-gp inducer, and moderate CYP2C8 inducer - 600 mg once daily) decreased the area-under-curve (AUC) of ozanimod, CC112273, and CC1084037 by 24%, 60%, and 55%, respectively.(1) Moderate CYP2C8 inducers linked to this monograph include: carbamazepine and rifampin.(2-3)

P-Glycoprotein (P-Gp) Inducers/Dabigatran

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

MECHANISM OF ACTION: Dabigatran is a substrate of the intestinal efflux transporter P-glycoprotein (P-gp), and has a low oral bioavailability of 3-7%.

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

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concurrent use of an inducer of P-gp such as apalutamide, carbamazepine, fosphenytoin, lorlatinib, phenytoin, rifampin, rifapentine or St. John's wort in patients maintained on dabigatran.(1) Consider alternatives to these agents in patients maintained on dabigatran. If therapy with an inducer of P-gp is required, alternatives to dabigatran may need to be considered. If a P-gp inducer is discontinued, dabigatran exposure will remain impaired for at least one week after the completion of therapy.(1,2)

DISCUSSION: Pretreatment with rifampin (an inducer of P-gp, 600 mg daily for 7 days) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of dabigatran by 66% and 67%, respectively.(1-3) One week after rifampin discontinuation, exposure to dabigatran was close to normal.(1,2) In a case report, a patient taking concomitant dabigatran (150 mg twice a day) and phenytoin (100 mg three times a day) had no detectable serum concentration of dabigatran 10 hours after the morning dabigatran dose.(6) Other inducers of P-glycoprotein include apalutamide, carbamazepine, fosphenytoin, lorlatinib, phenytoin, rifampin, rifapentine, and St. John's wort.(2-5)

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

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

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

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

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

PATIENT MANAGEMENT: The manufacturer of ravidasvir states concurrent use with P-gp inducers is contraindicated.(1)

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

P-Gp & Strong 3A4 Inducers; Phenobarb/Apixaban;Rivaroxaban

SEVERITY LEVEL: 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, carbamazepine, fosphenytoin, phenytoin, rifampin, rifapentine, and St. John's wort may induce the metabolism of apixaban(1-4) and rivaroxaban(5) by both P-gp and CYP3A4. Phenobarbital and primidone may also induce the metabolism of apixaban and rivaroxaban.(1-5)

CLINICAL EFFECTS: Concurrent or recent use of apalutamide, carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone, rifapentine, rifampin, or St. John's wort may result in decreased levels and effectiveness of apixaban(1-4) or rivaroxaban.(5)

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 apixaban and rivaroxaban states to avoid the concurrent use of agents that are combined P-gp and strong CYP3A4 inducers (such as apalutamide, carbamazepine, fosphenytoin, phenytoin, rifampin, rifapentine, and St. John's wort), phenobarbital, and primidone in patients receiving apixaban or rivaroxaban.

DISCUSSION: Concurrent rifampin decreased the area-under-curve (AUC) and maximum concentration (Cmax) of apixaban by 54% and 42%, respectively.(1-4) In a clinical trial, rifampin (600 mg daily) decreased the AUC and Cmax of a single dose of rivaroxaban (20 mg with food) by 50% and 22%,respectively. Similar decreases in pharmacodynamic effects were seen.(5) A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of rivaroxaban and phenytoin resulted in a ratio of rate ratios (95% CI) of 2.39 (1.33-3.29).(6)

P-Gp And Strong Cyp3a4 Inducers/Darolutamide

SEVERITY LEVEL: 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, 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)

P-Gp And Strong Cyp3a4 Inducers/Gilteritinib

SEVERITY LEVEL: 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 P-gp or CYP3A4 inducers may decrease absorption, increase elimination rate, or increase the metabolism of gilteritinib.(1)

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

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

PATIENT MANAGEMENT: The manufacturer recommends avoiding concomitant use of gilteritinib with agents which are inducers of both P-gp and CYP3A4 as coadministration may decrease gilteritinib exposure.(1)

DISCUSSION: In an interaction study, concurrent rifampin decreased the area-under-curve (AUC) and maximum concentration (Cmax) of gilteritinib by 70% and 30%, respectively.(1) Inducers of both P-gp and CYP3A4 linked to this monograph are apalutamide, carbamazepine, fosphenytoin, phenytoin, rifampin, rifapentine, and St. John's wort.

P-Gp Inducers; Phenobarbital/Selected Hepatitis C Agents

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

MECHANISM OF ACTION: Inducers of P-glycoprotein (P-gp) may decrease the absorption of ledipasvir,(1) sofosbuvir,(1-4) velpatasvir,(3,4) and voxilaprevir.(4)

CLINICAL EFFECTS: Concurrent or recent use of a P-gp inducer may result in decreased levels and effectiveness of ledipasvir,(1) sofosbuvir,(1-4) velpatasvir,(3,4) and voxilaprevir.(4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturers of ledipasvir-sofosbuvir,(1) sofosbuvir,(2) sofosbuvir/velpatasvir,(3) and sofosbuvir-velpatasvir-voxilaprevir,(4) do not recommend coadministration with inducers of P-gp.

DISCUSSION: A study of 24 healthy subjects found that carbamazepine (300 mg twice daily) decreased the maximum concentration (Cmax) and exposure (AUC, area-under-curve) of sofosbuvir both by 48%.(3) In a study in 31 subjects, rifampin (600 mg daily) decreased the Cmax and AUC of ledipasvir by 35% and 59%, respectively.(1) In a study in 17 subjects, rifampin (600 mg daily) decreased the Cmax and AUC of sofosbuvir by 77% and 72%, respectively.(2-4) In a study in 12 subjects, rifampin (600 mg daily) decreased the Cmax and AUC of velpatasvir by 71% and 82%, respectively.(3-4) In a study in 24 subjects, rifampin (600 mg daily) decreased the Cmax and AUC of voxilaprevir by 9% and 73%, respectively.(4) Agents linked to this monograph include apalutamide, carbamazepine, fosphenytoin, lorlatinib, phenobarbital, phenytoin, primidone, rifampin, rifapentine, St. John's wort, and tipranavir.(1-6)

Selected Cyp3a4 Inducers/Cobicistat-Elvitegravir

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

MECHANISM OF ACTION: Barbiturates, carbamazepine, fosphenytoin, phenobarbital, phenytoin and primidone may induce the metabolism of cobicistat and elvitegravir.(1)

CLINICAL EFFECTS: Concurrent use of cobicistat-elvitegravir with barbiturates, carbamazepine, fosphenytoin, phenobarbital, phenytoin or primidone may result in decreased levels of elvitegravir and development of resistance.(1)

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

PATIENT MANAGEMENT: Concurrent use of combination product containing cobicistat-elvitegravir-emtricitabine-tenofovir and barbiturates, carbamazepine, fosphenytoin, phenobarbital, phenytoin or primidone is contraindicated.(1)

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

Selected Cyp3a4 Inducers/Isavuconazonium; Voriconazole

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

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

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

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

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

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

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

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

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

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

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of betrixaban recommends avoiding the concurrent use of betrixaban with P-gp inducers.(1) Consider alternatives to the P-gp inducing agent. If therapy with an inducer of P-gp is required, alternatives to betrixaban may need to be considered. If a P-gp inducer is discontinued, betrixaban exposure will remain impaired for at least one week after the completion of therapy.

DISCUSSION: Pharmacokinetic interaction data on file with the manufacturer. Inducers of P-glycoprotein (P-gp) linked to this monograph include apalutamide, carbamazepine, fosphenytoin, lorlatinib, phenytoin, rifampin, rifapentine, and St. John's wort.(2,3)

Selected P-Gp Inducers/Berotralstat

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Selected Strong Cyp3a4 Inducers/Atazanavir

SEVERITY LEVEL: 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)

Selected Strong Cyp3a4 Inducers/Bortezomib

SEVERITY LEVEL: 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 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)

Selected Strong Cyp3a4 Inducers/Delavirdine; Etravirine

SEVERITY LEVEL: 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)

Selected Strong Cyp3a4 Inducers/Dronedarone

SEVERITY LEVEL: 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 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)

Selected Strong Cyp3a4 Inducers/Ensartinib

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

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

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

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

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

DISCUSSION: Ensartinib is predominately metabolized by CYP3A4.(1) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, encorafenib, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(2,3)

Selected Strong Cyp3a4 Inducers/Praziquantel

SEVERITY LEVEL: 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)

Selected Strong Cyp3a4 Inducers/Rilpivirine

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

MECHANISM OF ACTION: Apalutamide, barbiturates, carbamazepine, dexamethasone, 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.

Selected Ugt1a1 Inducers/Raltegravir

SEVERITY LEVEL: 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 UDP-glucuronosyltransferase 1A1 (UGT1A1) may induce the metabolism of raltegravir.(1)

CLINICAL EFFECTS: Concurrent use of carbamazepine, fosphenytoin, phenobarbital, phenytoin, or primidone may result in decreased levels and effectiveness of raltegravir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of raltegravir(1) and Department of Health and Human Services HIV guidelines(2) state that the concurrent use of carbamazepine, fosphenytoin, phenobarbital, phenytoin, or primidone with raltegravir is not recommended. The European AIDS Clinical Society HIV guidelines state that additional monitoring or dose adjustment is likely to be required if these agents are used concurrently.(3)

DISCUSSION: Concurrent rifampin (600 mg daily) with raltegravir (400 mg single dose) decreased raltegravir maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) by 38%, 40%, and 61%, respectively. When raltegravir was given at a dosage of 800 mg twice daily with rifampin (600 mg daily), the Cmax and AUC of raltegravir were increased 62% and 27%, respectively, and the Cmin was decreased 53% when compared to the administration of raltegravir (400 mg twice daily) alone.(1,4) Strong inducers of UGT1A1, such as carbamazepine, fosphenytoin, phenobarbital, phenytoin, and primidone are expected to produce similar results.(1,2)

Slt Moderate And Strong Cyp3a4 Inducers/Ixazomib

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

MECHANISM OF ACTION: Ixazomib is primarily metabolized by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of strong or selected moderate CYP3A4 inducers will result in decreased systemic concentrations of ixazomib.(1)

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

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

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

Slt Moderate-Strong Cyp3a4 Inducers/Slt Hepatitis C Agents

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

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

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

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

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

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

Slt Strong 3A4 Inducers/Nifedipine; Nimodipine; Nisoldipine

SEVERITY LEVEL: 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 barbiturates, carbamazepine, phenobarbital, phenytoin, or primidone may induce the CYP3A4 mediated metabolism of nifedipine,(1) and nimodipine,(2,3) and nisoldipine.(4) Nisoldipine is particularly susceptible to changes in CYP3A4 activity.(4,5)

CLINICAL EFFECTS: Concurrent use of barbiturates, carbamazepine, phenobarbital, phenytoin, or primidone may result in decreased levels and effectiveness of nifedipine(1), nimodipine or nisoldipine.(6)

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

PATIENT MANAGEMENT: Due to the risk for treatment failure, use an alternative agent if possible. The US manufacturer of nifedipine states that the concurrent use of strong CYP3A4 inducers such as carbamazepine, phenobarbital, phenytoin, or primidone is contraindicated because efficacy could be significantly reduced.(1) The UK manufacturer of nimodipine states that the concurrent use of carbamazepine, phenobarbital, phenytoin, or primidone is contraindicated.(2) The US manufacturer of nimodipine states that the concurrent use of strong CYP3A4 inducers should generally be avoided due to decreased nimodipine plasma concentrations and significantly reduced efficacy.(6) The US manufacturer of nisoldipine states it should generally not be coadministered with CYP3A4 inducers. Concurrent administration of phenytoin with nisoldipine (40 mg) decreased nisoldipine plasma concentrations below detectable levels.(7)

DISCUSSION: Coadministration of phenytoin with nifedipine (10 mg capsule and 60 mg extended-release tablet) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of nifedipine by 70%.(1) 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), and epileptic patients taking valproic acid (n=8). In patients taking enzyme-inducing anticonvulsants, nimodipine AUC, Cmax, and half-life (T1/2) were 86.2%, 89.2%, and 68.1%, respectively, lower than in controls. In patients taking valproic acid, nimodipine AUC was 54.5% higher than in control patients.(3) Concurrent administration of phenytoin with nisoldipine (40 mg) decreased nisoldipine plasma concentrations below detectable levels.(7) In a study comparing patients receiving chronic phenytoin therapy to healthy controls, phenytoin decreased the AUC of a single dose of nisoldipine by 89%.(8)

Str Cyp3a4 & P-Gp Inducer;Phenobarb/Glecaprevir-Pibrentasvir

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

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

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

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

PATIENT MANAGEMENT: Because of the risk of treatment failure, the manufacturer of glecaprevir-pibrentasvir states that concomitant use with rifampin is contraindicated.(1,2) The US manufacturer of glecaprevir-pibrentasvir states that the use of other P-gp inducers is not recommended.(1) The European manufacturer of glecaprevir-pibrentasvir states that strong P-gp and CYP3A4 inducers are contraindicated.(2)

DISCUSSION: In a single dose study in 12 subjects, a single dose of rifampin (600 mg) with glecaprevir/pibrentasvir (300mg/120 mg single dose) increased glecaprevir's maximum concentration (Cmax) and area-under-the-curve (AUC) by 6.52-fold and 8.55-fold, respectively. In another single dose study in 12 subjects, rifampin (600 mg daily) with glecaprevir/pibrentasvir (300 mg/120 mg single dose) decreased glecaprevir's Cmax and AUC by 86% and 88% and pibrentasvir's Cmax and AUC by 83% and 87%, respectively.(1) In a study in 10 subjects, carbamazepine (200 mg twice daily) administered concomitantly with glecaprevir/pibrentasvir (300/120 mg daily) decreased the Cmax and AUC of glecaprevir by 67% and 66%, and the Cmax and AUC of pibrentasvir by 50% and 51%, respectively.(1) Strong CYP3A4 and P-gp inducers linked to this monograph include: apalutamide, carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.

Strong & Moderate Cyp3a4 Inducers/Axitinib

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

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

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

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

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

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

Strong & Moderate Cyp3a4 Inducers/Bedaquiline

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

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

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

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

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

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

Strong & Moderate Cyp3a4 Inducers/Cobimetinib

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

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

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

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

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

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

Strong & Moderate Cyp3a4 Inducers/Quizartinib

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

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

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

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

PATIENT MANAGEMENT: Avoid the concurrent use of strong or moderate CYP3A4 inducers in patients receiving therapy with quizartinib.(1)

DISCUSSION: The area-under-curve (AUC) of quizartinib decreased by 90% and maximum concentration (Cmax) by 45% following concomitant use of a single 53 mg dose of quizartinib with efavirenz (a moderate CYP3A inducer). The AUC of active metabolite AC886 decreased by 96% and the Cmax by 68%. The effect of concomitant use with a strong CYP3A inducer may result in even greater effect on quizartinib pharmacokinetics based on mechanistic understanding of the drugs involved. Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate inducers of CYP3A4 include: bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, and tovorafenib.(2-3)

Strong & Moderate Cyp3a4 Inducers/Sonidegib

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

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

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

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

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

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

Strong And Moderate Cyp2c8 Inducers/Tovorafenib

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

MECHANISM OF ACTION: Tovorafenib is a substrate of CYP2C8. Strong and moderate inducers of CYP2C8 may induce the metabolism of tovorafenib.(1)

CLINICAL EFFECTS: Concurrent use of a strong or moderate inducer of CYP2C8 may result in decreased levels and effectiveness of tovorafenib.(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 tovorafenib states to avoid concurrent administration with strong and moderate CYP2C8 inducers.(1)

DISCUSSION: Strong and moderate CYP2C8 inducers are predicted to decrease tovorafenib exposure.(1) Moderate CYP2C8 inducers linked to this monograph include: carbamazepine, ivosidenib, and rifampin.(2-3)

Strong And Moderate Cyp3a4 Inducers/Capivasertib

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

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

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

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

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

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

Strong And Moderate Cyp3a4 Inducers/Capmatinib

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

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

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

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

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

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

Strong And Moderate Cyp3a4 Inducers/Elacestrant

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

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

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

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

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

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

Strong And Moderate Cyp3a4 Inducers/Fexinidazole

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

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

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

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2) Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Avoid the concurrent use of fexinidazole with medications that induce CYP3A4.(1) Avoid use of fexinidazole in patients who have a baseline QTcF interval greater than 470 msec, a history of torsades de pointes, congenital long QT syndrome, cardiac arrhythmias, uncompensated heart failure, or family history of sudden death, or uncorrected hypokalemia.(1) If patients are, or need to be, treated with drugs known to prolong the QTcF interval or to induce bradycardia, either do not initiate therapy with fexinidazole until such drugs are eliminated from the body (allow a washout period of 5 half-lives for such other drugs). Do not start such drugs until fexinidazole therapy is eliminated (allow a washout period of 7 days).(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Fexinidazole is metabolized to its active metabolites, M1 and M2, by CYP3A4. M2 plasma concentrations have been associated with the increased risk of QT prolongation.(1) In clinical studies, fexinidazole was associated with a concentration-dependent QTcF prolongation. At recommended therapeutic doses, the mean (upper 90% confidence interval) increase in QTcF is predicted to be 19.0 msec (23.3 msec). The observed increase in QTcF appears to be associated with the M2 (sulfone) metabolite of fexinidazole.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(3,4) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, modafinil, nafcillin, pexidartinib, rifabutin, sotorasib, telotristat ethyl, and tovorafenib.(3,4)

Strong And Moderate Cyp3a4 Inducers/Finerenone

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

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

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

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

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

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

Strong And Moderate Cyp3a4 Inducers/Ibrexafungerp

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

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

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

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

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

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

Strong And Moderate Cyp3a4 Inducers/Infigratinib

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

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

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

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

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

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

Strong And Moderate Cyp3a4 Inducers/Lemborexant

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

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

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

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

PATIENT MANAGEMENT: The manufacturer of lemborexant states that concurrent use with strong or moderate CYP3A4 inducers should be avoided.(1)

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

Strong And Moderate Cyp3a4 Inducers/Leniolisib

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

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

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

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

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

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

Strong And Moderate Cyp3a4 Inducers/Lonafarnib

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

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

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

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

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

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

Strong And Moderate Cyp3a4 Inducers/Neratinib

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

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

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

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

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

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

Strong And Moderate Cyp3a4 Inducers/Olutasidenib

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

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

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

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

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

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

Strong And Moderate Cyp3a4 Inducers/Omaveloxolone

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

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

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

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

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

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

Strong And Moderate Cyp3a4 Inducers/Palovarotene

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

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

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

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

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

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

Strong And Moderate Cyp3a4 Inducers/Pemigatinib

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

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

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

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

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

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

Strong And Moderate Cyp3a4 Inducers/Rimegepant

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

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

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

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

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

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

Strong And Moderate Cyp3a4 Inducers/Selpercatinib

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

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

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

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

PATIENT MANAGEMENT: The manufacturer of selpercatinib states that concurrent use with strong and moderate CYP3A4 inducers should be avoided.(1)

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

Strong And Moderate Cyp3a4 Inducers/Selumetinib

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

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

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

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

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

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

Strong And Moderate Cyp3a4 Inducers/Voclosporin

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

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

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

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

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

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

Strong Cyp3a4 & Ugt1a1 Inducers/Cabotegravir-Rilpivirine

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

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

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

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

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

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

Strong Cyp3a4 Inducers/Abemaciclib

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

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)

Strong Cyp3a4 Inducers/Abiraterone

SEVERITY LEVEL: 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 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)

Strong Cyp3a4 Inducers/Acalabrutinib

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

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)

Strong Cyp3a4 Inducers/Adagrasib

SEVERITY LEVEL: 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 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)

Strong Cyp3a4 Inducers/Artemether; Lumefantrine

SEVERITY LEVEL: 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)

Strong Cyp3a4 Inducers/Atrasentan

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

MECHANISM OF ACTION: 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)

Strong Cyp3a4 Inducers/Camizestrant

SEVERITY LEVEL: 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 camizestrant.(1)

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

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

PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP3A4 inducers in patients receiving therapy with camizestrant.(1) Consider the use of alternatives with little to no induction potential.

DISCUSSION: In a clinical study, camizestrant maximum concentration (Cmax) decreased to 41% and area-under-curve (AUC) decreased to 30% following concomitant administration of carbamazepine (strong CYP3A inducer) 100 mg once daily for 3 days, followed by 200 mg once daily for 3 days and then 300 mg once daily for 6 days.(1) Strong inducers of CYP3A4 include: apalutamide, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenytoin, rifampin, rifapentine, and St. John's wort.(2-3)

Strong Cyp3a4 Inducers/Catequentinib

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

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

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

DISCUSSION: Catequentinib is a CYP3A4 substrate.(1) In a PKPB model, rifampin (a strong CYP3A4 inducer) decreased the area-under-curve (AUC) and concentration maximum (Cmax) to 0.44 and 0.79, respectively.(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.(3,4)

Strong Cyp3a4 Inducers/Copanlisib

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

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)

Strong Cyp3a4 Inducers/Culmerciclib

SEVERITY LEVEL: 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 culmerciclib.(1)

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

DISCUSSION: In a drug interaction study, concurrent administration of rifampin 600 mg, a strong CYP3A4 inducer, decreased culmerciclib (180 mg) area-under-the-curve (AUC) and maximum concentration (Cmax) by 74.4% and 42.2%.(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)

Strong Cyp3a4 Inducers/Daclatasvir

SEVERITY LEVEL: 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 daclatasvir.(1)

CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 is expected to reduce levels and effectiveness of daclatasvir.(1)

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

PATIENT MANAGEMENT: The concurrent use of strong CYP3A4 with daclatasvir are contraindicated.(1)

DISCUSSION: Rifampin (600 mg daily) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of daclatasvir (60 mg) by 56% and 79%, 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.(1-3)

Strong Cyp3a4 Inducers/Defactinib

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

MECHANISM OF ACTION: 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)

Strong Cyp3a4 Inducers/Delamanid

SEVERITY LEVEL: 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 delamanid.(1)

CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of delamanid.(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 delamanid and strong CYP3A4 inducers is contraindicated.(1) If concurrent use is warranted, monitor the patient for potential treatment failure and decreased delamanid levels.

DISCUSSION: In a study in healthy subjects, administration of rifampin (300 mg daily) with delamanid (200 mg daily) for 15 days decreased the the exposure to delamanid by 45%. There was no significant effect on rifampin levels.(1) In a study in healthy subjects, there were no clinically significant effects on delamanid levels during concurrent use of efavirenz (600 mg daily), a weak CYP3A4 inducer, with delamanid (100 mg twice daily) for 10 days.(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)

Strong Cyp3a4 Inducers/Deuruxolitinib

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

MECHANISM OF ACTION: Drugs that are strong CYP3A4 inducers may increase the metabolism of deuruxolitinib.(1)

CLINICAL EFFECTS: Concurrent use with a strong CYP3A4 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 inducers.(1)

DISCUSSION: In a study, concomitant use of multiple doses of rifampin 600 mg (a strong CYP3A4 and moderate CYP2C9 inducer) and a single dose of deuruxolitinib 12 mg resulted in decreased deuruxolitinib area-under-curve (AUC) by 78% and maximum concentration (Cmax) by 41%.(1) Drugs that are strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifapentine, and St. John's Wort.(2-3)

Strong Cyp3a4 Inducers/Doravirine

SEVERITY LEVEL: 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)

Strong Cyp3a4 Inducers/Dordaviprone

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

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

CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may decrease the levels and effectiveness of dordaviprone.(1)

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

PATIENT MANAGEMENT: The manufacturer of dordaviprone states that co-administration with strong inducers of CYP3A4 should be avoided. Monitor patients for loss of efficacy or consider the use of alternative medicinal products.(1)

DISCUSSION: Concurrent use of rifampin (a strong CYP3A4 inducer) is predicted to decrease dordaviprone maximum concentration (Cmax) by 68% and area-under-curve (AUC) by 83%.(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.(2,3)

Strong Cyp3a4 Inducers/Doxorubicin

SEVERITY LEVEL: 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 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)

Strong Cyp3a4 Inducers/Elbasvir-Grazoprevir

SEVERITY LEVEL: 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)

Strong Cyp3a4 Inducers/Eliglustat

SEVERITY LEVEL: 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 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)

Strong Cyp3a4 Inducers/Ensitrelvir

SEVERITY LEVEL: 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 ensitrelvir.(1)

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

DISCUSSION: In a study of healthy volunteers, carbamazepine was titrated to 300 mg twice daily over 1 week and then maintained at 300 mg twice daily for 11 days and then coadministered with ensitrelvir. Carbamazepine decreased ensitrelvir area-under-curve (AUC) by 40-45%.(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)

Strong Cyp3a4 Inducers/Entrectinib

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

MECHANISM OF ACTION: Entrectinib is a substrate of CYP3A4. 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)

Strong Cyp3a4 Inducers/Erdafitinib

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

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)

Strong Cyp3a4 Inducers/Firmonertinib

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

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

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

DISCUSSION: Co-administration with rifampicin (strong CYP3A4 inducer) led to 86% and 60% decreases in firmonertinib area-under-curve (AUC) and maximum concentration (Cmax), respectively, as well as 17% decrease in AST5902 (an active metabolite) AUC and 1.09-fold increase in AST5902 Cmax. The total active ingredients (firmonertinib and AST5902) exhibited 62% and 39% decreases in AUC and Cmax, respectively.(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.(3,4)

Strong Cyp3a4 Inducers/Fostemsavir

SEVERITY LEVEL: 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)

Strong Cyp3a4 Inducers/Fruquintinib

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

MECHANISM OF ACTION: 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)

Strong Cyp3a4 Inducers/Futibatinib

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

MECHANISM OF ACTION: Futibatinib is primarily metabolized by CYP3A4. Agents that induce CYP3A4 may reduce the plasma levels of futibatinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers may result in decreased levels and effectiveness of futibatinib.(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 futibatinib states concurrent use with strong CYP3A4 inducers should be avoided.(1)

DISCUSSION: Coadministration with rifampin (strong CYP3A4 inducer) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of futibatinib by 53% and 64%, 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.(2,3)

Strong Cyp3a4 Inducers/Glasdegib

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

MECHANISM OF ACTION: 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)

Strong Cyp3a4 Inducers/Iberdomide

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

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

CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may decrease the levels and effectiveness of iberdomide.(1)

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

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

DISCUSSION: In a clinical study of healthy subjects, iberdomide area-under-curve (AUC) decreased by 10% and maximum concentration (Cmax) decreased by 29% following concomitant use of rifampin (strong CYP3A4 inducer).(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)

Strong Cyp3a4 Inducers/Ivacaftor

SEVERITY LEVEL: 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 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)

Strong Cyp3a4 Inducers/Ivosidenib

SEVERITY LEVEL: 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 ivosidenib. Ivosidenib induces its own metabolism.(1)

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

DISCUSSION: Coadministration of ivosidenib with a strong 3A4 inducer (600 mg rifampin once daily for 15 days) is predicted to decrease ivosidenib steady state area-under-the-curve (AUC) by 33%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2-3)

Strong Cyp3a4 Inducers/Lazertinib

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

MECHANISM OF ACTION: 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)

Strong Cyp3a4 Inducers/Lenacapavir

SEVERITY LEVEL: 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 for HIV treatment 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, and St. John's wort.(4,5)

Strong Cyp3a4 Inducers/Levoketoconazole

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

MECHANISM OF ACTION: 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)

Strong Cyp3a4 Inducers/Lirafugratinib

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

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

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

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

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

DISCUSSION: In a pharmacokinetic model, rifampin (a strong CYP3A4 inducer) 600 mg daily for 19 days is predicted to reduce lirafugratinib area-under-the-curve (AUC) by 75% and maximum concentration (Cmax) by 35%.(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)

Strong Cyp3a4 Inducers/Lorlatinib

SEVERITY LEVEL: 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)

Strong Cyp3a4 Inducers/Lumacaftor-Ivacaftor

SEVERITY LEVEL: 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 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)

Strong Cyp3a4 Inducers/Lurasidone

SEVERITY LEVEL: 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)

Strong Cyp3a4 Inducers/Lurbinectedin

SEVERITY LEVEL: 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 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)

Strong Cyp3a4 Inducers/Macimorelin

SEVERITY LEVEL: 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 macimorelin.(1)

CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 may result in decreased levels of macimorelin and may lead to false positive test results.(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 macimorelin states concurrent use with a strong CYP3A4 inducer may reduce the plasma macimorelin concentrations and may lead to false positive test results. Discontinue strong CYP3A4 inducers prior to macimorelin use. Sufficient washout time of strong CYP3A4 inducers prior to administration of macimorelin is recommended.(1)

DISCUSSION: In vitro data suggests CYP3A4 is the major metabolism pathway for macimorelin.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2-4)

Strong Cyp3a4 Inducers/Macitentan

SEVERITY LEVEL: 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 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)

Strong Cyp3a4 Inducers/Mavacamten

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

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

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

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

PATIENT MANAGEMENT: The US and Canadian manufacturers of mavacamten state concurrent use of mavacamten with strong CYP3A4 inducers is contraindicated.(1,2) The UK manufacturer of mavacamten states concomitant use with strong CYP3A4 inducers is dependent on CYP2C19 phenotype. Labeling recommends: -When initiating or increasing the dose of a strong 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 a strong 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 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 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.(3)

DISCUSSION: Concomitant use of mavacamten (a single 15 mg dose) with a strong CYP2C19 and CYP3A4 inducer (rifampin 600 mg daily dose) is predicted to decrease mavacamten area-under-curve (AUC) and maximum concentration (Cmax) by 87% and 22%, respectively, in CYP2C19 normal metabolizers, and by 69% and 4%, respectively, in CYP2C19 poor metabolizers.(1) Strong CYP3A4 inducers linked to this monograph include: barbiturates, carbamazepine, encorafenib, ivosidenib, lumacaftor, mitotane, phenobarbital, primidone, rifapentine, and St. John's wort.(4,5)

Strong Cyp3a4 Inducers/Mavorixafor

SEVERITY LEVEL: 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 mavorixafor.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may decrease the levels and effectiveness of mavorixafor.(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 mavorixafor should be avoided.(1) Consider the use of alternative agents with less enzyme induction potential.(1)

DISCUSSION: Mavorixafor is a CYP3A4 substrate. Concurrent use with strong CYP3A4 inducers is predicted to decrease the concentration maximum (Cmax) and area-under-curve (AUC) of mavorixafor.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, and rifapentine.(2)

Strong Cyp3a4 Inducers/Midostaurin

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

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)

Strong Cyp3a4 Inducers/Nerandomilast

SEVERITY LEVEL: 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 nerandomilast by CYP3A4.

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

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

PATIENT MANAGEMENT: Concurrent use of nerandomilast and strong CYP3A4 inducers should be avoided.(1)

DISCUSSION: Nerandomilast is primarily metabolized by CYP3A4.(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)

Strong Cyp3a4 Inducers/Nirmatrelvir-Ritonavir

SEVERITY LEVEL: 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)

Strong Cyp3a4 Inducers/Olverembatinib

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

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

CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may decrease the levels and effectiveness of olverembatinib.(1)

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

PATIENT MANAGEMENT: The manufacturer of olverembatinib states that co-administration with strong inducers of CYP3A4 should be avoided.(1)

DISCUSSION: In a clinical study of 15 healthy subjects, rifampin (600 mg daily for 8 days) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose olverembatinib 40 mg by 75.19% and 61.27%, respectively.(2) 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)

Strong Cyp3a4 Inducers/Orforglipron

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

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

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

DISCUSSION: In a clinical study, concurrent use of carbamazepine 300 mg twice daily (strong CYP3A4 inducer) decreased orforglipron area-under-curve (AUC) by 82% and maximum concentration (Cmax) by 55%.(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)

Strong Cyp3a4 Inducers/Oveporexton

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

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

CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may decrease the levels and effectiveness of oveporexton.(1)

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

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

DISCUSSION: In a clinical study, oveporexton area-under-curve (AUC) decreased by 81% and maximum concentration (Cmax) by 56% following concomitant use of phenytoin (strong CYP3A4 inducer).(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)

Strong Cyp3a4 Inducers/Pacritinib

SEVERITY LEVEL: 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)

Strong Cyp3a4 Inducers/Palbociclib

SEVERITY LEVEL: 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 palbociclib.(1)

CLINICAL EFFECTS: Concurrent use of strong 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 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.(2-3)

Strong Cyp3a4 Inducers/Panobinostat

SEVERITY LEVEL: 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 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)

Strong Cyp3a4 Inducers/Plitidepsin

SEVERITY LEVEL: 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 plitidepsin.(1)

CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inducer may result in a loss of plitidepsin 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 plitidepsin 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. Consider substituting with non-enzyme inducing therapies at least 2 weeks prior to initiation and while on treatment with plitidepsin therapy.(1)

DISCUSSION: In vitro studies indicate that CYP3A4 is the main enzyme involved in the metabolism of plitidepsin. The Australian manufacturer states that coadministration with strong CYP3A4 inducers should be avoided.(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)

Strong Cyp3a4 Inducers/Pyrotinib

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

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

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

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

PATIENT MANAGEMENT: The manufacturer of pyrotinib states that coadministration with strong CYP3A4 inducers should be avoided.(1)

DISCUSSION: In a study of healthy subjects, concurrent use of rifampin (a strong CYP3A4 inducer) decreased pyrotinib area-under-curve (AUC) by 96% and maximum concentration (Cmax) by 89%.(1) In a study of healthy subjects, concurrent use of efavirenz (a moderate CYP3A4 inducer) decreased pyrotinib AUC by 80% and Cmax by 66%.(1) Strong CYP3A4 inducers include: apalutamide, barbiturates, encorafenib, carbamazepine, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2-3)

Strong Cyp3a4 Inducers/Ranolazine

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

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

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

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

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

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

Strong Cyp3a4 Inducers/Regorafenib

SEVERITY LEVEL: 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 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)

Strong Cyp3a4 Inducers/Remibrutinib

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

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

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

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

PATIENT MANAGEMENT: Avoid the concurrent use of remibrutinib with strong CYP3A4 inducers.(1) Monitor patients receiving concurrent therapy for reduced efficacy.

DISCUSSION: Remibrutinib is primarily metabolized by CYP3A4.(1) In an interaction study, remibrutinib area-under-curve (AUC) decreased by 77% and concentration maximum (Cmax) decreased by 74% following concomitant use of carbamazepine (300 mg twice daily, strong CYP3A inducer) for 14 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.(2,3)

Strong Cyp3a4 Inducers/Revumenib

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

MECHANISM OF ACTION: 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)

Strong Cyp3a4 Inducers/Rilzabrutinib

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

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

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

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

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

DISCUSSION: Rilzabrutinib is primarily metabolized by CYP3A4.(1) Concomitant administration of rilzabrutinib with rifampin (a strong CYP3A4 inducer) resulted in a decrease in rilzabrutinib area under the curve (AUC) and maximum concentration (Cmax) by 80% and 80%, 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)

Strong Cyp3a4 Inducers/Ripretinib

SEVERITY LEVEL: 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 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. The Australian and UK manufacturers of ripretinib state if co-administration of a strong CYP3A4 inducer cannot be avoided, the dose of ripretinib can be increased from 150 mg once daily to 150 mg twice daily. Co-administration of ripretinib with a strong CYP3A4 inducer must be balanced against a risk of reduced efficacy due to reduced exposure. Monitor for clinical response and tolerability.(2,3) If the strong CYP3A4 inducer is discontinued, reduce the dose of ripretinib back to 150 mg once daily 14 days after discontinuation of the strong CYP3A4 inducer. If a dose of ripretinib is missed (in patients taking twice daily dosing): -If less than 4 hours have passed since missed dose, patient should take the dose as soon as possible and then take the next dose at the regularly scheduled time. -If more than 4 hours have passed since missed dose, patient should skip the missed dose and then take the next dose at the regularly scheduled time.(2,3)

DISCUSSION: The primary metabolism pathway for ripretinib and DP-5439 is via CYP3A4.(1) In an interaction study of rifampin (a strong CYP3A inducer) and ripretinib, concurrent use decreased ripretinib concentration maximum (Cmax) by 18% and area-under-curve (AUC) by 61%, as well as decreased the active metabolite DP-5439 AUC by 57% and increased Cmax by 37%.(1) In 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 the presence of a strong CYP3A inducer, a doubled ripretinib dose (twice daily rather than once daily), is predicted to result in a 40% reduction in combined AUC of ripretinib and active metabolite DP-5439, compared to the usual recommended once daily dose with no inducer present.(2) In an interaction study of itraconazole (a strong CYP3A4 inhibitor) and ripretinib, concurrent use increased ripretinib Cmax by 36% and AUC by 99%. Concurrent use increased the AUC of DP-5439 by 99% with no change in Cmax.(1) 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.(4,5)

Strong Cyp3a4 Inducers/Samidorphan

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

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)

Strong Cyp3a4 Inducers/Sebetralstat

SEVERITY LEVEL: 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 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)

Strong Cyp3a4 Inducers/Sonrotoclax

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

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

CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may decrease the levels and effectiveness of sonrotoclax.(1)

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

PATIENT MANAGEMENT: The manufacturer of sonrotoclax states that co-administration with strong inducers of CYP3A4 should be avoided.(1)

DISCUSSION: In a clinical study, sonrotoclax area-under-curve (AUC) decreased by 65% and maximum concentration (Cmax) by 42% following concomitant use of phenytoin (strong CYP3A4 inducer).(1) 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)

Strong Cyp3a4 Inducers/Sparsentan

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

MECHANISM OF ACTION: Sparsentan is 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)

Strong Cyp3a4 Inducers/Suzetrigine

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

MECHANISM OF ACTION: 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)

Strong Cyp3a4 Inducers/Taletrectinib

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

MECHANISM OF ACTION: 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)

Strong Cyp3a4 Inducers/Tamoxifen

SEVERITY LEVEL: 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)

Strong Cyp3a4 Inducers/Tavapadon

SEVERITY LEVEL: 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 tavapadon.(1)

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

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

PATIENT MANAGEMENT: Avoid concomitant use of strong CYP3A4 inducers during titration and maintenance of tavapadon.(1)

DISCUSSION: In a drug interaction study, concurrent administration of carbamazepine (300 mg twice daily), a strong CYP3A4 inducer, decreased tavapadon area-under-the-curve (AUC) and maximum concentration (Cmax) by 63% and 49%, 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)

Strong Cyp3a4 Inducers/Ticagrelor; Vorapaxar

SEVERITY LEVEL: 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)

Strong Cyp3a4 Inducers/Tolebrutinib

SEVERITY LEVEL: 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 accelerate the metabolism of tolebrutinib.(1-2)

CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers may alter the clinical effectiveness of tolebrutinib.(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 tolebrutinib with strong CYP3A4 inducers.(2) Monitor patients receiving concurrent therapy for reduced efficacy.

DISCUSSION: Tolebrutinib is a substrate of the CYP3A4 isoenzyme.(1) In an interaction study of healthy participants, tolebrutinib exposure decreased 6-fold following concomitant use of rifampicin (strong CYP3A inducer) 600 mg once daily for 8 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.(3,4)

Strong Cyp3a4 Inducers/Tolvaptan

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

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

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

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

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

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

Strong Cyp3a4 Inducers/Toremifene

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

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

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

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

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

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

Strong Cyp3a4 Inducers/Trabectedin

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

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)

Strong Cyp3a4 Inducers/Ubrogepant

SEVERITY LEVEL: 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 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)

Strong Cyp3a4 Inducers/Vincristine

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

MECHANISM OF ACTION: 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)

Strong Cyp3a4 Inducers/Vinflunine

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

MECHANISM OF ACTION: Vinflunine is metabolized primarily by CYP3A4 to inactive metabolites. Strong CYP3A4 inducers may accelerate the metabolism of vinflunine by CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may result in decreased levels and effectiveness of vinflunine and its active metabolite, 4-O-deacetylvinflunine (DVFL), which is formed by multiple esterases.(1)

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

PATIENT MANAGEMENT: The UK manufacturer of vinflunine states that the concurrent administration of strong CYP3A4 inducers should be avoided.(1)

DISCUSSION: In a phase I study, concurrent use of ketoconazole (a potent inhibitor of CYP3A4, 400 mg orally daily for 8 days) increased the exposure to vinflunine by 30%. Exposure to the active metabolite, 4-O-deacetylvinflunine (DVFL), was increased by 50%. Strong inducers of CYP3A4 are expected to substantially decrease levels of vinflunine and DVFL.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib lumacaftor, mitotane, phenobarbital, phenytoin, primidone, and rifapentine.(3,4)

Strong Cyp3a4 Inducers/Zanubrutinib

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

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)

Strong Cyp3a4 Inducers/Zidesamtinib

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

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

CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may decrease the levels and effectiveness of zidesamtinib.(1)

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

PATIENT MANAGEMENT: The manufacturer of zidesamtinib states that concurrent use of strong CYP3A4 inducers should be avoided.(1)

DISCUSSION: Zidesamtinib is a CYP3A4 substrate.(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.(2,3)

Strong Cyp3a4 Inducers/Ziftomenib

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

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

CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may decrease the levels and effectiveness of ziftomenib.(1)

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

PATIENT MANAGEMENT: The manufacturer of ziftomenib states that co-administration with strong inducers of CYP3A4 should be avoided. Monitor patients for loss of efficacy or consider the use of alternative medicinal products.(1)

DISCUSSION: Rifampin (strong CYP3A4 inducer) is estimated to decrease ziftomenib area-under-curve (AUC) by up to 80% and maximum concentration (Cmax) by up to 70%.(1) Efavirenz (moderate CYP3A4 inducer) is estimated to decrease ziftomenib AUC and Cmax by up to 70%. 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.(2,3)

Strong Cyp3a4 Inducers/Zilurgisertib

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

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

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

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

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

DISCUSSION: In a clinical study, rifampin (a strong CYP3A4 inducer) decreased zilurgisertib area-under-the-curve (AUC) by 79% and maximum concentration (Cmax) by 56%.(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)

Strong Cyp3a4 Inducers/Zoliflodacin

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

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

CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may decrease the levels and effectiveness of zoliflodacin.(1)

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

PATIENT MANAGEMENT: The manufacturer of zoliflodacin states that co-administration with strong inducers of CYP3A4 is contraindicated.(1)

DISCUSSION: Rifampin, a strong CYP3A4 inducer, is predicted to decrease the area-under-curve (AUC) of zoliflodacin by approximately 56%.(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)

Strong Cyp3a4 Inducers; Rifabutin/Brigatinib

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

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

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

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

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

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

Strong Cyp3a4 Inducers; Rifabutin/Ponatinib

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

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

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

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

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

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

Strong Cyp3a4 Inducers; Rifabutin/Romidepsin

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

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

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

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

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

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

Strong Or Moderate Cyp3a4 Inducers/Avacopan

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

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

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

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

PATIENT MANAGEMENT: The manufacturer of avacopan states that concurrent use with strong or moderate CYP3A4 inducers should be avoided.(1) The Australian manufacturer of avacopan states that patients anticipated to require long-term administration of a CYP3A4 inducer should not be treated with avacopan. If short term co-administration cannot be avoided in a patient already on avacopan, closely monitor for reoccurrence of disease activity.(4)

DISCUSSION: Co-administration of rifampin 600 mg once daily for 11 days, a strong CYP3A4 inducer, decreased the avacopan concentration maximum (Cmax) by 79% and area-under-curve (AUC) by 93%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate inducers of CYP3A4 include: belzutifan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, lesinurad, lorlatinib, modafinil, nafcillin, rifabutin, sotorasib, telotristat ethyl, thioridazine and tovorafenib.(2-3)

Strong Or Moderate Cyp3a4 Inducers/Avapritinib

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

MECHANISM OF ACTION: Strong or moderate CYP3A4 inducers may induce the metabolism of avapritinib.

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

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

PATIENT MANAGEMENT: The manufacturer of avapritinib states that concurrent use with strong or moderate CYP3A4 inducers should be avoided.(1)

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

Strong Or Moderate Cyp3a4 Inducers/Daridorexant

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

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

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

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

PATIENT MANAGEMENT: The manufacturer of daridorexant states that concurrent use with strong or moderate CYP3A4 inducers should be avoided.(1)

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

Strong Or Moderate Cyp3a4 Inducers/Mobocertinib

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

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

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

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

PATIENT MANAGEMENT: Avoid the concurrent use of mobocertinib with strong or moderate CYP3A4 inducers.(1)

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

Strong Or Moderate Cyp3a4 Inducers/Tazemetostat

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

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

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

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

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

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

Strong Or Moderate Cyp3a4 Inducers/Vonoprazan

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

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

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

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

PATIENT MANAGEMENT: The manufacturer of vonoprazan states that concurrent use with strong or moderate CYP3A4 inducers should be avoided.(1)

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

Ugt1a1 Inducers/Cabotegravir

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

MECHANISM OF ACTION: Carbamazepine, efavirenz, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin, primidone, rifapentine, rifampin, and ritonavir may induce the metabolism of cabotegravir by uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1).(1)

CLINICAL EFFECTS: Concurrent or recent use of carbamazepine, efavirenz, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin, primidone, rifapentine, rifampin, or ritonavir may result in decreased levels and effectiveness of cabotegravir, as well as the development of resistance.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of cabotegravir states that concurrent use of UGT1A1 inducers such as carbamazepine, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin, primidone, rifapentine, rifampin, and ritonavir 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 15 subjects, rifampin (600 mg daily) decreased the concentration maximum (Cmax), area-under-curve (AUC), and concentration minimum (Cmin) of cabotegravir by 6%, 59%, and 50%, respectively.(1) UGT1A1 inducers linked include: carbamazepine, efavirenz, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin, primidone, rifapentine, rifampin, and ritonavir.(1,2)

Ugt1a1 Inducers/Sacituzumab Govitecan

SEVERITY LEVEL: 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 UGT1A1 may increase the metabolism of SN-38, the topoisomerase inhibitor which is the antineoplastic component of sacituzumab govitecan.(1)

CLINICAL EFFECTS: Concurrent use of UGT1A1 inducers may result in decreased exposure to sacituzumab govitecan and therapeutic failure.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of UGT1A1 inducers in patients receiving sacituzumab govitecan.(1)

DISCUSSION: SN-38, the small molecule moiety of sacituzumab govitecan, is metabolized by UGT1A1, and inducers of UGT1A1 are expected to decrease SN-38 levels and effectiveness.(1) In a clinical trial, patients homozygous for decreased function UGT1A1*28 allele had a 26% incidence of Grade 4 neutropenia, compared to 13% of patients heterozygous for the UGT1A1*28 allele and 11% of patients homozygous for the wild type allele.(1) UGT1A1 inducers linked to this monograph include: carbamazepine, efavirenz, fosphenytoin, lorlatinib, phenobarbital, phenytoin, primidone, rifampin, ritonavir.

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

Carbamazepin/Antineoplastic Syst Enzyme Inh That Inhibit 3A4

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

MECHANISM OF ACTION: Ceritinib,(1) crizotinib,(2) duvelisib,(3) fedratinib,(4) idelalisib,(5) imatinib,(6) nilotinib,(7) ribociclib,(8) and tucatinib(9) are substrates and inhibitors of CYP3A4. Carbamazepine, a strong CYP3A4 inducer, may increase the metabolism of these agents, and they may inhibit the hepatic metabolism of carbamazepine.

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may decrease the levels and effectiveness of antineoplastic systemic enzyme inhibitors, including ceritinib,(1) crizotinib,(2) duvelisib,(3) fedratinib,(4) idelalisib,(5) imatinib,(6) nilotinib,(7) ribociclib,(8) sevabertinib,(15) and tucatinib.(9) In addition, serum carbamazepine levels may increase with subsequent increases in the pharmacological and toxic effects of carbamazepine, including dizziness, ataxia, blurred vision, or SIADH.(10)

PREDISPOSING FACTORS: Simultaneous use of other drugs, i.e. other anticonvulsants, or carbamazepine blood levels already near the toxic range before initiation of a CYP3A4 inhibitor may increase the risk of a severe interactions.(10)

PATIENT MANAGEMENT: Avoid the concurrent use of carbamazepine in patients receiving therapy with antineoplastic enzyme inhibitors. Consider the use of alternative agents with less enzyme induction potential.(1-9) Because of the nonlinear pharmacokinetic profile of nilotinib, increasing its dose is unlikely to compensate for enzyme induction.(7) If concurrent use of a CYP3A4 inducer cannot be avoided with imatinib, the dose of imatinib should be increased by at least 50% and clinical response should be carefully monitored. Dosages up to 1,200 mg/day (600 mg twice daily) have been used in patients receiving concurrent therapy with strong CYP3A4 inducers.(6) The manufacturer of carbamazepine states CYP3A4 inhibitors may increase plasma carbamazepine levels. If concurrent use is warranted, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required.(10) In patients receiving concurrent therapy with carbamazepine and a CYP3A4 inhibitor, carbamazepine levels should be monitored closely and the patient observed 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.(10)

DISCUSSION: In a study in 19 healthy subjects, rifampin (600 mg daily for 14 days) decreased the Cmax and AUC of a single dose of ceritinib by 44% and 70%, respectively.(1) In a study in healthy subjects, rifampin (600 mg daily for 8 days) decreased the Cmax and AUC of idelalisib (150 mg single dose) by 58% and 75%, respectively.(5) 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.(6,12) The Cmax of the CGP74588 metabolite increased by 88.6%, but the AUC of CGP74588 decreased by 11%.(12) In a study in healthy subjects, concurrent rifampin (600 mg daily for 12 days) decreased nilotinib AUC by 80%.(7) 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.(10,11) In a study, carbamazepine decreased sevabertinib's AUC 79% and Cmax 57%.(15)

Carbamazepine/Adenosine

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

MECHANISM OF ACTION: Both drugs may slow conduction through the AV node.(1-3)

CLINICAL EFFECTS: When adenosine is used to slow conduction in the AV node or accessory pathways, the presence of carbamazepine may lead to prolonged or higher degrees of heart block.(1) When adenosine is used during diagnostic imaging studies, carbamazepine may increase the risk for symptomatic AV block.(3)

PREDISPOSING FACTORS: History of an underlying cardiac conduction disorder is a risk factor for carbamazepine-induced AV block.(2)

PATIENT MANAGEMENT: When used for supraventricular tachycardias, Advanced Cardiac Life Support (ACLS) Guidelines recommend lowering initial adenosine dose to 3 mg.(4) Unless a functioning pacemaker is in place, when adenosine is used for myocardial imaging studies, the provider should weigh the risks versus benefits of adenosine administration in patients receiving chronic carbamazepine therapy.(3)

DISCUSSION: Carbamazepine has a tricyclic structure which may be partly responsible for its effects on neuronal and cardiac conduction. Numerous case reports have documented the potential AV node blocking capabilities of carbamazepine. In most cases patients had underlying heart disease; however cases without known risk factors have been reported.(5,6) Although this specific interaction has not been documented, the interaction is plausible based upon the pharmacology of both agents.

Carbamazepine/Aprepitant; Netupitant

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. Carbamazepine, a strong inducer of CYP3A4, may increase their metabolism and clearance via CYP3A4.(1,2) Aprepitant and netupitant, inhibitors of CYP3A4, may inhibit the hepatic metabolism of carbamazepine.(3,4)

CLINICAL EFFECTS: Concurrent use with carbamazepine may result in significantly decreased levels and effectiveness of aprepitant and netupitant.(1,2) In addition, serum carbamazepine levels may increase, with subsequent increases in the pharmacological and toxic effects of carbamazepine, including dizziness, ataxia, blurred vision, or SIADH.(3)

PREDISPOSING FACTORS: Simultaneous use of other drugs, i.e. other anticonvulsants, or carbamazepine blood levels already near the toxic range before initiation of a CYP3A4 inhibitor may increase the risk of a severe interaction.

PATIENT MANAGEMENT: The manufacturers of aprepitant and netupitant recommend avoiding strong CYP3A4 inducers.(1,2) Patients treated concurrently with carbamazepine should be monitored for decreased antiemetic efficacy. When possible and clinically appropriate, consider use of an alternative antiemetic or alternatives to carbamazepine. The manufacturer of carbamazepine states CYP3A4 inhibitors may increase plasma carbamazepine levels. If concurrent use is warranted, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required.(3) In patients receiving concurrent therapy with carbamazepine and a CYP3A4 inhibitor, carbamazepine levels should be monitored closely and the patient observed 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.(3)

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) Carbamazepine is almost completely metabolized to carbamazepine-10,11-epoxide, with only 5% of the drug excreted unchanged. Pharmacokinetics studies have indicated the major pathway for carbamazepine metabolism is catalyzed by CYP3A4, with minor contributions from CYP2C8 and CYP3A5.(3,4)

Carbamazepine/Clarithromycin; Telithromycin

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

MECHANISM OF ACTION: Carbamazepine may induce the metabolism of clarithromycin and telithromycin by CYP3A4.(1-4) Clarithromycin and telithromycin may inhibit the hepatic metabolism of carbamazepine by CYP3A4.(1-6)

CLINICAL EFFECTS: Concurrent use of carbamazepine with clarithromycin or telithromycin may result in decreased levels and effectiveness of the macrolide.(1-4) In addition, serum carbamazepine levels may increase, with subsequent increases in the pharmacological and toxic effects of carbamazepine, including dizziness, ataxia, blurred vision, or SIADH.(5-6)

PREDISPOSING FACTORS: Factors that may increase the risk of a severe interaction include simultaneous use of other drugs (i.e., other anticonvulsants) or high carbamazepine blood levels near the toxic range before initiation of a CYP3A4 inhibitor.

PATIENT MANAGEMENT: Concurrent use of carbamazepine with clarithromycin should be approached with caution and may require clarithromycin dose adjustment.(1) Consideration of alternative therapies to carbamazepine may be required.(1-2) Concurrent treatment of carbamazepine with telithromycin should be avoided.(4-5) The UK manufacturer of telithromycin states that treatment with telithromycin should be avoided during and for two weeks after treatment with carbamazepine.(4) The manufacturer of carbamazepine states CYP3A4 inhibitors may increase plasma levels. If concurrent use is warranted, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required.(5) In patients receiving concurrent therapy with carbamazepine and a CYP3A4 inhibitor, carbamazepine levels should be monitored closely and the patient observed 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.(5)

DISCUSSION: Concurrent use of telithromycin with potent CYP3A4 inducers such as carbamazepine could result in major reductions of telithromycin plasma concentrations and decreased telithromycin clinical effectiveness. The induction effect decreases during the two weeks following the discontinuation of the inducer.(3) 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)

Carbamazepine/Clozapine

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

MECHANISM OF ACTION: While clozapine is primarily metabolized by CYP1A2, CYP3A4 also plays a role. Carbamazepine induces both of these metabolic pathways. In addition, due to its anticholinergic activity, carbamazepine may compound the anticholinergic and anti-serotonergic effects of clozapine to inhibit gastrointestinal (GI) smooth muscle contraction, resulting in decreased peristalsis.(1-6)

CLINICAL EFFECTS: Concomitant administration may result in decreased concentration and effectiveness of clozapine. Additionally, concomitant administration of carbamazepine and clozapine may increase the risk for neutropenia or agranulocytosis,(7) as well as the risk of constipation (common) and serious bowel complications (uncommon), including complete bowel obstruction, fecal impaction, paralytic ileus and intestinal ischemia or infarction.(1-6)

PREDISPOSING FACTORS: Low white blood counts prior to initiation of the myelosuppressive agents may increase risk for clinically significant neutropenia. The risk for serious bowel complications is higher with increasing age and in patients on multiple anticholinergic agents.(5)

PATIENT MANAGEMENT: The manufacturer of clozapine states that clozapine should not be used concurrently with agents known to cause agranulocytosis because of the possibility of synergistic effects on the risk and/or severity of bone marrow suppression.(1) If concurrent therapy of clozapine with carbamazepine is required, close monitoring for increased clozapine toxicity and decreased clozapine efficacy is needed. Hematological effects: More frequent absolute neutrophil count (ANC) monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. The U.S. Food and Drug Administration (FDA) recommends that prescribers monitor patients' ANC according to the monitoring frequencies described in the prescribing information. Severe neutropenia remains a serious, potentially fatal risk that is greatest in the first several months of clozapine treatment. ANC monitoring can help identify neutropenia early to allow for timely intervention.(1,8) Australia, Canada and U.K.: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing. For most clozapine patients, clozapine treatment must be interrupted for a suspected clozapine-induced ANC < 1,000 cells/microliter. For patients with benign ethnic neutropenia (BEN), treatment must be interrupted for suspected clozapine-induced neutropenia < 500 cells/microliter.(1) Gastrointestinal effects: Evaluate the patient's bowel function regularly. Monitor for symptoms of constipation and GI hypomotility, including having bowel movements less than three times weekly or less than usual, difficulty having a bowel movement or passing gas, nausea, vomiting, and abdominal pain or distention.(2) Consider a prophylactic laxative in those with a history of constipation or bowel obstruction.(2) Review patient medication list for other anticholinergic agents. When possible, decrease the dosage or number of prescribed anticholinergic agents, particularly in the elderly. Counsel the patient about the importance of maintaining adequate hydration. Encourage regular exercise and eating a high-fiber diet.(2) Pharmacokinetic effects: The onset of induction is gradual. It may take as little as one week to more than 4 weeks to see maximal induction effects. In stable clozapine patients beginning treatment with carbamazepine, consider measurement of clozapine levels prior to start of concomitant therapy. The magnitude of this interaction can be large; combined CYP1A2 and CYP3A4 enzyme inducers may decrease clozapine levels = or > 50%. Adjust clozapine dose accordingly. After stabilization on concomitant therapy, if carbamazepine is subsequently discontinued, then the clozapine dosage will need to be gradually decreased to the original dose as the effects of enzyme induction wane over approximately 2-3 weeks.

DISCUSSION: Hematological effects: There is one published case report of fatal agranulocytosis during concurrent administration of carbamazepine and clozapine. The patient died ten weeks after the addition of clozapine to therapy with carbamazepine, lithium, benztropine, and clonazepam. Lithium was withdrawn from therapy one week prior to the patient's death.(7) There is one case report of neuroleptic malignant syndrome which developed three days after the addition of clozapine to therapy with carbamazepine. Symptoms resolved following the discontinuation of clozapine.(9) Gastrointestinal effects: In a prospective cohort study of 26,720 schizophrenic patients in the Danish Central Psychiatric Research Registry, the odds ratio (OR) for ileus was 1.99 with clozapine and 1.48 with anticholinergics. The OR for fatal ileus was 6.73 with clozapine and 5.88 with anticholinergics. Use of anticholinergics with 1st generation antipsychotics (FGA) increased the risk of ileus compare to FGA alone, but this analysis was not done with clozapine.(5) A retrospective cohort study of 24,970 schizophrenic patients from the Taiwanese National Health Insurance Research Database found that the hazard ratio (HR) for clozapine-induced constipation increased from 1.64 when clozapine is used alone, to 2.15 when used concomitantly with anticholinergics. However, there was no significant difference in the HR for ileus when clozapine is used with and without anticholinergics (1.95 and 2.02, respectively).(6) In the French Pharmacovigilance Database, 7 of 38 cases of antipsychotic-associated ischemic colitis or intestinal necrosis involved clozapine, and 5 of these cases involved use of concomitant anticholinergic agents. Three patients died, one of whom was on concomitant anticholinergics.(3) In a case series, 4 of 9 cases of fatal clozapine-associated GI dysfunction involved concurrent anticholinergic agents.(4) Pharmacokinetic effects: In two case reports, the discontinuation of carbamazepine from concurrent therapy with clozapine resulted in increased clozapine levels within two weeks of carbamazepine withdrawal. Clozapine levels increased from 1.4 to 2.4 mcg-mol/L and from 1.5 to 3.0 mcg-mol/L.(10) In three case reports, clozapine levels increased following the switch of carbamazepine to oxcarbazepine.(11) A retrospective chart review of eight patients found a decrease of 50% in the clozapine level-to-dose ratio during concurrent therapy with carbamazepine when compared to levels before concurrent therapy with carbamazepine.(12)

Carbamazepine/Efavirenz

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

MECHANISM OF ACTION: Efavirenz may induce the metabolism of carbamazepine via CYP3A4. Carbamazepine may induce the metabolism of efavirenz by CYP3A4 and CYP2B6.(1)

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

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of efavirenz states that alternative agents to carbamazepine should be used in patients receiving efavirenz.(1) If concurrent use is warranted, monitor levels of both efavirenz and carbamazepine.

DISCUSSION: In a study in 12 healthy subjects, administration of efavirenz (600 mg daily for 14 days) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of carbamazepine (200 mg daily for 3 days, 200 mg twice daily for 3 days, then 400 mg daily for 29 days) by 20%, 27%, and 35%, respectively. The Cmin of the epoxide metabolite of carbamazepine decreased by 13%. The Cmax, AUC, and Cmin of efavirenz decreased by 21%, 36%, and 47%, respectively.(1,2)

Carbamazepine/Enzalutamide

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

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

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

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

PATIENT MANAGEMENT: Avoid concurrent use of carbamazepine with enzalutamide. Consider the use of agents with no or minimal induction potential if possible.(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) Several studies have shown decreased carbamazepine serum concentrations when phenytoin (strong CYP3A4 inducer) was administered concurrently. In one study involving 22 patients, the carbamazepine serum concentration was shown to increase by 28% when the phenytoin dosage was reduced, indicating that phenytoin initially reduced carbamazepine levels.(3)

Carbamazepine/Gepotidacin

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

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

CLINICAL EFFECTS: Concurrent use of gepotidacin and carbamazepine may result in decreased levels and effectiveness of gepotidacin and increased levels and toxicities of carbamazepine, including dizziness, ataxia, blurred vision, and SIADH.(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 gepotidacin and carbamazepine.(1)

DISCUSSION: Gepotidacin is primarily metabolized by CYP3A4.(1) Concomitant administration of gepotidacin (single 1500 mg dose) with a strong inducer (rifampin; 600 mg once daily for 7 days) resulted in a decrease of 52% in gepotidacin area under the curve (AUC).(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)

Carbamazepine/Isoniazid

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

MECHANISM OF ACTION: Isoniazid may inhibit carbamazepine metabolism by CYP3A4.

CLINICAL EFFECTS: Concurrent use of isoniazid may result in elevated levels of and toxicity from carbamazepine and possibly isoniazid-induced hepatotoxicity.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If both drugs are administered, monitor plasma carbamazepine levels and observe the patient for signs and symptoms of carbamazepine and isoniazid toxicity. Adjust the doses of the drugs accordingly.

DISCUSSION: Several case reports have documented carbamazepine toxicity as shown by ataxia, nystagmus, lethargy, and somnolence during concurrent isoniazid.(1-10) Reports have also found isoniazid-induced hepatotoxicity during concurrent therapy.(1-5)

Carbamazepine/Lefamulin

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

MECHANISM OF ACTION: Lefamulin is a substrate of CYP3A4 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) Carbamazepine is a strong CYP3A4 inducer and a P-gp inducer.(2) Inhibitors of CYP3A4 may inhibit the hepatic metabolism of carbamazepine.(2,3) Lefamulin is an inhibitor of CYP3A4.(1)

CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 or P-gp inducer may result in decreased levels and effectiveness of lefamulin.(1) Increased serum carbamazepine levels with subsequent increases in the pharmacological and toxic effects of carbamazepine, including dizziness, ataxia, blurred vision, or SIADH.(2)

PREDISPOSING FACTORS: Simultaneous use of other drugs, i.e. other anticonvulsants, or carbamazepine blood levels already near the toxic range before initiation of a CYP3A4 inhibitor may increase the risk of a severe interaction.

PATIENT MANAGEMENT: The manufacturer of lefamulin states that concurrent use with strong CYP3A4 or P-gp inducers should be avoided. (1) The manufacturer of carbamazepine state CYP3A4 inhibitors may increase plasma carbamazepine levels. If concurrent use is warranted, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required.(2) In patients receiving concurrent therapy with carbamazepine and a CYP3A4 inhibitor, carbamazepine levels should be monitored closely and the patient observed 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: 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) 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)

Carbamazepine/Letermovir

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

MECHANISM OF ACTION: Letermovir is a substrate of the efflux transporter P-glycoprotein (P-gp) and of UDP-glucuronosyltransferase (UGT) 1A1/3 enzymes. P-gp induction may decrease systemic absorption of letermovir, while UGT1A1/3 induction may increase the metabolism of letermovir.(1) Inhibitors of CYP3A4 may inhibit the hepatic metabolism of carbamazepine.(2,3) Letermovir is a CYP3A4 inhibitor.(4)

CLINICAL EFFECTS: Concurrent or recent use of P-glycoprotein or UGT1A1/3 inducers may result in decreased levels and loss of effectiveness of letermovir.(1) Increased serum carbamazepine levels with subsequent increases in the pharmacological and toxic effects of carbamazepine, including dizziness, ataxia, blurred vision, or SIADH.

PREDISPOSING FACTORS: Simultaneous use of other drugs, i.e. other anticonvulsants, or carbamazepine blood levels already near the toxic range before initiation of a CYP3A4 inhibitor may increase the risk of a severe interaction.

PATIENT MANAGEMENT: The manufacturer of letermovir states that coadministration of P-gp inducers or UGT1A1/3 inducers is not recommended.(1) The manufacturer of carbamazepine states CYP3A4 inhibitors may increase plasma carbamazepine levels. If concurrent use is warranted, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required.(2) In patients receiving concurrent therapy with carbamazepine and a CYP3A4 inhibitor, carbamazepine levels should be monitored closely and the patient observed 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: In a study, at 24 hours after the last dose of rifampin (600 mg daily), a P-gp and UGT inducer, the AUC of letermovir was decreased by 85 %, compared to letermovir when taken alone.(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)

Carbamazepine/Macrolide Antibiotics

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

MECHANISM OF ACTION: Troleandomycin inhibits the hepatic metabolism of carbamazepine by CYP3A4. Erythromycin has a similar but lesser effect (1,2).

CLINICAL EFFECTS: Increased serum carbamazepine levels with subsequent increases in the pharmacological and toxic effects of carbamazepine.

PREDISPOSING FACTORS: Simultaneous use of other drugs, i.e. other anticonvulsants, or carbamazepine blood levels already near the toxic range before macrolide administration probably increase the risk of a severe interaction.

PATIENT MANAGEMENT: Avoid coadministration of these drugs. If given together, monitor carbamazepine serum concentration and observe patient for signs of toxicity (dizziness, ataxia, blurred vision, SIADH). Consider discontinuing either drug or decreasing the dose of carbamazepine.

DISCUSSION: There are numerous reports of elevated carbamazepine serum levels in patients receiving erythromycin concurrently. Frequently, symptoms of carbamazepine toxicity have accompanied these increased levels. The effects of this interaction may occur rapidly (i.e., in less than 24 hours).

Carbamazepine/Mifepristone

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

MECHANISM OF ACTION: Carbamazepine may induce the metabolism of mifepristone.(1,2) Mifepristone may inhibit the metabolism of carbamazepine.(3)

CLINICAL EFFECTS: Concurrent administration may result in decreased levels and effectiveness of mifepristone(1,2) and elevated levels of carbamazepine.(3)

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 mifepristone with carbamazepine should be avoided.(1,2) 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.(1,2) The manufacturer of carbamazepine states that CYP3A4 inhibitors may increase plasma carbamazepine levels. If concurrent use is warranted, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required.(3) In patients receiving concurrent therapy with carbamazepine and a CYP3A4 inhibitor, carbamazepine levels should be monitored closely and the patient should be observed 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.(3)

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) 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.(1,5) In a randomized, cross-over study of ten seizure patients, the effects of grapefruit juice on the pharmacokinetics of carbamazepine were determined. Results indicate a statistically significant increase in serum concentrations and area under the concentration-time curve (AUC) in the grapefruit juice arm.(6)

Carbamazepine/Mitapivat

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

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

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

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

PATIENT MANAGEMENT: Avoid the concurrent use of mitapivat with carbamazepine.(1)

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) Several studies have shown decreased carbamazepine serum concentrations when phenytoin (strong CYP3A4 inducer) was administered concurrently. In one study involving 22 patients, the carbamazepine serum concentration was shown to increase by 28% when the phenytoin dosage was reduced, indicating that phenytoin initially reduced carbamazepine levels.(3)

Carbamazepine/Nirogacestat

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

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

CLINICAL EFFECTS: Concurrent use of nirogacestat and carbamazepine may result in decreased levels and effectiveness of nirogacestat and increased levels and toxicities of carbamazepine, including dizziness, ataxia, blurred vision, and SIADH.(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 nirogacestat and carbamazepine.(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) 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)

Carbamazepine/Pexidartinib

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

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

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

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

PATIENT MANAGEMENT: Avoid concurrent use of carbamazepine with pexidartinib.(1)

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

Carbamazepine/Propoxyphene

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

MECHANISM OF ACTION: Propoxyphene may inhibit carbamazepine metabolism.

CLINICAL EFFECTS: Concurrent use of propoxyphene may result in elevated levels of and toxicity from carbamazepine.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If both drugs are administered, monitor plasma carbamazepine levels and observe the patient for signs and symptoms of carbamazepine toxicity. Adjust the dose of the drug accordingly.

DISCUSSION: In a study, carbamazepine levels increased 66% after 6 days of dextropropoxyphene. Additional increases were seen in 3 subjects after an additional 7 days of dextropropoxyphene.(1) In a study in 7 patients maintained on carbamazepine, the addition of propoxyphene increased carbamazepine levels by 45%-77%. Two patients discontinued propoxyphene after 2 days because of side effects. Three other patients had drug intoxication symptoms.(2) In a retrospective review, carbamazepine doses were lower but carbamazepine levels were higher in patients receiving concurrent propoxyphene.(3) There are several case reports of carbamazepine toxicity during concurrent propoxyphene.(4-8)

Carbamazepine/Protease Inhibitors

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

MECHANISM OF ACTION: Carbamazepine may induce the metabolism of the protease inhibitors at CYP3A4.(1-7) Ritonavir may inhibit the metabolism of carbamazepine by CYP3A4.(8,9)

CLINICAL EFFECTS: The concurrent use of indinavir and carbamazepine may result in higher than anticipated carbamazepine levels, decreased indinavir plasma levels, and antiretroviral therapy failure.(1,2) The concurrent use of amprenavir, fosamprenavir, lopinavir, nelfinavir, and saquinavir may result in decreased levels of these agents and antiretroviral therapy failure.(3-7) The concurrent use of darunavir/ritonavir(11) or ritonavir(7,9,11) and carbamazepine may result in elevated levels of carbamazepine and signs of carbamazepine toxicity.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Consider avoiding the concurrent use of carbamazepine and amprenavir, fosamprenavir, indinavir, lopinavir, nelfinavir, or saquinavir. If concurrent therapy is warranted, carbamazepine and protease inhibitor levels, as well as antiretroviral response, should be closely monitored. In patients receiving concurrent therapy with carbamazepine and darunavir/ritonavir(10) or ritonavir(8), carbamazepine levels should be closely monitored and the patient should be observed for signs of carbamazepine toxicity. The dosage of carbamazepine may need to be adjusted or carbamazepine may need to be discontinued. The manufacturer of lopinavir states that lopinavir/ritonavir should not be administered once daily to patients receiving carbamazepine.(5)

DISCUSSION: In a study in 16 subjects, concurrent carbamazepine (200 mg twice daily) with darunavir/ritonavir (600/100 mg twice daily) had no significant effects on darunavir pharmacokinetics. The maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of carbamazepine increased by 43%, 45%, and 54%, respectively. The Cmax, AUC, and Cmin of carbamazepine epoxide decreased by 54%, 54%, and 52%, respectively.(10) In a case report, an HIV-positive male restarted antiretroviral therapy with indinavir (800 mg every 8 hours), lamivudine (150 mg twice daily), and zidovudine (200 mg three times daily) in November of 1997. In January of 1998, carbamazepine (200 mg daily) was started for post-herpetic neuralgia. Despite the low dose of carbamazepine, carbamazepine levels were 6.7 mg/L and 8.9 mg/L in February, 1998 and March, 1998, respectively. At the end of March, 1998, carbamazepine was discontinued. In January and February of 1998, the patient's viral load was undetectable and his CD4+ count was 340x106/L and 400x106/L, respectively. By April of 1998, his HIV-RNA level had risen to 6x103 copies/ml and his CD4+ count decreased to 200x106/L. His HIV-RNA level increased to 300x103 copies/ml three months later. Prior to carbamazepine therapy, the patient's indinavir levels had been 61% of the reference population. During carbamazepine therapy, his indinavir levels decreased to a value of 4% of the reference population. Two weeks after carbamazepine was discontinued, his indinavir levels increased to a value of 173% of the reference population.(2) In a case report, a 36 year-old male HIV-positive patient was treated with phenytoin (400 mg/day) and carbamazepine (600 mg/day) in addition to his antiretroviral regimen that included zidovudine and zalcitabine. His HIV regimen was changed to stavudine, lamivudine, and indinavir, which resulted in a partial viral-load response. This regimen was then replaced with lamivudine, didanosine, ritonavir, and saquinavir, which resulted in the patient's viral load becoming undetectable. Levels of carbamazepine at this time were normal (6.5 mcg/ml). Over the next two months, the patient developed a progressive gait disorder and dizziness. His carbamazepine level increased to 18 mcg/ml. Carbamazepine was replaced with primidone.(9) In a case report, a 20 year-old male had been HIV-positive since age 8 and been maintained on carbamazepine (350 mg twice daily) since age 12. The patient was admitted for changes to his antiretroviral regimen. On day 2, his carbamazepine level was 9.5 mcg/ml and his aminotransferase (ALT) value was normal. On day 8, a single dose of ritonavir (200 mg) was administered. Within 12 hours, his carbamazepine level increased to 17.8 mcg/ml. On day 9, ritonavir (200 mg three times daily), but ritonavir was discontinued on day 10 because of intractable nausea and vertigo. On day 12, the patient's ALT level was 141 International Units/L. On day 13, ritonavir (200 mg every 24 hours) was restarted. The patient's carbamazepine level increased to 16.3 mcg/ml and ritonavir was discontinued.(10) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Carbamazepine/Repotrectinib

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

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

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

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

PATIENT MANAGEMENT: Avoid the concurrent use of repotrectinib and carbamazepine.(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) Several studies have shown decreased carbamazepine serum concentrations when phenytoin (strong CYP3A4 inducer) was administered concurrently. In one study involving 22 patients, the carbamazepine serum concentration was shown to increase by 28% when the phenytoin dosage was reduced, indicating that phenytoin initially reduced carbamazepine levels.(3)

Carbamazepine/Selected Barbiturates

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

MECHANISM OF ACTION: Phenobarbital and perhaps other barbiturates induce CYP3A4, which metabolizes carbamazepine.

CLINICAL EFFECTS: Concurrent use of barbiturates may result in decreased carbamazepine levels.

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

PATIENT MANAGEMENT: If a barbiturate is added to a regimen including carbamazepine, monitor carbamazepine levels and adjust dosages accordingly. Monitor patients for decreased carbamazepine efficacy (e.g. seizures). If the barbiturate is discontinued, monitor patients for carbamazepine toxicity and adjust carbamazepine dosages accordingly.

DISCUSSION: Phenobarbital has been shown to decrease serum carbamazepine half-life and plasma concentration levels when given in combination. Significant changes in carbamazepine serum concentrations were seen within five days after the addition of phenobarbital to the therapeutic regimen. Conversely, carbamazepine appears to have no effect on serum phenobarbital levels. Another study involving children with seizure disorders evaluated the effect of phenobarbital co-medication on carbamazepine serum levels. Patients had been maintained on either carbamazepine alone or concurrent carbamazepine and phenobarbital for at least one month. There were no significant differences in carbamazepine levels between patients receiving carbamazepine alone or with concurrent phenobarbital. However, the ratio of carbamazepine level to dose was significantly decreased in patients receiving concurrent phenobarbital (0.570?0.470 versus 0.627?0.353). The carbamazepine concentration ratios of two carbamazepine metabolites (the 10,11-epoxide metabolite and the 10,11-dihydroxy metabolite) were increased in patients receiving concurrent carbamazepine and phenobarbital compared to those receiving carbamazepine alone.

Carbamazepine/Selected Calcium Channel Blockers

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

MECHANISM OF ACTION: Diltiazem and verapamil may inhibit the metabolism of carbamazepine. Carbamazepine may induce the metabolism of calcium channel blockers.

CLINICAL EFFECTS: Concurrent diltiazem or verapamil may result in elevated levels of and toxicity from carbamazepine. Concurrent carbamazepine may reduce the levels and effectiveness of calcium channel blockers.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor serum carbamazepine levels when starting, stopping, or altering the dose of diltiazem or verapamil. Adjust the dose of carbamazepine accordingly. Monitor the effectiveness of calcium channel blockers in patients maintained on carbamazepine. An alternative antihypertensive agent may be needed. The manufacturer of diltiazem states that coadministration with CYP3A4 inducers should be avoided when possible.

DISCUSSION: Neurotoxicity has been reported during concurrent use of carbamazepine and diltiazem or verapamil. Diltiazem has been shown to increase carbamazepine levels by 40% to 72%. Verapamil has been shown to increase carbamazepine levels by 46%. Diltiazem levels have been shown to become undetectable when coadministered with rifampin, a strong CYP3A4 inducer.

Carbamazepine/Selected Cyp3a4 Inhibitors

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

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the hepatic metabolism of carbamazepine.(1,2)

CLINICAL EFFECTS: Increased serum carbamazepine levels with subsequent increases in the pharmacological and toxic effects of carbamazepine.

PREDISPOSING FACTORS: Simultaneous use of other drugs (i.e., other anticonvulsants) or carbamazepine blood levels already near the toxic range before initiation of a CYP3A4 inhibitor may increase the risk of a severe interaction.

PATIENT MANAGEMENT: The manufacturer of carbamazepine states that CYP3A4 inhibitors may increase plasma carbamazepine levels. If concurrent use is warranted, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required.(1) In patients receiving concurrent therapy with carbamazepine and a CYP3A4 inhibitor, carbamazepine levels should be monitored closely and the patient should be observed 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.(1)

DISCUSSION: 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.(1,2) In a randomized, cross-over study of ten seizure patients, the effects of grapefruit juice on the pharmacokinetics of carbamazepine were determined. Results indicate a statistically significant increase in serum concentrations and area under the concentration-time curve (AUC) in the grapefruit juice arm.(3) Selected CYP3A4 inhibitors linked to this monograph include: conivaptan, grapefruit, mibefradil, relacorilant, schisandra, and tofisopam.(4)

Carbamazepine/Sotorasib

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

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

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

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

PATIENT MANAGEMENT: Avoid the concurrent use of sotorasib and carbamazepine.(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) Several studies have shown decreased carbamazepine serum concentrations when phenytoin (strong CYP3A4 inducer) was administered concurrently. In one study involving 22 patients, the carbamazepine serum concentration was shown to increase by 28% when the phenytoin dosage was reduced, indicating that phenytoin initially reduced carbamazepine levels.(3)

Carbamazepine/Stiripentol

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

MECHANISM OF ACTION: Stiripentol is a substrate of CYP3A4 and CYP2C19. Strong inducers of CYP3A4 or CYP2C19 may increase the metabolism of stiripentol.(1) Carbamazepine is a strong CYP3A4 and CYP2C19 inducer.(2) Carbamazepine is a substrate of CYP3A4. Inhibitors of CYP3A4 may inhibit the hepatic metabolism of carbamazepine.(2,3) Stiripentol is a moderate inhibitor of CYP3A4.(4)

CLINICAL EFFECTS: The concurrent administration of strong CYP3A4 or CYP2C19 inducers may result in decreased levels and effectiveness of stiripentol.(1) Increased serum carbamazepine levels with subsequent increases in the pharmacological and toxic effects of carbamazepine, including dizziness, ataxia, blurred vision, or SIADH.(2)

PREDISPOSING FACTORS: Simultaneous use of other drugs, i.e. other anticonvulsants, or carbamazepine blood levels already near the toxic range before initiation of a CYP3A4 inhibitor may increase the risk of a severe interaction.

PATIENT MANAGEMENT: The manufacturer of stiripentol states avoid the concurrent use of stiripentol with strong CYP3A4 or strong CYP2C19 inducers.(1) If concurrent therapy cannot be avoided, consider a dose adjustment of stiripentol based on clinical monitoring and plasma levels.(1) The manufacturer of carbamazepine states CYP3A4 inhibitors may increase plasma carbamazepine levels. If concurrent use is warranted, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required.(2) In patients receiving concurrent therapy with carbamazepine and a CYP3A4 inhibitor, carbamazepine levels should be monitored closely and the patient observed 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: Stiripentol is a substrate of CYP3A4 and CYP2C19.(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)

Carbamazepine/Theophyllines

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

MECHANISM OF ACTION: Theophylline may induce the metabolism of carbamazepine. Carbamazepine may induce the metabolism of theophylline.

CLINICAL EFFECTS: Decreased levels of carbamazepine and theophylline may result in decreased clinical effectiveness of these agents.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: During concurrent therapy, theophylline and carbamazepine serum concentrations should be monitored. The dosage of one or both agents may need to be adjusted.

DISCUSSION: In one case report, concurrent administration of carbamazepine and theophylline resulted in sub-therapeutic levels of theophylline, a decrease in theophylline half-life, and a worsening of the patient's clinical condition. In another report, a patient maintained on carbamazepine for eight months experienced a convulsion eight days after beginning theophylline therapy. The patient had previously received theophylline three times without adverse effect. In a follow-up study in this patient, concurrent administration of theophylline and carbamazepine resulted in decreases in carbamazepine levels by 29.6-36.7%, a decrease in carbamazepine half-life by 11.8%, and another grand mal seizure. Theophylline levels in this patient were high; however, not enough information is given in the report to determine if carbamazepine inhibited the metabolism of theophylline.

Carbamazepine/Voxelotor

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

MECHANISM OF ACTION: Voxelotor is a substrate of CYP3A4. Strong or moderate inducers of CYP3A4 may induce the metabolism of voxelotor.(1) Carbamazepine is a strong CYP3A4 inducer.(2) Inhibitors of CYP3A4 may inhibit the hepatic metabolism of carbamazepine.(2,3) Voxelotor is an inhibitor of CYP3A4.(4)

CLINICAL EFFECTS: The concurrent administration of strong or moderate CYP3A4 inducers may result in decreased levels and effectiveness of voxelotor.(1) Increased serum carbamazepine levels with subsequent increases in the pharmacological and toxic effects of carbamazepine, including dizziness, ataxia, blurred vision, or SIADH.(2)

PREDISPOSING FACTORS: Simultaneous use of other drugs, i.e. other anticonvulsants, or carbamazepine blood levels already near the toxic range before initiation of a CYP3A4 inhibitor may increase the risk of a severe interaction.

PATIENT MANAGEMENT: The manufacturer of voxelotor states that concurrent use with strong or moderate CYP3A4 inducers should be avoided. If concomitant use is unavoidable in patients 12 years and older, increase the dose of voxelotor to 2,500 mg daily. For patients 4 years to less than 12 years who require concurrent carbamazepine, refer to voxelotor prescribing information for recommended weight-based voxelotor dose adjustments.(1) The manufacturer of carbamazepine states CYP3A4 inhibitors may increase plasma carbamazepine levels. If concurrent use is warranted, close monitoring of carbamazepine levels is indicated and dosage adjustment may be required.(2) In patients receiving concurrent therapy with carbamazepine and a CYP3A4 inhibitor, carbamazepine levels should be monitored closely and the patient observed 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: A pharmacokinetic model predicted that co-administration of rifampin, a strong CYP3A4 inducer, would decrease the area-under-curve (AUC) of voxelotor by 40%. Co-administration of efavirenz, a moderate CYP3A4 inducer, is predicted to decrease the AUC of voxelotor by 24%.(1) 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)

Combined Cyp2c8; Cyp2c9; Cyp3a4 Inducers/Etrasimod

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

MECHANISM OF ACTION: Inducers of CYP2C8, CYP2C9, and CYP3A4 may increase the metabolism of etrasimod.(1) Etrasimod is metabolized by CYP2C8, CYP2C9, and CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of a combined inducer of CYP2C8, CYP2C9, and CYP3A4 may result in decreased levels and effectiveness of etrasimod.(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 etrasimod with combined inducers of CYP2C8, CYP2C9, and CYP3A4 is not recommended.(1)

DISCUSSION: Concomitant use of etrasimod with rifampin (strong CYP3A4, moderate CYP2C8, and CYP2C9 inducer) decreased etrasimod area-under-curve (AUC) by 49%.(1) Combined inducers of CYP2C8, CYP2C9, and CYP3A4 include: carbamazepine and rifampin.(2,3)

Dual Inducers Of Cyp2c9 And Cyp3a4/Avatrombopag

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 persistent or chronic immune thrombocytopenia (ITP). When starting avatrombopag in a patient 6 years and older with persistent or chronic ITP already taking a dual CYP2C9 and CYP3A4 inducer, increase the dose of avatrombopag to 40 mg once daily. In pediatric patients 1 year to less than 6 years old who are on a dual CYP2C9 and CYP3A4 inducer, increase the starting dose of avatrombopag to 20 mg 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)

Dual Inducers Of Cyp2c9 And Cyp3a4/Siponimod

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)

Dual P-Gp & Strong 3A4 Induc/Relugolix-Hormonal Combinations

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

MECHANISM OF ACTION: Relugolix, estradiol, and norethindrone are substrates of the intestinal P-glycoprotein (P-gp) efflux transporter and are primarily metabolized by CYP3A4. Agents that induce both P-gp and CYP3A4 may reduce the plasma levels of relugolix, estradiol, and norethindrone.(1)

CLINICAL EFFECTS: Concurrent or recent use of P-gp and strong CYP3A4 inducers may result in decreased levels and effectiveness of relugolix, estradiol, and norethindrone.(1)

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

PATIENT MANAGEMENT: Avoid use of relugolix-estradiol-norethindrone with combined P-gp and strong CYP3A4 inducers.(1)

DISCUSSION: Coadministration with rifampin (P-gp and strong CYP3A4 inducer) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of relugolix by 55% and 23%, respectively.(1) Dual P-gp and CYP3A4 inducers linked to this monograph include: apalutamide, carbamazepine, fosphenytoin, phenytoin, rifampin, rifapentine, and St. John's wort.(2,3)

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

P-Glycoprotein (P-Gp) Inducers/Etoposide

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

P-Gp And Strong Cyp3a4 Inducers/Nintedanib

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 decrease absorption, increase elimination rate, or increase the metabolism of nintedanib.(1)

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

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

PATIENT MANAGEMENT: The manufacturer recommends avoiding concomitant use of nintedanib with agents which are inducers of both P-gp and CYP3A4 as coadministration may decrease nintedanib exposure by 50%.(1)

DISCUSSION: In an interaction study, concurrent rifampin decreased the area-under-curve (AUC) and maximum concentration (Cmax) of nintedanib by 50.3% and 60.3%, respectively.(1) Inducers of both P-gp and CYP3A4 linked to this monograph are apalutamide, carbamazepine, fosphenytoin, phenytoin, rifampin, rifapentine, and St. John's wort.

P-Gp And Strong Cyp3a4 Inducers/Relugolix

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

MECHANISM OF ACTION: Relugolix is a substrate of the intestinal P-glycoprotein (P-gp) efflux transporter and is primarily metabolized by CYP3A4. Agents that induce both P-gp and CYP3A4 may reduce the plasma levels of relugolix.(1)

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

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

PATIENT MANAGEMENT: If possible, avoid the concurrent use of agents that are combined P-gp and strong CYP3A4 inducers in patients receiving relugolix.(1) If coadministration is necessary, increase the dose of relugolix to 240 mg daily. If the P-gp/CYP3A4 inducer is discontinued, resume the recommended dose of 120 mg once daily.(1)

DISCUSSION: Concurrent rifampin (combined P-gp and strong CYP3A4 inducer) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of relugolix by 55% and 23%, respectively.(1) Dual P-gp and CYP3A4 inducers linked to this monograph include: apalutamide, carbamazepine, fosphenytoin, phenytoin, rifampin, rifapentine, and St. John's wort.(2,3)

Selected Anticonvulsants/Hormonal Contraceptives

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

MECHANISM OF ACTION: Carbamazepine is a strong inducer of CYP3A4; oxcarbazepine and rufinamide are weak inducers of CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use with carbamazepine, oxcarbazepine or rufinamide may result in decreased contraceptive levels, which may result in menstrual abnormalities or unintended pregnancy.

PREDISPOSING FACTORS: Intermittent compliance with oral contraceptives.

PATIENT MANAGEMENT: To avoid pregnancy, additional or alternative means of non-hormonal contraception should be utilized. If larger doses of hormonal contraceptives are utilized, titrating the dose against a response such as lack of spotting or breakthrough bleeding may not guarantee contraceptive efficacy. In women who wish to continue oral contraceptives with the addition of a second form of contraception, emphasize the importance of not missing doses of the oral contraceptive. For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.

DISCUSSION: In a study of four epileptic patients receiving an oral contraceptive containing ethinyl estradiol 50 mcg plus levonorgestrel 250 mcg carbamazepine reduced the area-under-curve (AUC) for ethinyl estradiol by 42% and for levonorgestrel by 40%. Pregnancy has been reported. Pregnancy has been reported in a woman receiving low-dose oral contraceptives six weeks after initiation of treatment with carbamazepine. In a randomized, open label study, concurrent administration of carbamazepine (600 mg daily) and Ortho Novum 1/35 (ethinyl estradiol, norethindrone) decreased the AUC of ethinyl estradiol and norethindrone by 42% and 58%, respectively. The apparent oral clearance of ethinyl estradiol and norethindrone increased by 127% and 69%, respectively. Concurrent use of rufinamide (800 mg twice daily) and ethinyl estradiol / norethindrone (35 mcg/1 mg) for 14 days decreased the AUC of ethinyl estradiol and norethindrone by 22% and 14%, respectively. The maximum concentration (Cmax) of ethinyl estradiol and norethindrone decreased by 31% and 18%, respectively. Double-blind, randomized, crossover study with 24 women (only 20 analyzed) given 20 micrograms ethinyl estradiol and 100 micrograms levonorgestrel and either carbamazepine 600 mg or a matched placebo for 4 months. Ethinyl estradiol and levonorgestrel levels were measured and mean AUC was significantly lower in those taking carbamazepine. Cmax of ethinyl estradiol was also significantly decreased. Additionally more cases of breakthrough bleeding and ovulation occurred with concurrent use of the carbamazepine. In a case report, a patient with an etonogestrel implant became pregnant while taking carbamazepine for epilepsy. Coadministration of immediate-release oxcarbazepine decreased mean ethinyl estradiol AUC levels in two different studies by 48% and 52%, respectively. Additionally, mean AUC of levonorgestrel was decreased in two different studies by 32% and 52%, respectively.

Selected Anticonvulsants/Maribavir

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

MECHANISM OF ACTION: Selected anticonvulsants that are strong inducers of CYP3A4 may accelerate the metabolism of maribavir.(1)

CLINICAL EFFECTS: The concurrent administration of selected anticonvulsants may result in decreased levels and effectiveness of maribavir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of maribavir states that concurrent use with selected anticonvulsants requires a dose adjustment of maribavir. If maribavir is coadministered with carbamazepine, increase the maribavir dose to 800 mg twice daily. If maribavir is coadministered with fosphenytoin, phenobarbital, phenytoin, or primidone, increase the maribavir dose to 1200 mg twice daily.(1) 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 200 subjects with concurrent maribavir 800 mg twice daily or 400 mg twice daily and carbamazepine 600 mg daily resulted in an increase in maribavir area-under-curve (AUC) and maximum concentration (Cmax) by 40% and 53%, respectively.(1) A study in 200 subjects with concurrent maribavir 1200 mg twice daily or 400 mg twice daily and phenobarbital 100 mg daily resulted in an increase in maribavir AUC and Cmax by 80% and 117%, respectively.(1) A study in 200 subjects with concurrent maribavir 1200 mg twice daily or 400 mg twice daily and phenytoin 300 mg daily resulted in an increase in maribavir AUC and Cmax by 70% and 205%, respectively.(1) Selected anticonvulsants linked include: barbiturates, carbamazepine, fosphenytoin, phenobarbital, phenytoin, and primidone.(2-3)

Selected Anticonvulsants/Posaconazole

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

MECHANISM OF ACTION: Posaconazole is primarily metabolized via glucuronidation (UGT).(1) Carbamazepine, phenobarbital, phenytoin, and primidone induce one or more UGT pathways.(3)

CLINICAL EFFECTS: Concurrent use of carbamazepine, phenobarbital, primidone,(1) and phenytoin(1,2) may result in decreased levels and clinical effectiveness of posaconazole.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of posaconazole states that concurrent use of phenytoin, a UGT inducer, should be avoided unless the benefit to the patient outweighs the risk of concurrent therapy.(1) The UK manufacturer of posaconazole states that concurrent use of carbamazepine, phenobarbital, primidone, and phenytoin should be avoided unless the benefit to the patient outweighs the risk of concurrent therapy. If concomitant therapy is required, therapeutic monitoring of posaconazole concentrations should be considered to assure posaconazole levels are sufficient(1) for prevention or treatment of fungal infections. In a posaconazole interaction study, concurrent low dose phenytoin (200 mg daily) decreased posaconazole area-under-curve (AUC) and maximum concentration (Cmax) by 50% and 41%, respectively.(1,2) When carbamazepine, phenobarbital, primidone, or phenytoin is started in a patient already taking posaconazole, the onset of induction is gradual; maximal induction of posaconazole metabolism may not occur for 1-3 weeks after initiation of the anticonvulsant.(3)

DISCUSSION: Posaconazole is primarily metabolized via glucuronidation (UGT).(1) Selected anticonvulsants, including carbamazepine, phenobarbital, phenytoin, and primidone, induce one or more UGT pathways.(3) Concurrent low dose phenytoin (200 mg daily) decreased posaconazole area-under-curve (AUC) and maximum concentration (Cmax) by 50% and 41%, respectively.(1,2)

Selected Anticonvulsants; Barbiturates/Fesoterodine

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

MECHANISM OF ACTION: Barbiturates, carbamazepine, phenobarbital, phenytoin, and primidone may induce the metabolism of fesoterodine by CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent use of barbiturates, carbamazepine, phenobarbital, phenytoin, or primidone with fesoterodine may result in decreased levels of fesoterodine as well as their 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: Concurrent or recent use may lead to subtherapeutic levels of fesoterodine. Monitor patients for decreased effectiveness. The UK manufacturer of fesoterodine suggests that the concomitant use of these agents is not recommended;(1) however, the US manufacturer states no dosage adjustment is necessary.(2)

DISCUSSION: In one clinical study, the induction of CYP3A4 by co-administration of rifampicin (600 mg once a day), another inducer of CYP3A4, maximum concentration (Cmax) and area-under-curve (AUC) of the active metabolite of fesoterodine decreased by 70% and 75%, respectively, following the oral administration of 8 mg of fesoterodine.(1,2)

Selected Anticonvulsants; Barbiturates/Slt Azole Antifungals

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

MECHANISM OF ACTION: Barbiturates, carbamazepine, phenobarbital and phenytoin induce and are metabolized by various CYP P-450 enzymes. Azole antifungals inhibit and are also metabolized by various CYP P-450 enzymes. Details for specific agents(1,2): - Carbamazepine is metabolized by CYP3A4 and is an inducer of CYP3A4, CYP2C9, and CYP2C19. - Phenobarbital and phenytoin are both metabolized by CYP2C9 and CYP2C19, and are inducers of CYP3A4, CYP2C9, and 2C19. - Barbiturates are inducers of CYP3A4. - Fluconazole is a strong inhibitor of CYP2C19 and is a dose-dependent inhibitor of CYP2C9 and CYP3A4. - Itraconazole is primarily metabolized by and is a strong inhibitor of CYP3A4. Fluconazole, itraconazole and ketoconazole may inhibit the metabolism of carbamazepine, phenobarbital and phenytoin by CYP3A4 and CYP2C9.(1-13) Barbiturates, carbamazepine, phenobarbital and phenytoin, strong inducers of CYP3A4, may increase the metabolism of itraconazole or ketoconazole(5,14-16) leading to lower systemic concentrations. Fluconazole is renally eliminated and less susceptible to induction.(16)

CLINICAL EFFECTS: Concurrent use of fluconazole, itraconazole or ketoconazole may result in elevated levels of and toxicity from carbamazepine, phenobarbital and phenytoin. Concurrent use of barbiturates, carbamazepine, phenobarbital or phenytoin with itraconazole or ketoconazole(5,14-16) may result in decreased effectiveness or failure of antifungal therapy.

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

PATIENT MANAGEMENT: When usual doses of itraconazole or ketoconazole are prescribed for patients maintained on carbamazepine, phenobarbital or phenytoin, suboptimal response or treatment failure of the antifungal agent may occur. If clinically appropriate consider using another antifungal agent. If itraconazole or ketoconazole is required, consider therapeutic drug monitoring to optimize antifungal dose-regimen. The dosage of carbamazepine, phenobarbital or phenytoin may need to be adjusted when initiating or discontinuing fluconazole, itraconazole or ketoconazole. Monitor carbamazepine or phenytoin levels and patient tolerance and adjust dose accordingly. Instruct patients to report adverse effects or toxicity. The US manufacturer of itraconazole states that concurrent administration with carbamazepine is not recommended two weeks before, during, or two weeks after itraconazole treatment.(6) The US manufacturer of itraconazole states that concomitant administration with phenytoin or phenobarbital is not recommended two weeks before and during itraconazole treatment.(6) The US manufacturer of ketoconazole states that concomitant administration with carbamazepine is not recommended during and up to one week after discontinuation of treatment with ketoconazole. If coadministration cannot be avoided, plasma concentrations should be measured.(7)

DISCUSSION: There are four case reports of elevated carbamazepine levels (levels ranged from 18 mcg/ml to 24.5 mcg/ml) following the addition of fluconazole (150 mg/day to 400 mg/day).(1-3) In two of the reports, the patients reported symptoms of carbamazepine toxicity such as blurred vision, dizziness, severe diplopia, oscillopsia, nausea, vomiting, gait instability, nystagmus,(1) lethargy, and lack of response to painful stimuli.(2) In the third report, the patient had no signs of carbamazepine toxicity.(3) In the fourth report, a patient treated with carbamazepine for bipolar disorder experienced carbamazepine toxicity symptoms of diplopia, dizziness, and nystagmus, but no other neurological effects typically seen in carbamazepine toxicity were noted. In a study of 8 subjects, concurrent ketoconazole (200 mg/day) increased carbamazepine (range 400 mg/day to 800 mg/day) levels by 25%. There were no effects on levels of carbamazepine-10-11-epoxide, the active metabolite of carbamazepine. There were no signs of carbamazepine toxicity or change in seizure frequency.(5) There are three case reports of undetectable levels and therapeutic failure of itraconazole in patients maintained on carbamazepine.(15,17) Controlled studies in healthy volunteers have found that concurrent administration of phenytoin and fluconazole increase the area under the concentration-time curve of phenytoin by 75% and increase serum phenytoin concentration.(9-11) Case reports have documented the occurrence of phenytoin toxicity when fluconazole was added to the treatment of patients receiving phenytoin.(12,13) A controlled study in healthy volunteers documented that concurrent administration of itraconazole and phenytoin resulted in a decrease in itraconazole area-under-curve (AUC) by 93% and half-life by 83%. Itraconazole increased phenytoin AUC by 10%.(15)

Selected Myelosuppressive Agents/Deferiprone

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

MECHANISM OF ACTION: Concurrent use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1)

CLINICAL EFFECTS: Concurrent use of deferiprone and myelosuppressive agents may result in severe neutropenia or agranulocytosis, which may be fatal.

PREDISPOSING FACTORS: Agranulocytosis may be less common in patients receiving deferiprone for thalassemia, and more common in patients treated for other systemic iron overload conditions (e.g. myelodysplastic syndromes, sickle cell disease).(2,3) Inadequate monitoring appears to increase the risk for severe outcomes. Manufacturer post market surveillance found that in all fatal cases of agranulocytosis reported between 1999 and 2005, data on weekly white blood count (WBC) monitoring was missing. In three fatal cases, deferiprone was continued for two to seven days after the detection of neutropenia or agranulocytosis.(2)

PATIENT MANAGEMENT: If possible, discontinue one of the drugs associated with risk for neutropenia or agranulocytosis. If alternative therapy is not available, documentation and adherence to the deferiprone monitoring protocol is essential. Baseline absolute neutrophil count (ANC) must be at least 1,500/uL prior to starting deferiprone. Monitor ANC weekly during therapy. If infection develops, interrupt deferiprone therapy and monitor ANC more frequently. If ANC is less than 1,500/uL but greater than 500/uL, discontinue deferiprone and any other drugs possibly associated with neutropenia. Initiate ANC and platelet counts daily until recovery (i.e. ANC at least 1,500/uL). If ANC is less than 500/uL, discontinue deferiprone, evaluate patient and hospitalize if appropriate. Do not resume deferiprone unless potential benefits outweigh potential risks.(1)

DISCUSSION: Drugs linked to this monograph have an FDA Boxed Warning for risk of neutropenia, agranulocytosis, or pancytopenia, or have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(1-25) In pooled clinical studies submitted to the FDA, 6.1% of deferiprone patients met criteria for neutropenia and 1.7% of patients developed agranulocytosis.(1) The time to onset of agranulocytosis was highly variable with a range of 65 days to 9.2 years (median, 161 days).(3)

Selected Myelosuppressive Agents/Dipyrone

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

MECHANISM OF ACTION: Concurrent use of dipyrone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1-29)

CLINICAL EFFECTS: Concurrent use of dipyrone with agents that cause bone marrow depression, including myelosuppressives, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding. Undetected severe neutropenia or agranulocytosis may be fatal.(1-29)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of dipyrone and myelosuppressive agents should be avoided. The European Medicines Agency states dipyrone is contraindicated in patients with a prior medical history of dipyrone-induced agranulocytosis (or from other pyrazolones/pyrazolidines), impaired bone marrow function or diseases of the hematopoietic system.(3) International labeling for dipyrone and methotrexate state that co-administration may increase the hematotoxicity of methotrexate, especially in elderly patients, and therefore should be avoided.(1-2) The European Medicines Agency advises if agranulocytosis is suspected with dipyrone, a complete blood count (including differential blood count) should be performed immediately, and treatment must be stopped while waiting for the results. If confirmed, treatment must not be reintroduced.(1-3)

DISCUSSION: A retrospective cohort study analyzed new users of dipyrone (n=444,972), non-steroidal anti-inflammatory drugs (n=3,814,367) which served as a reference cohort, and opioids-paracetamol (n=3,129,221) which was the negative control. During continuous treatment over a median of 37-40 days, 26 cases of hospitalized agranulocytosis occurred. With the assumption that agranulocytosis onset was 7 days prior to admission, the hazard ratio of agranulocytosis associated with dipyrone was 4.40 [0.90-21.57] compared to NSAIDs and 2.45 [0.68-8.83] compared to opioid-paracetamol. HR of neutropenia from dipyrone was 2.98 [1.57-5.65] compared to NSAIDs and not statistically significant compared to opioids-paracetamol. In a sensitivity analysis assuming that the onset of agranulocytosis was the date of hospitalization, the HR of dipyrone-induced agranulocytosis was 7.20 [95% confidence interval: 1.92-26.99] compared to NSAIDs and 3.31 [1.17-9.34] compared to opioids-paracetamol. Agranulocytosis was very rare but more than 4 times more common with dipyrone than other analgesics.(4) In a review of 1,448 reports of agranulocytosis attributed to dipyrone, patients with fatal outcomes were older and more often had also received methotrexate compared to those with non-fatal outcomes (odds ratio: 5.18; 95% confidence interval: 3.06-8.78).(5) Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(2,6-26)

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

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Selected Strong Cyp3a4 Inducers/Amiodarone

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) If the patient is on phenytoin, 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)

Selected Strong Cyp3a4 Inducers/Felodipine

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)

Selected Strong Cyp3a4 Inducers/Irinotecan

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

MECHANISM OF ACTION: Strong CYP3A4 inducers including barbiturates, carbamazepine, fosphenytoin, phenytoin, phenobarbital, and primidone may induce the metabolism of irinotecan by CYP3A4.(1-4)

CLINICAL EFFECTS: Concurrent use of barbiturates, carbamazepine, fosphenytoin, phenytoin, phenobarbital, or primidone with irinotecan 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 anticonvulsants at least 2 weeks prior to irinotecan therapy.(1) Levels of irinotecan and the active metabolites should be monitored in patients receiving concurrent carbamazepine, fosphenytoin, phenytoin, phenobarbital, or primidone. If these agents 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: 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/Ixabepilone

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)

Selected Strong Cyp3a4 Inducers/Nevirapine

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)

Selected Strong Cyp3a4 Inducers/Ulipristal

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)

Selected Ugt1a & Cyp3a4 Inducers/Dolutegravir

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)

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

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

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

CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 and P-gp inducers, phenobarbital, primidone, or rifabutin may result in decreased systemic levels of bictegravir and tenofovir alafenamide, virologic failure, and development of resistance.(1)

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

PATIENT MANAGEMENT: The manufacturer of bictegravir recommends considering alternatives to carbamazepine, phenobarbital, and phenytoin for patients on bictegravir.(1) The National Institute of Health HIV guidelines do not recommend coadministration of carbamazepine, phenobarbital or phenytoin with bictegravir.(2) Fosphenytoin and primidone are metabolized to phenytoin and phenobarbital, respectively. Other CYP3A4 inducers are not recommended to be coadministered with bictegravir.(1,2)

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

Str 3A4 Inducer;Slt Barbiturates,Hydantoin/Slt Antimalarials

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)

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

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

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

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

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

PATIENT MANAGEMENT: The manufacturer of vonoprazan states that concurrent use with strong or moderate CYP3A4 inducers should be avoided.(3)

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

Strong & Moderate Cyp3a4 Inducers/Guanfacine

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

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

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

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

PATIENT MANAGEMENT: Patients maintained on guanfacine may need dosage adjustments if strong or moderate inducers of CYP3A4 are initiated or discontinued. The manufacturer of extended-release guanfacine recommends a starting dose of extended-release guanfacine initiated at up to double the recommended level of the weight based dosing in patients receiving strong or moderate inducers of CYP3A4. If a patient has been maintained on extended-release guanfacine and is started on a strong or moderate CYP3A4 inducer, the dose of extended-release guanfacine should be increased up to double the recommended weight based dose over 1 to 2 weeks. If a patient has been maintained on extended-release guanfacine and a strong or moderate CYP3A4 inducer, and the strong or moderate CYP3A4 inducer is discontinued, the dose of extended-release guanfacine may need to be decreased to the recommended weight based dose over 1 to 2 weeks. Extended-release guanfacine target dose range for attention deficit hyperactivity disorder is 0.05-0.12 mg/kg/day. Doses above 4 mg/day have not been evaluated in children ages 6-12 years and doses above 7 mg/day have not been evaluated in adolescents ages 13-17 years.(1)

DISCUSSION: Rifampin (dosage not stated), a strong inducer of CYP3A4, decreased the maximum concentration (Cmax) and area-under-curve (AUC) of guanfacine (dosage not stated) by approximately 50%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(1-3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine, and tovorafenib.(1-3)

Strong & Moderate Cyp3a4 Inducers/Olaparib

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

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

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

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

PATIENT MANAGEMENT: Avoid the concurrent use of strong or moderate CYP3A4 inducers in patients receiving therapy with olaparib.(1) Consider the use of alternatives with little to no induction potential.

DISCUSSION: In a drug interaction trial, olaparib area-under-curve (AUC) and maximum concentration (Cmax) decreased 87% and 71% respectively when olaparib was administered with rifampin. Based upon simulated models, a moderate CYP3A4 inducer is predicted to decrease olaparib AUC by 50-60% and Cmax by 20-30%.(1-3) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate inducers of CYP3A4 include: bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(4-5)

Strong And Moderate Cyp3a4 Inducers/Cariprazine

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

MECHANISM OF ACTION: Cariprazine and its major active metabolite DDCAR are metabolized by CYP3A4. Strong and moderate inducers of CYP3A4 may accelerate the metabolism of cariprazine.(1-4)

CLINICAL EFFECTS: Concurrent use of a strong or moderate inducer of CYP3A4 may result in decreased levels and effectiveness of cariprazine.(1-4)

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

PATIENT MANAGEMENT: The US manufacturer of cariprazine does not recommend concurrent use of strong CYP3A4 inducers.(1) The Australian, Canadian, and UK manufacturers of cariprazine state that concurrent use of strong and moderate CYP3A4 inducers is contraindicated.(2-4)

DISCUSSION: Cariprazine and its active metabolites are primarily metabolized by CYP3A4. Coadministration with CYP3A4 inducers has not been studied and the net effect is unclear. Due to the long half life of the active metabolites, it takes several weeks for cariprazine to reach steady state after dosage changes.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(5-6) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(5-6)

Strong And Moderate Cyp3a4 Inducers/Pimavanserin

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

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

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

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

PATIENT MANAGEMENT: The US manufacturer of pimavanserin recommends avoiding concomitant use of strong or moderate CYP3A4 inducers.(1)

DISCUSSION: Pimavanserin is primarily metabolized by CYP3A4 while other metabolic enzymes CYP2J2, CYP2D6 and FMO play a lesser role.(1) In a study of subjects pretreated with 7 days of rifampin (600 mg daily, a strong CYP3A4 inducer), a single dose of pimavanserin (34 mg) produced an area-under-curve (AUC) and maximum concentration (Cmax) that was 91 % and 71 % lower, respectively, than when pimavanserin is given without rifampin.(1) A physiology-based pharmacokinetic model predicted that efavirenz (a moderate CYP3A4 inducer) would decrease pimavanserin AUC and Cmax by 70 % and 60 %, respectively.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(3-4) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, and tovorafenib.(3-4)

Strong And Moderate Cyp3a4 Inducers/Pretomanid

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

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

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

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

PATIENT MANAGEMENT: The manufacturer of pretomanid recommends avoiding concurrent use with strong or moderate CYP3A4 inducers during pretomanid therapy.(1) Patients receiving concurrent therapy with strong and moderate CYP3A4 inducers and pretomanid should be observed for decreased levels and clinical effectiveness.

DISCUSSION: In a clinical study, concurrent use of pretomanid 200 mg with efavirenz 600 mg for 7 days resulted in decreased mean area-under-curve (AUC) by 35% and maximum concentration (Cmax) by 28%.(1) In a clinical study, concurrent use of pretomanid 200 mg with rifampin 600 mg for 7 days resulted in decreased mean AUC by 66% and Cmax by 53%.(1) Strong and moderate CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate, dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, etravirine, fexinidazole, fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin, rifapentine, St. John's wort, sotorasib, telotristat, thioridazine, and tovorafenib.(1,2)

Strong Cyp1a2, Cyp2b6 Or Cyp3a4 Inducers/Fenfluramine

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)

Strong Cyp2b6 Inducers/Bupropion

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

MECHANISM OF ACTION: Strong CYP2B6 inducers may induce the metabolism of bupropion.(1)

CLINICAL EFFECTS: Concurrent or recent use of strong CYP2B6 inducers may decrease the effectiveness of bupropion.(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 bupropion and strong CYP2B6 inducers should be avoided. Consider the use of alternative agents in patients maintained on bupropion for psychiatric indications and inform patients that bupropion may not be effective for smoking cessation during concurrent therapy with strong CYP2B6 inducers. If concurrent use is warranted, monitor patients for decreased levels and effectiveness if strong CYP2B6 inducers are initiated. The dosage of bupropion may need to be increased; however, the maximum recommended dose of bupropion should not be exceed.(2)

DISCUSSION: In a study in 16 healthy subjects, rifampin (600 mg/day, a moderate CYP2B6 inducer) increased bupropion (150 mg single dose) apparent clearance 2-fold and decreased the bupropion half-life by 48%. In addition, concurrent rifampin increased the maximum concentration (Cmax) of hydroxybupropion by 43% and decreased the hydroxybupropion area-under-curve (AUC) by 38%.(2) In a study with 34 subjects, the effects of 150 mg of bupropion alone and 150 mg of bupropion with carbamazepine (a strong CYP2B6 inducer) were compared. Carbamazepine decreased bupropion AUC by 90% and peak Cmax by 87%. In addition, hydroxybupropion peak concentration Cmax by 71% and AUC by 50%.(3) Strong CYP2B6 inducers linked include: carbamazepine.(4,5)

Strong Cyp2b6 Inducers/Bupropion Combinations

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

MECHANISM OF ACTION: Strong CYP2B6 inducers may induce the metabolism of bupropion.(1,2) For the dextromethorphan/bupropion combination, the metabolism of dextromethorphan may also be increased.(1)

CLINICAL EFFECTS: Concurrent or recent use of strong CYP2B6 inducers may decrease the effectiveness of bupropion.(1,2) For the dextromethorphan/bupropion combination, the levels and effectiveness of dextromethorphan may also be decreased.(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 dextromethorphan/bupropion and naltrexone/bupropion state concurrent use with strong CYP2B6 inducers should be avoided.(1,2)

DISCUSSION: In a clinical study, carbamazepine 200 mg decreased the maximum concentration (Cmax) and area-under-curve (AUC) of bupropion by 74% and 76%, respectively, and decreased the Cmax and AUC of dextromethorphan by 59% and 64%, respectively.(1) In a study with 34 subjects, the effects of 150 mg of bupropion alone and 150 mg of bupropion with carbamazepine (a strong CYP2B6 inducer) were compared. Carbamazepine decreased bupropion AUC by 90% and peak Cmax by 87%. In addition, hydroxybupropion peak concentration Cmax by 71% and AUC by 50%.(3) In a study in 16 healthy subjects, rifampin (600 mg/day, a moderate CYP2B6 inducer) increased bupropion (150 mg single dose) apparent clearance 2-fold and decreased the bupropion half-life by 48%. In addition, concurrent rifampin increased the Cmax of hydroxybupropion by 43% and decreased the hydroxybupropion AUC by 38%.(4) Strong CYP2B6 inducers linked include: carbamazepine.(5,6)

Strong Cyp3a4 Inducer/Slt Long-Acting Aripiprazole Injection

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)

Strong Cyp3a4 Inducers/Alpelisib

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)

Strong Cyp3a4 Inducers/Apremilast; Roflumilast

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.

Strong Cyp3a4 Inducers/Atogepant

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 atogepant by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of strong 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 CYP3A4 inducers receive atogepant 60 mg once daily for prevention of episodic migraines and use of atogepant is not recommended for prevention of chronic migraines.(1) Patients receiving concurrent therapy with CYP3A4 inducers and atogepant should be observed for decreased clinical effectiveness.

DISCUSSION: In a study of healthy subjects, rifampin, a strong CYP3A4 inducer, decreased the area-under-curve (AUC) and maximum concentration (Cmax) of atogepant by 60% and 30%, respectively. Topiramate, a weak CYP3A4 inducer, decreased atogepant AUC and Cmax by 25% and 24%, respectively.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifapentine, and St. John's wort.(1,2)

Strong Cyp3a4 Inducers/Aumolertinib

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

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

CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may decrease the levels and effectiveness of aumolertinib.(1)

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

PATIENT MANAGEMENT: The manufacturer of aumolertinib states that concomitant use of strong CYP3A4 inducers is not recommended.(1)

DISCUSSION: In a clinical study, aumolertinib area-under-curve (AUC) decreased by approximately 90% following concomitant use of rifampin (strong CYP3A4 inducer).(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.(2,3)

Strong Cyp3a4 Inducers/Cabazitaxel

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)

Strong Cyp3a4 Inducers/Cabozantinib Lauryl Sulfate

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

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

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

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

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

DISCUSSION: In a study in healthy subjects, rifampin (600 mg daily for 31 days) decreased the AUC of a single dose of cabozantinib by 77%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(2,3)

Strong Cyp3a4 Inducers/Cabozantinib S-Malate Capsules

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

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

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

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

PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP3A4 inducers in patients receiving therapy with cabozantinib. Consider the use of alternative agents with less enzyme induction potential.(1) Dosage adjustments are specific to the formulation of cabozantinib prescribed. If concurrent use of a CYP3A4 inducer cannot be avoided, increase the daily dose of cabozantinib CAPsules by 40 mg (from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. The daily dose of cabozantinib should not exceed 180 mg. If the CYP3A4 inducer is discontinued, reduce the dosage of cabozantinib to the dose used prior to initiation of the inducer 2 to 3 days after discontinuation of the strong inducer.(1)

DISCUSSION: In a study in healthy subjects, rifampin (600 mg daily for 31 days) decreased the AUC of a single dose of cabozantinib by 77%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, and rifapentine.(1-3)

Strong Cyp3a4 Inducers/Cabozantinib S-Malate Tablets

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

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

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

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

PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP3A4 inducers in patients receiving therapy with cabozantinib. Consider the use of alternative agents with less enzyme induction potential.(1) Dosage adjustments are specific to the formulation of cabozantinib prescribed. If concurrent use of a strong 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)

DISCUSSION: In a study in healthy subjects, rifampin (600 mg daily for 31 days) decreased the AUC of a single dose of cabozantinib by 77%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(2,3)

Strong Cyp3a4 Inducers/Daraxonrasib

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

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

CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may decrease the levels and effectiveness of daraxonrasib.(1)

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

PATIENT MANAGEMENT: The manufacturer of daraxonrasib states that concomitant use of strong CYP3A4 inducers should be avoided. If concurrent use cannot be avoided, increase the dose of daraxonrasib to 400 mg once daily.(1)

DISCUSSION: In a clinical study, daraxonrasib area-under-curve (AUC) decreased by approximately 50% following concomitant use of phenytoin 100 mg three times daily (strong CYP3A4 inducer) and is predicted to decrease by 30% with concomitant use of rifampin 600 mg once daily (strong CYP3A4 inducer).(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)

Strong Cyp3a4 Inducers/Docetaxel

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)

Strong Cyp3a4 Inducers/Elinzanetant

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 elinzanetant by CYP3A4.(1,2)

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

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

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

DISCUSSION: Elinzanetant maximum concentration (Cmax) reduced by 44% and area-under-curve (AUC) reduced by 64% following concomitant use with carbamazepine (moderate to strong CYP3A4 inducer) 600 mg administered twice daily.(1) 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)

Strong Cyp3a4 Inducers/Encorafenib

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 encorafenib.(1)

CLINICAL EFFECTS: The concurrent use of strong CYP3A4 inducers and encorafenib may result in decreased levels and clinical effectiveness of encorafenib.(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 and encorafenib should be avoided. Concurrent use may decrease efficacy of encorafenib.(1)

DISCUSSION: Concurrent use of strong CYP3A4 inducers and encorafenib has not been studied. In clinical trials, steady-state encorafenib exposures were lower than encorafenib exposure after the first dose, suggesting CYP3A4 auto-induction.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, fosphenytoin, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2)

Strong Cyp3a4 Inducers/Eravacycline

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)

Strong Cyp3a4 Inducers/Exemestane

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)

Strong Cyp3a4 Inducers/Flibanserin

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

MECHANISM OF ACTION: Flibanserin is primarily metabolized by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers and flibanserin will result in decreased systemic concentrations of flibanserin and may lead to therapeutic failure.(1,6)

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

PATIENT MANAGEMENT: The manufacturer of flibanserin states that concomitant use with CYP3A4 inducers is not recommended. In an interaction study, rifampin decreased flibanserin exposure(AUC) 95%.(1) The onset of induction is gradual but may begin within one week for potent agents (e.g. rifampin). The time to maximal induction may be 2 or more weeks depending upon the half-life and dose of the inducer.

DISCUSSION: In an interaction study described in prescribing information, rifampin decreased flibanserin exposure (AUC) 95%.(1) FDA defines strong CYP inducers as agents which cause a > or = to 80% decrease in systemic exposure (area-under-curve or AUC) of a drug metabolized by a specific CYP enzyme.(2) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenytoin, primidone, rifabutin, rifampin, rifapentine and St. John's Wort.(3)

Strong Cyp3a4 Inducers/Fostamatinib

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)

Strong Cyp3a4 Inducers/Gepirone

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

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

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may decrease the levels and effectiveness of gepirone.(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 gepirone should be avoided.(1) Consider the use of alternative agents with less enzyme induction potential.(1)

DISCUSSION: In a study, rifampin 600 mg daily decrease the maximum concentration (Cmax) and area-under-curve (AUC) of gepirone by 20-fold and 29-fold, respectively. The Cmax and AUC of the active metabolite, 3'-OH gepirone, also decreased by 2.5-fold and 3-fold, respectively.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(2)

Strong Cyp3a4 Inducers/Imlunestrant

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 imlunestrant.(1)

CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers may alter the clinical effectiveness of imlunestrant.(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 imlunestrant with strong CYP3A4 inducers.(1) If concurrent use cannot be avoided, increase the dosage of imlunestrant to 600 mg once daily.(1) Monitor patients receiving concurrent therapy for reduced efficacy.

DISCUSSION: Imlunestrant is primarily metabolized by CYP3A4.(1) In an interaction study, imlunestrant area-under-curve (AUC) decreased by 42% and concentration maximum (Cmax) decreased by 29% following concomitant use of carbamazepine (strong CYP3A inducer) for multiple 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.(2,3)

Strong Cyp3a4 Inducers/Ivabradine

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.

Strong Cyp3a4 Inducers/Lercanidipine

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 lercanidipine.(1)

CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of lercanidipine.(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 inducers of CYP3A4 with lercanidipine is not recommended. If concurrent use is warranted, blood pressure should be monitored more frequently than usual.(1)

DISCUSSION: Lercanidipine is extensively metabolized by CYP3A4, with no parent drug found in urine or feces.(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)

Strong Cyp3a4 Inducers/Maraviroc

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.

Strong Cyp3a4 Inducers/Naldemedine

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)

Strong Cyp3a4 Inducers/Naloxegol

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)

Strong Cyp3a4 Inducers/Osimertinib

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)

Strong Cyp3a4 Inducers/Paclitaxel

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)

Strong Cyp3a4 Inducers/Paliperidone Intramuscular Injection

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)

Strong Cyp3a4 Inducers/Pirtobrutinib

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

MECHANISM OF ACTION: Pirtobrutinib is metabolized by CYP3A4. 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)

Strong Cyp3a4 Inducers/Pralsetinib

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)

Strong Cyp3a4 Inducers/Quetiapine (> 150 Mg)

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)

Strong Cyp3a4 Inducers/Ramelteon; Suvorexant; Tasimelteon

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)

Strong Cyp3a4 Inducers/Ritlecitinib

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)

Strong Cyp3a4 Inducers/Rivoceranib

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 rivoceranib.(1)

CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 inducer may result in decreased levels and effectiveness of rivoceranib.(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 rivoceranib states that concurrent use with strong CYP3A4 inducers should be avoided. If concurrent use is necessary, closely monitor for treatment response.(1)

DISCUSSION: In vitro data shows that rivoceranib is metabolized by CYP3A4.(1) In a study with rifampin, rivoceranib levels decreased by 5.6-fold in plasma clearance (CL/F) and 83% in plasma area-under-curve (AUC).(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, ivosidenib, lumacaftor, mitotane, phenobarbital, primidone, rifampin, rifapentine, and St. John's wort.(2-3)

Strong Cyp3a4 Inducers/Rolapitant

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)

Strong Cyp3a4 Inducers/Savolitinib

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 savolitinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may decrease the levels and effectiveness of savolitinib.(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 savolitinib should be avoided.(1) Consider the use of alternative agents with less enzyme induction potential.(1)

DISCUSSION: Rifampin decreased the maximum concentration (Cmax) and area-under-curve (AUC) of savolitinib by 55% and 61%, 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)

Strong Cyp3a4 Inducers/Selected Antipsychotics

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)

Strong Cyp3a4 Inducers/Selected Immunosuppressants

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

MECHANISM OF ACTION: Strong inducers of CYP3A4 may increase the metabolism of cyclosporine, everolimus, sirolimus, tacrolimus, and temsirolimus.(1)

CLINICAL EFFECTS: Concurrent use of strong inducers of CYP3A4 may result in decreased levels and effectiveness of cyclosporine, everolimus, sirolimus, tacrolimus, and temsirolimus.(1)

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

PATIENT MANAGEMENT: The American Society of Transplantation guidelines state that cyclosporine and tacrolimus should be avoided in combination with rifabutin and rifampin. Everolimus should be avoided in combination with rifampin and is contraindicated with rifabutin. Sirolimus is contraindicated with rifabutin and rifampin. If concurrent therapy of cyclosporine, everolimus, sirolimus, or tacrolimus with rifampin is needed, increase the dose of the immunosuppressant by 2-fold when the combination is initiated and monitor immunosuppressant concentrations frequently with rapid subsequent dose increases as needed. The reverse is recommended when rifampin is discontinued.(62) The US manufacturer of everolimus states that concurrent use with strong CYP3A4 inducers should be avoided. If concurrent use is warranted, consider increasing the dose of everolimus. In patients with advanced hormone receptor-positive, HER2-negative breast cancer (HR+BC); advanced pancreatic neuroendocrine tumors (PNET); or advanced renal cell carcinoma; or renal angiomyolipoma with TSC, double the daily dose of everolimus using 5 mg increments or less. If the inducer is discontinued, return the dose to that used prior to inducer therapy once the inducer has been stopped for 5 days. In patients with subependymal giant cell astrocytoma with TSC, double the dose of everolimus using 5 mg increments or less. Subsequent dosing should be individualized based on therapeutic drug monitoring. If the inducer is discontinued, return the dose of everolimus to the dose used prior to the inducer once the inducer has been stopped for 5 days, and assess everolimus trough levels 2 weeks later.(1) St. John's wort may decrease everolimus levels unpredictably and should be avoided entirely.(1) The US manufacturer of temsirolimus states that concurrent use of strong inducers of CYP3A4, such as carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, or rifampin should be avoided. If concurrent therapy is warranted, consider increasing the dosage of temsirolimus from 25 mg/week to 50 mg/week. If the inducer is discontinued, the dosage of temsirolimus should be returned to the previous dose.(2) If possible, consider alternatives to strong CYP3A4 inducers in patients maintained on cyclosporine, sirolimus, and tacrolimus. If concurrent therapy is warranted, monitor cyclosporine, sirolimus, and tacrolimus serum levels and observe the patient for graft rejection. The dosage of cyclosporine, sirolimus, and tacrolimus may need to be adjusted following the initiation or discontinuation of these agents. Strong CYP3A4 inducers linked to this monograph include: allobarbital, amobarbital, apalutamide, aprobarbital, barbexaclone, barbital, brallobarbital, butabarbital, butalbital, butethal, carbamazepine, cyclobarbital, difebarbamate, ethotoin, febarbamate, fosphenytoin, hexobarbital, lumacaftor, mephenytoin, mephobarbital, metharbital, mitotane, natisedine, pentobarbital, phenobarbital, phenytoin, primidone, probarbital, proxibarbal, rifabutin, rifampin, rifapentine, secobarbital, St. John's wort, talbutal, vinbarbital, and vinylbital.

DISCUSSION: In a study in 10 lung transplant patients, significantly higher doses of cyclosporine were required during nafcillin therapy to maintain therapeutic trough levels. Patients also developed higher serum creatinine levels and more renal dysfunction than patients not receiving nafcillin. In a case report, a patient experienced 70% and 85% drops in cyclosporine levels during two separate courses of nafcillin therapy. Trough cyclosporine concentrations have been found to decrease within 48 hours after starting phenytoin even when the dose of cyclosporine is increased. Conversely, cyclosporine concentrations may increase when the hydantoin is discontinued. The effect of the hydantoin on cyclosporine may reverse over a period of one to three weeks after stopping the hydantoin. Concurrent administration of cyclosporine and rifampin has been associated with lowering of cyclosporine to undetectable serum levels. Decreases in cyclosporine levels have been observed within 2 days of concomitant therapy but will probably not be maximal for 1 week. The effects of the interaction may persist for up to 3 weeks after rifampin is stopped. In an open-label study in 11 renal transplant patients, subjects received St. John's wort (600 mg daily) for 14 days in addition to their normal cyclosporine regimen. After 14 days of St. John's wort, dose-corrected cyclosporine area-under-curve (AUC), maximum concentration (Cmax), and minimum concentration (Cmin) decreased by 46%, 42%, and 41%, respectively. Mean cyclosporine dose increased from 2.7 mg/kg/day at 4.2 mg/kg/day at the end of the study. Subjects required their first cyclosporine dosage adjustment at Day 3. There are several case reports of decreased cyclosporine with concurrent carbamazepine, phenobarbital, and St. John's wort. In healthy subjects, concurrent use of rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 64% and 58%, respectively. Increasing the dosage of everolimus to 20 mg daily in patients taking a strong inducer of CYP3A4 is expected to increase the AUC of everolimus to levels seen without a concurrent inducer; however, there are no clinical data available with this dosage in patients receiving strong CYP3A4 inducers. In an open-label clinical trial, 10 male patients received ridaforolimus (40 mg daily, days 1 and 14) and rifampin (600 mg daily, days 1-21). Administration of rifampin resulted in a reduction in the mean whole-blood concentration of ridaforolimus (AUC-GMR 0.57, Cmax- GMR 0.66). The mean whole-blood concentration of ridaforolimus increased 1.5-fold following ketoconazole administration. In a study in 14 healthy subjects, pretreatment with rifampin (600 mg daily for 14 days) decreased the AUC and Cmax of a single dose of sirolimus (20 mg) by 82% and 71%, respectively. The oral clearance of sirolimus increased by 5.5-fold. There are case report of decreased sirolimus levels with concurrent phenytoin and rifampin. A study in six healthy subjects examined the effects of rifampin on single doses of oral (0.1 mg/kg) and intravenous (0.025 mg/kg/4 hours) tacrolimus. Rifampin increased tacrolimus clearance by 47% and decreased tacrolimus bioavailability by 51%. In a study in 10 healthy subjects, pretreatment with St. John's wort (300 mg 3 times daily for 18 days) decreased the AUC of a single dose of tacrolimus (0.1 mg/kg) by 35.3%. Tacrolimus apparent oral clearance and volume of distribution increased by 68% and 53%, respectively. In a study in 10 renal transplant patients, concurrent St. John's wort (600 mg daily) for 2 weeks increased tacrolimus dose requirements from a baseline of 4.5 mg/day to 8.0 mg/day. Dose-correct tacrolimus AUC decreased by 57.8%. There have been several case reports of decreased tacrolimus levels with concurrent carbamazepine, phenobarbital, phenytoin, rifampin, and St. John's wort. Phenobarbital and phenytoin have been used successfully to treat tacrolimus overdose. Concurrent rifampin had no significant effects on the AUC or Cmax of temsirolimus; however, sirolimus AUC and Cmax decreased by 56% and 65%, respectively. A dosage adjustment to 50 mg/week of temsirolimus in the presence of strong CYP3A4 inducers is predicted to adjust levels to those seen without inducers; however, there are no clinical data in patients using this dose. There is a case report of decreased temsirolimus effectiveness with concurrent rifampin.

Strong Cyp3a4 Inducers/Sunvozertinib

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 sunvozertinib.(1)

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

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

PATIENT MANAGEMENT: The manufacturer of sunvozertinib states that concomitant use of strong CYP3A4 inducers should be avoided.(1) If concurrent use cannot be avoided, increase sunvozertinib dose from 200 mg to 400 mg.(1) After stopping the CYP3A4 inducer, resume the prior sunvozertinib dose 7-14 days after stopping the CYP3A4 inducer.(1)

DISCUSSION: Sunvozertinib is primarily metabolized by CYP3A4.(1) Concomitant administration of sunvozertinib with a strong inducer (carbamazepine) resulted in a decrease in sunvozertinib area under the curve (AUC) and maximum concentration (Cmax) by 48% and 38%, respectively.(1) 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)

Strong Cyp3a4 Inducers/Surufatinib

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 surufatinib.(1)

CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 inducer may result in decreased levels and effectiveness of surufatinib.(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 surufatinib states that concurrent use with strong CYP3A4 inducers should be avoided. If concurrent use is necessary, closely monitor for treatment response.(1)

DISCUSSION: In vitro data shows that surufatinib is metabolized by CYP3A4. The manufacturer of surufatinib recommends avoiding concurrent use with strong CYP3A4 inducers.(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)

Strong Cyp3a4 Inducers/Tadalafil (Pah)

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)

Strong Cyp3a4 Inducers/Thiotepa

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)

Strong Cyp3a4 Inducers/Tivozanib

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)

Strong Cyp3a4 Inducers/Tofacitinib

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)

Strong Cyp3a4 Inducers/Tretinoin

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)

Strong Cyp3a4 Inducers/Upadacitinib

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)

Strong Cyp3a4 Inducers/Valbenazine

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)

Strong Cyp3a4 Inducers/Vanzacaftor-Tezacaftor-Deutivacaftor

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)

Strong Cyp3a4 Inducers/Venetoclax

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)

Strong Cyp3a4 Inducers/Vepdegestrant

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

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

CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may decrease the levels and effectiveness of vepdegestrant.(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 vepdegestrant states that concurrent use of strong CYP3A4 inducers should be avoided. In patients taking 200 mg daily of vepdegestrant, if concurrent use cannot be avoided, increase the dosage of vepdegestrant to 300 mg daily. After the CYP3A4 inducer is discontinued for 7 to 14 days, resume vepdegestrant 200 mg daily. Patients on vepdegestrant 100 mg daily should avoid coadministration of strong CYP3A4 inducers.(1)

DISCUSSION: Vepdegestrant is a CYP3A4 substrate. In a study, carbamazepine 200 mg three times daily (a strong CYP3A4 inducer) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of vepdegestrant by 64% and 80%, 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.(2,3)

Strong Cyp3a4 Inducers/Zongertinib

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 zongertinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of a strong CYP3A4 inducer may result in decreased levels and effectiveness of zongertinib.(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 zongertinib states that concomitant use of strong CYP3A4 inducers should be avoided.(1) If concurrent use cannot be avoided, increase the zongertinib dose based on body weight: - Less than 90 kg: increase from 120 mg to 240 mg dose - Greater than or equal to 90 kg: increase from 180 mg to 360 mg dose After stopping the CYP3A4 inducer, resume the prior zongertinib dose 7-14 days after stopping the CYP3A4 inducer.(1)

DISCUSSION: Zongertinib area-under-curve (AUC) and maximum concentration (Cmax) decreased by 63% and 43%, respectively, following concomitant use of carbamazepine (strong CYP3A4 inducer) 600 mg once daily for 7 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)

Strong Cyp3a4 Inducers; Rifabutin/Larotrectinib

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

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

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

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

PATIENT MANAGEMENT: The manufacturer of larotrectinib states that the concurrent use of strong CYP3A4 inducers should be avoided, and that alternative treatments with less CYP3A4 induction should be considered.(1,2) The Canadian manufacturer includes rifabutin on its list of CYP3A4 inducers that should be avoided.(2) If coadministration of a strong 3A4 inducer cannot be avoided, double the larotrectinib dose. After the strong 3A4 inducer has been discontinued for 3 to 5 elimination half-lives, resume the larotrectinib dose at the dose taken prior to initiating the 3A4 inducer.(1,2)

DISCUSSION: In a study with healthy subjects, co-administration of rifampin (strong 3A4 inducer) with a single dose of larotrectinib (100 mg), decreased larotrectinib area-under-curve (AUC) by 81% and maximum concentration (Cmax) by 71%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(3-4)

Strong Cyp3a4 Inducers; Rifabutin/Vemurafenib

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

MECHANISM OF ACTION: Vemurafenib is a substrate of CYP3A4. Strong inducers of CYP3A4 and rifabutin may increase the metabolism of vemurafenib.(1-3)

CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 or rifabutin may result in decreased levels and effectiveness of vemurafenib.(1-3)

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

PATIENT MANAGEMENT: The manufacturer of vemurafenib states to avoid concurrent use with strong CYP3A4 inducers and replace these drugs with alternative drugs when possible.(1-3) The Canadian and UK manufacturers include rifabutin on their lists of CYP3A4 inducers that are to be avoided.(2,3) If concurrent administration with a strong CYP3A4 inducer is unavoidable, increase the dose of vemurafenib by 240 mg (one tablet) as tolerated.(1) If concurrent use of a strong CYP3A4 inducer is discontinued, allow a 2 week period to lapse and then resume the dose of vemurafenib that was taken prior to initiation of the strong CYP3A4 inducer.(1)

DISCUSSION: In a study in healthy subjects, coadministration of single dose vemurafenib 960 mg with rifampin (600 mg daily, a strong CYP3A inducer) decreased vemurafenib area-under-curve (AUC) by 40% (90% CI: 24%, 53%) with no effect on maximum concentration (Cmax), when compared to vemurafenib alone.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(4-5)

Strong Or Moderate Cyp3a4 Inducers/Ganaxolone

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

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

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

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

PATIENT MANAGEMENT: The manufacturer of ganaxolone states that concurrent use with strong or moderate CYP3A4 inducers should be avoided. If concurrent use is unavoidable, consider increasing the dose of ganaxolone. Do not exceed the recommended maximum daily dose.(1) In patients who are stable on ganaxolone and are initiated on anticonvulsants that are CYP3A4 inducers, consider increasing the dose of ganaxolone. Do not exceed the recommended maximum daily dose.(1)

DISCUSSION: Co-administration of rifampin, a strong CYP3A4 inducer, decreased the ganaxolone concentration maximum (Cmax) by 57% and area-under-curve (AUC) by 68%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2-3)

Strong Or Moderate Cyp3a4 Inducers/Simeprevir

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

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

CLINICAL EFFECTS: Concurrent or recent use of strong or moderate CYP3A4 inducers may lower simeprevir minimum concentrations (Cmin) leading to a loss of virologic response to simeprevir.(1)

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

PATIENT MANAGEMENT: The US manufacturer of simeprevir states that concurrent administration of strong or moderate inducers of CYP3A4 is not recommended due risk for simeprevir treatment failure.(1)

DISCUSSION: In a study in 18 subjects, rifampin (600 mg daily for 7 days) decreased the area-under-curve (AUC) and Cmin of simeprevir (200 mg daily for 7 days) by 48% and 92%, respectively. The simeprevir maximum concentration (Cmax) increased 1.31-fold.(1) Strong and moderate inducers of CYP3A4 linked to this monograph include apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate, dabrafenib, dexamethasone, elagolix, encorafenib, enzalutamide, fosphenytoin, ivosidenib, fexinidazole, lesinurad, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, modafinil, nafcillin, oxcarbazepine, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifampin, rifabutin, rifapentine, St. John's wort, sotorasib, telotristat, and tovorafenib.(1-3)

Strong P-Gp Or Cyp3a4 Inducer/Linagliptin

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

MECHANISM OF ACTION: Strong P-gp or CYP3A4 inducers may increase the metabolism of linagliptin.(1)

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

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

PATIENT MANAGEMENT: If possible, use an alternative agent to strong P-gp or CYP3A4 inducers in patients maintained on linagliptin. If concurrent therapy is required, patients may need adjustment to their diabetes therapy, including replacement of linagliptin.(1)

DISCUSSION: Concurrent rifampin (600 mg daily) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of linagliptin (5 mg daily) by 40% and 44%, respectively.(1) Strong P-gp or CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, efavirenz, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lorlatinib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(2)

Strong Ugt Inducers/Deferasirox

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

MECHANISM OF ACTION: Strong inducers of UDP-glucuronosyltransferase (UGT) may induce the metabolism of deferasirox.(1)

CLINICAL EFFECTS: Concurrent use of carbamazepine, efavirenz, etravirine, fosphenytoin, phenobarbital, phenytoin, primidone, rifampin, or ritonavir may result in decreased levels and effectiveness of deferasirox.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong UGT inducers with deferasirox. If concurrent therapy is warranted, consider increasing the initial dose of deferasirox by 50%. Further dosage adjustments should be made based upon serum ferritin levels and clinical response. Doses above 40 mg/kg are not recommended.(1)

DISCUSSION: In a study in healthy subjects, administration of rifampin (600 mg/day for 9 days) decreased the area-under-curve (AUC) of a single dose of deferasirox (30 mg/kg) by 44%.(1) Other strong inducers of UGT, such as carbamazepine, efavirenz, fosphenytoin, phenobarbital, phenytoin, primidone, and ritonavir are expected to produce similar results.(1)

Tricyclic Compounds; Carbamazepine/Tapentadol

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

MECHANISM OF ACTION: Tapentadol and tricyclic compounds may lower the seizure threshold.(1) Tapentadol and tricyclic compounds may result in additive effects on serotonin levels.(1) Although not used therapeutically as an antidepressant, carbamazepine is a tricyclic compound.

CLINICAL EFFECTS: Concurrent use of tapentadol and a tricyclic compound may result in seizures or serotonin syndrome.(1)

PREDISPOSING FACTORS: Risk of seizures may be increased in patients with epilepsy, a history of seizures, head trauma, metabolic disorders, alcohol or drug withdrawal, or infections of the central nervous system.(1)

PATIENT MANAGEMENT: Tapentadol should be used with caution in patients taking tricyclic compounds, including carbamazepine. Monitor patients closely for serotonin syndrome.(1)

DISCUSSION: Concurrent use of tapentadol with tricyclic compounds may result in additive blockage of serotonin reuptake, leading to central serotonergic hyperstimulation. Cases of serotonin syndrome have been reported with tapentadol in combination with other serotonergic drugs.(1) Use of tapentadol has been associated with increased seizure frequency in patients with seizure disorders.(1)

Tricyclic Compounds; Carbamazepine/Tramadol

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

MECHANISM OF ACTION: Tramadol and tricyclic compounds may lower the seizure threshold.(1) Tramadol inhibits the reuptake of serotonin and norepinephrine but has weak opioid effects. M1, tramadol's active metabolite, is a stronger opioid and up to 6 times more potent than tramadol in producing analgesia.(1) Carbamazepine induces the metabolism of this tramadol opioid metabolite.

CLINICAL EFFECTS: Concurrent use of tramadol and a tricyclic compound may result in seizures or serotonin syndrome and may increase the risk of suicide.(1) Concurrent use of tramadol and carbamazepine may significantly reduce the analgesic effect of tramadol.(1) Although not used therapeutically as an antidepressant, carbamazepine is a tricyclic compound.

PREDISPOSING FACTORS: Risk of seizures may be increased in patients with epilepsy, a history of seizures, head trauma, metabolic disorders, alcohol or drug withdrawal, or infections of the central nervous system.(1)

PATIENT MANAGEMENT: Tramadol should be used with caution in patients taking tricyclic compounds.(1) The use of tramadol and carbamazepine is not recommended.(1) Carbamazepine induces metabolism (glucuronidation) of the tramadol opioid metabolite (M1). In patients on long-term carbamazepine when tramadol is started, achieving adequate analgesia may be difficult. Prescribing higher tramadol doses would be associated with higher parent drug levels which may result in serotonin and norepinephrine associated adverse effects. In patients receiving chronic tramadol treatment when carbamazepine is started, anticipate a reduction in analgesic effects. The maximal effects of carbamazepine on tramadol efficacy may not be seen for 2 or more weeks. Monitor for decreased tramadol efficacy, including symptoms of opioid withdrawal, after carbamazepine is initiated or when carbamazepine dosage is increased. If carbamazepine is to be discontinued in patients stabilized on the combination of tramadol and carbamazepine, gradually decrease the carbamazepine dose to decrease the risk of withdrawal seizures. As carbamazepine induction wanes, systemic tramadol metabolite concentrations will rise. The tramadol dose may need to be decreased to prevent tramadol toxicity.

DISCUSSION: The use of tramadol in patients treated with tricyclic compounds may increase the risk of seizures.(1) A review of 124 reports of seizures following tramadol therapy received by the FDA through July 31, 1996 revealed that 23% of the patients were also taking tricyclic antidepressants.(2) Therefore, the manufacturer of tramadol states that tramadol should be used with caution in patients treated with tricyclic compounds.(1) The manufacturer of tramadol also states that the use of tramadol with carbamazepine is not recommended.(1) In a case report, a 79 year-old female developed serotonin syndrome three days after the addition of tramadol to amitriptyline therapy. Over the next four days, her condition deteriorated and she died.(3)

Tricyclic; Tetracyclic Agents; Carbamazepine/Linezolid

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

MECHANISM OF ACTION: Linezolid is a weak, reversible inhibitor of monoamine oxidase.(1) Tricyclic and tetracyclic compounds may sensitize post-synaptic receptors to amines that are accumulating extraneuronally as a result of MAO inhibition.(2) Carbamazepine is structurally related to the tricyclic antidepressants.(3) Similarity between cyclobenzaprine and tricyclics warrants consideration of tricyclic interactions for cyclobenzaprine.(4) Mirtazapine, a tetracyclic antidepressant, should also be considered for this interaction.(5)

CLINICAL EFFECTS: Concurrent use with linezolid may result in a severe reaction including hyperpyrexia, convulsions, excitability, fluctuations in blood pressure, convulsions, grand mal seizures, serotonin syndrome, coma, and death.(1) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(6)

PREDISPOSING FACTORS: High doses of tricyclics or tetracyclics, or concurrent use of multiple drugs which increase CNS serotonin levels may increase risk for serotonin syndrome.

PATIENT MANAGEMENT: The manufacturers of the tricyclic antidepressants, carbamazepine, cyclobenzaprine and mirtazapine state that coadministration with MAO inhibitors is contraindicated. Concurrent linezolid is specifically contraindicated by the manufacturers of clomipramine, desipramine, mirtazapine, nortriptyline, and trimipramine.(1,3-5,7-12) The manufacturer of linezolid does not contraindicate the use of serotonergic agents but states that they should not be coadministered unless clinically appropriate and the patient is closely monitored.(1) This recommendation is consistent with the 2011 FDA Drug Safety Communication on linezolid and serotonergic psychiatric medications.(13,14) In non-emergency situations in patients maintained on tricyclics or tetracyclics when linezolid therapy is planned, discontinue the patient's tricyclic or tetracyclic at least 2 weeks in advance of linezolid therapy. In emergency situations in patients maintained on tricyclics or tetracyclics, weigh the availability and safety of alternatives to linezolid against the risk of serotonin syndrome. If linezolid therapy is required, the patient's tricyclic or tetracyclic should be immediately discontinued. Patients should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid, whichever comes first. The patient's tricyclic or tetracyclic therapy may be resumed 24 hours after the last dose of linezolid.(13) Clinical studies have found a low incidence of serotonin syndrome in patients on concomitant linezolid and serotonergic agents, ranging from 0.24% to 4%, depending on the quality and size of the study. While linezolid-associated serotonin syndrome is potentially serious and fatal, if treated early, it is quickly reversible with discontinuation of offending agents and supportive care. Therefore, some authors suggest that use of serotonergic medications should not preclude the use of linezolid but that the clinical situation should be assessed. If concurrent use or use of linezolid without a washout is warranted, the patient should be closely monitored.(15-20) If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: It should be noted that if this interaction occurs, the consequences will be immediate and severe. Effects may continue to be seen for several days after discontinuing linezolid. The FDA FAERS contains reports of serotonin syndrome with the concurrent use of linezolid and citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine. The risk of serotonin syndrome with other psychiatric drugs is unclear.(14)

Ugt And Selected Cyp3a4 Inducers/Acoramidis

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

MECHANISM OF ACTION: UGT and selected CYP3A4 inducers may induce the metabolism of acoramidis, which is glucuronidated by UGT1A9, UGT1A1, and UGT2B7.(1)

CLINICAL EFFECTS: Concurrent use of UGT and selected CYP3A4 inducers may result in decreased levels and effectiveness of acoramidis.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of acoramidis states to avoid concomitant use of acoramidis with UGT inducers and strong CYP3A inducers.(1)

DISCUSSION: UGT and selected CYP3A4 inducers linked to this monograph include: carbamazepine, efavirenz, fosphenytoin, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and ritonavir.

Ugt Inducers/Canagliflozin

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

MECHANISM OF ACTION: UGT inducers may induce the metabolism of canagliflozin, which is glucuronidated by UGT1A9 and UGT2B4.(1)

CLINICAL EFFECTS: Concurrent use of an inducer of UGT may result in decreased levels and effectiveness of canagliflozin.(1)

PREDISPOSING FACTORS: This interaction may be more severe in patients who have a eGFR of less than 60 ml/min/1.73m2.(1)

PATIENT MANAGEMENT: In patients with a eGFR of 60 ml/min/1.73m2 or more who are currently tolerating canagliflozin 100 mg daily and require therapy with an inducer of UGT, the manufacturer of canagliflozin recommends increasing the dose of canagliflozin to 200 mg daily. Patients currently tolerating canagliflozin 200 mg daily and require additional glycemic control may have their dose increased to 300 mg daily.(1) In patients with a eGFR of less than 60 ml/min/1.73m2 who are currently tolerating canagliflozin 100 mg daily and receiving therapy with a UGT inducer, increase the dose of canagliflozin to 200 mg daily. Consider other antihyperglycemic agents in patients who require additional glycemic control.(1)

DISCUSSION: Pretreatment with rifampin (600 mg daily for 8 days) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of canagliflozin (300 mg) by 51% and 28%, respectively.(1) Inducers of UGT include: carbamazepine, efavirenz, fosphenytoin, lorlatinib, phenobarbital, phenytoin, primidone, rifampin, and ritonavir.(1)

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

Agents With Hyponatremia Risk/Desmopressin

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

MECHANISM OF ACTION: Carbamazepine, chlorpromazine, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants increase the risk of hyponatremia.(1-3)

CLINICAL EFFECTS: Concurrent use may increase the risk of hyponatremia with desmopressin.(1-3)

PREDISPOSING FACTORS: Predisposing factors for hyponatremia include: polydipsia, renal impairment (eGFR < 50 ml/min/1.73m2), illnesses that can cause fluid/electrolyte imbalances, age >=65, medications that cause water retention and/or increase the risk of hyponatremia (glucocorticoids, loop diuretics).

PATIENT MANAGEMENT: The concurrent use of agents with a risk of hyponatremia with desmopressin may increase the risk of hyponatremia. If concurrent use is deemed medically necessary, make sure serum sodium levels are normal before beginning therapy and consider using the desmopressin nasal 0.83 mcg dose. Consider measuring serum sodium levels more frequently than the recommended intervals of: within 7 days of concurrent therapy initiation, one month after concurrent therapy initiation and periodically during treatment. Counsel patients to report symptoms of hyponatremia, which may include: headache, nausea/vomiting, feeling restless, fatigue, drowsiness, dizziness, muscle cramps, changes in mental state (confusion, decreased awareness/alertness), seizures, coma, and trouble breathing. Counsel patients to limit the amount of fluids they drink in the evening and night-time and to stop taking desmopressin if they develop a stomach/intestinal virus with nausea/vomiting or any nose problems (blockage, stuffy/runny nose, drainage).(1)

DISCUSSION: In clinical trials of desmopressin for the treatment of nocturia, 4 of 5 patients who developed severe hyponatremia (serum sodium <= 125 mmol/L) were taking systemic or inhaled glucocorticoids. Three of these patients were also taking NSAIDs and one was receiving a thiazide diuretic.(2) Drugs associated with hyponatremia may increase the risk, including loop diuretics, carbamazepine, chlorpromazine, glucocorticoids, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants.(1,3-4)

Apalutamide; Carbamazepine/Amlodipine

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

MECHANISM OF ACTION: Concurrent use of apalutamide or carbamazepine may induce the CYP3A4 mediated metabolism of amlodipine.(1-3)

CLINICAL EFFECTS: Concurrent use of apalutamide or carbamazepine may decrease levels and effectiveness of amlodipine.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of apalutamide recommends substituting amlodipine with a drug not metabolized by CYP3A4 when possible. If concurrent therapy with apalutamide or carbamazepine is necessary, monitor the patient for a decrease in the therapeutic effects of amlodipine. The dose of amlodipine may need to be adjusted.(1-3)

DISCUSSION: Apalutamide is a strong inducer of CYP3A4. Amlodipine is metabolized by CYP3A4 and has been shown to be affected by other strong CYP3A4 inducers. In a study in 16 hypertensive chronic kidney disease patients, amlodipine levels decreased an average of 82% after initiation of rifampin. In eight of the 16 patients, the levels were undetectable.(4) A case report describes a 53-year-old women with schizophrenia and hypertension who was stable on paliperidone and amlodipine 5 mg daily. Upon carbamazepine initiation, amlodipine levels decreased by 68%, and blood pressure increased from a baseline of 138/91 to 160/103. Blood pressure normalized after discontinuation of carbamazepine.(5)

Carbamazepine/Caspofungin

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

MECHANISM OF ACTION: Carbamazepine may induce the metabolism of caspofungin by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent administration of caspofungin with carbamazepine may result in decreased levels and clinical effectiveness of caspofungin.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: In adult patients receiving concurrent therapy with carbamazepine, the US manufacturer of caspofungin recommends that an increase in the daily dose of caspofungin to 70 mg (following the usual 70 mg loading dose) be considered.(1) In pediatric patients receiving concurrent therapy with carbamazepine, the US manufacturer of caspofungin recommends that an increase in the daily dose of caspofungin to 70 mg/m2 (to a maximum of 70 mg daily, following the usual 70 mg/m2 loading dose) be considered.(1)

DISCUSSION: Regression analyses of patient pharmacokinetic data suggests that administration of caspofungin with inducers and or mixed inducers/ inhibitors of drug clearance may result in clinically significant decreases in caspofungin concentrations. Therefore, the manufacturer of caspofungin recommends that an increase in the daily dose of caspofungin to 70 mg (following the usual 70 mg loading dose) be considered. The efficacy of a 70 mg daily dose in patients who are not responding to the 50 mg daily dose is not known, but limited safety data suggests that it is well tolerated.(1)

Carbamazepine/Cimetidine

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

MECHANISM OF ACTION: Inhibition of carbamazepine metabolism by CYP3A4.

CLINICAL EFFECTS: The pharmacologic and toxic effects of carbamazepine may be increased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor serum carbamazepine and observe the patient for signs of carbamazepine toxicity when starting, stopping or altering the dose of cimetidine. Administration of an alternative H-2 antagonist, such as famotidine or ranitidine, may circumvent this interaction.

DISCUSSION: Elevated plasma carbamazepine concentrations and toxicity have been reported in patients stabilized on carbamazepine after cimetidine has been started. The effects of this interaction appear to dissipate within one week, at which time carbamazepine returns to the level observed prior to the addition of cimetidine. However, toxicity may still occur as long as these drugs are administered concomitantly.

Carbamazepine/Danazol

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

MECHANISM OF ACTION: Danazol-induced inhibition of CYP3A4, resulting in a decrease in carbamazepine metabolism.

CLINICAL EFFECTS: May see an increase in the pharmacologic activity of carbamazepine, including carbamazepine toxicity.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: It may be necessary to reduce the dose of carbamazepine during concurrent administration of danazol. Monitor serum carbamazepine levels and monitor the patient for symptoms of carbamazepine toxicity. Adjust the dose accordingly.

DISCUSSION: In six patients with epilepsy and fibrocystic breast disease the concentration in serum of antiepileptic drugs was obtained before, during, and after danazol therapy. (1) Carbamazepine serum level increased almost twofold in the presence of danazol. Danazol led to a pronounced inhibition of CBZ metabolism in an epileptic patient. (2) During danazol coadministration, CBZ elimination half-life increased from a pretreatment value of 11 to 24.3 h. Carbamazepine plasma clearance decreased from 57.7 to 23.2 ml/h/kg. Observations in five other female patients confirm that the steady-state plasma concentrations of CBZ increase between 50 and 100% during coadministration of danazol.

Carbamazepine/Esomeprazole; Omeprazole

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

MECHANISM OF ACTION: Esomeprazole and omeprazole are primarily metabolized by CYP2C19. CYP3A4 plays a smaller role in metabolism.(1,2) Carbamazepine is a strong inducer of CYP2C19 and CYP3A4.(2) Esomeprazole and omeprazole are weak CYP3A4 inhibitors and may also affect the metabolism of carbamazepine by CYP3A4.(2)

CLINICAL EFFECTS: Concurrent use of agents which induce both CYP2C19 and CYP3A4 decrease systemic exposure and may result in decreased effectiveness of esomeprazole and omeprazole. Concurrent use of esomeprazole or omeprazole with carbamazepine may increase systemic exposure and may result in increased toxicity of carbamazepine.(1-8)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with carbamazepine for reduced proton pump inhibitor (PPI) effectiveness. Although specific dosing recommendations are not available, a higher dose of esomeprazole or omeprazole may be considered to maintain PPI efficacy. Monitor patients receiving concurrent therapy for increased carbamazepine effects. Therapeutic drug monitoring should be completed routinely when carbamazepine is coadministered with esomeprazole or omeprazole.(7,8)

DISCUSSION: In an interaction study, omeprazole increased the maximum concentration (Cmax), area-under-curve (AUC) and elimination half-life (t1/2) of carbamazepine. The effect of carbamazepine on omeprazole was not studied in these trials (3,4) or in other investigations. The effects of other CYP2C19 inducers on the pharmacokinetics of omeprazole have been reported. In an interaction study, subjects with prostate cancer received omeprazole before and after enzalutamide 160 mg daily (an inducer of CYP2C19 and CYP3A4) for at least 55 days. Enzalutamide decreased omeprazole AUC by 70.5%.(2,5) In an interaction study, rifampin 600 mg daily (an inducer of CYP2C19 and CYP3A4) for 7 days decreased omeprazole AUC by 89.5%.(2,6) In an interaction study, St. John's wort (an inducer of CYP2C19 and CYP3A4) decreased the Cmax and AUC of omeprazole by 37.5% and 49.6%, respectively. The Cmax and AUC of omeprazole sulfone (via CYP2C19) increased by 160.3% and 136.6%, respectively. The Cmax and AUC of 5-hydroxyomeprazole (via CYP3A4) increased by 38.1% and 37.2%, respectively.(7,8)

Carbamazepine/Felbamate

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

MECHANISM OF ACTION: Unknown. However, felbamate probably increases the metabolism of carbamazepine to the epoxide metabolite and/or inhibits the conversion of the epoxide metabolite of carbamazepine to the diol metabolite. In addition, carbamazepine increases the metabolism of felbamate.

CLINICAL EFFECTS: Both serum carbamazepine and felbamate concentrations may be decreased reducing their therapeutic effects.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Serum concentrations of both drugs should be monitored and patients should be observed for changes in seizure control if therapy with either agent is started, stopped or altered. Adjust therapy as indicated. The US manufacturer of felbamate recommends decreasing the dosage of carbamazepine by 20% when initiating felbamate therapy.

DISCUSSION: In patients stabilized on carbamazepine monotherapy, addition of felbamate produced a decrease in plasma carbamazepine concentrations. The effect on serum carbamazepine concentrations was evident following one week of felbamate coadministration, reached a plateau between the second and fourth weeks and persisted during concomitant therapy with both anticonvulsants. Serum carbamazepine concentrations returned to original levels within 3 weeks of discontinuing felbamate. Although serum levels of carbamazepine decreased, the active epoxide metabolite of carbamazepine increased by 46%. Addition of carbamazepine to regimen of patients receiving felbamate results in a decrease in felbamate plasma concentrations.

Carbamazepine/Hydantoins; Anticonvulsant Barbiturates

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

MECHANISM OF ACTION: Phenobarbital, phenytoin, primidone, and perhaps other barbiturates and hydantoins, induce CYP3A4, which metabolizes carbamazepine. Carbamazepine may induce the CYP2C19 mediated metabolism of phenytoin. The mechanism behind carbamazepine-induced increases in phenytoin levels is unknown.

CLINICAL EFFECTS: Concurrent use of barbiturates, phenytoin, and primidone may result in decreased carbamazepine levels. Concurrent use of carbamazepine may result in increased or decreased phenytoin levels.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: These medications are commonly used concurrently. The greatest risk for a clinically significant interaction occurs when therapy is modified. If carbamazepine is added to or discontinued from a regimen including phenytoin, phenytoin levels may be altered, with some patients experiencing increased levels and some decreased levels. Monitor phenytoin serum levels and adjust accordingly. Monitor patients for both decreased efficacy (e.g. seizures) and phenytoin toxicity. Patients taking phenytoin or barbiturates may require higher than expected dosages of carbamazepine to achieve therapeutic levels. Monitor patients closely. If barbiturates, phenytoin, or primidone are added to a regimen including carbamazepine, monitor carbamazepine levels and adjust dosages accordingly. Monitor patients for decreased carbamazepine efficacy (e.g. seizures). If barbiturates, phenytoin, or primidone are discontinued, monitor patients for carbamazepine toxicity and adjust carbamazepine dosages accordingly.

DISCUSSION: In several studies, phenytoin's half-life and/or serum concentrations were found to decrease when carbamazepine therapy was instituted. In one study, the half-life of phenytoin decreased from 10.6 hours to 6.4 hours (39.6%) after at least nine days of concomitant therapy and the phenytoin levels decreased up to 50% in three of seven patients. However, other studies have shown that phenytoin plasma levels increase when carbamazepine is administered concomitantly. In one study involving 24 patients maintained on phenytoin, the initiation of carbamazepine therapy resulted in an 81.3% increase in phenytoin concentrations and an 82.9% increase in the phenytoin concentration/dose ratio in 12 of the patients. Five of the patients developed symptoms of acute phenytoin toxicity. The other 12 patients did not experience any change in phenytoin levels. In another study involving 32 patients, the mean phenytoin plasma concentration became significantly higher (36.9%) secondary to increased doses of carbamazepine. The phenytoin concentration/dose ratio also significantly increased (39.3%). Several studies have shown decreased carbamazepine serum concentrations when phenytoin was administered concurrently. In one study involving 22 patients, the carbamazepine serum concentration was shown to increase by 28% when the phenytoin dosage was reduced, indicating that phenytoin initially reduced carbamazepine levels. Phenobarbital has been shown to decrease serum carbamazepine half-life and plasma concentration levels when given in combination. Significant changes in carbamazepine serum concentrations were seen within five days after the addition of phenobarbital to the therapeutic regimen. Conversely, carbamazepine appears to have no effect on serum phenobarbital levels. Another study involving children with seizure disorders evaluated the effect of phenobarbital co-medication on carbamazepine serum levels. Patients had been maintained on either carbamazepine alone or concurrent carbamazepine and phenobarbital for at least one month. There were no significant differences in carbamazepine levels between patients receiving carbamazepine alone or with concurrent phenobarbital. However, the ratio of carbamazepine level to dose was significantly decreased in patients receiving concurrent phenobarbital (0.570 +/- 0.470 versus 0.627 +/- 0.353). The carbamazepine concentration ratios of two carbamazepine metabolites (the 10,11-epoxide metabolite and the 10,11-dihydroxy metabolite) were increased in patients receiving concurrent carbamazepine and phenobarbital compared to those receiving carbamazepine alone.

Carbamazepine/Lamotrigine

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

MECHANISM OF ACTION: Carbamazepine may induce the metabolism of lamotrigine.(1)

CLINICAL EFFECTS: The concurrent use of carbamazepine with lamotrigine without valproate and without dosage adjustments may result in decreased levels and clinical effectiveness of lamotrigine.(1) Coadministration of lamotrigine and valproic acid with carbamazepine may result in elevated lamotrigine concentrations.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with lamotrigine and carbamazepine without valproate should be observed for decreased lamotrigine levels and clinical effectiveness. The dose of lamotrigine may need to be adjusted if carbamazepine is added to or removed from lamotrigine therapy. Refer to the current lamotrigine prescribing information for information on dosage adjustments. Lamotrigine levels for patients whose therapeutic regimens include coadministration of lamotrigine with carbamazepine should be monitored for elevation. The dose of lamotrigine should be adjusted accordingly while the medication is being coadministered with valproic acid and other antiepileptic drugs.

DISCUSSION: In 24 epileptic adults taking carbamazepine, phenytoin, phenobarbital, or primidone, the time to maximum concentration (Tmax), half-life, and apparent plasma clearance for a single dose of lamotrigine were 2.3 hours, 14.4 hours, and 1.10 ml/min/kg, respectively. In 179 healthy adults taking no other medications, these values were 2.2 hours, 32.8 hours, and 0.44 ml/min/kg, respectively.(1) In 17 epileptic adults taking carbamazepine, phenytoin, phenobarbital, or primidone, the Tmax, half-life, and apparent plasma clearance of multiple dose lamotrigine were 2.0 hours, 12.6 hours, and 1.21 ml/min/kg. These values were 1.7 hours, 25.4 hours, and 0.58 ml/min/kg, respectively, in 36 healthy adults taking no other medications.(1) In 10 pediatric patients with epilepsy aged 10 months to 5.3 years who were taking carbamazepine, phenytoin, phenobarbital, or primidone, lamotrigine Tmax, half-life, and apparent plasma clearance were 3.0 hours, 7.7 hours, and 3.62 ml/min/kg, respectively. In 7 patients in the same age range who where not taking other medications known to affect lamotrigine clearance, these values were 5.2 hours, 19.0 hours, and 1.2 ml/min/kg, respectively.(1) In 527 adult patients with epilepsy, the mean oral clearance of lamotrigine in patients receiving one concomitant enzyme-inducing anti-epileptic agent and not valproic acid was estimated to be 1 ml/min/kg.(3) One study of 302 patients looked at the results of combining lamotrigine with carbamazepine, phenytoin, or phenobarbital with or without valproic acid. The study found when the lamotrigine combinations contained valproic acid that lamotrigine concentrations were two times higher when compared to patients taking either lamotrigine alone or in combination with one of the other antiepileptic drugs even when the lamotrigine doses were halved.(2)

Carbamazepine/Lithium

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

MECHANISM OF ACTION: The exact mechanism of the interaction is unknown. Neurotoxicity symptoms (confusion, delirium, seizures, encephalopathy, and EKG changes) may be due to potentiation or an additive effect of the antipsychotic agent and the lithium.

CLINICAL EFFECTS: Neurotoxicity with therapeutic serum lithium levels has been reported.

PREDISPOSING FACTORS: Large doses of lithium, central nervous system disease and a history of lithium neurotoxicity may predispose this interaction.

PATIENT MANAGEMENT: Monitor patients for lithium toxicity during concomitant administration of carbamazepine. Adjust therapy accordingly.

DISCUSSION: Although lithium and carbamazepine have been given concurrently to successfully treat manic episodes and rapid-cycling bipolar affective disorder, other investigators have reported central nervous system toxicity, including ataxia, hyperreflexia, lethargy, muscular weakness and tremor.

Carbamazepine/Selected Anticoagulants (Vit K Antagonists)

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

MECHANISM OF ACTION: Carbamazepine may induce the metabolism of warfarin by CYP2C9 and CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of carbamazepine may result in decreased levels and effectiveness of warfarin, which may increase the risk of clotting.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor INR response closely in patients maintained on warfarin when initiating, titrating, and discontinuing carbamazepine. Patients maintained on carbamazepine may require higher dosages of warfarin.(1) The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: A retrospective cohort study in 57 patients had an increase in warfarin dose with concurrent carbamazepine use. After initiation of carbamazepine, the mean weekly warfarin dose and ratio of dose/INR increased by 7.6 mg (24%) and 5.7 mg/INR (43%), respectively. Patients experienced no bleeding or thromboembolic events during the study period.(2) This interaction has also been documented in case reports.(3-7)

Carbamazepine/Selected Ssris

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

MECHANISM OF ACTION: The exact mechanism is unknown. The SSRIs may inhibit the metabolism of carbamazepine, although evidence is conflicting.

CLINICAL EFFECTS: Possible increased levels of carbamazepine and clinical toxicity.

PREDISPOSING FACTORS: One set of authors speculated that the interaction may be less prevalent in long-term recipients of carbamazepine in whom carbamazepine has resulted in enzyme induction. Carbamazepine-induced enzyme induction could possibly decrease the amount of SSRI available to interact with carbamazepine.(1)

PATIENT MANAGEMENT: Consider monitoring carbamazepine levels when SSRI therapy is initiated or withdrawn. Patients receiving concurrent therapy should be monitored for clinical signs of toxicity.

DISCUSSION: Information on this interaction is conflicting. In a study in subjects maintained on carbamazepine (CBZ), the addition of fluoxetine or fluvoxamine to their regimens resulted in no changes in either CBZ or carbamazepine-10,11-epoxide (CBZ-E).(1) Another study compared subjects receiving concurrent therapy with CBZ and fluoxetine to subjects receiving CBZ therapy alone. There were no differences in the ratios of CBZ to CBZ-E levels between the groups, although there was a trend towards lower CBZ clearance in the group receiving concurrent therapy. The in-vitro section of this study found that fluoxetine did not inhibit the metabolism of CBZ until fluoxetine reached levels 20 times greater than those found clinically. In contrast, another study in healthy subjects found a 30% increase in area-under-curve (AUC) of CBZ and CBZ-E during concurrent therapy with fluoxetine.(3) There have been four case reports of parkinsonism developing after the addition of fluoxetine to CBZ therapy. (4-6) There have been two case reports of increased CBZ levels(7) and one report of serotonin syndrome(8) following the addition of fluoxetine therapy. Information on fluvoxamine is also conflicting. Although the addition of fluvoxamine to carbamazepine regimens resulted in no changes in either CBZ or CBZ-E levels in one study,(1) there have been five case reports of increases in CBZ levels, with clinical toxicity in two reports, during concurrent therapy.(9-10) Information on sertraline is also conflicting. Although the addition of sertraline to carbamazepine regimens resulted in no changes in either CBZ or CBZ-E levels in one study,(11) there has been one case report of increased CBZ levels with clinical toxicity during concurrent therapy.(12) One study has demonstrated that paroxetine had no effect on CBZ levels or effectiveness.(13)

Carbamazepine/Valproic Acid

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

MECHANISM OF ACTION: Valproic acid may displace carbamazepine from protein binding sites and inhibit the metabolism of the active metabolite of carbamazepine. In addition, carbamazepine may increase the metabolism of valproic acid.

CLINICAL EFFECTS: Loss of seizure control due to decreased serum valproic acid concentrations. Toxicity due to increased concentrations of the active metabolite of carbamazepine.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor serum concentrations of both drugs. Adjust the dose of either drug as needed.

DISCUSSION: After discontinuing carbamazepine therapy, valproic acid levels increased in one patient producing pancreatitis. Acute psychosis was reported in another patient 8 days after adding carbamazepine to the patient's valproic acid regimen. Numerous studies have found that carbamazepine can decrease serum valproic acid concentrations. While the effects of valproic acid on carbamazepine levels are variable, serum concentrations of the active metabolite of carbamazepine are increased.

Carbamazepine; Rifampin/Vortioxetine

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

MECHANISM OF ACTION: While vortioxetine is primarily metabolized by CYP2D6, many other CYP enzymes also play a role, including CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6.(1) Carbamazepine and rifampin may induce these enzymes.(2-3)

CLINICAL EFFECTS: The concurrent administration of carbamazepine or rifampin may result in decreased levels and effectiveness of vortioxetine.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of vortioxetine states that patients receiving strong CYP enzyme inducers for greater than 14 days may require an increase in their dosage of vortioxetine, up to a maximum of three times the original dose.(1) If carbamazepine or rifampin is discontinued in a patient who has been maintained on vortioxetine, the dose of vortioxetine should be reduced to the original level within 14 days.(1)

DISCUSSION: In a study of 14 healthy volunteers, rifampin decreased the area-under-curve (AUC) and maximum concentration (Cmax) of vortioxetine by 72.3% and 50.9%, respectively, compared to vortioxetine when given alone.(4)

Carbamazepine;Phenobarb/Tricyclic Antidepressants; Mianserin

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

MECHANISM OF ACTION: Carbamazepine and phenobarbital may induce the metabolism of tricyclic antidepressants (TCAs) and mianserin by the CYP P450 isoenzyme system.(1,2)

CLINICAL EFFECTS: The concurrent administration of TCAs or mianserin with carbamazepine or phenobarbital may result in decreased levels and clinical effects of the TCA or mianserin.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving both of these medications should be alerted to the possibility of decreased effects of the TCA or mianserin.(1,2) Observe the patient for loss of the therapeutic effect of the TCA or mianserin and consider monitoring TCA or mianserin levels during concurrent therapy.(3,4) Consider dose adjustment of the TCA or mianserin if carbamazepine or phenobarbital is added to or discontinued from concurrent therapy.(2,4)

DISCUSSION: A study of 22 psychiatric patients examined the effects of carbamazepine on serum levels of several antidepressants. Carbamazepine lowered amitriptyline levels by 60%, doxepin levels by 55%, and mianserin levels by 70%. The authors recommended carefully monitoring antidepressant drug levels when carbamazepine is coadministered.(3) A large retrospective study found that patients on carbamazepine with amitriptyline or nortriptyline had concentration/dose (C/D) ratios for the antidepressants that were about 50% lower than the C/D ratios for patients not on carbamazepine. The authors suggest that therapeutic drug monitoring is valuable for managing drug interactions.(4) In healthy volunteers, carbamazepine 200 mg twice daily for 28 days increased desipramine clearance by 31%.(6) In a study of 13 patients with depression, carbamazepine 400 mg per day decreased total imipramine levels by 39.5% and desipramine levels by 24.5% but levels of the pharmacologically active free drugs were not affected. The authors suggested that dose adjustment of imipramine may not be necessary.(7) A pharmacokinetic study found that carbamazepine 400 mg per daily for 4 weeks decreased plasma concentrations of mianserin by 34-45%. A doubling of the mianserin dose was proposed when coadministered with carbamazepine.(5)

Cyp2b6 And Selected Cyp3a4 Inducers/Levomethadone; Methadone

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

MECHANISM OF ACTION: CYP2B6 inducers, phenytoin, and St. John's wort may increase the metabolism of levomethadone and methadone.(1-7)

CLINICAL EFFECTS: Concurrent use of CYP2B6 inducers, phenytoin, or St. John's wort may result in decreased levels of levomethadone and methadone, which may result in decreased effectiveness and may precipitate withdrawal symptoms.(1-7)

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 levomethadone or methadone may require dosage adjustments if a CYP2B6 inducer, phenytoin, or St. John's wort is initiated or discontinued. The effects of the interaction may last for several weeks after the discontinuation of the inducer.

DISCUSSION: In a study, efavirenz (600 mg daily) given for 3 weeks in patients on levomethadone led to a decrease in maximum concentration (Cmax) and area-under-curve (AUC) of levomethadone of 48 % and 57 %, respectively.(2) There are three case reports of patients in methadone maintenance programs who experienced withdrawal symptoms following the initiation of rifampin for tuberculosis therapy.(7,8) In one of these patients, the methadone clearance was measured at 8.97 ml/min/kg during concurrent administration of rifampin, compared with 2.11 ml/min/kg during methadone alone.(7) Other reports have documented that methadone-treated patients who received concurrent antituberculosis therapy which included rifampin experienced withdrawal symptoms while methadone-treated patients who received antituberculosis therapy which did not include rifampin did not.(9-12) Subsequently, it was determined that methadone plasma concentrations were decreased 33% to 68% in patients receiving concurrent rifampin compared with patients on non-rifampin regimens.(9,11-12) In a study in five patients maintained on methadone, the addition of phenytoin to their regimens resulted in moderately severe withdrawal symptoms and a decrease in the area-under-curve (AUC) for methadone. Methadone plasma concentrations returned to baseline levels two to three days after the discontinuation of phenytoin.(6) In a study in four patients in a methadone maintenance program, the addition of St. John's wort (900 mg daily) decreased methadone levels by 47% (range: 19%-60%). Two patients reported withdrawal symptoms.(7) CYP2B6 inducers linked to this monograph include: carbamazepine, dipyrone, isavuconazonium, ledipasvir/sofosbuvir, phenobarbital, primidone, rifampin, and sparsentan. Fosphenytoin, phenytoin and St. John's wort are also linked.

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

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

MECHANISM OF ACTION: Afatinib is a substrate of the intestinal efflux transporter P-glycoprotein (P-gp). Apalutamide, carbamazepine, efavirenz, lorlatinib, phenytoin, rifabutin, rifampin, rifapentine, and St. John's wort induce production of P-gp which may lead to decreased exposure to afatinib.(1,2) Phenobarbital may also induce the metabolism of afatinib.(1) Primidone is metabolized to phenobarbital.

CLINICAL EFFECTS: Concurrent or recent use of P-glycoprotein inducers (apalutamide, carbamazepine, efavirenz, lorlatinib, phenytoin, rifabutin, rifampin, rifapentine, or St. John's wort), phenobarbital, or primidone may result in decreased levels and effectiveness of afatinib.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of afatinib recommends an increase of afatinib dose by 10 mg per day as tolerated in patients receiving chronic therapy with a P-gp inducer or phenobarbital.(1) Onset of induction is gradual and maximal induction may be delayed for many days or longer, depending upon the inducing agent and dose. If the P-gp inducer, phenobarbital, or primidone is stopped, the manufacturer of afatinib recommends resumption of previous afatinib dose 2 to 3 days after discontinuation of the inducing agent.(1)

DISCUSSION: In a drug interaction study, co-administration of rifampin 600 mg once daily for 7 days decreased afatinib exposure 34%.(1) P-gp inducers include apalutamide, carbamazepine, efavirenz, lorlatinib, phenytoin, rifabutin, rifampin, rifapentine, and St. John's wort.(1,2) Based on 2 case reports(3,4) and in vitro studies,(5,6) the manufacturer of afatinib also includes phenobarbital as a P-gp inducer.(1)

Selected Anticonvulsants; Barbiturates/Tiagabine

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

MECHANISM OF ACTION: Barbiturates, carbamazepine, phenobarbital, phenytoin, and primidone may induce the metabolism of tiagabine by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of barbiturates, carbamazepine, phenobarbital, phenytoin, or primidone with tiagabine may result in decreased levels and clinical effectiveness of tiagabine.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with tiagabine and barbiturates, carbamazepine, phenobarbital, phenytoin, or primidone should be observed for decreased tiagabine levels and clinical effectiveness. The dose of tiagabine should be adjusted accordingly when coadministered with enzyme-inducing antiepileptic drugs. The US manufacturer of tiagabine provides dosing titration recommendations for tiagabine when used concurrently with enzyme-inducing antiepileptic drugs. In patients 12-18 years old, tiagabine should be initiated at 4 mg daily and increased by 4 mg weekly until clinical response is achieved, to a maximum of 32 mg/day. In adults, tiagabine should be initiated at 4 mg daily and increased by 4-8 mg weekly until clinical response is achieved, to a maximum of 56 mg/day. The dose of tiagabine may need to be adjusted if these agents are added to or removed from tiagabine therapy. It may be useful to obtain plasma levels of tiagabine before and after changes are made in the therapeutic regimen.(1)

DISCUSSION: Population pharmacokinetic studies have shown that tiagabine clearance is 60% greater in patients taking carbamazepine, phenytoin, phenobarbital, or primidone than in patients not on an enzyme inducer.(1)

Selected Cyp1a2 Inducers/Olanzapine

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

MECHANISM OF ACTION: Inducers of CYP1A2 may increase the metabolism of olanzapine.(1,2)

CLINICAL EFFECTS: Concurrent use of a CYP1A2 inducer may result in decreased 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: Patients receiving concurrent therapy with olanzapine and a CYP1A2 inducer may require increased dosages of olanzapine. The dosage of olanzapine may need to be adjusted if concurrent therapy with a CYP1A2 inducer is initiated or discontinued.(1,2) If a CYP1A2 inducer is initiated in a patient maintained on olanzapine, monitor for decreased effectiveness of olanzapine. If a CYP1A2 inducer is discontinued in a patient maintained on olanzapine, monitor for olanzapine toxicity.

DISCUSSION: Concurrent use of carbamazepine, a CYP1A2 inducer, increased olanzapine clearance by 50%.(1,2)

Selected Cyp2c And Cyp3a4 Inducers/Ospemifene

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.

Selected Cyp3a4 Inducers/Selected Benzodiazepines

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

MECHANISM OF ACTION: CYP3A4 inducers may induce the metabolism of some benzodiazepines.

CLINICAL EFFECTS: Concurrent or recent use of CYP3A4 inducers may result in decreased levels and loss of effectiveness of some benzodiazepines.

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

PATIENT MANAGEMENT: Monitor patients receiving CYP3A4 inducers or who have received these agents in the previous 2 weeks for decreased benzodiazepine effectiveness. The dose of the benzodiazepine may need to be adjusted or an alternative agent used. If the CYP3A4 inducer is discontinued, benzodiazepine levels will gradually rise as induction effects diminish. Monitor for increased benzodiazepine effects and adjust the dose accordingly.

DISCUSSION: In a study in 95 healthy subjects, rifampin (450 mg daily for 5 days) decreased the plasma concentrations of a single oral dose of alprazolam (1 mg) by 79%.(1) In another study in 4 healthy subjects, rifampin (given for 4 days) decreased the area-under-curve (AUC) of a single oral dose of alprazolam (1 mg) by 88%.(2) In a double-blind, randomized, cross-over trial in 13 healthy subjects, rifampin (450 mg daily for 7 days) decreased the maximum concentration (Cmax), AUC, and half-life of a single oral dose of brotizolam (0.5 mg) by 69%, 90%, and 69%, respectively. Concurrent rifampin increased scores on the Digit Symbol Substitution Test (DSST) and decreased scores on the Stanford Sleepiness Scale.(3) In a study in 21 healthy subjects, rifampin (600 mg or 1200 mg daily for 7 days) increased total body clearance of diazepam by 300%.(4) An in vitro study in human hepatocytes found that rifampin increased the biotransformation of diazepam and midazolam by 1.9-fold.(5) In a study in 24 healthy subjects, rifampin (600 mg daily for 10 days) increased the clearance of a single intravenous dose of lorazepam by 140%.(6) In an open-label cross-over study in 19 healthy subjects, rifampin (600 mg daily for 9 days) increased the clearance of a single oral dose of midazolam (0.075 mg/kg) by 7-fold.(7) In a study in 57 healthy subjects, rifampin increased the systemic and oral clearance of midazolam by 2-fold and 16-fold, respectively.(8) In a study in 8 healthy subjects, rifampin (given for 6 days) significantly increased the clearance of midazolam.(9) In a study in 9 healthy subjects, received a single oral dose of midazolam (15 mg) before, one day after the administration of rifampin (600 mg daily for 5 days), and 4 days after the last dose of rifampin. One day after rifampin, the AUC of midazolam was decreased by 97.7% when compared to the administration of midazolam prior to rifampin. Four days after the completion of rifampin, the AUC of midazolam was decreased by 87% when compared to the administration of midazolam prior to rifampin.(10) In a double-blind, randomized, cross-over study in 10 healthy subjects, rifampin (600 mg daily for 5 days) decreased the Cmax, AUC, and half-life of a single oral dose of midazolam (15 mg) by 94%, 96%, and 58%, respectively. The pharmacodynamic effects of midazolam were also significantly decreased during rifampin therapy.(11) In a study in 16 healthy subjects, rifampin (600 mg daily for 7 days) increased the clearance of nitrazepam by 83%. There were no significant effects on the pharmacokinetics of temazepam.(12) In a randomized, double-blind, cross-over study in 10 healthy subjects, rifampin (600 mg daily for 5 days) decreased the Cmax, AUC, and half-life of a single dose of triazolam (0.5 mg) by 87.6%, 94.9%, and 54%, respectively. The pharmacodynamic effects of triazolam were also significantly decreased during rifampin therapy.(13) In an open-label, randomized, cross-over study in 27 healthy subjects, rifaximin (200 mg three times daily for 7 days) had no effect on the pharmacokinetics of single doses of oral or intravenous midazolam.(14) In a study in 98 patients with schizophrenia or bipolar disorder, the expression of CYP3A4 was found to be the major determinant of clonazepam plasma concentrations normalized by the dose and bodyweight (1263 +/- 482.9 and 558.5 +/- 202.4 ng/mL per mg/kg bodyweight in low and normal expressers, respectively, p<0.0001).(18) Selected CYP3A4 inducers linked to this monograph include: apalutamide, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenytoin, rifabutin, rifampin, rifapentine, and St. John's wort.

Selected P-Gp Inducers; Phenobarbital/Tenofovir Alafenamide

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

MECHANISM OF ACTION: Tenofovir alafenamide (TAF) is a substrate of the intestinal efflux transporter P-glycoprotein (P-gp). Inducers of P-gp may decrease systemic absorption of TAF.(1-4) Phenobarbital may also induce the metabolism of tenofovir alafenamide.(1-4) Primidone is metabolized to phenobarbital.

CLINICAL EFFECTS: Concurrent or recent use of P-gp inducers, phenobarbital, or primidone may result in decreased systemic levels and effectiveness of tenofovir alafenamide.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Recommendations regarding concurrent use of tenofovir alafenamide and P-gp inducers vary depending on the region and drug formulation. The European manufacturer of tenofovir alafenamide (DESCOVY for HIV infection and VEMLIDY for hepatitis B) states that concurrent use is not recommended with carbamazepine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, or St. John's wort.(1,2) The US manufacturer of DESCOVY states that rifabutin, rifampin, rifapentine, and St. John's wort are not recommended. Alternatives should be considered for carbamazepine, phenobarbital, phenytoin, and primidone.(3) The Australian and US manufacturers of tenofovir alafenamide (VEMLIDY for hepatitis B) states that concurrent use with phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, or St. John's wort is not recommended. If concurrent therapy with carbamazepine is indicated during treatment for Hepatitis B, the manufacturer recommends increasing the dose of tenofovir alafenamide to two tablets (50 mg) once daily.(4-5)

DISCUSSION: When tenofovir alafenamide (TAF) was coadministered with carbamazepine, the maximum concentration (Cmax) and area-under-curve (AUC) were decreased 57% and 55%, respectively.(1-4) A subsequent study suggests that this interaction may not have clinically significant effects on intracellular levels of tenofovir diphosphate, the active metabolite of tenofovir alafenamide. In a study of 23 healthy volunteers, the intracellular Cmax and AUC of tenofovir diphosphate were 38% and 36% lower, respectively, when tenofovir alafenamide was coadministered with rifampin than without rifampin. However, these levels of tenofovir diphosphate were 4.4- and 4.21-fold higher, respectively, than levels obtained from tenofovir disoproxil 300 mg daily without rifampin.(6) Selected P-gp inducers linked to this monograph include: apalutamide, carbamazepine, fosphenytoin, lorlatinib, phenytoin, rifabutin, rifampin, rifapentine, or St. John's wort.(1-7) The manufacturer of tenofovir alafenamide also classifies phenobarbital as a P-gp inducer.(1-4)

Selected Strong Cyp3a4 Inducers/Corticosteroids

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

MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of corticosteroids. Corticosteroids may affect the metabolism of phenytoin.

CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers may result in decreased levels and effectiveness of corticosteroids. Dexamethasone has been shown to increase and decrease phenytoin levels.

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

PATIENT MANAGEMENT: Patients receiving concurrent therapy with a strong CYP3A4 inducer should be monitored for decreased effectiveness of their corticosteroid. Increased dosage of corticosteroid may be required during concurrent therapy and for several weeks after completing concurrent therapy. If concurrent therapy is discontinued, the dosage of the corticosteroid may need to be adjusted. Phenytoin levels should be closely monitored in patients receiving corticosteroids. The dosage of phenytoin may need to be adjusted if corticosteroids are initiated or discontinued.

DISCUSSION: Carbamazepine has been shown to increase the metabolism of methylprednisolone, prednisolone, and prednisone, resulting in decreased levels and effectiveness of these agents. Phenobarbital has been shown to increase the metabolism of dexamethasone, methylprednisolone, and prednisolone. Primidone is metabolized to phenobarbital. Phenytoin has been shown to increase the metabolism of dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone, resulting in decreased levels and effectiveness of these agents Rifampin has been shown to increase the metabolism of cortisol, dexamethasone, methylprednisolone, prednisolone, and prednisone. Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifapentine, rifampin, and St. John's wort.

Selected Strong Cyp3a4 Inducers/Haloperidol

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)

Selected Strong Cyp3a4 Inducers/Levomethadyl

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 levomethadyl.(1)

CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inducer may result in decreased levels of levomethadyl, which may result in decreased effectiveness and may precipitate withdrawal symptoms.(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 levomethadyl 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.

DISCUSSION: Interaction studies have not been conducted in humans. The primary metabolism pathway for levomethadyl is CYP3A4. The addition of drugs that induce CYP3A4 may increase levels of the active metabolite.(1) Selected strong CYP3A4 inducers linked to this monograph include: apalutamide, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenytoin, rifampin, rifapentine, and St. John's Wort.

Selected Strong Cyp3a4 Inducers/Selected Opioids

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.

Selected Ugt And Strong Cyp3a4 Inducers/Oxcarbazepine

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, ivosidenib, lorlatinib, lumacaftor, mitotane, rifampin, rifapentine, and St. John's wort.(1-2)

Slt Dual Cyp2c19 & Cyp3a4 Inducers/Citalopram; Escitalopram

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)

Sodium Channel Blocker; Potassium Channel Blocker/Lacosamide

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

MECHANISM OF ACTION: Lacosamide may enhance the slow inactivation of voltage-gated sodium channels and may cause dose-dependent bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)

CLINICAL EFFECTS: Concurrent use of lacosamide and agents that affect cardiac conduction (sodium channel blockers and potassium channel blockers) may increase the risk of bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lacosamide should be used with caution in patients on concomitant medications that affect cardiac conduction, including sodium channel blockers and potassium channel blockers.(1) If concurrent use is needed, obtain an ECG before lacosamide therapy and after lacosamide dose is titrated to steady-state.(1) Patients should be monitored closely when lacosamide is given intravenously.(1)

DISCUSSION: In a clinical trial in patients with partial-onset seizures, asymptomatic first-degree atrioventricular (AV) block occurred in 4/944 (0.4%) of patient who received lacosamide compared to 0/364 (0%) with placebo.(1) In a clinical trial in patients with diabetic neuropathy, asymptomatic first-degree AV block occurred in 5/1023 (0.5%) of patients who received lacosamide compared to 0/291 (0%) with placebo.(1) Second-degree and complete AV block have been reported in patients with seizures.(1) One case of profound bradycardia was observed in a patient during a 15-minute infusion of 150 mg of lacosamide.(1) A case report of a 49 year old male with refractory complex partial and generalized seizures described the development of ventricular tachycardia four months after addition of lacosamide 400 mg/day to the existing regimen of carbamazepine, lamotrigine, clonazepam, and valproate. The patient's ECG showed first-degree AV block, posterior left fascicular block, and severe widening of the QRS complex, all of which resolved upon discontinuation of lacosamide.(2)

Strong 3A4 Inducers/Aripiprazole Lauroxil

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)

Strong And Moderate Cyp3a4 Inducers/Perampanel

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

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

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

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

PATIENT MANAGEMENT: Patients receiving concurrent therapy with strong and moderate CYP3A4 inducers and perampanel should be observed for decreased anticonvulsant levels and clinical effectiveness. The manufacturer of perampanel recommends a starting dose of 4 mg once daily at bedtime in patients receiving concurrent therapy with CYP3A4 inducers. Dose increases are recommended by 2 mg increments once daily based on clinical response and tolerability, no more frequently than at weekly intervals. The highest studied dose with concurrent enzyme-inducing antiepileptic drugs was 12 mg once daily.(1) The dose of the anticonvulsant may need to be adjusted if a strong or moderate CYP3A4 inducer is added to or removed from therapy.(1)

DISCUSSION: In a study in healthy subjects, carbamazepine 300 mg BID decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single 2 mg tablet dose of perampanel by 26% and 67%, respectively. The half-life (t1/2) of perampanel was shortened from 56.8 hours to 25 hours. In clinical studies examining partial-onset and primary generalized tonic-clonic seizures, a population pharmacokinetic analysis showed that perampanel AUC was reduced by 64% in patients on carbamazepine compared to the AUC in patients not on enzyme-inducing antiepileptic drugs.(1) In a study in partial-onset and primary generalized tonic-clonic seizures, a population pharmacokinetic analysis showed that perampanel AUC was reduced by 48% in patients on oxcarbazepine compared to patients not on enzyme-inducing antiepileptic drugs.(1) In a study in partial-onset and primary generalized tonic-clonic seizures, a population pharmacokinetic analysis showed that perampanel AUC was reduced by 43% in patients on phenytoin compared to patients not on enzyme-inducing antiepileptic drugs.(1) In a study in partial-onset and primary generalized tonic-clonic seizures in clinical trials (40 patients co-administered phenobarbital and 9 patients co-administered primidone), no significant effect on perampanel AUC was found. A modest effect of phenobarbital and primidone on perampanel concentrations cannot be excluded.(1) In a study in 76 patients, concentration-to-dose (CD) ratio of perampanel was assessed with and without concurrent antiepileptic agents. In patients only on perampanel the mean CD ratio was 3963 ng/mL/mg/kg (range: 1793-13,299) compared to the mean CD ratio in patients using enzyme-inducing AEDs [1760 (range: 892-3090), 2256 (range: 700-4703), and 1120 (range: 473-1853) ng/mL/mg/kg in patients taking phenytoin, phenobarbital, and carbamazepine, respectively], and carbamazepine had a significantly greater reduction in the CD ratio compared with phenytoin or phenobarbital (P < 0.001).(3) Strong and moderate CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, bosentan, carbamazepine, cenobamate, dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, eslicarbazepine, etravirine, fexinidazole, fosphenytoin, ivosidenib, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, modafinil, nafcillin, oxcarbazepine, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(1,2)

Strong And Moderate Cyp3a4 Inducers/Sildenafil (Pah)

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

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

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

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

PATIENT MANAGEMENT: Concomitant use of sildenafil with strong or moderate CYP3A4 inducers should be monitored closely. An increased dosage of sildenafil may be needed. Reduce sildenafil dose to 20 mg three times daily when discontinuing treatment with strong and moderate CYP3A4 inducers.(1)

DISCUSSION: Population pharmacokinetic analysis of data from patients in clinical trials found that sildenafil clearance increased about 3-fold when coadministered with mild CYP3A4 inducers.(1) A randomized, double-blind, placebo-controlled, parallel-group study of 55 healthy volunteers found that 10 days of bosentan (125 mg twice daily), a moderate CYP3A4 inducer, decreased the maximum concentration (Cmax) and area-under-curve (AUC) of sildenafil by 55.4% and 62.6%, respectively. Sildenafil increased bosentan Cmax and AUC by 42% and 49.8%, respectively. The combination was well tolerated without serious adverse events.(2) In a study of 15 HIV-negative subjects, etravirine (800 mg twice daily for 14 days), a moderate CYP3A4 inducer, decreased the Cmax and AUC of sildenafil by 45% and 57%, respectively.(3) The authors of a review article on drug interactions in pulmonary arterial hypertension therapy state that phenytoin and rifampin (strong CYP3A4 inducers) are not recommended with sildenafil due to an expected near-complete clearance of sildenafil.(4) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(5,6) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(5,6)

Strong Cyp3a4 Inducers/Aficamten

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

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

CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers may decrease the levels and effectiveness of aficamten and increase the risk of developing heart failure due to systolic dysfunction.(1)

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

PATIENT MANAGEMENT: In patients who are on stable concurrent therapy with aficamten and a moderate to strong CYP3A4 inducer, reduce the dose of aficamten when discontinuing the inducer as follows: -If the current dose is 20 mg daily, reduce to 10 mg daily. -If the current dose is 15 mg daily, reduce to 5 mg daily. -If the current dose is 10 mg daily, reduce to 5 mg daily. -If the current dose is 5 mg daily, maintain 5 mg daily. Assess LVEF 2 to 8 weeks after discontinuation of such inducers and adjust the dose of aficamten accordingly.(1)

DISCUSSION: In a study, carbamazepine (strong CYP3A4 inducer, weak CYP2C9 inducer) decreased aficamten's area-under-curve (AUC) 51%.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifapentine, and St. John's Wort.(2,3)

Strong Cyp3a4 Inducers/Belumosudil

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)

Strong Cyp3a4 Inducers/Belumosudil (400 Mg)

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)

Strong Cyp3a4 Inducers/Cannabidiol; Tetrahydrocannabinol

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)

Strong Cyp3a4 Inducers/Clindamycin

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)

Strong Cyp3a4 Inducers/Crinecerfont

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)

Strong Cyp3a4 Inducers/Cyclophosphamide

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)

Strong Cyp3a4 Inducers/Dabrafenib

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 dabrafenib.(1-4)

CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may decrease the levels and effectiveness of dabrafenib.(1-4)

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

PATIENT MANAGEMENT: Recommendations for management of this interaction vary in different regions. The Australian, Canadian, and UK manufacturers of dabrafenib state that co-administration with strong inducers of CYP3A4 should be avoided due to the possibility of subtherapeutic exposure to dabrafenib. Monitor patients for loss of efficacy or consider the use of alternative medicinal products.(1-3) The US manufacturer of dabrafenib does not provide recommendations with strong inducers of CYP3A4.(4)

DISCUSSION: Concurrent use of rifampin (a strong CYP3A4 inducer) 600 mg once daily and dabrafenib 150 mg twice daily resulted in a decrease in repeat-dose dabrafenib maximum concentration (Cmax) by 27% and area-under-curve (AUC) by 34%. No relevant change in AUC was noted for hydroxy-dabrafenib. There was an increase in AUC of 73% for carboxy-dabrafenib and a decrease in AUC of 30% for desmethyl-dabrafenib.(1-4) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenytoin, primidone, rifamycins, and St. John's Wort.(5-6)

Strong Cyp3a4 Inducers/Disopyramide; Propafenone

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

MECHANISM OF ACTION: Disopyramide and propafenone are partially metabolized by CYP3A4. Strong CYP3A4 inducers may increase the hepatic metabolism of disopyramide and propafenone(1-2).

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may result in decreased levels and effectiveness of disopyramide and propafenone(1-2).

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

PATIENT MANAGEMENT: Monitor patient's cardiac function and serum disopyramide or propafenone levels. Adjust the dosage accordingly.(1)

DISCUSSION: In a study of 8 smokers and 8 non-smokers, phenobarbital (100 mg daily for 21 days) decreased single-dose disopyramide area-under-curve (AUC) and half life by 35%, and increased metabolic clearance by 120% in all subjects.(3) During concomitant administration of disopyramide and rifampin to patients with tuberculosis, serum disopyramide concentrations decreased by approximately 50% while the concentration of an active metabolite of disopyramide increased.(4) Concurrent administration of disopyramide and rifampin to a 62-year-old patient produced subtherapeutic disopyramide levels and a failure in correcting the patient's arrhythmia. Five days after stopping rifampin, disopyramide levels increased and the arrhythmia was abolished.(5) In a study in six elderly subjects, pretreatment with rifampin (600 mg daily for 9 days) decreased the bioavailability of a single dose of oral propafenone (300 mg) by 86%. Maximum QRS prolongation after oral propafenone was decreased by 50%. There were no significant effects on intravenous propafenone.(6) In a study in six extensive CYP2D6 metabolizers and six poor CYP2D6 metabolizers, pretreatment with rifampin (600 mg daily for 9 days) decreased the bioavailability of a single dose of oral propafenone by 67% and by 41% in extensive and poor metabolizers, respectively. Maximum QRS prolongation after oral propafenone decreased by 38% and by 40% in extensive and poor metabolizers, respectively. There were no effects on intravenous propafenone.(7) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, and St. John's wort.

Strong Cyp3a4 Inducers/Doxycycline

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.

Strong Cyp3a4 Inducers/Lenacapavir (Prep)

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

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

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

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

PATIENT MANAGEMENT: The manufacturer of lenacapavir for PrEP states that concurrent use of strong CYP3A inducers requires supplemental doses of lenacapavir. Strong CYP3A inducers may be initiated starting at least 2 days after the first dose of lenacapavir. Recommendations for supplemental doses of lenacapavir state: -On the day strong CYP3A inducer is initiated (at least 2 days after first dose of lenacapavir): Step 1 - Supplement with 927 mg subcutaneously and 600 mg orally. -On the day after strong CYP3A inducer is initiated: Step 2 - Supplement with 600 mg orally. -If strong CYP3A inducer is coadministered longer than 6 months: Every 6 months after CYP3A inducer is initiated, supplement lenacapavir following Step 1 and Step 2 above. After a strong CYP3A inducer is stopped, continue the scheduled continuation doses of lenacapavir every 6 months.(1)

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.(2,3)

Strong Cyp3a4 Inducers/Paltusotine

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 paltusotine.(1)

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

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

PATIENT MANAGEMENT: Patients taking strong CYP3A4 inducers may require an increased dosage of paltusotine.(1) The manufacturer of paltusotine states do not exceed three-fold the paltusotine dosage prior to concomitant use or 120 mg daily, whichever is less.(1) Monitor patients receiving concurrent therapy for reduced efficacy.

DISCUSSION: Paltusotine is metabolized by CYP3A4.(1) In an interaction study, paltusotine concentration maximum (Cmax) and area-under-curve (AUC) decreased by 44% and 70%, respectively, following concomitant administration of carbamazepine (strong CYP3A inducer).(1) 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)

Strong Cyp3a4 Inducers/Pitolisant

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)

Strong Cyp3a4 Inducers/Quetiapine (<= 150 Mg)

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)

Strong Cyp3a4 Inducers/Risperidone Im Every 2 Weeks

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)

Strong Cyp3a4 Inducers/Risperidone Intramuscular Monthly

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)

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: Patients receiving risperidone should be closely monitored in the first 4-8 weeks of starting an inducer of CYP3A4. The dosage of risperidone may need to be adjusted.(1) The US manufacturer of risperidone for monthly intramuscular injections (Risvan) states that patients on concurrent strong CYP3A4 inducers should have their risperidone dosage increased as follows: - If patient is on risperidone 75 mg monthly, increase to 100 mg monthly. - If patient is on risperidone 100 mg monthly, consider additional oral risperidone. If the CYP3A4 inducer is discontinued, reevaluate the risperidone dose and lower it as needed. In a patient taking 75 mg monthly, continue the 75 mg dose unless risperidone treatment interruption is judged to be necessary.(1)

DISCUSSION: In a clinical study, carbamazepine decreased the steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine were not significantly affected.(1) 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.(2) 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.(3) 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.(4) 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.(5) 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.(6) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenytoin, primidone, rifampin, rifapentine and St. John's Wort.(7,8)

Strong Cyp3a4 Inducers/Risperidone Sq Every 1-2 Months

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)

Strong Cyp3a4 Inducers/Risperidone Subcutaneous Monthly

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)

Strong Cyp3a4 Inducers/Select Sedative Hypnotics; Buspirone

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)

Strong Cyp3a4 Inducers/Vilazodone

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)

Strong Ugt Inducers; Nevirapine/Artesunate

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

MECHANISM OF ACTION: Strong inducers of UDP-glucuronosyltransferase (UGT) and nevirapine may increase the metabolism of dihydroartemisinin (DHA, the active metabolite of artesunate).(1)

CLINICAL EFFECTS: Concurrent use of carbamazepine, efavirenz, etravirine, fosphenytoin, nevirapine, phenobarbital, phenytoin, primidone, rifampin, or ritonavir may result in decreased levels and effectiveness of DHA.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If coadministration of strong UGT inducers or nevirapine with artesunate is necessary, monitor for possible reduced antimalarial efficacy.(1)

DISCUSSION: In a study, nevirapine decreased the maximum concentration (Cmax) and area-under-curve (AUC) of DHA by 59% and 68%, respectively.(1) In a study of healthy volunteers, ritonavir (100 mg twice daily for 7 days) decreased the Cmax and AUC of DHA by 27% and 38%, respectively.(1,2) A study of healthy subjects who were coadministered lopinavir-ritonavir 400 mg-100 mg twice daily for 14 days) and artesunate-mefloquine found that artesunate Cmax and AUC decreased by 37% and 45%, respectively, compared to artesunate-mefloquine alone.(3) Agents linked to this monograph include: carbamazepine, efavirenz, fosphenytoin, nevirapine, phenobarbital, phenytoin, primidone, rifampin, and ritonavir.

There is no enhanced messaging for this drug.

• Hepatic porphyria

• Bone marrow depression
• HLa-A *31:01 positive
• HLa-B *15:02 positive
• Pregnancy
• Suicidal ideation

• Chronic heart failure
• Complete atrioventricular block
• Coronary artery disease
• Depression
• Disease of liver
• Glaucoma
• Hypercholesterolemia
• Hypertension
• Hyponatremia
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Mood changes
• Ocular hypertension
• SIADH syndrome
• Urinary retention

There is no enhanced messaging for this drug.

More Frequent

• Ataxia
• Blurred vision
• Diplopia
• Nystagmus

Less Frequent

• Behavioral disorders
• Hyponatremia
• Lupus-like syndrome
• SIADH syndrome
• Stevens-johnson syndrome
• Toxic epidermal necrolysis

Rare or Very Rare

• Abnormal hepatic function tests
• Accidental fall
• Acute generalized exanthematous pustulosis
• Acute intermittent porphyria
• Agranulocytosis
• Anaphylaxis
• Anemia
• Angioedema
• Aplastic anemia
• Atrioventricular block
• Bone marrow depression
• Cardiac arrhythmia
• Cholestasis
• Chronic heart failure
• Depression
• DRESS syndrome
• Edema
• Eosinophilia
• Erythema multiforme
• Exfoliative dermatitis
• Hepatic failure
• Hepatitis
• Hypersensitivity pneumonitis
• Hypertension
• Hypocalcemia
• Hypogammaglobulinemia
• Hypotension
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Leukocytosis
• Leukopenia
• Lymphadenopathy
• Nephritis
• Neuroleptic malignant syndrome
• Non-infective meningitis
• Obstructive hyperbilirubinemia
• Osteopenia
• Pancreatitis
• Pancytopenia
• Peripheral neuropathy
• Porphyria
• Renal failure
• Suicidal
• Suicidal ideation
• Syncope
• Thrombocytopenic disorder
• Thromboembolic disorder
• Thrombophlebitis
• Urticaria

More Frequent

• Acute cognitive impairment
• Dizziness
• Drowsy
• Nausea
• Unsteady gait
• Vomiting

Less Frequent

• Constipation
• Paresthesia
• Pruritus of skin
• Vertigo

Rare or Very Rare

• Acute abdominal pain
• Alopecia
• Anorexia
• Anticholinergic toxicity
• Arthralgia
• Cataracts
• Conjunctivitis
• Cramps in legs
• Diarrhea
• Dysarthria
• Dyschromia
• Erectile dysfunction
• Fatigue
• Fever
• Gastrointestinal irritation
• General weakness
• Glossitis
• Headache disorder
• Hirsutism
• Hyperacusis
• Hypercholesterolemia
• Hyperhidrosis
• Increased urinary frequency
• Maculopapular rash
• Muscle fasciculation
• Myalgia
• Nail disorders
• Ocular hypertension
• Purpura
• Skin photosensitivity
• Skin rash
• Stomatitis
• Tinnitus
• Urinary retention
• Xerostomia

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Safe use of carbamazepine during pregnancy has not been established. Adverse fetal effects have been observed in reproduction studies in rats. Although several reports suggest an association between use of anticonvulsants in pregnant, epileptic women and an increased incidence of birth defects in children born to these women, a causal relationship to many of these drugs has not been established. However, epidemiologic data suggest that an association between carbamazepine use during pregnancy and certain congenital abnormalities such as spina bifida may exist. Other congenital anomalies and developmental disorders (e.g., craniofacial defects, cardiovascular malformations, anomalies involving various body systems) also have been reported in association with carbamazepine use.

Anticonvulsants should not be discontinued in pregnant women in whom the drugs are administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases, when the severity and frequency of the seizure disorder are such that discontinuance of therapy does not pose a serious threat to the patient, discontinuance of the drugs may be considered prior to and during pregnancy; however, it cannot be said with any certainty that even minor seizures do not pose some hazard to the fetus. Clinicians should carefully weigh these considerations in treating or counseling epileptic women of childbearing potential. Because carbamazepine can cause fetal harm when administered to pregnant women, the benefits of therapy must be weighed against the risks in women of childbearing potential. If carbamazepine is used during pregnancy, or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus. Tests to detect fetal abnormalities using currently accepted procedures should be considered part of routine prenatal care in women of childbearing potential receiving carbamazepine.

There have been a few cases of seizures and/or respiratory depression in neonates born to women receiving carbamazepine concomitantly with other anticonvulsant agents. A few cases of vomiting, diarrhea, and/or decreased feeding also have been reported in neonates born to women receiving carbamazepine; these symptoms may represent a neonatal withdrawal syndrome.

Women who are pregnant while receiving carbamazepine should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 888-233-2334. Information on the registry also can be found on the website https://www.aedpregnancyregistry.org.

Carbamazepine and its epoxide metabolite (carbamazepine 10,11-epoxide (CBZ-E)) are distributed into milk. Safe use of carbamazepine during lactation has not been established. Because of the potential for serious adverse reactions from carbamazepine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman. Following daily oral administration of carbamazepine in nursing women, the milk-to-maternal plasma ratio of carbamazepine is about 0.4 and that of CBZ-E is about 0.5; it is estimated that neonates may receive about 2-5 and 1-2 mg of carbamazepine and CBZ-E, respectively, daily.

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