Pyrukynd (mitapivat sulfate)
Antihemolytic - Pyruvate Kinase (PK) Activator Oral Tablet; Oral Tablet, Dose Pack
Last reviewed · Source: First Databank (FDB) drug data
Overview
Mitapivat sulfate is a pyruvate kinase activator.
Mitapivat sulfate is a pyruvate kinase activator. The drug binds allosterically to the pyruvate kinase tetramer and increases pyruvate kinase activity. Mitapivat also improves energy homeostasis, red blood cell longevity, ineffective erythropoiesis, and hemolysis by increasing pyruvate kinase activity in models of beta-thalassemia.
The red blood cell pyruvate kinase (PKR) enzyme catalyzes the conversion of phosphoenol pyruvate to pyruvate in the last step of glycolysis, which produces adenosine triphosphate (ATP). The mutated PKR enzyme present in patients with pyruvate kinase deficiency results in defective glycolysis, manifesting as build-up of the upstream metabolite 2,3-diphosphoglycerate (2,3-DPG) and deficiency in ATP. Red blood cells rely wholly on this glycolysis pathway for ATP production and the lack of ATP negatively affects red blood cell homeostasis by shortening red blood cell lifespan and changing the red blood cell membrane integrity increasing the risk for hemolysis.
Mitapivat restores the enzyme activity of PKR. In ex vivo studies, mitapivat increased PKR activity over a broad range of types of PKR defects. In healthy volunteers, mitapivat decreased 2,3-DPG and increased ATP levels.
Systemic exposure to mitapivat increases in an approximately dose-proportional manner over a dosage range of 5 to 50 mg twice daily. Minimal accumulation of the drug occurs with repeated dosing. Peak plasma concentrations of the drug are attained 0.5 to 1 hour following oral administration.
The absolute bioavailability of a single dose of mitapivat is approximately 73%. Oral administration of a single dose of mitapivat with a high-fat meal did not substantially alter the AUC of mitapivat, but decreased the maximum plasma concentration by 42% and delayed the time to maximum plasma concentration 2.3 hours compared with dosing under fasted conditions. Mitapivat is approximately 97.7% bound to plasma proteins and the red blood cell to plasma ratio is 0.37.
Mitapivat is metabolized principally by cytochrome P-450 (CYP) 3A4. Following administration of a single 120 mg radiolabeled dose of mitapivat, approximately 49.6% of the dose was recovered in urine (2.6% as unchanged drug) and 39.6% was recovered in feces (<1% as unchanged drug). The mean effective half-life of mitapivat ranges from 3 to 5 hours in patients with pyruvate kinase deficiency.
The pharmacokinetics of mitapivat do not appear to be substantially affected by age, sex, race, or body weight.
USES: This medication is used to treat hemolytic anemia. It works by slowing the breakdown of red blood cells. It may help to improve symptoms of anemia (such as shortness of breath, tiredness) and decrease the need for blood transfusion.
Generic name: mitapivat sulfate
Pronunciation: (MYE-ta-PIV-at)
Drug class: Antihemolytic - Pyruvate Kinase (PK) Activator
Therapeutic class: Hematological Agents
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
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Indications
The following indications are listed for Pyrukynd:
- Hemolytic Anemia Due To Pyruvate Kinase Deficiency
Also known as: Congenital Nonspherocytic Hemolytic Anemia Due To Pyruvate Kinase Deficiency, Hemolytic Anemia Due To Pk (Pyruvate Kinase) Deficiency, Hereditary Nonspherocytic Hemolytic Anemia Due To Pyruvate Kinase Deficiency.
Dosing
Dosage of mitapivat sulfate is expressed in terms of mitapivat.
The manufacturer recommends avoiding concomitant use of mitapivat with strong CYP3A inhibitors and strong CYP3A inducers.
The maximum dosage of mitapivat (Pyrukynd(R)) for patients using concomitant moderate CYP3A inhibitors is 20 mg twice daily.
For patients taking moderate CYP3A inducers, consider alternative therapies that are not moderate CYP3A inducers during treatment.
Pyrukynd(R): For those who cannot use alternative therapies, monitor the patient's hemoglobin response and titrate beyond the 50 mg twice daily dosage if necessary, but do not exceed a maximum recommended dosage of 100 mg twice daily.
Aqvesme(R): For those who cannot use alternative therapies, monitor the patient's hemoglobin response and do not exceed a maximum recommended dosage of 100 mg twice daily.
In patients experiencing an adverse reaction or hemoglobin levels greater than normal, dosage of mitapivat (Pyrukynd(R)) may be decreased to the next lower dosage level (20 mg twice daily or 5 mg twice daily). If mitapivat needs to be discontinued, follow the recommended dosage taper schedule. In situations where the risk to the patient due to the adverse reaction or hemoglobin above normal is greater than the risk of acute hemolysis due to sudden withdrawal of the drug, treatment may be stopped without taper and patients should be monitored for signs of acute hemolysis.
No dosing information is available for this tab.
| Drug label | Dosing type | Instructions |
|---|---|---|
| Pyrukynd 5 Mg Tablet | Maintenance | Take 1 tablet (5 mg) by oral route 2 times per day. |
| Pyrukynd 5 Mg Taper Pack | Maintenance | Take 1 tablet (5 mg) by oral route 2 times per day. |
| Pyrukynd 20 Mg Taper Pack | Maintenance | Take 1 tablet (20 mg) by oral route 2 times per day. |
| Pyrukynd 20 Mg Tablet | Maintenance | Take 1 tablet (20 mg) by oral route 2 times per day. |
| Pyrukynd 50 Mg Taper Pack | Maintenance | Take 1 tablet (50 mg) by oral route 2 times per day. |
| Pyrukynd 50 Mg Tablet | Maintenance | Take 1 tablet (50 mg) by oral route 2 times per day. |
| Pyrukynd 20-5 Mg Taper Pack | Maintenance | Take by oral route once daily per package directions. |
| Pyrukynd 50-20 Mg Taper Pack | Maintenance | Take by oral route once daily per package directions. |
No dosing information is available for this tab.
Drug interactions
Mitapivat is metabolized principally by cytochrome P-450 (CYP) 3A4.
Clinical studies and model-based approaches show that mitapivat induces CYP3A and inhibits P-glycoprotein (P-gp). In vitro studies suggest that mitapivat induces CYP2B6, CYP2C8, CYP2C9, CYP2C19, and uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A1.
In vitro studies also suggest that mitapivat is a substrate of P-gp.
Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
Cyp3a4 Inducers/Lumateperone
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Lumateperone is a substrate of CYP3A4. Inducers of CYP3A4 may induce the metabolism of lumateperone.(1)
CLINICAL EFFECTS: The concurrent administration of a CYP3A4 inducer may decrease the exposure to lumateperone.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of lumateperone states that concurrent use with CYP3A4 inducers should be avoided.(1)
DISCUSSION: Coadministration of lumateperone with rifampin, a strong CYP3A4 inducer, resulted in a 98% reduction in area-under-curve (AUC) and a 90% reduction in concentration maximum (Cmax).(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, repotrectinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 include: amprenavir, armodafinil, aumolertinib, bexarotene, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, garlic, genistein, gingko, ginseng, glycyrrhizin, nevirapine, omaveloxolone, oxcarbazepine, pioglitazone, quercetin, rufinamide, sotorasib, sulfinpyrazone, sunvozertinib, tecovirimat, terbinafine, ticlopidine, troglitazone, vemurafenib, and vinblastine.(2,3)
Cyp3a4 Inducers/Zuranolone
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of zuranolone.(1)
CLINICAL EFFECTS: Concurrent use of a CYP3A4 inducer may result in a loss of zuranolone efficacy.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Avoid the concurrent use of zuranolone with CYP3A4 inducers.(1)
DISCUSSION: Coadministration of zuranolone with rifampin decreased the maximum concentration (Cmax) by 0.31-fold and area-under-curve (AUC) by 0.15-fold.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib. Weak CYP3A4 inducers linked to this monograph include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, flucloxacillin, garlic, genistein, ginseng, glycyrrhizin, methylprednisolone, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)
Dual Moderate Cyp3a4 Inducers And Substrates/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: Fexinidazole is a CYP3A4 substrate and a moderate CYP3A4 inducer. Moderate inducers of CYP3A4 may accelerate the metabolism of fexinidazole to its active metabolites. Also, the metabolism of CYP3A4 substrates may be induced by fexinidazole.(1)
CLINICAL EFFECTS: Concomitant use of fexinidazole with agents that are dual moderate CYP3A4 inducers and substrates may result in increased levels of fexinidazole's active metabolites (M1 and M2), which may lead to an increased risk of adverse reactions including life-threatening cardiac arrhythmias like torsades de pointes. Fexinidazole may also decrease the levels and effectiveness of the CYP3A4 substrate.(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: The net effect of this two-way interaction is unknown and optimal doses of the drugs when used concurrently have not been determined. Some manufacturers provide recommendations for dose modifications for drug interactions, but it is unknown if the recommendations apply with a two-way interaction. Dose modifications mentioned below are informational only. Avoid the concurrent use of fexinidazole with medications that induce CYP3A4.(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) 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) - Lorlatinib: The manufacturer of lorlatinib recommends avoiding concurrent administration of moderate CYP3A4 inducers. If concurrent use cannot be avoided, increase the dose of lorlatinib to 125 mg daily.(3) - Mitapivat: The manufacturer of mitapivat recommends considering alternative therapies that are not moderate CYP3A4 inducers. If concurrent use is necessary, monitor hemoglobin closely and titrate mitapivat dose, not to exceed a maximum dose of 100 mg twice daily.(4,5) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
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) A clinical drug-drug interaction study found that fexinidazole (1,800 mg for 4 days then 1,200 mg on day 5) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose midazolam (2 mg) by 57% and 39%, respectively.(1) Agents that are both moderate CYP3A4 inducers and CYP3A4 substrates linked to this monograph include: lorlatinib and mitapivat.(4)
Mitapivat (50 Mg Bid)/Moderate Cyp3a4 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: Moderate inhibitors of CYP3A4 may inhibit the metabolism of mitapivat.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels of and effects from mitapivat including decreased estrone and estradiol levels in males, increased urate, back pain, and arthralgias.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The concurrent use of moderate CYP3A4 inhibitors with mitapivat should be monitored closely for increased risk of adverse reactions. Mitapivat dose should not exceed 20 mg twice daily with concurrent moderate CYP3A4 inhibitors.(1)
DISCUSSION: Mitapivat is a CYP3A4 substrate. In a pharmacokinetic study with mitapivat 5, 20, or 50 mg twice daily dosing, fluconazole increased mitapivat area-under-curve (AUC) and concentration maximum (Cmax) by 2.6-fold and 1.6-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, letermovir, netupitant, nilotinib, schisandra, stiripentol, treosulfan, tofisopam, and verapamil.(2)
Mitapivat/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 inhibitors of CYP3A4 may inhibit the metabolism of mitapivat.(1) Lonafarnib is a strong CYP3A4 inhibitor. Strong and moderate CYP3A4 inducers may increase the metabolism of lonafarnib.(2) Mitapivat is a moderate CYP3A4 inducer.
CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels of and effects from mitapivat including decreased estrone and estradiol levels in males, increased urate, back pain, and arthralgias.(1) Concurrent use of strong and moderate CYP3A4 inducers may decrease the serum levels and effectiveness of lonafarnib.(2)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The use of strong or moderate CYP3A4 inducers with lonafarnib is contraindicated.(2) The concurrent use of strong CYP3A4 inhibitors with mitapivat should be avoided.(1)
DISCUSSION: Mitapivat is a CYP3A4 substrate. In a pharmacokinetic study with mitapivat 20 mg single dose, itraconazole increased mitapivat area-under-curve (AUC) and concentration maximum (Cmax) by 4.9-fold and 1.7-fold, respectively. In a pharmacokinetic study with mitapivat 50 mg twice daily, itraconazole increased mitapivat AUC and Cmax by 3.6-fold and 2.2-fold, respectively. With ketoconazole, mitapivat doses of 5, 20, or 50 mg twice daily had an AUC and Cmax increased by 3.9-fold and 2.4-fold, respectively.(1) 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 AUC was reduced by 98% and the Cmax was reduced by 92%.(2)
Mitapivat/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: Mavacamten and mitapivat are both CYP3A4 substrates and inducers. Moderate inducers of CYP3A4 may increase the metabolism of mavacamten.(1-3) Mitapivat is a moderate CYP3A4 inducer. Moderate inducers of CYP3A4 are expected to increase the metabolism of mitapivat.(4) Mavacamten is a moderate CYP3A4 inducer.
CLINICAL EFFECTS: Concurrent use may result in decreased levels and effectiveness of both mavacamten and mitapivat.(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 and Canadian manufacturers of mavacamten state concurrent use of mavacamten with moderate CYP3A4 inducers is contraindicated.(1,2) The UK manufacturer of mavacamten states that management of mavacamten during concomitant use with moderate CYP3A4 inducers is dependent on CYP2C19 phenotype. Labeling recommends: -When initiating or increasing the dose of a moderate inducer in patients who are CYP2C19 poor metabolizers, monitor patients closely and adjust mavacamten dose based on clinical response. -When discontinuing or decreasing the dose of a moderate inducer in patients who are CYP2C19 poor metabolizers, decrease the dose of mavacamten to 2.5 mg, or pause therapy if dose is 2.5 mg. -No dose adjustment is warranted with moderate inducers in patients who are CYP2C19 intermediate, normal, rapid, or ultrarapid metabolizers.(3) The manufacturer of mitapivat states that concurrent use of mitapivat with medications that are moderate CYP3A4 inducers should be monitored closely. Mitapivat dose should not exceed a maximum dose of 100 mg twice daily with concurrent moderate CYP3A4 inducers.(4)
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) Mitapivat is a CYP3A4 substrate. In a pharmacokinetic study with 5 or 20 mg twice daily of mitapivat, efavirenz decreased AUC and Cmax by 60% and 30%, respectively. After mitapivat doses of 50 mg twice daily, efavirenz decreased AUC and Cmax by 55% and 24%, respectively.(4)
Mitapivat/Strong Cyp3a4 Inducers
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Strong inducers of CYP3A4 may decrease the metabolism of mitapivat.(1)
CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inducer may result in decreased levels and effectiveness of mitapivat.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Avoid the concurrent use of mitapivat with medications that are strong CYP3A4 inducers.(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) Strong inducers of CYP3A4 include: apalutamide, barbiturates, encorafenib, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3)
Mitapivat/Strong Cyp3a4 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: Strong inhibitors of CYP3A4 may inhibit the metabolism of mitapivat.(1)
CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels of and effects from mitapivat including decreased estrone and estradiol levels in males, increased urate, back pain, and arthralgias.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The concurrent use of strong CYP3A4 inhibitors with mitapivat should be avoided.(1)
DISCUSSION: Mitapivat is a CYP3A4 substrate. In a pharmacokinetic study with mitapivat 20 mg single dose, itraconazole increased mitapivat area-under-curve (AUC) and concentration maximum (Cmax) by 4.9-fold and 1.7-fold, respectively. In a pharmacokinetic study with mitapivat 50 mg twice daily, itraconazole increased mitapivat AUC and Cmax by 3.6-fold and 2.2-fold, respectively. With ketoconazole, mitapivat doses of 5, 20, or 50 mg twice daily had an AUC and Cmax increased by 3.9-fold and 2.4-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2)
Moderate Cyp3a4 Inducers/Atrasentan
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of atrasentan.(1)
CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may reduce the clinical effectiveness of atrasentan.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of atrasentan states that concurrent use of moderate CYP3A4 inducers should be avoided.(1)
DISCUSSION: In a study, atrasentan trough concentration (Ctrough) decreased by 90% following coadministration of a single dose of 10 mg of atrasentan with rifampin (strong CYP3A4 inducer).(1) The effects of a moderate CYP3A4 inducer on atrasentan concentrations has not been studied. Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Daraxonrasib (< 400 Mg)
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Daraxonrasib is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of daraxonrasib.(1)
CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of daraxonrasib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of daraxonrasib states that concomitant use of moderate CYP3A4 inducers requires a dose increase of daraxonrasib to 400 mg once daily.(1)
DISCUSSION: In a clinical study, daraxonrasib area-under-curve (AUC) is predicted to decrease by 50-84% with concomitant use of efavirenz 600 mg once daily and modafinil 400 mg once daily (moderate CYP3A4 inducers).(1) Moderate CYP3A4 inducers linked to this monograph include: asunaprevir, belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lopinavir, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Defactinib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Moderate CYP3A4 inducers may accelerate the metabolism of defactinib by CYP3A4.(1)
CLINICAL EFFECTS: The concurrent use of defactinib and a moderate CYP3A4 inducer may result in decreased levels and effectiveness of defactinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of defactinib states that the concurrent use of moderate CYP3A4 inducers should be avoided.(1)
DISCUSSION: The impact of moderate CYP3A4 inhibitors on the pharmacokinetics of defactinib has not been investigated in clinical studies. In a study, defactinib maximum concentration (Cmax) decreased by 83% and area-under-curve (AUC) by 87% following coadministration with phenytoin (strong CYP3A4 inducer) three times daily for 23 days and a single dose of defactinib 200 mg (1.0 times the approved recommended dose) on Day 14. The AUC and Cmax of N-desmethyl amide (M4), a major active metabolite of defactinib, decreased by 79% and 70%, respectively.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(2)
Moderate Cyp3a4 Inducers/Dordaviprone
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Dordaviprone is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of dordaviprone.(1)
CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of dordaviprone.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of dordaviprone states that co-administration with moderate inducers of CYP3A4 should be avoided. Monitor patients for loss of efficacy or consider the use of alternative medicinal products.(1)
DISCUSSION: Concurrent use of rifampin (a strong CYP3A4 inducer) is predicted to decrease dordaviprone maximum concentration (Cmax) by 68% and area-under-curve (AUC) by 83%. Concurrent use of efavirenz (a moderate CYP3A4 inducer) is predicted to decrease dordaviprone Cmax by 44% and AUC by 65%.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Entrectinib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Entrectinib is a substrate of CYP3A4. Moderate inducers of CYP3A4 may induce the metabolism of entrectinib.(1)
CLINICAL EFFECTS: The concurrent administration of a moderate CYP3A4 inducer may result in decreased levels and effectiveness of entrectinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of entrectinib states that concurrent use with moderate CYP3A4 inducers should be avoided. (1)
DISCUSSION: Concomitant administration of rifampin (strong CYP3A4 inducer) with a single 600 mg entrectinib dose decreased entrectinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 56% and 77%.(1) Coadministration with a moderate CYP3A4 inducer is predicted to decrease entrectinib's AUC and Cmax by 56% and 43%.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, and tovorafenib.(2-3)
Moderate Cyp3a4 Inducers/Fruquintinib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of fruquintinib.(1)
CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of fruquintinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: If possible, avoid concurrent use of moderate inducers of CYP3A4 with fruquintinib. If concurrent use cannot be avoided, continue to administer fruquintinib at the recommended dosage.(1)
DISCUSSION: Concomitant use with efavirenz (moderate CYP3A4 inducer) is predicted to decrease the fruquintinib maximum concentration (Cmax) by 4% and the area-under-curve (AUC) by 32%.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Glasdegib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Glasdegib is a substrate of CYP3A4. Moderate inducers of CYP3A4 may induce the metabolism of glasdegib.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of glasdegib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of glasdegib states to avoid concurrent administration with moderate CYP3A4 inducers. If concurrent use cannot be avoided, increase the daily dose of glasdegib as tolerated as follows: - If current dose of glasdegib is 100 mg once daily, increase to 200 mg once daily - If current dose of glasdegib is 50 mg once daily, increase to 100 mg once daily After the moderate CYP3A4 inducer has been discontinued for 7 days, resume the glasdegib dose that was tolerated prior to initiation of the inducer.(1)
DISCUSSION: A population-based pharmacokinetic model predicts that efavirenz would decrease glasdegib area-under-curve (AUC) by 55% and maximum concentration (Cmax) by 25%.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, and tovorafenib.(2-3)
Moderate Cyp3a4 Inducers/Iberdomide
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Iberdomide is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of iberdomide.(1)
CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of iberdomide.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of iberdomide states that concomitant use of moderate CYP3A4 inducers should be avoided.(1)
DISCUSSION: In a PBPK model in patients with cancer, iberdomide area-under-curve (AUC) was predicted to be decreased by 30% and maximum concentration (Cmax) by 50% following concomitant use with efavirenz (moderate CYP3A4 inducer).(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Lazertinib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of lazertinib via this pathway.(1)
CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may reduce the clinical effectiveness of lazertinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The US manufacturer of lazertinib states that concurrent use of moderate CYP3A4 inducers should be avoided. Consider an alternative concomitant medication with no potential to induce CYP3A4.(1)
DISCUSSION: In a pharmacokinetic modelling study, concomitant use of efavirenz (moderate CYP3A4 inducer) is predicted to decrease lazertinib steady state concentration maximum (Cmax) and area-under-curve (AUC) by at least 32% and 44%, respectively.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Lirafugratinib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of lirafugratinib.(1)
CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of lirafugratinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Avoid concomitant use of moderate CYP3A4 inducers with lirafugratinib.(1)
DISCUSSION: In a pharmacokinetic model, efavirenz (a moderate CYP3A4 inducer) 600 mg daily for 19 days is predicted to reduce lirafugratinib area-under-the-curve (AUC) by 57% and maximum concentration (Cmax) by 15%.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Nerandomilast (9 Mg)
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Moderate CYP3A4 inducers may induce the metabolism of nerandomilast by CYP3A4.
CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may reduce the clinical effectiveness of nerandomilast.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The recommended dose of nerandomilast with moderate CYP3A4 inducers is 18 mg twice daily. For patients who are unable to tolerate 18 mg twice daily, do not reduce the dosage to 9 mg twice daily in patients taking moderate CYP3A4 inducers.(1)
DISCUSSION: Nerandomilast is primarily metabolized by CYP3A4.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Olverembatinib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Olverembatinib is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of olverembatinib.(1)
CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of olverembatinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of olverembatinib states that co-administration with moderate inducers of CYP3A4 should be avoided.(1)
DISCUSSION: In a clinical study of 15 healthy subjects, rifampin (600 mg daily for 8 days), a strong CYP3A4 inducer, decreased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose olverembatinib 40 mg by 75.19% and 61.27%, respectively.(2) In a PBPK model, efavirenz (600 mg daily for 8 days), a moderate CYP3A4 inducer, decreased the AUC and Cmax of olverembatinib 40 mg by 65% and 52%, respectively.(3) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(4,5)
Moderate Cyp3a4 Inducers/Oveporexton
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Oveporexton is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of oveporexton.(1)
CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of oveporexton.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of oveporexton states that concomitant use of moderate CYP3A4 inducers should be avoided.(1)
DISCUSSION: In a PBPK model, oveporexton area-under-curve (AUC) was predicted to be decreased by 73% and maximum concentration (Cmax) by 55% following concomitant use of a moderate CYP3A4 inducer.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Pyrotinib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of pyrotinib.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of pyrotinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of pyrotinib states that coadministration with moderate CYP3A4 inducers should be avoided.(1)
DISCUSSION: In a study of healthy subjects, concurrent use of rifampin (a strong CYP3A4 inducer) decreased pyrotinib area-under-curve (AUC) by 96% and maximum concentration (Cmax) by 89%.(1) In a study of healthy subjects, concurrent use of efavirenz (a moderate CYP3A4 inducer) decreased pyrotinib AUC by 80% and Cmax by 66%.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Remibrutinib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Moderate CYP3A4 inducers may induce the metabolism of remibrutinib.(1)
CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may alter the clinical effectiveness of remibrutinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Avoid the concurrent use of remibrutinib with moderate CYP3A4 inducers.(1) Monitor patients receiving concurrent therapy for reduced efficacy.
DISCUSSION: Remibrutinib is primarily metabolized by CYP3A4.(1) Remibrutinib concentration maximum (Cmax) is predicted to decrease by approximately 60% and area-under-curve (AUC) is predicted to decrease by approximately 64% following concomitant administration with efavirenz (a moderate CYP3A4 inducer) 600 mg once daily for 14 days.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Revumenib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Moderate CYP3A4 inducers may induce the metabolism of revumenib by CYP3A4 and increase formation of the M1 metabolite which contributes to revumenib's effects on the QTc interval.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inducers may result in decreased levels and effectiveness of revumenib and increased risk of QT prolongation due to increased exposure to revumenib's M1 metabolite. The risk of potentially life-threatening arrhythmias including torsades de pointes may be increased.(1)
PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of revumenib states that concomitant use of moderate CYP3A4 inducers should be avoided.(1)
DISCUSSION: Revumenib is primarily metabolized by CYP3A4. Concomitant use of a moderate CYP3A4 inducer may decrease revumenib concentrations and increase M1 systemic exposure, resulting in decreased revumenib efficacy or increased risk of QT prolongation.(1) In clinical trials, QTc interval prolongation was reported as an adverse event in 29% of 135 patients treated with the recommended dosage of revumenib; 12% of patients had Grade 3 QTc prolongation. Revumenib increased the QTc interval in a concentration-dependent manner. At the mean steady-state Cmax using the highest approved recommended dosage of revumenib without CYP3A4 inhibitors, QTc increase was predicted to be 27 msec (upper bound of 90% confidence interval = 30 msec). At the steady-state Cmax using the highest approved recommended dosage of revumenib with CYP3A4 inhibitors, QTc increase was predicted to be 19 msec (upper bound of 90% confidence interval = 22 msec).(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, and tovorafenib.(3)
Moderate Cyp3a4 Inducers/Sevabertinib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Sevabertinib is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of sevabertinib.(1)
CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of sevabertinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of sevabertinib states that co-administration with moderate inducers of CYP3A4 should be avoided. Monitor patients for loss of efficacy or consider the use of alternative medicinal products.(1)
DISCUSSION: In a study, carbamazepine (strong CYP3A4 inducer) decreased sevabertinib's area-under-curve (AUC) 79% and maximum concentration (Cmax) 57%.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Sonrotoclax
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Sonrotoclax is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of sonrotoclax.(1)
CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of sonrotoclax.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of sonrotoclax states that co-administration with moderate inducers of CYP3A4 should be avoided.(1)
DISCUSSION: The impact of moderate CYP3A4 inducers on the pharmacokinetics of sonrotoclax has not been investigated in clinical studies. In a clinical study, sonrotoclax area-under-curve (AUC) decreased by 65% and maximum concentration (Cmax) by 42% following concomitant use of phenytoin (strong CYP3A4 inducer).(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Suzetrigine
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of suzetrigine.(1)
CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may reduce the clinical effectiveness of suzetrigine.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The US manufacturer of suzetrigine states that concurrent use of moderate CYP3A4 inducers should be avoided.(1)
DISCUSSION: Concomitant administration of efavirenz (moderate CYP3A inducer) with suzetrigine is predicted to decrease suzetrigine and active metabolite M6-SUZ area-under-curve (AUC) by 63% and 60%, respectively, while suzetrigine maximum concentration (Cmax) is predicted to decrease by 29% and M6-SUZ Cmax is predicted to increase by 1.3-fold, respectively.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Taletrectinib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Moderate CYP3A4 inducers may induce the metabolism of taletrectinib.(1)
CLINICAL EFFECTS: Concurrent or recent use of a moderate CYP3A4 inducer may result in decreased levels and effectiveness of taletrectinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of taletrectinib states that concomitant use of moderate CYP3A4 inducers should be avoided.(1)
DISCUSSION: Taletrectinib is primarily metabolized by CYP3A4.(1) Concomitant administration of taletrectinib with a moderate inducer (efavirenz) is predicted to decrease taletrectinib area under the curve (AUC) and maximum concentration (Cmax) by 66% and 40%, respectively.(1) Concomitant administration of taletrectinib with a strong inducer (rifampin; 600 mg once daily) resulted in a decrease in taletrectinib area under the curve (AUC) and maximum concentration (Cmax) by 86% and 42%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, and tovorafenib.(2)
Moderate Cyp3a4 Inducers/Venetoclax
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of venetoclax.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of venetoclax.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The US manufacturer of venetoclax states that the concurrent use of CYP3A4 inducers should be avoided, and that alternative treatments with less CYP3A4 induction should be considered.(1)
DISCUSSION: In a study with 10 healthy subjects, co-administration of rifampin (600 mg daily for 13 days), decreased venetoclax area-under-curve (AUC) by 71% and maximum concentration (Cmax) by 42%.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, telotristat, thioridazine, tipranavir/ritonavir, and tovorafenib.(2-3)
Moderate Cyp3a4 Inducers/Zidesamtinib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Zidesamtinib is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of zidesamtinib.(1)
CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of zidesamtinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of zidesamtinib states that concurrent use of moderate CYP3A4 inducers should be avoided.(1)
DISCUSSION: Zidesamtinib is a CYP3A4 substrate.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Ziftomenib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Ziftomenib is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of ziftomenib.(1)
CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of ziftomenib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of ziftomenib states that co-administration with moderate inducers of CYP3A4 should be avoided. Monitor patients for loss of efficacy or consider the use of alternative medicinal products.(1)
DISCUSSION: Efavirenz (moderate CYP3A4 inducer) is estimated to decrease ziftomenib area-under-curve (AUC) and maximum concentration (Cmax) by up to 70%.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Zilurgisertib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of zilurgisertib.(1)
CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of zilurgisertib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Avoid concomitant use of moderate CYP3A4 inducers with zilurgisertib.(1)
DISCUSSION: In a pharmacokinetic model, efavirenz (a moderate CYP3A4 inducer) is predicted to decrease zilurgisertib area-under-the-curve (AUC) by 60% and maximum concentration (Cmax) by 25%.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Zoliflodacin
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Zoliflodacin is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of zoliflodacin.(1)
CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of zoliflodacin.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of zoliflodacin states that co-administration with moderate inducers of CYP3A4 is contraindicated.(1)
DISCUSSION: Efavirenz, a moderate CYP3A4 inducer, is predicted to decrease the area-under-curve (AUC) of zoliflodacin by approximately 41%.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)
Selected Cyp3a4 Inducers/Docetaxel
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Inducers of CYP3A4 may accelerate the metabolism of docetaxel.(1) Mitapivat, pexidartinib, and sotorasib are moderate CYP3A4 inducers.(2-6)
CLINICAL EFFECTS: Concurrent or recent use of an inducer of CYP3A4 may result in decreased levels and effectiveness of docetaxel.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Avoid concurrent use of inducers of CYP3A4 with docetaxel.(1) Consider the use of agents with no or minimal induction potential if possible. Monitor patients for decreased response to therapy.
DISCUSSION: Docetaxel is metabolized by CYP3A4 and inducers of this isoenzyme are expected to decrease levels of docetaxel.(1) In a study in 10 cancer patients, St. John's wort, a strong CYP3A4 inducer, decreased the area-under-curve (AUC) of docetaxel by 11.6%. There were no significant decreases in docetaxel maximum concentration (Cmax) or half-life. Docetaxel-related toxicities were lower during coadministration of St. John's wort.(7) In an in vitro study, hyperforin, a constituent of St. John's wort, induced the metabolism of docetaxel in a dose-dependent fashion with induction ranging from 2.6-fold to 7-fold greater than controls. In this same experiment, rifampin induced docetaxel metabolism 6.8-fold to 32-fold.(8) Selected CYP3A4 inducers linked to this monograph include: aumolertinib, fexinidazole, mitapivat, pexidartinib, and sotorasib.(2-6)
Selected Moderate Cyp3a4 Inducers/Ensartinib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of ensartinib.(1)
CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may reduce the clinical effectiveness of ensartinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The US manufacturer of ensartinib states that concurrent use of moderate CYP3A4 inducers should be avoided.(1)
DISCUSSION: Ensartinib is predominately metabolized by CYP3A4.(1) Moderate CYP3A4 inducers linked to this monograph are: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, pacritinib, repotrectinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3)
Slt Moderate And Strong Cyp3a4 Inducers/Ixazomib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Ixazomib is primarily metabolized by CYP3A4.(1)
CLINICAL EFFECTS: Concurrent use of strong or selected moderate CYP3A4 inducers will result in decreased systemic concentrations of ixazomib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of ixazomib states that concomitant use with CYP3A4 inducers should be avoided. In an interaction study, rifampin decreased ixazomib exposure(AUC) by 74%.(1) Use an alternative to the inducing agent when possible. The onset of induction is gradual but may begin within one week for potent agents (e.g. rifampin). The time to maximal induction may be 2 or more weeks depending upon the half-life and dose of the inducer.
DISCUSSION: In an interaction study, coadministration with rifampin decreased ixazomib AUC 74% and maximum concentration (Cmax) by 54%(1) Selected moderate and strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, belzutifan, carbamazepine, cenobamate, dabrafenib, elagolix, encorafenib, enzalutamide, fexinidazole, fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin, rifapentine, St. John's Wort, sotorasib, telotristat, and tovorafenib.(2)
Slt Moderate-Strong Cyp3a4 Inducers/Slt Hepatitis C Agents
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Strong or moderate inducers of CYP3A4 may induce the metabolism of asunaprevir or ombitasvir-paritaprevir-ritonavir treatment for hepatitis C.(1-3) Asunaprevir is also a substrate for the OATP1B1 transporter. OATP1B1 facilitated transport into the liver is thought to be associated with asunaprevir efficacy. While rifampin a strong CYP3A4 inducer, is also an OATP1B1 inhibitor and so may further decrease asunaprevir efficacy by inhibiting its transport into the liver.
CLINICAL EFFECTS: The combination of asunaprevir or ombitasvir-paritaprevir-ritonavir, with or without dasabuvir, may not be effective for the treatment of hepatitis C.(1-3)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Because of the risk for treatment failure, the manufacturers of asunaprevir, and ombitasvir-paritaprevir-ritonavir state that concomitant use with strong or moderate CYP3A4 inducers is contraindicated.(1-3)
DISCUSSION: In an interaction study with 12 subjects, carbamazepine 200 mg once daily followed by 200 mg twice daily decreased antiviral exposure (area-under-curve or AUC) of ombitasvir by 31%, paritaprevir by 70%, ritonavir by 87%, and dasabuvir by 55%.(1) Strong and moderate CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate, dabrafenib, encorafenib, enzalutamide, etravirine, fexinidazole, fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifapentine, sotorasib, telotristat, and tovorafenib.
Strong & Moderate Cyp3a4 Inducers/Axitinib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Agents that induce the CYP3A4 isoenzyme may induce the metabolism of axitinib.(1)
CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inducers may decrease the levels and effectiveness of axitinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Avoid the concurrent use of strong or moderate CYP3A4 inducers in patients receiving therapy with axitinib.(1) Consider the use of alternatives with little to no induction potential.(1)
DISCUSSION: Rifampin (600 mg daily for 9 days), a strong CYP3A4 inducer, decreased the maximum concentration (Cmax) and area-under-curve (AUC) of axitinib to less than half and less than 25% of levels seen without concurrent rifampin.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, dexamethasone, encorafenib, enzalutamide, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort. Moderate inducers of CYP3A4 include: bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat ethyl, thioridazine and tovorafenib.(1-3)
Strong & Moderate Cyp3a4 Inducers/Bedaquiline
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Strong and moderate CYP3A4 inducers may induce the metabolism of bedaquiline.(1)
CLINICAL EFFECTS: Concurrent or recent use of strong or moderate CYP3A4 inducers may result in decreased levels and effectiveness of bedaquiline.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The concurrent administration of strong or moderate CYP3A4 inducers and bedaquiline should be avoided.(1)
DISCUSSION: In a study in healthy subjects, concurrent administration of rifampin (600 mg daily) and bedaquiline (300 mg daily) for 21 days decreased the area-under-curve (AUC) of bedaquiline by 52%.(1) In a study in healthy subjects, pretreatment with efavirenz (600 mg daily for 27 days) decreased the AUC of a single dose of bedaquiline by 20%. There was no effect on bedaquiline Cmax. The AUC and Cmax of the primary metabolite of bedaquiline increased by 70% and 80%, respectively.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort.(1-3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, sotorasib, telotristat and tovorafenib.(1-3)
Strong & Moderate Cyp3a4 Inducers/Cobimetinib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Agents that induce the CYP3A4 isoenzyme may induce the metabolism of cobimetinib.(1)
CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inducers may decrease the levels and effectiveness of cobimetinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Avoid the concurrent use of strong or moderate CYP3A4 inducers in patients receiving therapy with cobimetinib.(1) Consider the use of alternatives with little to no induction potential.
DISCUSSION: Based upon simulations, coadministration of cobimetinib with a strong CYP3A4 inducer may decrease cobimetinib exposure by 83%, with a moderate CYP3A4 inducer by 73%, leading to a reduction in efficacy.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, cenobamate, encorafenib, enzalutamide, ivosidenib, lorlatinib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort. Moderate inducers of CYP3A4 include: bosentan, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(1-3)
Strong & Moderate Cyp3a4 Inducers/Quizartinib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Agents that induce the CYP3A4 isoenzyme may induce the metabolism of quizartinib.(1)
CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inducers may decrease the levels and effectiveness of quizartinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Avoid the concurrent use of strong or moderate CYP3A4 inducers in patients receiving therapy with quizartinib.(1)
DISCUSSION: The area-under-curve (AUC) of quizartinib decreased by 90% and maximum concentration (Cmax) by 45% following concomitant use of a single 53 mg dose of quizartinib with efavirenz (a moderate CYP3A inducer). The AUC of active metabolite AC886 decreased by 96% and the Cmax by 68%. The effect of concomitant use with a strong CYP3A inducer may result in even greater effect on quizartinib pharmacokinetics based on mechanistic understanding of the drugs involved. Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate inducers of CYP3A4 include: bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, and tovorafenib.(2-3)
Strong & Moderate Cyp3a4 Inducers/Sonidegib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Agents that induce the CYP3A4 isoenzyme may induce the metabolism of sonidegib.(1)
CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inducers may decrease the levels and effectiveness of sonidegib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Avoid the concurrent use of strong or moderate CYP3A4 inducers in patients receiving therapy with sonidegib.(1) Consider the use of alternatives with little to no induction potential.
DISCUSSION: In an interaction study, 16 healthy subjects received a single dose of sonidegib 800mg alone or 5 days after receiving rifampin 600 mg daily for 14 days. Mean sonidegib area-under-curve (AUC) was decreased by 75% and maximum concentration (Cmax) decreased 54% when taken with rifampin. Based upon population based pharmacokinetic (PBPK) simulations, a moderate CYP3A4 inducer such as efavirenz given for 14 days is predicted to decrease sonidegib AUC 56% in cancer patients taking sonidegib 200 mg daily. Coadministration with a moderate CYP3A4 inducer for 4 months is predicted to decrease sonidegib exposure (AUC) by 69%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate inducers of CYP3A4 include: bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2-3)
Strong And Moderate Cyp3a4 Inducers/Capivasertib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Strong and moderate inducers of CYP3A4 may increase the metabolism of capivasertib.(1)
CLINICAL EFFECTS: Concurrent use of a strong or moderate inducer of CYP3A4 may result in decreased levels and effectiveness of capivasertib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Avoid concomitant use of capivasertib with strong and moderate CYP3A4 inducers.(1)
DISCUSSION: Rifampin (strong CYP3A4 inducer) is predicted to decrease capivasertib area-under-curve (AUC) by 70% and maximum concentration (Cmax) by 60%.(1) Efavirenz (moderate CYP3A4 inducer) is predicted to decrease capivasertib AUC by 60% and Cmax by 50%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, and tovorafenib.(2,3)
Strong And Moderate Cyp3a4 Inducers/Capmatinib
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Strong and moderate CYP3A4 inducers may increase the metabolism of capmatinib by CYP3A4.(1)
CLINICAL EFFECTS: The concurrent use of strong and moderate CYP3A4 inducers and capmatinib may result in decreased exposure to capmatinib and decreased anti-tumor activity.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Avoid concomitant use of strong and moderate CYP3A4 inducers with capmatinib.(1)
DISCUSSION: Coadministration with rifampin (a strong CYP3A4 inducer) decreased capmatinib area-under-curve (AUC) by 67% and maximum concentration (Cmax) by 56%. Coadministration with efavirenz (a moderate CYP3A4 inducer) was predicted to decrease capmatinib AUC by 44% and Cmax by 34%.(1) Strong and moderate CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate, dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, etravirine, fexinidazole, fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin, rifapentine, St. John's wort, sotorasib, telotristat, thioridazine, and tovorafenib.(2)
Strong And Moderate Cyp3a4 Inducers/Elacestrant
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Elacestrant is metabolized by CYP3A4. Strong and moderate inducers of CYP3A4 may increase the metabolism of elacestrant.(1)
CLINICAL EFFECTS: Concurrent use of a strong or moderate inducer of CYP3A4 may result in decreased levels and effectiveness of elacestrant.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The US manufacturer of elacestrant states avoid concomitant use of elacestrant with strong or moderate CYP3A4 inducers.(1) The US manufacturer of elacestrant does not provide dose modification recommendations with strong and moderate CYP3A4 inducers. The Australian and UK manufacturers of elacestrant state concomitant use of strong or moderate CYP3A4 inducers should be avoided and an alternative concomitant medicinal product with no or minimal potential to induce CYP3A4 should be considered. If a strong or moderate CYP3A4 inducer must be used for a short duration of time (i.e. less than or equal to 3 days) or intermittently (i.e. treatment periods less than or equal to 3 days separated by at least 2 weeks or 1 week + 5 half-lives of the CYP3A4 inducer, whichever is longer), continue elacestrant without increasing the dose.(2,3)
DISCUSSION: Coadministration of 200 mg dose of elacestrant with rifampin (a strong CYP3A inducer) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of elacestrant by 73% and 86%, respectively.(1) Efavirenz is predicted to decrease the Cmax and AUC of elacestrant by 44 to 63% and 55% to 73%, respectively.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(4,5) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(4,5)
Strong And Moderate Cyp3a4 Inducers/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/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 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)
Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
Cyp3a4 Inducers/Erlotinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of erlotinib.(1)
CLINICAL EFFECTS: Concurrent or recent use of a CYP3A4 inducer may result in decreased levels and effectiveness of erlotinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Avoid the concurrent use of CYP3A4 inducers in patients receiving therapy with erlotinib. Consider the use of alternative agents with less enzyme induction potential.(1) Consider increasing the dosage of erlotinib by 50 mg increments as tolerated at two week intervals (to a maximum of 450 mg) while closely monitoring the patient. The highest dosage studied with concurrent rifampin is 450 mg. If the dosage of erlotinib is increased, it will need to be decreased when the inducer is discontinued.(1)
DISCUSSION: Pretreatment and concurrent therapy with rifampin increased erlotinib clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by 66% to 80%. This is equivalent to a dose of about 30 mg to 50 mg in NSCLC.(1) In a study, pretreatment with rifampin for 11 days decreased the AUC of a single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single 150 mg dose of erlotinib.(1) In a case report, coadministration of phenytoin (180mg daily) and erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from 1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold (from 3.53 L/h to 41.7 L/h).(2) In a study, concurrent use of sorafenib (400 mg twice daily) and erlotinib (150 mg daily) decreased the concentration minimum (Cmin), concentration maximum (Cmax), and AUC of erlotinib.(3) In an animal study, concurrent use of dexamethasone and erlotinib decreased the AUC of erlotinib by 0.6-fold.(4) Strong inducers of CYP3A4 include: barbiturates, encorafenib, enzalutamide, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(5,6) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine, and tovorafenib.(5,6) Weak inducers of CYP3A4 include: amprenavir, armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dicloxacillin, echinacea, eslicarbazepine, flucloxacillin, garlic, genistein, ginkgo, ginseng, glycyrrhizin, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(5,6)
Mitapivat/Avacopan
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Avacopan and mitapivat are both substrates of CYP3A4. Avacopan, a moderate CYP3A4 inhibitor, may inhibit the metabolism of mitapivat. Mitapivat, a moderate CYP3A4 inducer, may induce the metabolism of avacopan.(1,2)
CLINICAL EFFECTS: The concurrent use of avacopan with moderate CYP3A4 inducers may result in decreased levels and effectiveness of avacopan.(1) Concurrent use of mitapivat with moderate inhibitors of CYP3A4 may result in increased levels of and effects from mitapivat including decreased estrone and estradiol levels in males, increased urate, back pain, and arthralgias.(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 avacopan and mitapivat.(1,2) The effect of the two-way inhibition and induction of avacopan and mitapivat metabolism is unknown. The optimal doses of avacopan and mitapivat when used concurrently have not been determined. Dose modifications mentioned below are informational only. When mitapivat is used for the treatment of hemolytic anemia in patients with pyruvate kinase deficiency, the US manufacturer of mitapivat states that mitapivat dose should not exceed 20 mg twice daily with concurrent moderate CYP3A4 inhibitors.(2) When mitapivat is used for the treatment of anemia in patients with alpha- or beta-thalassemia, the US manufacturer of mitapivat states that concurrent moderate CYP3A4 inhibitors should be avoided.(3) The Middle Eastern manufacturer of mitapivat states that alternative agents that do not inhibit CYP3A4 should be considered. If concomitant use of a moderate CYP3A4 inhibitor is unavoidable, the dose of mitapivat should not exceed 100 mg once daily.(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) In a pharmacokinetic study with mitapivat 5, 20, or 50 mg twice daily dosing, fluconazole increased mitapivat AUC and Cmax by 2.6-fold and 1.6-fold, respectively.(2) In a pharmacokinetic study, midazolam (a CYP3A4 substrate) area-under-curve (AUC) and maximum concentration (Cmax) decreased by 65% and 59%, respectively, with mitapivat 100 mg twice daily.(3)
Mitapivat/Carbamazepine
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Carbamazepine is a strong CYP3A4 inducer and may increase the CYP3A4-mediated metabolism of 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)
Mitapivat/Crizotinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of mitapivat.(1-3) Crizotinib is a moderate CYP3A4 inhibitor. Agents that induce the CYP3A4 isoenzyme may induce the metabolism of crizotinib.(4) Mitapivat is a moderate CYP3A4 inducer.
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels of and effects from mitapivat including decreased estrone and estradiol levels in males, increased urate, back pain, and arthralgias.(1-3) Concurrent use of moderate CYP3A4 inducers may decrease the levels and effectiveness of crizotinib.(4)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid the concurrent use of moderate CYP3A4 inducers in patients receiving therapy with crizotinib. Consider the use of alternative agents with less enzyme induction potential.(4) When mitapivat is used for the treatment of hemolytic anemia in patients with pyruvate kinase deficiency, the US manufacturer of mitapivat states that mitapivat dose should not exceed 20 mg twice daily with concurrent moderate CYP3A4 inhibitors.(1) When mitapivat is used for the treatment of anemia in patients with alpha- or beta-thalassemia, the US manufacturer of mitapivat states that concurrent moderate CYP3A4 inhibitors should be avoided.(2) The Middle Eastern manufacturer of mitapivat states that alternative agents that do not inhibit CYP3A4 should be considered. If concomitant use of a moderate CYP3A4 inhibitor is unavoidable, the dose of mitapivat should not exceed 100 mg once daily.(3)
DISCUSSION: Mitapivat is a CYP3A4 substrate. In a pharmacokinetic study with mitapivat 5, 20, or 50 mg twice daily dosing, fluconazole increased mitapivat area-under-curve (AUC) and concentration maximum (Cmax) by 2.6-fold and 1.6-fold, respectively.(1) Rifampin (600 mg daily), a strong CYP3A4 inducer, decreased the Cmax and AUC of a single dose of crizotinib (250 mg) by 69% and 82%, respectively.(4)
Mitapivat/Duvelisib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of mitapivat.(1-3) Duvelisib is a moderate CYP3A4 inhibitor. Moderate inducers of CYP3A4 may accelerate the metabolism of duvelisib.(4) Mitapivat is a moderate CYP3A4 inducer.
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels of and effects from mitapivat including decreased estrone and estradiol levels in males, increased urate, back pain, and arthralgias.(1-3) Concurrent or recent use of moderate CYP3A4 inducers may alter the clinical effectiveness of duvelisib.(4)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid the concurrent use of duvelisib with moderate CYP3A4 inducers.(4) When possible, select alternative agents in place of the moderate CYP3A4 inducer. If the moderate CYP3A4 inducer cannot be avoided, increase the dose of duvelisib on day 12 of concurrent therapy as follows: - If the initial dose of duvelisib is 25 mg twice daily, increase the duvelisib dose to 40 mg twice daily. - If the initial dose of duvelisib is 15 mg twice daily, increase the duvelisib dose to 25 mg twice daily. Monitor patients receiving concurrent therapy for reduced efficacy.(4) If the moderate CYP3A4 inducer is discontinued, reduce the dose of duvelisib back to the initial dose 14 days after discontinuation of the moderate CYP3A4 inducer.(4) When mitapivat is used for the treatment of hemolytic anemia in patients with pyruvate kinase deficiency, the US manufacturer of mitapivat states that mitapivat dose should not exceed 20 mg twice daily with concurrent moderate CYP3A4 inhibitors.(1) When mitapivat is used for the treatment of anemia in patients with alpha- or beta-thalassemia, the US manufacturer of mitapivat states that concurrent moderate CYP3A4 inhibitors should be avoided.(2) The Middle Eastern manufacturer of mitapivat states that alternative agents that do not inhibit CYP3A4 should be considered. If concomitant use of a moderate CYP3A4 inhibitor is unavoidable, the dose of mitapivat should not exceed 100 mg once daily.(3)
DISCUSSION: Mitapivat is a CYP3A4 substrate. In a pharmacokinetic study with mitapivat 5, 20, or 50 mg twice daily dosing, fluconazole increased mitapivat area-under-curve (AUC) and concentration maximum (Cmax) by 2.6-fold and 1.6-fold, respectively.(1) In an interaction study, etravirine (a moderate CYP3A inducer) 200 mg twice daily decreased the Cmax and AUC of single dose duvelisib 25 mg by 16% and 35%, respectively.(4)
Mitapivat/Enzalutamide
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Both mitapivat and enzalutamide are CYP3A4 substrates and inducers. Strong inducers of CYP3A4 may increase the metabolism of mitapivat.(1) Enzalutamide is a strong CYP3A4 inducer. Moderate inducers of CYP3A4 may increase the metabolism of enzalutamide.(2) Mitapivat is a moderate CYP3A4 inducer.
CLINICAL EFFECTS: Concurrent use may result in decreased levels and effectiveness of both mitapivat and enzalutamide.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid the concurrent use of mitapivat with enzalutamide.(1,2)
DISCUSSION: Mitapivat is a CYP3A4 substrate. In a pharmacokinetic study with a single 50 mg dose of mitapivat, rifampin decreased area-under-curve (AUC) and concentration maximum (Cmax) by 91% and 77%, respectively. After mitapivat doses of 5, 20, or 50 mg twice daily, rifampin decreased AUC and Cmax by 95% and 85%, respectively.(1) Coadministration of rifampin (strong CYP3A4 inducer and moderate CYP2C8 inducer) decreased the composite AUC of enzalutamide and its active metabolite by 37%.(2)
Mitapivat/Fedratinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Fedratinib and mitapivat are substrates of CYP3A4.(1-4) Fedratinib, a moderate CYP3A4 inhibitor, may inhibit the metabolism of mitapivat.(1) Mitapivat, a moderate CYP3A4 inducer, may induce the metabolism of fedratinib.(2-4)
CLINICAL EFFECTS: Concurrent use of fedratinib with moderate CYP3A4 inducers such as mitapivat may result in decreased levels and effectiveness of fedratinib.(1) Concurrent use of mitapivat with moderate CYP3A4 inhibitors such as fedratinib may result in increased levels of and effects from mitapivat including decreased estrone and estradiol levels in males, increased urate, back pain, and arthralgias.(2-4)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid the concurrent use of fedratinib and mitapivat.(1-4) The effect of the two-way inhibition and induction of fedratinib and mitapivat metabolism is unknown. The optimal doses of fedratinib and mitapivat when used concurrently have not been determined. Dose modifications mentioned below are informational only. When mitapivat is used for the treatment of hemolytic anemia in patients with pyruvate kinase deficiency, the US manufacturer of mitapivat states that mitapivat dose should not exceed 20 mg twice daily with concurrent moderate CYP3A4 inhibitors.(2) When mitapivat is used for the treatment of anemia in patients with alpha- or beta-thalassemia, the US manufacturer of mitapivat states that concurrent moderate CYP3A4 inhibitors should be avoided.(3) The Middle Eastern manufacturer of mitapivat states that alternative agents that do not inhibit CYP3A4 should be considered. If concomitant use of a moderate CYP3A4 inhibitor is unavoidable, the dose of mitapivat should not exceed 100 mg once daily.(4)
DISCUSSION: The effect of CYP3A4 inducers has not been studied. Fedratinib is metabolized by CYP3A4.(1) Mitapivat is a CYP3A4 substrate. In a pharmacokinetic study with mitapivat 5, 20, or 50 mg twice daily dosing, fluconazole increased mitapivat area-under-curve (AUC) and concentration maximum (Cmax) by 2.6-fold and 1.6-fold, respectively.(2) In a pharmacokinetic study, midazolam (a CYP3A4 substrate) area-under-curve (AUC) and maximum concentration (Cmax) decreased by 65% and 59%, respectively, with mitapivat 100 mg twice daily.(3)
Mitapivat/Hormonal Contraceptives
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Mitapivat is a moderate CYP3A4 inducer. Coadministration of mitapivat with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding due to decreased hormonal concentrations.(1)
CLINICAL EFFECTS: Concurrent use of mitapivat can lead to ineffective hormonal contraceptive and cause unintended pregnancy.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraceptives (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Pregnant women and females of reproductive potential should be counseled on the potential risk to the fetus.(1) Advise females of reproductive potential to use effective non-hormonal contraception during treatment with mitapivat.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2)
DISCUSSION: Mitapivat is a moderate CYP3A4 inducer. Mitapivat has not been studied with hormonal contraceptives. It can render some hormonal contraceptives ineffective and may cause unintended pregnancy. Women should use non-hormonal contraception during therapy.(1) In an animal reproduction study, oral administration of mitapivat to pregnant rats and rabbits during the period of organogenesis was not teratogenic at doses up to 13 and 3 times the maximum recommended ose.(1)
Mitapivat/Idelalisib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of mitapivat.(1) Idelalisib is a strong CYP3A4 inhibitor. Agents that induce CYP3A4 may induce the metabolism of idelalisib.(2) Mitapivat is a moderate CYP3A4 inducer.
CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels of and effects from mitapivat including decreased estrone and estradiol levels in males, increased urate, back pain, and arthralgias.(1) Concurrent use of moderate CYP3A4 inducers may decrease the levels and effectiveness of idelalisib.(2)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The concurrent use of strong CYP3A4 inhibitors with mitapivat should be avoided.(1) Avoid the concurrent use of moderate CYP3A4 inducers in patients receiving therapy with idelalisib.(1) Consider the use of alternative agents with less enzyme induction potential.(2)
DISCUSSION: Mitapivat is a CYP3A4 substrate. In a pharmacokinetic study with mitapivat 20 mg single dose, itraconazole increased mitapivat area-under-curve (AUC) and concentration maximum (Cmax) by 4.9-fold and 1.7-fold, respectively. In a pharmacokinetic study with mitapivat 50 mg twice daily, itraconazole increased mitapivat AUC and Cmax by 3.6-fold and 2.2-fold, respectively. With ketoconazole, mitapivat doses of 5, 20, or 50 mg twice daily had an AUC and Cmax increased by 3.9-fold and 2.4-fold, 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.(2)
Mitapivat/Lenacapavir
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inducers of CYP3A4 may accelerate the metabolism of lenacapavir.(1-3) Mitapivat is a moderate CYP3A4 inducer. Moderate inhibitors of CYP3A4 may inhibit the metabolism of mitapivat.(4) Lenacapavir is a moderate CYP3A4 inhibitor.
CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may alter the clinical effectiveness of lenacapavir.(1-3) Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels of and effects from mitapivat including decreased estrone and estradiol levels in males, increased urate, back pain, and arthralgias.(4)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The concurrent use of lenacapavir with moderate CYP3A4 inducers is not recommended.(1-3) Lenacapavir has a long half-life and may increase the levels of CYP3A4 substrates initiated within 9 months after the last dose of subcutaneous lenacapavir.(1-3) When mitapivat is used for the treatment of hemolytic anemia in patients with pyruvate kinase deficiency, the US manufacturer of mitapivat states that mitapivat dose should not exceed 20 mg twice daily with concurrent moderate CYP3A4 inhibitors.(4) When mitapivat is used for the treatment of anemia in patients with alpha- or beta-thalassemia, the US manufacturer of mitapivat states that concurrent moderate CYP3A4 inhibitors should be avoided.(5) The Middle Eastern manufacturer of mitapivat states that alternative agents that do not inhibit CYP3A4 should be considered. If concomitant use of a moderate CYP3A4 inhibitor is unavoidable, the dose of mitapivat should not exceed 100 mg once daily.(6)
DISCUSSION: In a study, efavirenz 600 mg once daily (inducer of CYP3A4 [moderate] and P-glycoprotein) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of lenacapavir by 36% and 56%, respectively.(1) Mitapivat is a CYP3A4 substrate. In a pharmacokinetic study with mitapivat 5, 20, or 50 mg twice daily dosing, fluconazole (a moderate CYP3A4 inhibitor) increased mitapivat AUC and Cmax by 2.6-fold and 1.6-fold, respectively.(4) In a pharmacokinetic study, midazolam (a CYP3A4 substrate) area-under-curve (AUC) and maximum concentration (Cmax) decreased by 65% and 59%, respectively, with mitapivat 100 mg twice daily.(3)
Mitapivat/Lorlatinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Mitapivat and lorlatinib are both CYP3A4 substrates and inducers. Moderate inducers of CYP3A4 may increase the metabolism of mitapivat.(1) Lorlatinib is a moderate CYP3A4 inducer. Moderate inducers of CYP3A4 are expected to increase the metabolism of lorlatinib.(2) Mitapivat is a moderate CYP3A4 inducer.
CLINICAL EFFECTS: Concurrent use may result in decreased levels and effectiveness of both mitapivat and lorlatinib.(1,2)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid concurrent administration of moderate inducers of CYP3A4 with lorlatinib.(2) If concurrent use of lorlatinib and moderate CYP3A4 inducers cannot be avoided, increase the dose of lorlatinib to 125 mg daily.(2) Concurrent use of mitapivat with medications that are moderate CYP3A4 inducers should be monitored closely. Mitapivat dose should not exceed a maximum dose of 100 mg twice daily with concurrent moderate CYP3A4 inducers.(1)
DISCUSSION: Mitapivat is a CYP3A4 substrate. In a pharmacokinetic study with 5 or 20 mg twice daily of mitapivat, efavirenz decreased area-under-curve (AUC) and concentration maximum (Cmax) by 60% and 30%, respectively. After mitapivat doses of 50 mg twice daily, efavirenz decreased AUC and Cmax by 55% and 24%, respectively.(1) Modafinil (a moderate CYP3A4 inducer) decreased the AUC and Cmax of a single 100 mg dose of lorlatinib by 23% and 22%, respectively.(2)
Mitapivat/Moderate Cyp3a4 Inducers
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inducers of CYP3A4 may increase the metabolism of mitapivat.(1)
CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inducer may result in decreased levels and effectiveness of mitapivat.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Consider alternative therapies that are not moderate CYP3A4 inducers in patients who are on mitapivat. If concurrent use is necessary, monitor hemoglobin closely and titrate mitapivat dose, not to exceed a maximum dose of 100 mg twice daily.(1)
DISCUSSION: Mitapivat is a CYP3A4 substrate. In a pharmacokinetic study with 5 or 20 mg twice daily of mitapivat, efavirenz decreased area-under-curve (AUC) and concentration maximum (Cmax) by 60% and 30%, respectively. After mitapivat doses of 50 mg twice daily, efavirenz decreased AUC and Cmax by 55% and 24%, respectively.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad, modafinil, nafcillin, pacritinib, pexidartinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)
Mitapivat/Nirogacestat
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of mitapivat.(1-2) Nirogacestat is a moderate CYP3A4 inhibitor. Moderate inducers of CYP3A4 may accelerate the metabolism of nirogacestat.(3) Mitapivat is a moderate CYP3A4 inducer.
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels of and effects from mitapivat including decreased estrone and estradiol levels in males, increased urate, back pain, and arthralgias.(1-2) Concurrent or recent use of moderate CYP3A4 inducers may alter the clinical effectiveness of nirogacestat.(3)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of nirogacestat states that concurrent use with strong or moderate CYP3A4 inducers should be avoided.(3) When mitapivat is used for the treatment of hemolytic anemia in patients with pyruvate kinase deficiency, the US manufacturer of mitapivat states that mitapivat dose should not exceed 20 mg twice daily with concurrent moderate CYP3A4 inhibitors.(1) When mitapivat is used for the treatment of anemia in patients with alpha- or beta-thalassemia, the US manufacturer of mitapivat states that concurrent moderate CYP3A4 inhibitors should be avoided.(2) The Middle Eastern manufacturer of mitapivat states that alternative agents that do not inhibit CYP3A4 should be considered. If concomitant use of a moderate CYP3A4 inhibitor is unavoidable, the dose of mitapivat should not exceed 100 mg once daily.(4)
DISCUSSION: Mitapivat is a CYP3A4 substrate. In a pharmacokinetic study with mitapivat 5, 20, or 50 mg twice daily dosing, fluconazole increased mitapivat area-under-curve (AUC) and concentration maximum (Cmax) by 2.6-fold and 1.6-fold, respectively.(1) In a PKPB model, coadministration of rifampin, a strong CYP3A4 inducer, following multiple doses of nirogacestat (150 mg BID) is predicted to decrease the AUC of nirogacestat by 85%.(3) In a PKPB model, coadministration of efavirenz, a moderate CYP3A4 inducer, following multiple doses of nirogacestat (150 mg BID) is predicted to decrease the AUC of nirogacestat by 67%.(3)
Mitapivat/Oral Lefamulin
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Lefamulin and mitapivat are both metabolized by CYP3A4. Mitapivat is a moderate CYP3A4 inducer while oral lefamulin is a moderate CYP3A4 inhibitor.(1-4)
CLINICAL EFFECTS: The concurrent administration of a moderate CYP3A4 inducer may result in decreased levels and effectiveness of lefamulin.(1) Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels of and effects from mitapivat including decreased estrone and estradiol levels in males, increased urate, back pain, and arthralgias.(2-4)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of lefamulin states that concurrent use with moderate CYP3A4 inducers should be avoided.(1) When mitapivat is used for the treatment of hemolytic anemia in patients with pyruvate kinase deficiency, the US manufacturer of mitapivat states that mitapivat dose should not exceed 20 mg twice daily with concurrent moderate CYP3A4 inhibitors.(2) When mitapivat is used for the treatment of anemia in patients with alpha- or beta-thalassemia, the US manufacturer of mitapivat states that concurrent moderate CYP3A4 inhibitors should be avoided.(3) The Middle Eastern manufacturer of mitapivat states that alternative agents that do not inhibit CYP3A4 should be considered. If concomitant use of a moderate CYP3A4 inhibitor is unavoidable, the dose of mitapivat should not exceed 100 mg once daily.(4)
DISCUSSION: In a study, concurrent administration of rifampin (a strong inducer) with lefamulin injection decreased lefamulin area-under-the-curve (AUC) and maximum concentration (Cmax) by 28% and 8%.(1) In a study, concurrent administration of rifampin (a strong inducer) with oral lefamulin (tablets) decreased lefamulin AUC and Cmax by 72% and 57%.(1) In a study, oral lefamulin tablets administered concomitantly with and at 2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200% and 100%, respectively. No clinically significant effect on midazolam pharmacokinetics was observed when co-administered with lefamulin injection.(1) In a pharmacokinetic study with mitapivat 5, 20, or 50 mg twice daily dosing, fluconazole (a moderate CYP3A4 inhibitor) increased mitapivat area-under-curve (AUC) and concentration maximum (Cmax) by 2.6-fold and 1.6-fold, respectively.(2) In a pharmacokinetic study, midazolam (a CYP3A4 substrate) area-under-curve (AUC) and maximum concentration (Cmax) decreased by 65% and 59%, respectively, with mitapivat 100 mg twice daily.(3)
Mitapivat/Rilzabrutinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Rilzabrutinib and mitapivat are substrates of CYP3A4.(1-4) Rilzabrutinib, a moderate CYP3A4 inhibitor, may inhibit the metabolism of mitapivat.(1) Mitapivat, a moderate CYP3A4 inducer, may induce the metabolism of rilzabrutinib.(2-4)
CLINICAL EFFECTS: Concurrent use of rilzabrutinib with moderate CYP3A4 inducers such as mitapivat may result in decreased levels and effectiveness of rilzabrutinib.(1) Concurrent use of mitapivat with moderate CYP3A4 inhibitors such as rilzabrutinib may result in increased levels of and effects from mitapivat including decreased estrone and estradiol levels in males, increased urate, back pain, and arthralgias.(2-4)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid the concurrent use of rilzabrutinib and mitapivat.(1,2) The effect of the two-way inhibition and induction of rilzabrutinib and mitapivat metabolism is unknown. The optimal doses of rilzabrutinib and mitapivat when used concurrently have not been determined. Dose modifications mentioned below are informational only. When mitapivat is used for the treatment of hemolytic anemia in patients with pyruvate kinase deficiency, the US manufacturer of mitapivat states that mitapivat dose should not exceed 20 mg twice daily with concurrent moderate CYP3A4 inhibitors.(2) When mitapivat is used for the treatment of anemia in patients with alpha- or beta-thalassemia, the US manufacturer of mitapivat states that concurrent moderate CYP3A4 inhibitors should be avoided.(3) The Middle Eastern manufacturer of mitapivat states that alternative agents that do not inhibit CYP3A4 should be considered. If concomitant use of a moderate CYP3A4 inhibitor is unavoidable, the dose of mitapivat should not exceed 100 mg once daily.(4)
DISCUSSION: Concomitant use of a single dose of rilzabrutinib 400 mg with midazolam (sensitive CYP3A inhibitor) increased midazolam maximum concentration (Cmax) and area-under-curve (AUC) by 2.2-fold. Midazolam AUC is predicted to increase up to 3-fold in patients with immune thrombocytopenia following coadministration with 400 mg rilzabrutinib twice daily.(1) Mitapivat is a CYP3A4 substrate. In a pharmacokinetic study with mitapivat 5, 20, or 50 mg twice daily dosing, fluconazole increased mitapivat AUC and Cmax by 2.6-fold and 1.6-fold, respectively.(2) In a pharmacokinetic study with mitapivat 100 mg twice daily dosing, fluconazole increased mitapivat AUC and Cmax by 2.7-fold and 1.7-fold, respectively.(3) In a pharmacokinetic study, midazolam (a CYP3A4 substrate) area-under-curve (AUC) and maximum concentration (Cmax) decreased by 65% and 59%, respectively, with mitapivat 100 mg twice daily.(3)
Mitapivat/Selected Cyp3a4 Substrates
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Mitapivat is a moderate inducer of CYP3A4 and may increase the metabolism of drugs metabolized by the CYP3A4 enzyme.
CLINICAL EFFECTS: Concurrent use of mitapivat may lead to decreased serum levels and effectiveness of drugs metabolized by the CYP3A4 pathway.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: When mitapivat is used for the treatment of hemolytic anemia in patients with pyruvate kinase deficiency, the US manufacturer of mitapivat states that co-administration of CYP3A4 substrates for which minimal concentration decreases may lead to serious therapeutic failure should be monitored for loss of efficacy. If concomitant use is unavoidable, increase the dose of the CYP3A4 substrate in accordance with approved product labeling.(1) When mitapivat is used for the treatment of anemia in patients with alpha- or beta-thalassemia, the US manufacturer of mitapivat states that coadministration of sensitive CYP3A4 substrates with narrow therapeutic indices should be avoided.(2) The Middle Weatern manufacturer of mitapivat states that alternative agents should be considered or the coadministered CYP3A4 substrate should be monitored for loss of efficacy.(3)
DISCUSSION: In a clinical study, coadministration of mitapivat 5 mg twice daily with midazolam, a sensitive CYP3A4 substrate, decreased midazolam area-under-curve (AUC) and maximum concentration (Cmax) by 21% and 19%, respectively. Midazolam AUC and Cmax were decreased by 43% and 39%, respectively with mitapivat 20 mg twice daily by 57% and 32%, respectively with mitapivat 50 mg twice daily, and by 65% and 59%, respectively with mitapivat 100 mg twice daily.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: cyclosporine, everolimus, sirolimus, tacrolimus, and temsirolimus.(4-9)
Mitapivat/Voxelotor
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Voxelotor and mitapivat are both metabolized by CYP3A4. Mitapivat is a moderate CYP3A4 inducer while voxelotor is a moderate CYP3A4 inhibitor.(1-4)
CLINICAL EFFECTS: The concurrent administration of a moderate CYP3A4 inducer may result in decreased levels and effectiveness of voxelotor.(1) Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels of and effects from mitapivat including decreased estrone and estradiol levels in males, increased urate, back pain, and arthralgias.(2-4)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of voxelotor states that concurrent use with moderate CYP3A4 inducers should be avoided. If concomitant use is unavoidable, increase the dose of voxelotor as follows: Patients 12 years and older on concurrent moderate CYP3A4 inducers: increase voxelotor dose to 2,000 mg daily. Patients 4 years to less than 12 years on concurrent moderate CYP3A4 inducers: refer to prescribing information for recommended weight-based dosage adjustments.(1) When mitapivat is used for the treatment of hemolytic anemia in patients with pyruvate kinase deficiency, the US manufacturer of mitapivat states that mitapivat dose should not exceed 20 mg twice daily with concurrent moderate CYP3A4 inhibitors.(2) When mitapivat is used for the treatment of anemia in patients with alpha- or beta-thalassemia, the US manufacturer of mitapivat states that concurrent moderate CYP3A4 inhibitors should be avoided.(3) The Middle Eastern manufacturer of mitapivat states that alternative agents that do not inhibit CYP3A4 should be considered. If concomitant use of a moderate CYP3A4 inhibitor is unavoidable, the dose of mitapivat should not exceed 100 mg once daily.(4)
DISCUSSION: A pharmacokinetic model predicted that co-administration of rifampin, a strong CYP3A4 inducer, would decrease the area-under-curve (AUC) of voxelotor by 40%. Co-administration of efavirenz, a moderate CYP3A4 inducer, is predicted to decrease the AUC of voxelotor by 24%.(1) In a pharmacokinetic study with mitapivat 5, 20, or 50 mg twice daily dosing, fluconazole (a moderate CYP3A4 inhibitor) increased mitapivat area-under-curve (AUC) and concentration maximum (Cmax) by 2.6-fold and 1.6-fold, respectively.(2) In a pharmacokinetic study, midazolam (a CYP3A4 substrate) area-under-curve (AUC) and maximum concentration (Cmax) decreased by 65% and 59%, respectively, with mitapivat 100 mg twice daily.(3)
Moderate Cyp3a4 Inducer/Vanzacaftor-Tezacaftor-Deutivacaftor
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of vanzacaftor, tezacaftor, and deutivacaftor.(1)
CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of vanzacaftor, tezacaftor, and deutivacaftor.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Concurrent use of moderate CYP3A4 inducers in patients maintained on vanzacaftor-tezacaftor-deutivacaftor is not recommended.(1)
DISCUSSION: Concurrent administration with efavirenz (a moderate inducer of CYP3A4) is predicted to decrease vanzacaftor and deutivacaftor area-under-curve (AUC) by 69% and 73%, respectively, and maximum concentration (Cmax) by 65% and 56%, respectively.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Abemaciclib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Abemaciclib is a substrate of CYP3A4. Moderate inducers of CYP3A4 may induce the metabolism of abemaciclib.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of abemaciclib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of abemaciclib states to avoid concurrent administration with moderate CYP3A4 inducers and consider alternative agents.(1)
DISCUSSION: Abemaciclib is a substrate of CYP3A4.(1) Concurrent administration of rifampin (600 mg once daily, a strong CYP3A4 inducer) with a single 200 mg dose of abemaciclib decreased the relative potency adjusted unbound area-under-curve (AUC) of abemaciclib and its active metabolites (M2, M18, and M20) by 70% in healthy subjects.(1) Concurrent administration of efavirenz, bosentan, and modafinil (moderate CYP3A4 inducers) are predicted to decrease the relative potency adjusted unbound AUC of abemaciclib and its active metabolites (M2, M18, and M20) by 53%, 41%, and 29%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, tipranavir/ritonavir and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Atogepant
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate CYP3A4 inducers may increase the metabolism of atogepant by CYP3A4.(1)
CLINICAL EFFECTS: The concurrent use of moderate CYP3A4 inducers with atogepant may result in decreased levels and clinical effectiveness of atogepant.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of atogepant recommends that patients on concomitant moderate CYP3A4 inducers receive atogepant 60 mg once daily for prevention of episodic migraines and use of atogepant is not recommended for prevention of chronic migraines.(1) Patients receiving concurrent therapy with CYP3A4 inducers and atogepant should be observed for decreased clinical effectiveness.
DISCUSSION: In a study of healthy subjects, rifampin, a strong CYP3A4 inducer, decreased the area-under-curve (AUC) and maximum concentration (Cmax) of atogepant by 60% and 30%, respectively. Topiramate, a weak CYP3A4 inducer, decreased atogepant AUC and Cmax by 25% and 24%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine and tovorafenib.(1,2)
Moderate Cyp3a4 Inducers/Aumolertinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Aumolertinib is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of aumolertinib.(1)
CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of aumolertinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of aumolertinib states that concomitant use of moderate CYP3A4 inducers is not recommended.(1)
DISCUSSION: The impact of moderate CYP3A4 inducers on the pharmacokinetics of aumolertinib has not been investigated in clinical studies. In a clinical study, aumolertinib area-under-curve (AUC) decreased by approximately 90% following concomitant use of rifampin (strong CYP3A4 inducer).(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, telotristat, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Brigatinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Brigatinib is a substrate of CYP3A4. Moderate inducers of CYP3A4 may induce the metabolism of brigatinib.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of brigatinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of brigatinib states to avoid concurrent administration with moderate CYP3A4 inducers. If concurrent use cannot be avoided, increase the daily dose of brigatinib in 30 mg increments every 7 days, as tolerated, to a maximum of twice the brigatinib dose that was tolerated prior to initiation of the moderate CYP3A4 inducer. After discontinuation of a moderate CYP3A4 inducer, resume the brigatinib dose that was tolerated prior to initiation of the inducer.(1)
DISCUSSION: Brigatinib is a substrate of CYP3A4.(1) Concurrent administration of rifampin (600 mg daily, a strong CYP3A4 inducer) with a single 180 mg dose of brigatinib decreased the brigatinib maximum concentration (Cmax) by 60% and area-under-curve (AUC) by 80% compared to brigatinib alone. Moderate CYP3A4 inducers are expected to decrease the AUC of brigatinib by 50%.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat ethyl, thioridazine, tipranavir/ritonavir and tovorafenib.(2-3)
Moderate Cyp3a4 Inducers/Cabozantinib Lauryl Sulfate
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of cabozantinib.(1)
CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of cabozantinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Avoid the concurrent use of moderate CYP3A4 inducers in patients receiving therapy with cabozantinib. Consider the use of alternative agents with less enzyme induction potential.(1) If concurrent use of a moderate CYP3A4 inducer cannot be avoided, increase the daily dose of cabozantinib CAPsules by 11.5 mg (from 34.5 mg to 46 mg daily, or from 23 mg to 34.5 mg daily, or from 11.5 mg to 23 mg daily) as tolerated. The daily dose of cabozantinib should not exceed 46 mg. If the CYP3A4 inducer is discontinued, reduce the dosage of cabozantinib to the dose used prior to initiation of the inducer 2 to 3 days after discontinuation of the moderate inducer.(1)
DISCUSSION: The impact of moderate CYP3A4 inducers on the pharmacokinetics of cabozantinib has not been investigated in clinical studies. In a study in healthy subjects, rifampin (strong CYP3A4 inducer, 600 mg daily for 31 days) decreased the AUC of a single dose of cabozantinib by 77%.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Cabozantinib S-Malate Tablets
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of cabozantinib.(1)
CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of cabozantinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Avoid the concurrent use of moderate CYP3A4 inducers in patients receiving therapy with cabozantinib. Consider the use of alternative agents with less enzyme induction potential.(1) If concurrent use of a moderate CYP3A4 inducer cannot be avoided, increase the daily dose of cabozantinib TABlets by 20 mg (e.g. from 60 mg to 80 mg daily) as tolerated. The daily dose should not exceed 80 mg. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the moderate inducer.(1)
DISCUSSION: The impact of moderate CYP3A4 inducers on the pharmacokinetics of cabozantinib has not been investigated in clinical studies. In a study in healthy subjects, rifampin (strong CYP3A4 inducer, 600 mg daily for 31 days) decreased the AUC of a single dose of cabozantinib by 77%.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Camizestrant
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Agents that induce the CYP3A4 isoenzyme may induce the metabolism of camizestrant.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inducers may decrease the levels and effectiveness of camizestrant.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Dosage modifications for concomitant use of moderate CYP3A4 inducers differ depending on the CDK4/6 inhibitor used in combination with camizestrant.(1) Avoid the use of moderate CYP3A4 inducers for patients who are receiving camizestrant in combination with abemaciclib or palbociclib.(1) If concomitant use of a moderate CYP3A4 inducer cannot be avoided in patients who are receiving camizestrant in combination with abemaciclib or palbociclib, increase the camizestrant dosage from 75 mg once daily to 150 mg once daily. After the moderate CYP3A4 inducer has been discontinued for at least 14 days, resume the camizestrant dosage used prior to initiation of the moderate CYP3A4 inducer. For patients who are receiving camizestrant in combination with ribociclib concomitantly with a moderate CYP3A4 inducer, no camizestrant dosage modification is recommended.(1)
DISCUSSION: Camizestrant maximum concentration (Cmax) is predicted to decrease to 58%, and the area-under-curve (AUC) is predicted to decrease to 43% following concomitant administration of phenobarbital (moderate CYP3A4 inducer) 100 mg once daily for 17 days. Phenobarbital or efavirenz (moderate CYP3A4 inducer) are predicted to have minimal effects on camizestrant AUC and Cmax when camizestrant is given in combination with 400 mg or 600 mg ribociclib. Moderate inducers of CYP3A4 include: barbiturates, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, phenobarbital, primidone, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Doravirine
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate CYP3A4 inducers are expected to increase the metabolism of doravirine.(1-3)
CLINICAL EFFECTS: Concurrent or recent use of a moderate CYP3A4 inducer may result in decreased levels and effectiveness of doravirine.(1-3)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Recommendations for concurrent use of moderate CYP3A4 inducers with doravirine vary depending on the reference. The manufacturer of the fixed dose combination of doravirine-islatravir states concurrent use with moderate CYP3A4 inducers is not recommended.(3) The DHHS HIV guidelines state when coadministering doravirine with bosentan, dexamethasone, and eslicarbazepine (moderate CYP3A4 inducers): consider an alternative antiretroviral or alternative drug to the moderate CYP3A4 inducer. It would be prudent to consider alternative drugs to other moderate CYP3A4 inducers. If co-administration is necessary monitor virologic response.(4) The University of Liverpool HIV Drug Interactions Database states concurrent use with moderate CYP3A4 inducers should be avoided. If concurrent use cannot be avoided, dose adjustment of doravirine to 100 mg twice daily is recommended and should be maintained for at least 2 weeks following cessation of the moderate CYP3A4 inducer. If a patient is on eslicarbazepine, doravirine should not be coadministered.(5) The manufacturer of single ingredient doravirine and the fixed dose combination of doravirine-lamivudine-tenofovir does not have a recommendation for concurrent use with moderate CYP3A4 inducers.(1,3)
DISCUSSION: Doravirine is metabolized by CYP3A4. Moderate CYP3A4 inducers are expected to reduce doravirine levels, which may lead to loss of response.(1) In a study in 12 subjects, rifabutin (300 mg daily), a moderate CYP3A4 inducer, decreased the area-under-curve (AUC) and 24 hour concentration (C24) of a single dose of doravirine (100 mg) by 50% and 68%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dexamethasone, dipyrone, elagolix, eslicarbazepine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine and tovorafenib.(3-4)
Moderate Cyp3a4 Inducers/Elbasvir-Grazoprevir
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of elbasvir and grazoprevir.(1,2)
CLINICAL EFFECTS: Concurrent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of elbasvir and grazoprevir.(1,2)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Concurrent use of elbasvir-grazoprevir and a moderate CYP3A4 inducers is not recommended.(1,2) If concurrent use is required, monitor the patient for potential treatment failure and decreased elbasvir and grazoprevir levels.
DISCUSSION: In single dose studies, rifampin increased levels of both elbasvir and grazoprevir. In a study in 14 subjects, rifampin (600 mg single IV dose) increased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of a single dose of elbasvir (50 mg) by 41%, 22%, and 31%, respectively. In a study in 14 subjects, rifampin (600 mg single oral dose) increased the Cmax, AUC, and Cmin of a single dose of elbasvir (50 mg) by 29%, 17%, and 21%, respectively. In a study in 12 subjects, rifampin (600 mg single IV dose) increased the Cmax, AUC, and Cmin of a single dose of grazoprevir (200 mg) by 10.94-fold, 10.21-fold, and 1.77-fold, respectively. In a study in 12 subjects, rifampin (600 mg single oral dose) increased the Cmax, AUC, and Cmin of a single dose of grazoprevir (200 mg) by 6.52-fold, 8.35-fold, and 1.61-fold, respectively.(1) However, multiple dose studies with rifampin showed decreased grazoprevir levels. In a study in 12 subjects, rifampin (600 mg orally) decreased the AUC and Cmin of grazoprevir (200 mg daily) by 7% and 90%, respectively. Cmax increased 16%.(1) In a study in 12 subjects, efavirenz (600 mg daily) decreased the Cmax, AUC, and Cmin of elbasvir (50 mg daily) by 45%, 34%, and 59%, respectively.(1) In a study in 12 subjects, efavirenz (600 mg daily) decreased the Cmax, AUC, and Cmin of grazoprevir (200 mg daily) by 87%, 82%, and 69%, respectively.(1) Moderate inducers of CYP3A4 include belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(1-4)
Moderate Cyp3a4 Inducers/Elinzanetant
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate CYP3A4 inducers may induce the metabolism of elinzanetant by CYP3A4.(1,2)
CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may reduce the clinical effectiveness of elinzanetant.(1,2)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The US manufacturer of elinzanetant states concurrent use with moderate CYP3A4 inducers should be avoided.(1) The Canadian manufacturer of elinzanetant states no dose adjustment is recommended for the concomitant use of elinzanetant with CYP3A4 and P-gp inducers.(2)
DISCUSSION: Elinzanetant maximum concentration (Cmax) reduced by 44% and area-under-curve (AUC) reduced by 64% following concomitant use with carbamazepine (moderate to strong CYP3A4 inducer) 600 mg administered twice daily.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(3,4)
Moderate Cyp3a4 Inducers/Erdafitinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Erdafitinib is a substrate of CYP2C9 and CYP3A4. Moderate inducers of CYP3A4 may induce the metabolism of erdafitinib.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of erdafitinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of erdafitinib states that if a moderate CYP3A4 inducer must be co-administered, increase the erdafitinib dose to 9 mg daily. If a moderate CYP3A4 inducer is discontinued, continue erdafitinib at the same dose in the absence of drug-related toxicity.(1)
DISCUSSION: Carbamazepine (a strong CYP3A4 inducer and weak CYP2C9 inducer) decreased the mean maximum concentration (Cmax) and area-under-curve (AUC) of erdafitinib by 78% and 45%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2-3)
Moderate Cyp3a4 Inducers/Gepotidacin
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate CYP3A4 inducers may induce the metabolism of gepotidacin.(1)
CLINICAL EFFECTS: Concurrent or recent use of a moderate CYP3A4 inducer may result in decreased antimicrobial activity of gepotidacin.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of gepotidacin states that concomitant use of moderate CYP3A4 inducers in patients being treated for uncomplicated urogenital gonorrhea should be avoided.(1) For patients being treated for uncomplicated UTI, no dosage adjustment is needed when taken with moderate CYP3A4 inducers.(1)
DISCUSSION: Gepotidacin is primarily metabolized by CYP3A4.(1) Concomitant administration of efavirenz (moderate CYP3A4 inducer) and a single 1,500 mg dose of gepotidacin is predicted to decrease area-under-curve (AUC) and maximum concentration (Cmax) by 49% and 34%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, lesinurad, lorlatinib, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Ibrutinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Agents that induce the CYP3A4 isoenzyme may induce the metabolism of ibrutinib.(1)
CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inducers may decrease the levels and effectiveness of ibrutinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Avoid the concurrent use of moderate CYP3A4 inducers in patients receiving therapy with ibrutinib.(1) Consider the use of alternative agents with less enzyme induction potential.(1)
DISCUSSION: The coadministration of rifampin decreased the maximum concentration (Cmax) and area-under-curve (AUC) of ibrutinib by more than 13-fold and 10-fold.(1) In a pharmacokinetic model, efavirenz (600 mg daily), a moderate CYP3A4 inducer, was predicted to decrease the Cmax and AUC of ibrutinib (560 mg) by 2.4-fold and 2.5-fold, respectively.(2) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(4)
Moderate Cyp3a4 Inducers/Intravenous Lefamulin
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Lefamulin is a substrate of CYP3A4. Moderate inducers of CYP3A4 may induce the metabolism of lefamulin.(1)
CLINICAL EFFECTS: The concurrent administration of a moderate CYP3A4 inducer may result in decreased levels and effectiveness of lefamulin.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of lefamulin states that concurrent use with moderate CYP3A4 inducers should be avoided.(1)
DISCUSSION: In a study, concurrent administration of rifampin (a strong inducer) with lefamulin injection decreased lefamulin area-under-the-curve (AUC) and maximum concentration (Cmax) by 28% and 8%.(1) Moderate inducers of CYP3A4 linked to this monograph include: mitapivat and repotrectinib.(2-3)
Moderate Cyp3a4 Inducers/Pirtobrutinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Pirtobrutinib is metabolized by CYP3A4. Moderate inducers of CYP3A4 may increase the metabolism of pirtobrutinib.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of pirtobrutinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Avoid concomitant use of pirtobrutinib with moderate CYP3A4 inducers.(1) If concomitant use of moderate CYP3A4 inducers is unavoidable, and the current dose of pirtobrutinib is 200 mg daily, increase the dose to 300 mg daily. If the current pirtobrutinib dosage is 50 mg or 100 mg once daily, increase the dose by 50 mg.(1)
DISCUSSION: Efavirenz and bosentan (moderate CYP3A inducers) are predicted to decrease the area-under-curve (AUC) of pirtobrutinib by 49% and 27%, respectively.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, and thioridazine.(2,3)
Moderate Cyp3a4 Inducers/Pralsetinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of pralsetinib.(1)
CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inducer may result in a loss of pralsetinib efficacy.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Avoid the concurrent use of pralsetinib with moderate CYP3A4 inducers.(1) If coadministration with a moderate CYP3A4 inducer cannot be avoided, increase the dose of pralsetinib on day 7 of coadministration with pralsetinib as follows: -If the current dose is 400 mg once daily, increase the dose to 600 mg daily. -If the current dose is 300 mg once daily, increase the dose to 500 mg daily. -If the current dose is 200 mg once daily, increase the dose to 300 mg daily. After discontinuation of a moderate CYP3A4 inducer for at least 14 days, resume the previous pralsetinib dose prior to initiating the moderate CYP3A4 inducer.(1) Monitor patients receiving concurrent therapy for reduced efficacy.
DISCUSSION: Coadministration of efavirenz 600 mg once daily is expected to decrease pralsetinib concentration maximum (Cmax) by 18% and area-under-curve (AUC) by 45%.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2-3)
Moderate Cyp3a4 Inducers/Praziquantel
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of praziquantel.(1,2)
CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of praziquantel.(1,2)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The US manufacturer of praziquantel recommends avoiding concomitant administration with moderate CYP3A4 inducers due to the risk of a clinically significant decrease in praziquantel plasma concentration which may lead to reduced therapeutic effect of praziquantel.(2) In patients receiving a clinically significant CYP3A4 inducer drug who need immediate treatment for schistosomiasis, alternative agents for schistosomiasis should be considered, where possible. If praziquantel treatment is necessary immediately, increase monitoring for reduced anthelmintic efficacy associated with praziquantel, when used in combination with a moderate CYP3A4 inducer.(2) In patients receiving a clinically significant CYP3A4 inducer drug whose treatment could be delayed, discontinue the CYP3A4 inducer drug at least 2 to 4 weeks before administration of praziquantel and, where possible, consider starting alternative medications that are not CYP3A4 inducers. The CYP3A4 inducer drug can be restarted 1 day after completion of praziquantel treatment, if needed.(2)
DISCUSSION: In a crossover study, 20 healthy subjects ingested a single 40 mg/kg oral dose of praziquantel following pre-treatment with oral efavirenz (400 mg daily for 13 days). Oral efavirenz reduced the mean praziquantel area-under-curve (AUC) by 77% and maximum concentration (Cmax) by 79%, when coadministered with praziquantel compared to praziquantel given alone.(2) Moderate CYP3A4 inducers include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(3-4)
Moderate Cyp3a4 Inducers/Ranolazine
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of ranolazine.(1,2)
CLINICAL EFFECTS: Concurrent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of ranolazine.(1,2)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The US manufacturer of ranolazine states that the concurrent use of CYP3A4 inducers such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John's wort is contraindicated. Concurrent use of moderate CYP3A4 inducers should be avoided.(1) The UK manufacturer of ranolazine states that ranolazine should not be used in patients receiving CYP3A4 inducers.(2)
DISCUSSION: Concurrent rifampin (600 mg daily), strong inducer of CYP3A4, decreased ranolazine plasma concentrations by 95%.(1,2) The effects of a moderate CYP3A4 inducer on ranolazine concentrations has not been studied. Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, lesinurad, lorlatinib, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, sotorasib, telotristat, and tovorafenib.(1-4)
Moderate Cyp3a4 Inducers/Ripretinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of ripretinib via this pathway.(1) Ripretinib and the active metabolite DP-5439 contribute to anticancer activity. CYP3A4 is the primary metabolism pathway for both ripretinib and the active metabolite DP-5439.(1)
CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may alter the clinical effectiveness of ripretinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Avoid the concurrent use of ripretinib with moderate CYP3A4 inducers.(1-3) When possible, select alternative agents in place of the moderate CYP3A4 inducer. If the moderate CYP3A4 inducer cannot be avoided, increase the dose of ripretinib from 150 mg once daily to 150 mg twice daily during concurrent therapy. Monitor patients receiving concurrent therapy for reduced efficacy.(1-3) If the moderate CYP3A4 inducer is discontinued, reduce the dose of ripretinib back to 150 mg once daily 14 days after discontinuation of the moderate CYP3A4 inducer.(1-3) If a dose of ripretinib is missed (in patients taking twice daily dosing): -If less than 4 hours have passed since missed dose, patient should take the dose as soon as possible and then take the next dose at the regularly scheduled time. -If more than 4 hours have passed since missed dose, patient should skip the missed dose and then take the next dose at the regularly scheduled time.(1-3)
DISCUSSION: The primary metabolism pathway for ripretinib and DP-5439 is via CYP3A4.(1) In an interaction study of rifampin (a strong CYP3A inducer) and ripretinib, concurrent use decreased ripretinib concentration maximum (Cmax) by 18% and area-under-curve (AUC) by 61%, as well as decreased the active metabolite DP-5439 AUC by 57% and increased Cmax by 37%.(1) In a pharmacokinetic model of efavirenz (a moderate CYP3A inducer), concurrent use was predicted to decrease ripretinib Cmax by 24% and decrease AUC by 56%.(1) In the presence of a moderate CYP3A inducer, a doubled ripretinib dose (twice daily rather than once daily), is predicted to result in a 17% reduction in combined AUC of ripretinib and active metabolite DP-5439, compared to the usual recommended once daily dose with no inducer present.(2) In an interaction study of itraconazole (a strong CYP3A4 inhibitor) and ripretinib, concurrent use increased ripretinib Cmax by 36% and AUC by 99%. Concurrent use increased the AUC of DP-5439 by 99% with no change in Cmax.(1) Moderate CYP3A4 inducers linked to this monograph are: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(4,5)
Moderate Cyp3a4 Inducers/Sebetralstat
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate CYP3A4 inducers may accelerate the metabolism of sebetralstat by CYP3A4.(1)
CLINICAL EFFECTS: The concurrent use of sebetralstat and a moderate CYP3A4 inducer may result in decreased levels and effectiveness of sebetralstat.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of sebetralstat states that the concurrent use of moderate CYP3A4 inducers should be avoided.(1)
DISCUSSION: Sebetralstat maximum concentration (Cmax) decreased by 63% and area-under-curve (AUC) decreased by 79% following concomitant administration with efavirenz (a moderate CYP3A4 inducer) 600 mg once daily for 14 days. Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(2)
Moderate Cyp3a4 Inducers/Sunvozertinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Moderate CYP3A4 inducers may induce the metabolism of sunvozertinib.(1)
CLINICAL EFFECTS: Concurrent or recent use of a moderate CYP3A4 inducer may result in decreased levels and effectiveness of sunvozertinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of sunvozertinib states that concomitant use of moderate CYP3A4 inducers should be avoided.(1) If concurrent use cannot be avoided, increase sunvozertinib dose from 200 mg to 400 mg.(1) After stopping the CYP3A4 inducer, resume the prior sunvozertinib dose 7-14 days after stopping the CYP3A4 inducer.(1)
DISCUSSION: Sunvozertinib is primarily metabolized by CYP3A4.(1) Concomitant administration of sunvozertinib with a strong inducer (carbamazepine) resulted in a decrease in sunvozertinib area under the curve (AUC) and maximum concentration (Cmax) by 48% and 38%, respectively.(1) Sunvozertinib's AUC is predicted to decrease 44% with concurrent administration of efavirenz (600 mg daily; moderate CYP3A4 inducer).(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, rifabutin, repotrectinib, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2)
Moderate Cyp3a4 Inducers/Zanubrutinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Zanubrutinib is a substrate of CYP3A4. Moderate inducers of CYP3A4 may induce the metabolism of zanubrutinib.(1)
CLINICAL EFFECTS: The concurrent administration of moderate CYP3A4 inducers may result in decreased levels and effectiveness of zanubrutinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of zanubrutinib states that concurrent use with moderate CYP3A4 inducers should be avoided. If concurrent use cannot be avoided, increase zanubrutinib dosage to 320 mg twice daily.(1)
DISCUSSION: Co-administration of multiple doses of efavirenz, a moderate CYP3A4 inducer, is predicted to decrease zanubrutinib Cmax by 58% and AUC by 60%.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, suzetrigine, telotristat ethyl, thioridazine, and tovorafenib.(2-3)
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 3A4 Inducers & Substrates/Repotrectinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Repotrectinib,(1) lorlatinib,(2) and mitapivat(3) are all CYP3A4 substrates and moderate CYP3A4 inducers. CYP3A4 inducers may induce the metabolism of repotrectinib.(1) Repotrectinib may induce the metabolism of CYP3A4 substrates, such as lorlatinib and mitapivat.(1)
CLINICAL EFFECTS: Coadministration of repotrectinib with a CYP3A4 inducer decreases repotrectinib plasma concentrations, which may decrease efficacy of repotrectinib.(1) Coadministration of repotrectinib with a CYP3A4 substrate decreases the CYP3A4 substrate plasma concentrations, which may decrease efficacy of the CYP3A4 substrate.(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 should be avoided. The manufacturer of repotrectinib states that concurrent use with strong or moderate CYP3A4 inducers should be avoided.(1) The manufacturer of repotrectinib states to avoid concomitant use with CYP3A4 substrates where minimal concentration changes can cause reduced efficacy unless otherwise recommended in the prescribing information for the CYP3A4 substrate. If concomitant use is unavoidable, increase the CYP3A4 substrate dosage in accordance with approved product labeling.(1) The manufacturer of lorlatinib states that concurrent use with moderate CYP3A4 inducers, such as repotrectinib, should be avoided. If concurrent use of lorlatinib cannot be avoided, increase the dose of lorlatinib to 125 mg daily.(2) The manufacturer of mitapivat states that alternative therapies should be considered that are not moderate CYP3A4 inducers in patients who are on mitapivat. If concurrent use is necessary, monitor hemoglobin closely and titrate mitapivat dose, not to exceed a maximum dose of 100 mg twice daily.(3)
DISCUSSION: Coadministration of repotrectinib with rifampin, a strong CYP3A4 and P-glycoprotein inducer, decreased the maximum concentration (Cmax) of repotrectinib by 79% and area-under-curve (AUC) by 92%.(1) Coadministration of repotrectinib once daily for 14 days followed by 160 mg twice daily for 7 days with midazolam (a sensitive CYP3A4 substrate) decreased midazolam AUC and Cmax by 69% and 48%, respectively.(1) Modafinil (a moderate CYP3A4 inducer) decreased the AUC and Cmax of a single 100 mg dose of lorlatinib by 23% and 22%, respectively.(2) In a pharmacokinetic study with 5 or 20 mg twice daily of mitapivat, efavirenz (a moderate CYP3A4 inducer) decreased the AUC and Cmax of mitapivat by 60% and 30%, respectively. After mitapivat doses of 50 mg twice daily, efavirenz decreased mitapivat AUC and Cmax by 55% and 24%, respectively.(3)
Strong And Moderate Cyp3a4 Inducers/Cariprazine
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Cariprazine and its major active metabolite DDCAR are metabolized by CYP3A4. Strong and moderate inducers of CYP3A4 may accelerate the metabolism of cariprazine.(1-4)
CLINICAL EFFECTS: Concurrent use of a strong or moderate inducer of CYP3A4 may result in decreased levels and effectiveness of cariprazine.(1-4)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The US manufacturer of cariprazine does not recommend concurrent use of strong CYP3A4 inducers.(1) The Australian, Canadian, and UK manufacturers of cariprazine state that concurrent use of strong and moderate CYP3A4 inducers is contraindicated.(2-4)
DISCUSSION: Cariprazine and its active metabolites are primarily metabolized by CYP3A4. Coadministration with CYP3A4 inducers has not been studied and the net effect is unclear. Due to the long half life of the active metabolites, it takes several weeks for cariprazine to reach steady state after dosage changes.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(5-6) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(5-6)
Strong And Moderate Cyp3a4 Inducers/Pimavanserin
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Strong or moderate inducers of CYP3A4 may induce the metabolism of pimavanserin.(1)
CLINICAL EFFECTS: Concurrent use of a strong or moderate inducer of CYP3A4 may result in decreased levels and effectiveness of pimavanserin.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The US manufacturer of pimavanserin recommends avoiding concomitant use of strong or moderate CYP3A4 inducers.(1)
DISCUSSION: Pimavanserin is primarily metabolized by CYP3A4 while other metabolic enzymes CYP2J2, CYP2D6 and FMO play a lesser role.(1) In a study of subjects pretreated with 7 days of rifampin (600 mg daily, a strong CYP3A4 inducer), a single dose of pimavanserin (34 mg) produced an area-under-curve (AUC) and maximum concentration (Cmax) that was 91 % and 71 % lower, respectively, than when pimavanserin is given without rifampin.(1) A physiology-based pharmacokinetic model predicted that efavirenz (a moderate CYP3A4 inducer) would decrease pimavanserin AUC and Cmax by 70 % and 60 %, respectively.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(3-4) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, and tovorafenib.(3-4)
Strong And Moderate Cyp3a4 Inducers/Pretomanid
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Strong and moderate CYP3A4 inducers may induce the metabolism of pretomanid by CYP3A4.(1)
CLINICAL EFFECTS: The concurrent use of strong and moderate CYP3A4 inducers and pretomanid may result in decreased levels and clinical effectiveness of pretomanid.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of pretomanid recommends avoiding concurrent use with strong or moderate CYP3A4 inducers during pretomanid therapy.(1) Patients receiving concurrent therapy with strong and moderate CYP3A4 inducers and pretomanid should be observed for decreased levels and clinical effectiveness.
DISCUSSION: In a clinical study, concurrent use of pretomanid 200 mg with efavirenz 600 mg for 7 days resulted in decreased mean area-under-curve (AUC) by 35% and maximum concentration (Cmax) by 28%.(1) In a clinical study, concurrent use of pretomanid 200 mg with rifampin 600 mg for 7 days resulted in decreased mean AUC by 66% and Cmax by 53%.(1) Strong and moderate CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate, dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, etravirine, fexinidazole, fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin, rifapentine, St. John's wort, sotorasib, telotristat, thioridazine, and tovorafenib.(1,2)
Strong And Moderate Cyp3a4 Inducers/Velpatasvir
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Strong or moderate CYP3A4 inducers may induce the metabolism of velpatasvir via CYP3A4.(1,2)
CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inducers may result in decreased levels and effectiveness of velpatasvir.(1,2)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The concurrent use of velpatasvir with strong or moderate CYP3A4 inducers is not recommended.(1,2)
DISCUSSION: In an interaction study, efavirenz 600 mg daily (in combination with emtricitabine-tenofovir DF) decreased velpatasvir concentration maximum (Cmax) and area-under-curve (AUC) by 47% and 53%, respectively.(1) In an interaction study, rifampin 600 mg daily decreased velpatasvir Cmax and AUC by 71% and 82%, respectively.(1) Strong and moderate CYP3A4 inducers include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, enzalutamide, fexinidazole, ivosidenib, lesinurad, lumacaftor, mavacamten, methimazole, mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib, sotorasib, telotristat, thioridazine, and tovorafenib.(3)
Strong Or Moderate Cyp3a4 Inducers/Ganaxolone
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Ganaxolone is a substrate of CYP3A4. Strong or moderate inducers of CYP3A4 may induce the metabolism of ganaxolone.(1)
CLINICAL EFFECTS: The concurrent administration of strong or moderate CYP3A4 inducers may result in decreased levels and effectiveness of ganaxolone.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of ganaxolone states that concurrent use with strong or moderate CYP3A4 inducers should be avoided. If concurrent use is unavoidable, consider increasing the dose of ganaxolone. Do not exceed the recommended maximum daily dose.(1) In patients who are stable on ganaxolone and are initiated on anticonvulsants that are CYP3A4 inducers, consider increasing the dose of ganaxolone. Do not exceed the recommended maximum daily dose.(1)
DISCUSSION: Co-administration of rifampin, a strong CYP3A4 inducer, decreased the ganaxolone concentration maximum (Cmax) by 57% and area-under-curve (AUC) by 68%.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2-3)
Strong Or Moderate Cyp3a4 Inducers/Simeprevir
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Strong or moderate inducers of CYP3A4 may induce the metabolism of simeprevir.(1)
CLINICAL EFFECTS: Concurrent or recent use of strong or moderate CYP3A4 inducers may lower simeprevir minimum concentrations (Cmin) leading to a loss of virologic response to simeprevir.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The US manufacturer of simeprevir states that concurrent administration of strong or moderate inducers of CYP3A4 is not recommended due risk for simeprevir treatment failure.(1)
DISCUSSION: In a study in 18 subjects, rifampin (600 mg daily for 7 days) decreased the area-under-curve (AUC) and Cmin of simeprevir (200 mg daily for 7 days) by 48% and 92%, respectively. The simeprevir maximum concentration (Cmax) increased 1.31-fold.(1) Strong and moderate inducers of CYP3A4 linked to this monograph include apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate, dabrafenib, dexamethasone, elagolix, encorafenib, enzalutamide, fosphenytoin, ivosidenib, fexinidazole, lesinurad, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, modafinil, nafcillin, oxcarbazepine, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifampin, rifabutin, rifapentine, St. John's wort, sotorasib, telotristat, and tovorafenib.(1-3)
Moderate Interaction: Assess the risk to the patient and take action as needed.
Mitapivat (<= 20 Mg Bid)/Moderate Cyp3a4 Inhibitors
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of mitapivat.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels of and effects from mitapivat including decreased estrone and estradiol levels in males, increased urate, back pain, and arthralgias.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The concurrent use of moderate CYP3A4 inhibitors with mitapivat should be monitored closely for increased risk of adverse reactions. Mitapivat dose should not exceed 20 mg twice daily with concurrent moderate CYP3A4 inhibitors.(1)
DISCUSSION: Mitapivat is a CYP3A4 substrate. In a pharmacokinetic study with mitapivat 5, 20, or 50 mg twice daily dosing, fluconazole increased mitapivat area-under-curve (AUC) and concentration maximum (Cmax) by 2.6-fold and 1.6-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2)(2)
Moderate And Weak Cyp3a4 Inducers/Ubrogepant
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate or weak CYP3A4 inducers may induce the metabolism of ubrogepant.(1)
CLINICAL EFFECTS: Concurrent use of a moderate or weak CYP3A4 inducer may result in decreased levels and effectiveness of ubrogepant.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when coadministered with moderate or weak CYP3A4 inducers. Initial dose of ubrogepant should be 100 mg. If a second dose is needed, the dose of ubrogepant should be 100 mg.(1)
DISCUSSION: Coadministration of ubrogepant with rifampin, a strong CYP3A4 inducer, resulted in an 80% reduction in ubrogepant exposure. No dedicated drug interaction studies were conducted to assess concomitant use with moderate or weak CYP3A4 inducers. Dose adjustment for concomitant use of ubrogepant with moderate or weak CYP3A4 inducers is recommended based on a conservative prediction of 50% reduction in exposure of ubrogepant.(1) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, dexamethasone, dicloxacillin, echinacea, elafibranor, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, meropenem-vaborbactam, methylprednisolone, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, relugolix, repotrectinib, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)
Moderate Cyp3a4 Inducers/Aficamten
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Aficamten is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of aficamten.(1)
CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may decrease the levels and effectiveness of aficamten and increase the risk of developing heart failure due to systolic dysfunction.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: In patients who are on stable concurrent therapy with aficamten and a moderate to strong CYP3A4 inducer, reduce the dose of aficamten when discontinuing the inducer as follows: -If the current dose is 20 mg daily, reduce to 10 mg daily. -If the current dose is 15 mg daily, reduce to 5 mg daily. -If the current dose is 10 mg daily, reduce to 5 mg daily. -If the current dose is 5 mg daily, maintain 5 mg daily. Assess LVEF 2 to 8 weeks after discontinuation of such inducers and adjust the dose of aficamten accordingly.(1)
DISCUSSION: In a study, carbamazepine (moderate to strong CYP3A4 inducer, weak CYP2C9 inducer) decreased aficamten's area-under-curve (AUC) 51%.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Crinecerfont
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of crinecerfont.(1)
CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may reduce the clinical effectiveness of crinecerfont.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The US manufacturer of crinecerfont states that concurrent use of moderate CYP3A4 inducers requires a dose adjustment of crinecerfont. Increase the evening dose of crinecerfont by 2-fold. Do not increase the morning dose. In adults, increase the dosage of crinecerfont to 100 mg in the morning and 200 mg in the evening. In pediatric patients 4 years and older weighing: - 10 kg to <20 kg: increase the crinecerfont dosage to 25 mg in the morning and 50 mg in the evening, - 20 kg to <55 kg: increase the crinecerfont dosage to 50 mg in the morning and 100 mg in the evening, - >=55 kg: increase the crinecerfont dosage to 100 mg in the morning and 200 mg in the evening.(1)
DISCUSSION: In a study, concomitant use of rifampin (strong CYP3A4 inducer) decreased crinecerfont maximum concentration (Cmax) by 23% and area-under-curve (AUC) by 62%.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Daclatasvir
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of daclatasvir.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inducer of CYP3A4 without a dosage adjustment of daclatasvir is expected to reduce levels and effectiveness of daclatasvir.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The dose of daclatasvir should be increased to 90 mg once daily in patients receiving moderate inducers of CYP3A4.(1)
DISCUSSION: Efavirenz (600 mg daily) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of daclatasvir by 17%, 32%, and 59%, respectively.(1) Moderate inducers of CYP3A4 include belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(1-3)
Moderate Cyp3a4 Inducers/Daraxonrasib (>= 400 Mg)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Daraxonrasib is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of daraxonrasib.(1)
CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may decrease the levels and effectiveness of daraxonrasib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of daraxonrasib states that concomitant use of moderate CYP3A4 inducers requires a dose increase of daraxonrasib to 400 mg once daily.(1)
DISCUSSION: In a clinical study, daraxonrasib area-under-curve (AUC) is predicted to decrease by 50-84% with concomitant use of efavirenz 600 mg once daily and modafinil 400 mg once daily (moderate CYP3A4 inducers).(1) Moderate CYP3A4 inducers linked to this monograph include: asunaprevir, belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lopinavir, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Larotrectinib
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inducers of CYP3A4 may increase the metabolism of larotrectinib.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of larotrectinib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of larotrectinib states that the concurrent use of moderate CYP3A4 inducers requires a dose modification. Double the dose of larotrectinib when coadministered with moderate CYP3A4 inducers. After the moderate CYP3A4 inducer has been discontinued for 3 to 5 elimination half-lives, resume the larotrectinib dose at the dose taken prior to initiating the CYP3A4 inducer.(1)
DISCUSSION: In a study, efavirenz (a moderate CYP3A4 inducer) was predicted to decrease area-under-curve (AUC) and maximum concentration (Cmax) by 72% and 60%, respectively, compared to larotrectinib administered alone.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(3-4)
Moderate Cyp3a4 Inducers/Paltusotine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate CYP3A4 inducers may induce the metabolism of paltusotine.(1)
CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may alter the clinical effectiveness of paltusotine.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Patients taking moderate CYP3A4 inducers may require an increased dosage of paltusotine.(1) The manufacturer of paltusotine states do not exceed two-fold the paltusotine dosage prior to concomitant use or 120 mg daily, whichever is less.(1) Monitor patients receiving concurrent therapy for reduced efficacy.
DISCUSSION: Paltusotine is metabolized by CYP3A4.(1) Moderate CYP3A4 inducers such as efavirenz are predicted to decrease concentration maximum (Cmax) and area-under-curve (AUC) of paltusotine approximately 5% and 30%, respectively.(1) In an interaction study, paltusotine concentration maximum (Cmax) and area-under-curve (AUC) decreased by 44% and 70%, respectively, following concomitant administration of carbamazepine (strong CYP3A inducer).(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Rolapitant
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Rolapitant is metabolized primarily by CYP3A4. Moderate inducers of CYP3A4 may increase the metabolism and clearance of rolapitant via CYP3A4.(1)
CLINICAL EFFECTS: Concurrent use with moderate inducers of CYP3A4 may result in significantly decreased levels and effectiveness of rolapitant.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The UK manufacturer of rolapitant states that rolapitant is not recommended in patients already taking moderate CYP3A4 inducers.(1) If concomitant use is warranted, monitor the patient for decreased antiemetic efficacy. When possible and clinically appropriate, consider use of an alternative antiemetic or alternatives to the moderate CYP3A4 inducer.
DISCUSSION: The effect of moderate CYP3A4 inducers on rolapitant has not been studied. The UK manufacturer of rolapitant does not recommend the concurrent use of rolapitant with moderate CYP3A4 inducers. Rifampin (600 mg daily for 14 days), a strong CYP3A4 inducer, decreased the Cmax and AUC of a single dose of rolapitant (180 mg on Day 7) by 30% and 85%, respectively. The half-life of rolapitant decreased from 176 hours to 41 hours.(3) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)
Moderate Cyp3a4 Inducers/Tavapadon
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of tavapadon.(1)
CLINICAL EFFECTS: Concurrent or recent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of tavapadon.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: For patients initiating tavapadon who are already taking a moderate CYP3A4 inducer, the following tavapadon titration regimen is recommended: - Days 1 to 4: 0.25 mg twice daily - Days 5 to 8: 0.5 mg twice daily - Days 9 to 12: 0.75 mg twice daily - Days 13 to 16: 1 mg twice daily - Days 17 to 20: 1.5 mg twice daily - Days 21 to 24: 2.25 mg twice daily - Days 25 to 40: 3 mg twice daily - Days 41 and after: 5 mg twice daily If needed, based on clinical response and tolerability, the maintenance dosage may be increased to 5 mg three times a day. If further escalation is needed, the dose may be increased by 5 mg every 15 days administered in divided doses (either twice a day or three times a day), to the maximum recommended daily dosage of 45 mg daily (15 mg three times daily). For patients on tavapadon maintenance dosage who are initiating a moderate CYP3A4 inducer, the following dose modifications are recommended: - Days 1 to 7 of concomitant use: continue the current maintenance dosage of tavapadon (5 mg, 10 mg, or 15 mg once daily) - Day 8 and thereafter during concomitant use: increase the frequency of the maintenance dosage of tavapadon to twice daily. If needed, based on clinical response and tolerability, the maintenance dosage can be increased to three times daily. Upon discontinuation of moderate CYP3A4 inducers, gradually reduce the tavapadon dosage to once daily. Monitor patients for clinical response and tolerability.(1)
DISCUSSION: Concurrent administration of efavirenz (600 mg), a moderate CYP3A4 inducer, with 15 mg tavapadon is predicted to decrease the area-under-the-curve (AUC) and maximum concentration (Cmax) by 70% and 58%.(1) When a moderate CYP3A4 inducer is initiated during maintenance therapy (5, 10, or 15 mg doses) of tavapadon, with increased dosing frequency from once daily to three times daily, steady state AUC and Cmax are not predicted to differ significantly relative to once daily dosing without an inducer.(1) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)
Select Moderate Cyp3a4 Inducer/Emtricitabine-Rilpivirine-Taf
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate CYP3A4 inducers may induce the metabolism of rilpivirine.(1-2)
CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may result in decreased levels and effectiveness of rilpivirine, as well as the development of resistance.(1-2)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The US DHHS HIV guidelines state that concurrent use of bosentan or mavacamten (moderate CYP3A4 inducers) with oral rilpivirine should be monitored closely. Consider alternative therapies that do not affect CYP3A4 or alternative antiretroviral agents. If concurrent use is necessary, virologic response should be monitored.(3) The US manufacturer of oral rilpivirine states that concurrent use of rifabutin (moderate CYP3A4 inducer) warrants dose adjustment. When administering moderate CYP3A4 inducers with oral rilpivirine, increase the dose of rilpivirine to 50 mg once daily. When rifabutin co-administration is stopped, the rilpivirine dose should be decreased to 25 mg once daily. It may take several weeks after the discontinuation of an enzyme inducer for enzyme activity to return to normal.(2)
DISCUSSION: In a study in 18 subjects, rifabutin (300 mg daily) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of rilpivirine (25 mg orally daily) by 31%, 42%, and 48%, respectively.(1) A study in 18 subjects compared rilpivirine administered alone (25 mg orally daily) to coadministration with rifabutin (300 mg daily) and rilpivirine (50 mg orally daily). A significant difference was not found with the Cmax (1.43), AUC (1.16), or Cmin (0.93) of rilpivirine. (2) Selected moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, eslicarbazepine, fexinidazole, lesinurad, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine and tovorafenib.(3)
Selected Cyp3a4 Inducers/Alfentanil
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of alfentanil.(1)
CLINICAL EFFECTS: Concurrent use of a CYP3A4 inducer may result in decreased levels of alfentanil, which may result in decreased effectiveness and may precipitate withdrawal symptoms. In addition, discontinuation of the CYP3A4 inducer may result in an increased levels and toxicity of alfentanil, including serious respiratory depression.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Patients maintained on alfentanil may require dosage adjustments if a CYP3A4 inducer is initiated or discontinued. Patients should be monitored closely. The effects of the interaction may last for several weeks after the discontinuation of the inducer.(1)
DISCUSSION: In a clinical study of 10 healthy volunteers, rifampin (a strong CYP3A4 inducer) decreased the area-under-curve (AUC) of oral alfentanil by 96% and of IV alfentanil by 42%.(5) Selected CYP3A4 inducers linked to this monograph include: aumolertinib, fexinidazole, mitapivat, pexidartinib, and sotorasib.
Selected Moderate And Strong Cyp3a4 Inducers/Siponimod
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Drugs that are moderate or strong inducers of CYP3A4 may increase the metabolism of siponimod.(1) Patients with a CYP2C9*1/*3 or *2/*3 genotype who are more dependent on CYP3A4 for the metabolism of siponimod would experience a greater effect of CYP3A4 induction.
CLINICAL EFFECTS: Concurrent use of a siponimod with a moderate or strong CYP3A4 inducer in patients with a CYP2C9*1/*3 or *2/*3 genotype may result in decreased levels and effectiveness of siponimod.(1)
PREDISPOSING FACTORS: Patients with a CYP2C9*1/*3 or *2/*3 genotype who are more dependent on CYP3A4 for the metabolism of siponimod would experience a greater effect of CYP3A4 induction. Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Monitor the combination of siponimod with a moderate or strong CYP3A4 inducer in patients with a CYP2C9*1/*3 or *2/*3 genotype for loss of efficacy.(1) Agents that are both moderate CYP3A4 inducers and moderate CYP2C9 inducers (e.g., lorlatinib) should be used with caution regardless of the patient's CYP2C9 genotype.(1)
DISCUSSION: In a study, efavirenz (a moderate CYP3A4 inducer) decreased the area-under-curve (AUC) of siponimod by up to 52% across CYP2C9 genotypes. Drugs that are moderate or strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, belzutifan, bosentan, cenobamate, dabrafenib, elagolix, etravirine, fosphenytoin, lesinurad, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, modafinil, nafcillin, pexidartinib, phenobarbital, phenytoin, primidone, rifabutin, rifapentine, St John's Wort, sotorasib, telotristat ethyl, and tovorafenib.(2-3)
Selected Moderate Cyp3a4 Inducers/Rilpivirine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Moderate CYP3A4 inducers may induce the metabolism of rilpivirine.(1)
CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may result in decreased levels and effectiveness of rilpivirine, as well as the development of resistance.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The US DHHS HIV guidelines state that concurrent use of bosentan or mavacamten (moderate CYP3A4 inducers) with oral or intramuscular rilpivirine should be monitored closely. Consider alternative therapies that do not affect CYP3A4 or alternative antiretroviral agents. If concurrent use is necessary, virologic response should be monitored.(2) The US manufacturer of oral rilpivirine states that concurrent use of rifabutin (moderate CYP3A4 inducer) warrants dose adjustment. When administering moderate CYP3A4 inducers with oral rilpivirine, increase the dose of rilpivirine to 50 mg once daily. When rifabutin co-administration is stopped, the rilpivirine dose should be decreased to 25 mg once daily. It may take several weeks after the discontinuation of an enzyme inducer for enzyme activity to return to normal.(1)
DISCUSSION: In a study in 18 subjects, rifabutin (300 mg daily) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of rilpivirine (25 mg orally daily) by 31%, 42%, and 48%, respectively.(1) A study in 18 subjects compared rilpivirine administered alone (25 mg orally daily) to coadministration with rifabutin (300 mg daily) and rilpivirine (50 mg orally daily). A significant difference was not found with the Cmax (1.43), AUC (1.16), or Cmin (0.93) of rilpivirine. (1) Selected moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, eslicarbazepine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine and tovorafenib.(3)
Selected Moderate-Weak Cyp3a4 Inducers/Exemestane
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: CYP3A4 inducers may induce the metabolism of exemestane.(1)
CLINICAL EFFECTS: Concurrent use of a CYP3A4 inducer may result in decreased levels and effectiveness of exemestane.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The US manufacturer of exemestane recommends that patients receiving concurrent therapy with a strong CYP3A4 inducer receive 50 mg of exemestane daily after a meal.(1) It may be prudent to consider a dosage increase for patients receiving weaker CYP3A4 inducers.
DISCUSSION: In a study in 10 healthy postmenopausal subjects, pretreatment with rifampin (a strong CYP3A4 inducer, 600 mg daily for 14 days) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of exemestane (25 mg) by 54% and 41%, respectively.(1) Strong inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 80% or more and include: carbamazepine, enzalutamide, mitotane, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's wort.(1-3) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, elafibranor, enasidenib, eslicarbazepine, floxacillin, garlic, gingko, ginseng, glycyrrhizin, lorlatinib, meropenem-vaborbactam, methylprednisolone, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)
Strong & Moderate Cyp3a4 Inducers/Apixaban; Rivaroxaban
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Apixaban and rivaroxaban are both substrates of CYP3A4 and P-glycoprotein (P-gp). Apixaban is about 20% metabolized and rivaroxaban is about 18% metabolized, mainly by CYP3A4.(1-8) Strong and moderate CYP3A4 inducers may induce the metabolism of apixaban and rivaroxaban by CYP3A4.
CLINICAL EFFECTS: Concurrent or recent use of a CYP3A4 inducer may result in decreased levels and effectiveness of apixaban(1-4) or rivaroxaban,(5-8) especially in the setting of concurrent therapy with an agent that induces P-gp.
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. Drug-associated risk factors include concurrent use of P-gp inducers.
PATIENT MANAGEMENT: The US, Australian, Canadian, and UK manufacturers of apixaban provide recommendations regarding concurrent use with strong inducers of both CYP3A4 and P-gp, but do not provide guidance for concurrent use with agents that induce CYP3A4 alone.(1) The US manufacturer of rivaroxaban provides recommendations regarding concurrent use with strong inducers of both CYP3A4 and P-gp, but does not provide guidance for concurrent use with agents that induce CYP3A4 alone.(5) The Australian manufacturer of rivaroxaban states that concurrent use of strong CYP3A4 inducers should be approached with caution.(6) The Canadian and UK labels for rivaroxaban state that concurrent use of strong CYP3A4 inducers should be avoided.(7-8) When considering concurrent therapy with a strong or moderate CYP3A4 inducer with either apixaban or rivaroxaban, evaluate the patient's other concurrent therapy for CYP3A4 and P-gp effects. In patients who are taking strong CYP3A4 inducers and are also on concurrent P-gp inducers, consider the manufacturer recommendations for use with dual CYP3A4 and P-gp inducers. The US manufacturers of apixaban and rivaroxaban both state to avoid the concurrent use of agents that are combined P-gp and strong CYP3A4 inducers in patients receiving apixaban or rivaroxaban.(1-8) In patients who are taking moderate CYP3A4 inducers and are also on concurrent P-gp inducers, it may be prudent to consider alternative therapy or monitor the patient closely. For patients taking efavirenz or etravirine, the US and European HIV guidelines recommend considering alternative therapies or performing additional monitoring.(9-10)
DISCUSSION: The concurrent use of apixaban or rivaroxaban with strong CYP3A4 inducers that are not also P-gp inducers has not been studied. Apixaban and rivaroxaban are metabolized primarily by CYP3A4. Strong CYP3A4 inducers may decrease the levels and effectiveness of apixaban and rivaroxaban. The US manufacturer of apixaban states that apixaban dose reduction is recommended when apixaban exposure increases by more than 50%, while efficacy is maintained when exposure is 25% lower. Therefore, no dose adjustment of apixaban is recommended for drug interactions that affect apixaban exposure by 75% to 150%.(11) An article evaluating the clinical significance of efflux transporters like P-gp and BCRP in apixaban exposure analyzed pharmacokinetic data from drug-drug interaction studies and concluded that all apixaban interactions can be explained by inhibition of intestinal CYP3A4. The authors explain that apixaban is a highly permeable and soluble compound, so its ability to undergo passive diffusion renders the role of membrane transporters irrelevant, as evidenced by a lack of change in apixaban absorption rate in the presence of drugs known to inhibit P-gp and BCRP.(12) Strong CYP3A4 inducers linked to this monograph include: barbiturates, encorafenib, ivosidenib, lumacaftor, and mitotane.(13,14) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(13,14)
Strong And Moderate Cyp3a4 Inducers/Perampanel
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Strong and moderate CYP3A4 inducers may induce the metabolism of perampanel by CYP3A4.(1)
CLINICAL EFFECTS: The concurrent use of strong and moderate CYP3A4 inducers and perampanel may result in decreased levels and clinical effectiveness of perampanel.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Patients receiving concurrent therapy with strong and moderate CYP3A4 inducers and perampanel should be observed for decreased anticonvulsant levels and clinical effectiveness. The manufacturer of perampanel recommends a starting dose of 4 mg once daily at bedtime in patients receiving concurrent therapy with CYP3A4 inducers. Dose increases are recommended by 2 mg increments once daily based on clinical response and tolerability, no more frequently than at weekly intervals. The highest studied dose with concurrent enzyme-inducing antiepileptic drugs was 12 mg once daily.(1) The dose of the anticonvulsant may need to be adjusted if a strong or moderate CYP3A4 inducer is added to or removed from therapy.(1)
DISCUSSION: In a study in healthy subjects, carbamazepine 300 mg BID decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single 2 mg tablet dose of perampanel by 26% and 67%, respectively. The half-life (t1/2) of perampanel was shortened from 56.8 hours to 25 hours. In clinical studies examining partial-onset and primary generalized tonic-clonic seizures, a population pharmacokinetic analysis showed that perampanel AUC was reduced by 64% in patients on carbamazepine compared to the AUC in patients not on enzyme-inducing antiepileptic drugs.(1) In a study in partial-onset and primary generalized tonic-clonic seizures, a population pharmacokinetic analysis showed that perampanel AUC was reduced by 48% in patients on oxcarbazepine compared to patients not on enzyme-inducing antiepileptic drugs.(1) In a study in partial-onset and primary generalized tonic-clonic seizures, a population pharmacokinetic analysis showed that perampanel AUC was reduced by 43% in patients on phenytoin compared to patients not on enzyme-inducing antiepileptic drugs.(1) In a study in partial-onset and primary generalized tonic-clonic seizures in clinical trials (40 patients co-administered phenobarbital and 9 patients co-administered primidone), no significant effect on perampanel AUC was found. A modest effect of phenobarbital and primidone on perampanel concentrations cannot be excluded.(1) In a study in 76 patients, concentration-to-dose (CD) ratio of perampanel was assessed with and without concurrent antiepileptic agents. In patients only on perampanel the mean CD ratio was 3963 ng/mL/mg/kg (range: 1793-13,299) compared to the mean CD ratio in patients using enzyme-inducing AEDs [1760 (range: 892-3090), 2256 (range: 700-4703), and 1120 (range: 473-1853) ng/mL/mg/kg in patients taking phenytoin, phenobarbital, and carbamazepine, respectively], and carbamazepine had a significantly greater reduction in the CD ratio compared with phenytoin or phenobarbital (P < 0.001).(3) Strong and moderate CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, bosentan, carbamazepine, cenobamate, dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, eslicarbazepine, etravirine, fexinidazole, fosphenytoin, ivosidenib, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, modafinil, nafcillin, oxcarbazepine, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(1,2)
Strong And Moderate Cyp3a4 Inducers/Sildenafil (Pah)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Sildenafil is metabolized by CYP3A4. Strong and moderate inducers of CYP3A4 may increase the metabolism of sildenafil.(1)
CLINICAL EFFECTS: Concurrent use of a strong or moderate inducer of CYP3A4 may result in substantially decreased levels and effectiveness of sildenafil.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: Concomitant use of sildenafil with strong or moderate CYP3A4 inducers should be monitored closely. An increased dosage of sildenafil may be needed. Reduce sildenafil dose to 20 mg three times daily when discontinuing treatment with strong and moderate CYP3A4 inducers.(1)
DISCUSSION: Population pharmacokinetic analysis of data from patients in clinical trials found that sildenafil clearance increased about 3-fold when coadministered with mild CYP3A4 inducers.(1) A randomized, double-blind, placebo-controlled, parallel-group study of 55 healthy volunteers found that 10 days of bosentan (125 mg twice daily), a moderate CYP3A4 inducer, decreased the maximum concentration (Cmax) and area-under-curve (AUC) of sildenafil by 55.4% and 62.6%, respectively. Sildenafil increased bosentan Cmax and AUC by 42% and 49.8%, respectively. The combination was well tolerated without serious adverse events.(2) In a study of 15 HIV-negative subjects, etravirine (800 mg twice daily for 14 days), a moderate CYP3A4 inducer, decreased the Cmax and AUC of sildenafil by 45% and 57%, respectively.(3) The authors of a review article on drug interactions in pulmonary arterial hypertension therapy state that phenytoin and rifampin (strong CYP3A4 inducers) are not recommended with sildenafil due to an expected near-complete clearance of sildenafil.(4) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(5,6) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(5,6)
Contraindications
*None.
- Child-pugh class B hepatic impairment
- Child-pugh class C hepatic impairment
- Disease of liver
There are no moderate contraindications for this drug.
Adverse reactions
The most common adverse reactions including laboratory abnormalities (>=10%) in patients with pyruvate kinase deficiency receiving mitapivat were decreased estrone (males), increased urate, back pain, decreased estradiol (males), and arthralgia.
The most common adverse reactions in patients with alpha- or beta-thalassemia receiving mitapivat were headache and insomnia.
More Frequent
- Hyperuricemia
Less Frequent
- Atrial fibrillation
- Hypertension
More Frequent
- Arthralgia
- Back pain
- Decreased estrogen level in male patient
- Hypertriglyceridemia
Less Frequent
- Constipation
- Drug-induced hot flash
- Flushing
- Gastroenteritis
- Mastalgia
- Pain in oropharynx
- Paresthesia
- Tachycardia
- Transient testosterone increase in male
- Xerostomia
Precautions
No enhanced messaging available.
Safety and efficacy of mitapivat in pediatric patients have not been established.
There are insufficient data in humans to evaluate for risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes associated with mitapivat. Decreased maternal net body weight gain; enlarged or fused placenta; distended amniotic sac; increased post-implantation loss; decreased mean number of viable fetuses; lower mean fetal weights; external, visceral, and skeletal malformations; dystocia; and prolonged parturition were observed in rats at exposures greater than the maximum recommended human dose.
Providers should consider the potential risks and benefits in using mitapivat during pregnancy.
It is not known whether mitapivat or its metabolites distribute into human or animal milk or if the drug has any effect on milk production or the nursing infant. The risks and benefits of breastfeeding during mitapivat therapy should be considered.
The manufacturer does not state any specific dosage adjustments for geriatric patients.
The clinical studies for mitapivat included insufficient numbers of patients 65 years of age and older to determine whether there is a difference in response compared with younger patients.
ICD codes
| Code | Type | Description |
|---|---|---|
| Hemolytic anemia due to pyruvate kinase deficiency | ||
| D55.21 | ICD10CM | Anemia due to pyruvate kinase deficiency |
ICD code information from First Databank (FDB).
Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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