Etcamah (camizestrant)

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

Camizestrant/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: Camizestrant is a CYP3A4 substrate and strong CYP2C19 inhibitor. Mavacamten is a moderate CYP3A4 inducer and may accelerate the metabolism of camizestrant. Mavacamten is also a CYP2C19 substrate, and its metabolism may be decreased by camizestrant.(1,2)

CLINICAL EFFECTS: Concurrent use of strong CYP2C19 inhibitors increases plasma exposure of mavacamten, which may increase the incidence and severity of adverse reactions of mavacamten.(2) Concurrent use of moderate CYP3A4 inducers are predicted to decrease plasma exposure and effectiveness of camizestrant.(1) The net effect of this two-way interaction is unknown.

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 that concomitant use with a strong CYP2C19 inhibitor is contraindicated.(2,3) While the UK manufacturer provides different recommendations depending on a patient's CYP2C19 phenotype,(4) it is unknown how those recommendations apply given the bi-directional effects of this drug pair.

DISCUSSION: Concomitant use of mavacamten 15 mg with omeprazole 20 mg (a weak CYP2C19 inhibitor) once daily increased mavacamten area-under-curve (AUC) by 48% with no effect on maximum concentration (Cmax) in healthy CYP2C19 normal metabolizers and rapid metabolizers.(2) Camizestrant AUC is predicted to decrease to 43% and Cmax to 58% following concomitant administration of phenobarbital (moderate CYP3A4 inducer) 100 mg once daily for 17 days. Phenobarbital and efavirenz (moderate CYP3A inducers) are predicted to have minimal effects on camizestrant AUC and Cmax when camizestrant is given in combination with 400 mg or 600 mg ribociclib.(1) Camizestrant is predicted to increase the AUC and Cmax of omeprazole (sensitive CYP2C19 substrate) by 8.5-fold and 3.3-fold, respectively, and of lansoprazole (moderately sensitive CYP2C19 substrate) by 5.7-fold and 1.5-fold, respectively.(1)

Camizestrant/Strong Cyp3a4 Inducers

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

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

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

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

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

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

Dual Moderate To Strong Cyp2c9 And Cyp2c19 Inhib/Abrocitinib

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

MECHANISM OF ACTION: Abrocitinib is primarily metabolized by CYP2C9 and CYP2C19. Agents that are inhibitors of both CYP2C9 and CYP2C19 may decrease the metabolism of abrocitinib.(1)

CLINICAL EFFECTS: Concurrent use of a dual inhibitor of CY2C9 and CYP2C19 increases plasma exposure of abrocitinib which may increase the incidence and severity of adverse reactions of abrocitinib. This may increase the risk of infections, major adverse cardiovascular events, or thrombosis.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of abrocitinib states that the use of abrocitinib with a moderate to strong dual inhibitor of CYP2C9 and CYP2C19 should be avoided.(1) The Australian and UK manufacturers of abrocitinib do not provide recommendations specifically for dual inhibitors of CYP2C9 and CYP2C19. They recommend that patients receiving concomitant strong CYP2C19 inhibitors, including fluconazole, have their dose of abrocitinib decreased by half.(2,3) The Australian manufacturer further states that the 100 mg daily dose of abrocitinib should be reserved for patients not responding to 12 weeks of treatment with 50 mg daily.(2)

DISCUSSION: In a study, fluconazole (400 mg on Day 1 and 200 mg daily on Days 2-7), a strong CYP2C19 and moderate CYP2C9 inhibitor, increased the maximum concentration (Cmax) and area-under-curve (AUC) of abrocitinib (100 mg) by 1.23-fold and 2.55-fold, respectively.(1) Moderate to strong dual inhibitors of CYP2C9 and CYP2C19 include: camizestrant, fluconazole, and marijuana.(2,3)

Slt Strong & Moderate 2C19 Inhibitor/Cilostazol (> 50Mg Bid)

SEVERITY LEVEL: 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 inhibitors of CYP2C19 may inhibit the metabolism of cilostazol.(1-4)

CLINICAL EFFECTS: Concurrent use of strong or moderate inhibitors of CYP2C19 may result in elevated levels of 3,4-dehydro-cilostazol, a metabolite of cilostazol that is 4-7 times as active as cilostazol.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The dose of cilostazol should be limited to 50 mg twice daily in patients receiving concurrent therapy with strong and moderate inhibitors of CYP2C19.(1) The Australian manufacturer of esomeprazole states concomitant use with cilostazol is contraindicated.(5)

DISCUSSION: In a study in 20 subjects examined the effects of omeprazole (40 mg daily) on a single dose of cilostazol (100 mg). Concurrent omeprazole increased the cilostazol maximum concentration (Cmax) and area-under-curve (AUC) by 18% and 26%, respectively. The Cmax and AUC of the 3,4-dehydro-cilostazol metabolite of cilostazol increased 29% and 69%, respectively. The Cmax and AUC of the OPC-13213 metabolite of cilostazol decreased by 22% and 31%, respectively.(4)

Strong & Moderate Cyp2c9 Inhibitors/Deuruxolitinib

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

MECHANISM OF ACTION: Strong or moderate CYP2C9 inhibitors may inhibit the metabolism of deuruxolitinib.(1)

CLINICAL EFFECTS: Concurrent use of deuruxolitinib with a strong or moderate inhibitor of CYP2C9 may result in elevated levels of and toxicity from deuruxolitinib, including hematologic toxicities (neutropenia, lymphopenia, anemia), lipid abnormalities, infection, and thrombosis.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of deuruxolitinib states that concomitant treatment with a strong or moderate CYP2C9 inhibitor is contraindicated.(1)

DISCUSSION: Concurrent use with strong CYP2C9 inhibitors has not been studied. Based on pharmacokinetic modelling, deuruxolitinib area-under-curve (AUC) is predicted to be increased by 200% and maximum concentration (Cmax) by 25% following concomitant use of multiple dosages of a strong CYP2C9 inhibitor with a single dose of 12 mg deuruxolitinib (1.5 times the licensed 8 mg dose).(1) Deuruxolitinib AUC increased by 140% and Cmax by 21% following concomitant use of multiple dosages of 200 mg fluconazole (dual moderate CYP3A4 and CYP2C9 inhibitor) with a single dose of 12 mg deuruxolitinib (1.5 times the licensed 8 mg dose).(1) Strong CYP2C9 inhibitors linked to this monograph include: camizestrant and sulfaphenazole.(2-3) Moderate CY2C9 inhibitors linked to this monograph include: amiodarone, apazone, benzbromarone, fluconazole, miconazole, mifepristone, milk thistle, nitisinone, oxandrolone, phenylbutazone, and piperine.(2-3)

Weak Cyp3a4 Inhibitors/Lemborexant (> 5 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: Inhibitors of CYP3A4 may inhibit the metabolism of lemborexant.(1)

CLINICAL EFFECTS: Concurrent use of an inhibitor of CYP3A4 may result in increased levels of and effects from lemborexant, including somnolence, fatigue, CNS depressant effects, daytime impairment, headache, and nightmare or abnormal dreams.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The maximum recommended dose of lemborexant with concurrent use of a weak CYP3A4 inhibitors should not exceed 5 mg per dose.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

DISCUSSION: Lemborexant is a CYP3A4 substrate. In a PKPB model, concurrent use of lemborexant with itraconazole increased area-under-curve (AUC) and concentration maximum (Cmax) by 3.75-fold and 1.5-fold, respectively. Concurrent use of lemborexant with fluconazole increased AUC and Cmax by 4.25-fold and 1.75-fold, respectively.(1) Weak inhibitors of CYP3A4 include: amiodarone, amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, and ziftomenib.(1,3)

Weak Cyp3a4 Inhibitors/Ubrogepant (> 50 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: Weak inhibitors of CYP3A4 may inhibit the metabolism of ubrogepant.(1)

CLINICAL EFFECTS: Concurrent use of ubrogepant with weak CYP3A4 inhibitors may result in an increase in exposure of ubrogepant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when used concomitantly with weak CYP3A4 inhibitors. Initial dose of ubrogepant should not exceed 50 mg when used concomitantly with weak inhibitors of CYP3A4. A second dose may be given within 24 hours but should not exceed 50 mg when used concurrently with weak CYP3A4 inhibitors.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

DISCUSSION: Coadministration of ubrogepant with verapamil, a moderate CYP3A4 inhibitor, resulted in a 3.5-fold and 2.8-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively. No dedicated drug interaction study was conducted to assess concomitant use with weak CYP3A4 inhibitors. The conservative prediction of the maximal potential increase in ubrogepant exposure with weak CYP3A4 inhibitors is not expected to be more than 2-fold.(1) Weak inhibitors of CYP3A4 include: amiodarone, amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, delavirdine, deutivacaftor, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, maribavir, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, pirtobrutinib, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, rucaparib, simeprevir, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, and ziftomenib. (3,4)

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

Camizestrant/Agents That Cause Bradycardia

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

MECHANISM OF ACTION: Camizestrant may cause symptomatic bradycardia. Additional agents that cause bradycardia further increase the risk for symptomatic bradycardia.(1)

CLINICAL EFFECTS: Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of camizestrant recommends avoiding concurrent use of camizestrant and other agents known to cause bradycardia.(1) If combination therapy is unavoidable, monitor heart rate and blood pressure regularly. Monitor heart rate more frequently during the first 30 days of treatment with camizestrant in patient with bradycardia (heart rate less than 60 beats per minute (bpm)) and those on concomitant medications known to lower heart rate.(1) If bradycardia occurs, symptomatic or Grade 2 or above, withhold camizestrant until symptoms resolve. Obtain an ECG to evaluate the etiology of the symptomatic bradycardia. If a contributing concomitant medication is identified, modify the dosage or discontinue the medication as appropriate until bradycardia symptoms resolve and then resume camizestrant. Consider reassessing the heart rate after restarting camizestrant. Permanently discontinue camizestrant for persistent bradycardia.(1) The manufacturer of camizestrant recommends performing an ECG prior to initiating camizestrant, then every week for the first 2 weeks of treatment, and periodically during treatment as clinically indicated.(1)

DISCUSSION: In a clinical trial, bradycardia occurred in 8% of patients on camizestrant. The mean heart rate decrease from baseline was approximately 13 beats per minute with camizestrant, with the maximum decrease observed on Day 15. The median time to onset of adverse reaction was 17 days (range 13 to 283 days) after starting camizestrant. Bradycardia led to dose interruption of camizestrant in 3.9% of patients.(1) Agents that may cause bradycardia and linked to this monograph include: beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, digoxin, and moxonidine.

Camizestrant/Belzutifan

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

MECHANISM OF ACTION: Camizestrant is a CYP3A4 substrate and strong inhibitor of CYP2C19.(1) Belzutifan is primarily metabolized by CYP2C19 and UGT2B17 and is a moderate inducer of CYP3A4.(2-4) Agents that induce the CYP3A4 isoenzyme may induce the metabolism of camizestrant.(1) Strong CYP2C19 inhibitors may inhibit the CYP2C19 mediated metabolism of belzutifan.(2)

CLINICAL EFFECTS: Concurrent use of camizestrant and belzutifan may decrease the levels and effectiveness of camizestrant(1) while increasing levels and toxicity of belzutifan including increasing the incidence or severity of anemia or hypoxia that can require a blood transfusion.(2)

PREDISPOSING FACTORS: UGT2B17 and CYP2C19 ultrarapid metabolizers may have increased risk or severity of adverse effects, including anemia.(1)

PATIENT MANAGEMENT: The effect of the two-way inhibition and induction of camizestrant and belzutifan metabolism is unknown. The optimal doses of camizestrant and belzutifan when used concurrently have not been determined. Concurrent use should be avoided. Dose modifications mentioned below are informational only. The US manufacturer of camizestrant states that dosage recommendations for concomitant use of moderate CYP3A4 inducers differ depending on the CDK4/6 inhibitor used in combination with camizestrant: - Avoid concomitant use of moderate CYP3A4 inducers for patients who are receiving camizestrant in combination with abemaciclib and palbociclib. If concomitant use cannot be avoided, increase the camizestrant dosage from 75 mg once daily to 150 mg once daily for patients who are receiving camizestrant in combination with abemaciclib or palbociclib. After the moderate CYP3A4 inducer has been discontinued for at least 14 days, resume the camizestrant dosage used prior to initiation of the moderate CYP3A4 inducer. - No camizestrant dosage modification is recommended for patients who are receiving camizestrant in combination with ribociclib concomitantly with a moderate CYP3A4 inducer.(1) The manufacturer of belzutifan states that concurrent administration of CYP2C19 inhibitors increases plasma exposure which may increase the incidence and severity of anemia or hypoxemia. Monitor patients closely for anemia or hypoxemia and reduce the dose of belzutifan as recommended. See full prescribing information for dose modifications and recommendations.(2) Monitor for anemia before initiation of, and periodically throughout, treatment with belzutifan. Closely monitor patients who are dual UGT2B17 and CYP2C19 poor metabolizers due to potential increases in exposure that may increase the incidence or severity of anemia.(2) For patients with hemoglobin less than 9 g/dL, withhold belzutifan until the hemoglobin is greater than or equal to 9 g/dL, then resume at reduced dose or permanently discontinue belzutifan, depending on the severity of anemia.(2)

DISCUSSION: The combined use of camizestrant and belzutifan has not been studied. Camizestrant AUC is predicted to decrease to 43% and Cmax to 58% following concomitant administration of phenobarbital (moderate CYP3A4 inducer) 100 mg once daily for 17 days. Phenobarbital and efavirenz (moderate CYP3A inducers) are predicted to have minimal effects on camizestrant AUC and Cmax when camizestrant is given in combination with 400 mg or 600 mg ribociclib.(1)

Camizestrant/Bosentan

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

MECHANISM OF ACTION: Camizestrant is a CYP3A4 substrate and strong inhibitor of CYP2C9.(1) Bosentan is a CYP2C9 substrate and moderate inducer of CYP3A4.(2) Agents that induce the CYP3A4 isoenzyme may induce the metabolism of camizestrant.(1) Strong CYP2C9 inhibitors may inhibit the CYP2C9 mediated metabolism of bosentan.(2)

CLINICAL EFFECTS: Concurrent use of camizestrant and bosentan may decrease the levels and effectiveness of camizestrant(1) while increasing levels and toxicity of bosentan.(2)

PREDISPOSING FACTORS: Concurrent use of bosentan, camizestrant, and a strong or moderate CYP3A4 inhibitor could lead to blockade of both major metabolic pathways for bosentan, resulting in large increases in bosentan plasma concentrations.(2,3)

PATIENT MANAGEMENT: The effect of the two-way inhibition and induction of camizestrant and bosentan metabolism is unknown. The optimal doses of camizestrant and bosentan when used concurrently have not been determined. Concurrent use should be avoided. Dose modifications mentioned below are informational only. Review the patient's medication list to see if the patient is also receiving a CYP3A4 inhibitor. Concomitant use of both a CYP2C9 and CYP3A4 inhibitor with bosentan is not recommended as the combination may lead to large increases in bosentan plasma concentrations.(2) For patients stabilized on bosentan when a CYP2C9 inhibitor is initiated, monitor tolerance to concomitant therapy and adjust bosentan dose if needed. The US manufacturer of camizestrant states that dosage recommendations for concomitant use of moderate CYP3A4 inducers differ depending on the CDK4/6 inhibitor used in combination with camizestrant: - Avoid concomitant use of moderate CYP3A4 inducers for patients who are receiving camizestrant in combination with abemaciclib and palbociclib. If concomitant use cannot be avoided, increase the camizestrant dosage from 75 mg once daily to 150 mg once daily for patients who are receiving camizestrant in combination with abemaciclib or palbociclib. After the moderate CYP3A4 inducer has been discontinued for at least 14 days, resume the camizestrant dosage used prior to initiation of the moderate CYP3A4 inducer. - No camizestrant dosage modification is recommended for patients who are receiving camizestrant in combination with ribociclib concomitantly with a moderate CYP3A4 inducer.(1)

DISCUSSION: The combined use of camizestrant and bosentan has not been studied. Camizestrant area-under-curve (AUC) is predicted to decrease to 43% and maximum concentration (Cmax) to 58% following concomitant administration of phenobarbital (moderate CYP3A4 inducer) 100 mg once daily for 17 days. Phenobarbital and efavirenz (moderate CYP3A inducers) are predicted to have minimal effects on camizestrant AUC and Cmax when camizestrant is given in combination with 400 mg or 600 mg ribociclib.(1) Camizestrant is predicted to increase the AUC and Cmax of warfarin (sensitive CYP2C9 substrate) by 13-fold and 1.1-fold, respectively, and of siponimod (moderately sensitive CYP2C9 substrate) by 5.3-fold and 1.1-fold, respectively.(1)

Camizestrant/Moderate Cyp3a4 Inducers

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

MECHANISM OF ACTION: Agents that induce the CYP3A4 isoenzyme may induce the metabolism of 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)

Selected Cyp3a4 Inhibitors/Colchicine

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

MECHANISM OF ACTION: CYP3A4 inhibitors may inhibit the metabolism of colchicine.(1-3)

CLINICAL EFFECTS: Concurrent use of CYP3A4 inhibitors may result in elevated levels of and toxicity from colchicine. Symptoms of colchicine toxicity include muscle weakness or pain; numbness or tingling in the fingers or toes; myelosuppression; abdominal pain; nausea; severe diarrhea or vomiting; feeling weak or tired; increased infections; and pale or gray color of the lips, tongue, or palms of hands.(1-3)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with renal and/or hepatic impairment.(1-3)

PATIENT MANAGEMENT: Monitor patients receiving CYP3A4 inhibitors for signs of colchicine toxicity. Depending on the potency of CYP3A4 inhibition, the indication for colchicine, and the patient's renal and hepatic function, concurrent use may be contraindicated or may require a decreased dosage of colchicine. Refer to colchicine prescribing information for specific recommendations.(1-3) The manufacturers of gepotidacin and sevabertinib state that concurrent use of drugs that are extensively metabolized by CYP3A4 and have a narrow therapeutic window like colchicine should be avoided.(4,5) Patients should be instructed to immediately report any signs of colchicine toxicity, such as muscle weakness/pain, numbness/tingling in fingers/toes, unusual bleeding or bruising, infections, weakness/tiredness, pale/gray color of the lips/tongue/palms of hands, and/or severe diarrhea/vomiting.

DISCUSSION: In a clinical study, coadministration of single-dose midazolam 2 mg (a sensitive CYP3A4 substrate) with gepotidacin (3,000 mg every 12 hours for 2 doses) increased the area-under-curve (AUC) of midazolam by 1.9-fold.(2) Selected CYP3A4 inhibitors linked to this monograph include: camizestrant, gepotidacin, and sevabertinib.

Selected Cyp3a4 Inhibitors/Cyclosporine

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

MECHANISM OF ACTION: CYP3A4 inhibitors may inhibit the metabolism of cyclosporine.(1)

CLINICAL EFFECTS: Concurrent use of CYP3A4 inhibitors may result in elevated levels of and toxicity from cyclosporine.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor cyclosporine levels and renal function in patients receiving concurrent therapy. Cyclosporine dosages may need to be decreased.(1) The manufacturers of gepotidacin and sevabertinib state that concurrent use of drugs that are extensively metabolized by CYP3A4 and have a narrow therapeutic window like cyclosporine should be avoided.(2,3)

DISCUSSION: In a study, renal and cardiac patients required a cyclosporine dose reduction of 15% to 48% when diltiazem, a moderate CYP3A4 inhibitor, was co-administered to maintain a cyclosporine trough similar to cyclosporine alone.(4) In a study, cyclosporine required a 25% dose reduction when co-administered with fluconazole, a moderate CYP3A4 inhibitor, to maintain a goal serum concentration similar to cyclosporine alone.(5) In a clinical study, coadministration of single-dose midazolam 2 mg (a sensitive CYP3A4 substrate) with gepotidacin (3,000 mg every 12 hours for 2 doses) increased the area-under-curve (AUC) of midazolam by 1.9-fold.(2) Selected CYP3A4 inhibitors linked to this monograph include: camizestrant, gepotidacin, and sevabertinib.

Selected Cyp3a4 Inhibitors/Everolimus

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

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

CLINICAL EFFECTS: Concurrent use of CYP3A4 inhibitors may result in elevated levels of and toxicity from everolimus.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Closely monitor for an increase in everolimus levels and for adverse effects from everolimus during concurrent therapy with CYP3A4 inhibitors. Dose adjustment of everolimus may be necessary.(2) The manufacturers of gepotidacin and sevabertinib state that concurrent use of drugs that are extensively metabolized by CYP3A4 and have a narrow therapeutic window like everolimus should be avoided.(3,4)

DISCUSSION: In a study in healthy subjects, concurrent use of ketoconazole, a strong CYP3A4 inhibitor and a P-gp inhibitor, increased everolimus area-under-curve (AUC) and maximum concentration (Cmax) by 3.9-fold and 15.0-fold, respectively. Erythromycin (a P-gp and moderate CYP3A4 inhibitor) increased everolimus AUC and Cmax by 4.4-fold and 2-fold, respectively, while verapamil (a P-gp and moderate CYP3A4 inhibitor) increased everolimus AUC and Cmax by 3.5-fold and 2.3-fold, respectively.(1) In a clinical study, coadministration of single-dose midazolam 2 mg (a sensitive CYP3A4 substrate) with gepotidacin (3,000 mg every 12 hours for 2 doses) increased the area-under-curve (AUC) of midazolam by 1.9-fold.(3) Selected CYP3A4 inhibitors linked to this monograph include: camizestrant, gepotidacin, and sevabertinib.

Selected Cyp3a4 Inhibitors/Quinidine; Quinine

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

MECHANISM OF ACTION: Inhibitors of CYP3A4 may decrease the metabolism of quinidine or quinine.(1,2)

CLINICAL EFFECTS: Concurrent use of quinidine or quinine with CYP3A4 inhibitors may lead to increased serum levels and adverse effects of quinidine or quinine, including potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1,2)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)

PATIENT MANAGEMENT: Patients receiving concurrent CYP3A4 inhibitors should be monitored for increased effects of quinidine or quinine.(1-2) The manufacturer of sevabertinib states that concurrent use of drugs that are extensively metabolized by CYP3A4 and have a narrow therapeutic window like quinidine or quinine should be avoided.(3) 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: Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have been reported in patients taking quinidine in combination with CYP3A4 inhibitors.(1) In a study of healthy volunteers, ketoconazole (100 mg twice daily for 3 days) increased the area-under-curve (AUC) of single-dose quinine (500 mg) by 45% compared to quinine alone.(2) In a clinical study, coadministration of midazolam (a sensitive CYP3A4 substrate) with sevabertinib (20 mg twice daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 2-fold and 1.8-fold.(3) Selected CYP3A4 inhibitors linked to this monograph include: camizestrant, relacorilant, and sevabertinib.(5,6)

Selected Cyp3a4 Inhibitors/Sirolimus

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

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

CLINICAL EFFECTS: Concurrent use of CYP3A4 inhibitors may result in elevated levels of and toxicity from sirolimus.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Closely monitor for an increase in sirolimus levels and for renal dysfunction during concurrent therapy with CYP3A4 inhibitors, especially at initiation and discontinuation of therapy. Dose adjustment of sirolimus may be necessary.(1,2) The manufacturers of gepotidacin and sevabertinib state that concurrent use of drugs that are extensively metabolized by CYP3A4 and have a narrow therapeutic window like sirolimus should be avoided.(3,4)

DISCUSSION: In a clinical study, coadministration of single-dose midazolam 2 mg (a sensitive CYP3A4 substrate) with gepotidacin (3,000 mg every 12 hours for 2 doses) increased the area-under-curve (AUC) of midazolam by 1.9-fold.(3) Selected CYP3A4 inhibitors linked to this monograph include: camizestrant, gepotidacin, and sevabertinib.

Strong Cyp2c9 Inhibitors/Siponimod

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

MECHANISM OF ACTION: Inhibitors of CYP2C9 may inhibit the metabolism of siponimod.(1)

CLINICAL EFFECTS: Concurrent use of an inhibitor of CYP2C9 may result in elevated levels of and clinical effects of siponimod, including immunosuppression and increased risk of infection.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of siponimod states that concomitant use of siponimod with strong CYP2C9 inhibitors is not recommended.(1) The US manufacturer of camizestrant (strong CYP2C9 inhibitor) states avoid concomitant use of camizestrant with CYP2C9 substrates during treatment with camizestrant and at least 2 weeks after the last dose of camizestrant, unless otherwise recommended in the prescribing information of the CYP2C9 substrate.(2)

DISCUSSION: Siponimod is metabolized by CYP2C9 (79.3%) and CYP3A4 (18.5%). Concurrent use of fluconazole (a dual moderate inhibitor of CYP2C9 and CYP3A4, 200 mg at steady state) in healthy subjects with the CYP2C9*1/*1 genotype increased the area-under-curve (AUC) of siponimod (4 mg single dose) by 2-fold. Siponimod half-life increased by 50%. Fluconazole increased siponimod area-under-curve (AUC) by 2-fold to 4-fold across all CYP2C9 genotypes.(1) Strong CYP2C9 inhibitors linked to this monograph include: camizestrant.(2,3)

Strong Cyp3a4 Or Strong & Moderate Cyp2c9 Inhib/Erdafitinib

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

MECHANISM OF ACTION: Erdafitinib is metabolized by CYP3A4 and CYP2C9. Strong inhibitors of CYP3A4 or moderate inhibitors of CYP2C9 may inhibit the metabolism of erdafitinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 or moderate CYP2C9 inhibitors may increase the levels and effects of erdafitinib, including retinopathy and hyperphosphatemia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US prescribing information states that concurrent use of erdafitinib with strong CYP3A4 inhibitors or moderate CYPC9 inhibitors should be avoided. If concurrent use cannot be avoided, monitor closely for adverse reactions and consider a dose modification based on prescribing information. If the strong CYP3A4 or moderate CYP2C9 inhibitor is discontinued, consider increasing the erdafitinib dose if patient does not have any drug-related toxicity.(1) If concurrent use with nitisinone cannot be avoided, the manufacturer of nitisinone recommends reducing the dosage of a CYP2C9 substrate like erdafitinib by one-half.(2)

DISCUSSION: In PKPB models, concurrent use of fluconazole (a moderate CYP2C9 and CYP3A4 inhibitor) resulted in erdafitinib mean ratios for concentration maximum (Cmax) and area-under-curve (AUC) of 121% and 148% , respectively, compared to erdafitinib alone.(1) In PKPB models, concurrent use of itraconazole (a strong CYP3A4 inhibitor and P-gp inhibitor) resulted in erdafitinib mean ratios for Cmax and AUC of 105% and 134%, respectively, compared to erdafitinib alone.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3,4) Strong CYP2C9 inhibitors include: camizestrant.(3,4) Moderate inhibitors of CYP2C9 include: adagrasib, amiodarone, apazone, asciminib, benzbromarone, fluconazole, miconazole, mifepristone, milk thistle, nitisinone, oxandrolone, phenylbutazone, and sulfaphenazole.(3,4)

Strong; Selected Moderate Cyp2c19 Inhibitors/Clobazam

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

MECHANISM OF ACTION: Clobazam's active metabolite, N-desmethylclobazam, is metabolized by the CYP2C19 isoenzyme.(1) The FDA categorizes N-desmethylclobazam as a sensitive substrate for CYP2C19. Sensitive substrates are drugs whose plasma area-under-curve (AUC) have been shown to increase 5-fold or higher when co-administered with a strong inhibitor of the enzyme.(2)

CLINICAL EFFECTS: Concurrent use of a strong or selected moderate inhibitor of CYP2C19 may result in elevated levels of and toxicity from the active metabolite of clobazam, including profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The dosage of clobazam may need to be adjusted when initiating or discontinuing a strong or selected moderate inhibitor of CYP2C19.(1) When initiating a strong or selected moderate inhibitor of CYP2C19 in a patient maintained on clobazam, monitor closely for increased effects from clobazam and adjust dose accordingly.(1) If possible, use an alternative treatment which does not inhibit CYP2C19. When initiating clobazam in a patient maintained on a strong or moderate inhibitor of CYP2C19, it would be prudent to follow the manufacturer's recommendations for dosage adjustments in patients who are CYP2C19 poor metabolizers. In these patients, consider a starting dose of 5 mg/day and reduce weekly dosage adjustments to half the normal increase. Based on clinical response, the dosage may be titrated to normal dosage levels based on weight group at Day 21.(1)

DISCUSSION: The active metabolite of clobazam, N-desmethylclobazam, is metabolized by CYP2C19. Levels of N-desmethylclobazam are 3-5 times higher in poor metabolizers of CYP2C19 and 2 times higher in intermediate metabolizers of CYP2C19. Thus, strong and moderate inhibitors of CYP2C19 are expected to result in a 3 to 5-fold increase in levels of N-desmethylclobazam as well.(1) Strong and selected moderate inhibitors of CYP2C19 include: camizestrant, esomeprazole, fluconazole, fluvoxamine, omeprazole, stiripentol, and ticlopidine.(2) Esomeprazole and omeprazole are irreversible inhibitors of CYP2C19. Although intermittent use may lead to moderate CYP2C19 inhibition, routine use may lead to inactivation of all available CYP2C19, converting patient to the CYP2C19 poor metabolizer phenotype.(3) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Weak Cyp3a4 Inhibitors/Eliglustat

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

MECHANISM OF ACTION: Weak inhibitors of CYP3A4 may inhibit the metabolism of eliglustat. If the patient is also taking an inhibitor of CYP2D6, eliglustat metabolism can be further inhibited.(1)

CLINICAL EFFECTS: Concurrent use of an agent that is a weak inhibitor of CYP3A4 may result in elevated levels of and clinical effects of eliglustat, including prolongation of the PR, QTc, and/or QRS intervals, which may result in life-threatening cardiac arrhythmias.(1)

PREDISPOSING FACTORS: If the patient is also taking an inhibitor of CYP2D6, is a poor metabolizer of CYP2D6, and/or has hepatic impairment, eliglustat metabolism can be further inhibited.(1) 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)

PATIENT MANAGEMENT: The concurrent use of eliglustat with weak inhibitors of CYP3A4 in poor metabolizers of CYP2D6 should be avoided.(1) The dosage of eliglustat with weak inhibitors of CYP3A4 in extensive metabolizers of CYP2D6 with mild (Child-Pugh Class A) hepatic impairment should be limited to 84 mg daily.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(3)

DISCUSSION: Ketoconazole (400 mg daily), a strong inhibitor of CYP3A4, increased eliglustat (84 mg BID) maximum concentration (Cmax) and area-under-curve (AUC) by 4-fold and 4.4-fold, respectively, in extensive metabolizers. Physiologically-based pharmacokinetic (PKPB) models suggested ketoconazole would increase eliglustat Cmax and AUC by 4.4-fold and 5.4-fold, respectively, in intermediate metabolizers. PKPB models suggested ketoconazole may increase the Cmax and AUC of eliglustat (84 mg daily) by 4.3-fold and 6.2-fold, respectively, in poor metabolizers.(1) PKPB models suggested fluconazole, a moderate inhibitor of CYP3A4, would increase eliglustat Cmax and AUC by 2.8-fold and 3.2-fold, respectively, in extensive metabolizers and by 2.5-fold and 2.9-fold, respectively in intermediate metabolizers. PKPB models suggest that concurrent eliglustat (84 mg BID), paroxetine (a strong inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 16.7-fold and 24.2-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 7.5-fold and 9.8-fold, respectively.(1) PKPB models suggest that concurrent eliglustat (84 mg BID), terbinafine (a moderate inhibitor of CYP2D6), and ketoconazole would increase eliglustat Cmax and AUC by 10.2-fold and 13.6-fold, respectively, in extensive metabolizers. In intermediate metabolizers, eliglustat Cmax and AUC would be expected to increase 4.2-fold and 5-fold, respectively.(1) Weak inhibitors of CYP3A4 include: amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranolazine, resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, vonoprazan, and ziftomenib.(4,5)

Weak Cyp3a4 Inhibitors/Lomitapide

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

MECHANISM OF ACTION: Weak inhibitors of CYP3A4 may inhibit the metabolism of lomitapide.(1) Lomitapide is very susceptible to CYP3A4 inhibition. For example, in an interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide exposure was increased 27-fold.(2) Thus even weak CYP3A4 inhibitors may affect lomitapide exposure (AUC, area-under-curve).

CLINICAL EFFECTS: Concurrent use of a weak inhibitor of CYP3A4 may result in 2-fold increases in lomitapide levels and toxicity from lomitapide.(1)

PREDISPOSING FACTORS: This interaction may be more severe in patients with hepatic impairment or with end-stage renal disease.(1)

PATIENT MANAGEMENT: When initiating lomitapide in patients taking a stable dose of a weak CYP3A4 inhibitor, follow the recommended dose and titration schedule per labeling. When initiating a weak CYP3A4 inhibitor in patients taking lomitapide, decrease the dose of lomitapide by 50%. The maximum recommended lomitapide dose with concurrent weak CYP3A4 inhibitors should be: -Adults (age 18 years and older): 30 mg daily, -Age group 11 to 17 years: 20 mg daily, -Age group 2 to 10 years: 10 mg daily. Due to lomitapide's long half-life, it may take 1 to 2 weeks to see the full effect of this interaction.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

DISCUSSION: Lomitapide is very susceptible to CYP3A4 inhibition. For example, in an interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide exposure was increased 27-fold.(2) Based upon interactions with stronger inhibitors, weak inhibitors of CYP3A4 are predicted to increase lomitapide area-under-curve(AUC) 2-fold.(1) Weak CYP3A4 inhibitors linked to this interaction include: amiodarone, amlodipine, anamorelin, asciminib, atorvastatin, avapritinib, azithromycin, Baikal skullcap, belumosudil, bicalutamide, blueberry juice, brodalumab, camizestrant, cannabidiol, capivasertib, cilostazol, cimetidine, ciprofloxacin, chlorzoxazone, clotrimazole, cranberry juice, cyclosporine, daridorexant, delavirdine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lurasidone, maribavir, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, rucaparib, selpercatinib, sevabertinib, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, ziftomenib, and zileuton.(1-3)

Weak Cyp3a4 Inhibitors/Pimozide

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

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

CLINICAL EFFECTS: Concurrent use with weak CYP3A4 inhibitors may increase the levels and effects of pimozide including QTc prolongation and potentially life-threatening cardiac arrhythmias like torsades de pointes.(1-2) Concurrent use may also result in extrapyramidal symptoms such as akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, and oculogyric crisis.(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.(3) 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 increased 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).(3) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: The US manufacturer of pimozide states that concomitant treatment with strong CYP3A4 inhibitors is contraindicated and treatment with less potent inhibitors of CYP3A4 should also be avoided.(1) The UK manufacturer of pimozide contraindicates concomitant use of pimozide with CYP3A4 inhibitors and CYP2D6 inhibitors, stating that inhibition of either or both CYP3A4 and CYP2D6 may result in the elevation of pimozide blood concentration and increase the possibility of QT-prolongation.(2) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(5) If concurrent use cannot be avoided, then correct or minimize QT prolonging risk factors, use the lowest effective dose of pimozide, and discontinue other concurrent QT prolonging agents or CYP3A4 or CYP2D6 inhibitors if possible. 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: Pimozide is metabolized at CYP3A.(1,5) Elevated levels of pimozide may prolong the QTc interval resulting in life-threatening ventricular arrhythmias.(1) Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have been reported in patients taking pimozide in combination with itraconazole and/or other CYP3A4 inhibitors.(1,2) Weak CYP3A4 inhibitors include: amlodipine, asciminib, avapritinib, belumosudil, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, capivasertib, chlorzoxazone, cimetidine, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fostamatinib, ginkgo, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, marijuana, olaparib, palbociclib, peppermint, piperine, pirtobrutinib, propiverine, ranitidine, resveratrol, scutellarin, sevabertinib, simeprevir, sitaxsentan, teriflunomide, ticagrelor, tolvaptan, trofinetide, viloxazine, and vonoprazan.(7,8)

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

Moderate And Weak Cyp3a4 Inhibitors/Tacrolimus

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

MECHANISM OF ACTION: Moderate and weak inhibitors of CYP3A4 may inhibit the metabolism of tacrolimus.(1)

CLINICAL EFFECTS: Concurrent use of a CYP3A4 inhibitor may result in elevated levels of and toxicity from tacrolimus, including nephrotoxicity, neurotoxicity, and prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(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 torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of tacrolimus recommends monitoring tacrolimus whole blood trough concentrations and reducing tacrolimus dose if needed.(1) 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: In a study of 26 renal transplant recipients, conjugated estrogens 3.75 mg daily increased the tacrolimus dose-corrected concentration of tacrolimus by 85.6%. Discontinuation of the conjugated estrogens led to a decrease in tacrolimus concentration of 46.6%.(3) A case report describes a 65-year-old kidney transplant recipient who was stable on tacrolimus 9 mg per day with trough levels of 5 to 7.5 ng/mL. Ten days after starting on estradiol gel 0.5 mg per day, her tacrolimus level rose to 18.3 ng/mL and serum creatinine (Scr) rose from 1.1 mg/dL at baseline to 2 mg/dL. Tacrolimus dose was reduced by 60%, and trough levels and Scr normalized after two weeks.(4) A study of 16 healthy volunteers found that elbasvir 50 mg/grazoprevir 200 mg daily increased the area-under-curve (AUC) of tacrolimus by 43%, while the maximum concentration (Cmax) of tacrolimus was decreased by 40%.(5) An analysis of FAERS data from 2004-2017, found a significant association between transplant rejection and concurrent use of tacrolimus and clotrimazole (reporting odds ratio 1.92, 95% CI). A retrospective study of 7 heart transplant patients on concurrent tacrolimus and clotrimazole troche showed a significant correlation between tacrolimus trough concentration and AUC after clotrimazole discontinuation. Tacrolimus clearance and bioavailability after clotrimazole discontinuation was 2.2-fold greater (0.27 vs. 0.59 L/h/kg) and the trough concentration decreased from 6.5 ng/mL at 1 day to 5.3 ng/mL at 2 days after clotrimazole discontinuation.(7) A retrospective study of 26 heart transplant patients found that discontinuation of concurrent clotrimazole with tacrolimus in the CYP3A5 expresser group had a 3.3-fold increase in apparent oral clearance and AUC of tacrolimus (0.27 vs. 0.89 L/h/kg) compared to the CYP3A5 non expresser group with a 2.2-fold mean increase (0.18 vs. 0.39 L/h/kg).(8) A study of 6 adult kidney transplant recipients found that clotrimazole (5-day course) increased the tacrolimus AUC 250% and the blood trough concentrations doubled (27.7 ng/ml versus 27.4 ng/ml). Tacrolimus clearance decreased 60% with coadministration of clotrimazole.(9) A case report describes a 23-year-old kidney transplant recipient who was stable on tacrolimus 5 mg twice daily, mycophenolate mofetil 30 mg daily, prednisone (30 mg daily tapered over time to 5 mg), and clotrimazole troche 10 mg four times daily. Discontinuation of clotrimazole resulted in a decrease in tacrolimus trough levels from 13.7 ng/ml to 5.4 ng/ml over a period of 6 days. Clotrimazole was restarted with tacrolimus 6 mg resulting in an increased tacrolimus level of 19.2 ng/ml.(10) A retrospective study in 95 heart transplant recipients on concurrent clotrimazole and tacrolimus found a median tacrolimus dose increase of 66.7% was required after clotrimazole discontinuation. Tacrolimus trough concentration was found to have decreased 42.5% after clotrimazole discontinuation.(11) A retrospective study in 65 pancreas transplant patients on concurrent tacrolimus, clotrimazole, cyclosporine, and prednisone found that clotrimazole discontinuation at 3 months after transplantation may cause significant tacrolimus trough level reductions.(12) A case report describes a 6-year-old kidney transplant recipient who was on a regimen of tacrolimus and mycophenolate mofetil. The patient was started letermovir 240 mg via G-tube 2 months post kidney transplant. One week after starting letermovir, the routine tacrolimus level showed a supratherapeutic concentration of 22.9 ng/L. A 36% dose reduction of tacrolimus was required. Upon discontinuation of letermovir, the tacrolimus level decreased by 42%.(13) Moderate CYP3A4 inhibitors linked to this monograph include: berotralstat, conivaptan, fluvoxamine, lenacapavir, letermovir, netupitant, nirogacestat, sevabertinib, stiripentol, and tofisopam.(6) Weak CYP3A4 inhibitors linked to this monograph include: avacopan, baikal skullcap, berberine, bicalutamide, blueberry, brodalumab, camizestrant, chlorzoxazone, cimetidine, cranberry juice, daclatasvir, daridorexant, delavirdine, diosmin, elinzanetant, estrogens, flibanserin, fostamatinib, ginkgo biloba, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lazertinib, linagliptin, lomitapide, lumateperone, lurasidone, peppermint oil, piperine, propiverine, ranitidine, resveratrol, rimegepant, simeprevir, sitaxsentan, skullcap, ticagrelor, tolvaptan, trofinetide, viloxazine, and vonoprazan-amoxicillin.(6)

Selected Cyp2c9 Inhibitors/Selected Nsaids

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

MECHANISM OF ACTION: The major metabolic pathway for many non-steroidal anti-inflammatory agents (NSAIDs) is CYP2C9. Inhibitors of CYP2C9 include: amiodarone, asciminib, diosmin, fluconazole, ketoconazole, miconazole, nitisinone, oxandrolone, piperine, voriconazole, and zafirlukast.(1,2)

CLINICAL EFFECTS: Concurrent use of NSAIDs with inhibitors of CYP2C9 may result in increased levels of and adverse effects from NSAIDs, including increased risk for bleeding. NSAIDs linked to this monograph are celecoxib, diclofenac, flurbiprofen, ibuprofen, meloxicam, naproxen, parecoxib, piroxicam and valdecoxib.

PREDISPOSING FACTORS: Higher doses of either agent would be expected to increase the risk for serious adverse effects such as gastrointestinal bleeding (GIB) or renal failure. Patients who smoke, are elderly, debilitated, dehydrated, have renal impairment, or who have a history of GIB due to NSAIDs are also at increased risk for serious adverse events.(3-7) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Patients on routine NSAID therapy when an inhibitor of CYP2C9 is started should be evaluated for patient-specific risk factors for NSAID toxicity. Based upon this risk assessment, consider dose reduction of the NSAID or close monitoring for adverse effects. For a patient already receiving a CYP2C9 inhibitor when an NSAID is started, consider initiating the NSAID at a lower than usual dose, particularly when predisposing risk factors for harm are present. The manufacturer of celecoxib recommends that celecoxib be introduced at the lowest recommended dose in patients receiving fluconazole therapy.(3) The manufacturer of fluconazole states that half the dose of celecoxib may be necessary when fluconazole is added.(4) It would be prudent to follow this recommendation with other CYP2C9 inhibitors and to decrease the dose of celecoxib in patients in whom CYP2C9 inhibitors are added to celecoxib therapy. The manufacturer of diclofenac-misoprostol states that the total daily dose of diclofenac should not exceed the lowest recommended dose of 50 mg twice daily in patients taking CYP2C9 inhibitors.(5) It would be prudent to use the lowest recommended dose of other diclofenac formulations in patients taking CYP2C9 inhibitors. The manufacturer of parecoxib states that the dose of parecoxib should be reduced in those patients who are receiving fluconazole therapy.(6) It would be prudent to follow this recommendation with other CYP2C9 inhibitors. The manufacturer of nitisinone recommends reducing the dosage of a CYP2C9 substrate by one-half.(7) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: The concomitant administration of celecoxib and fluconazole (200 mg daily) resulted in a 2-fold increase in celecoxib plasma concentration.(3) In vitro studies in human hepatocytes found that amiodarone inhibited diclofenac metabolism.(8) In two separate studies, single doses of diclofenac (50 mg) or ibuprofen (400 mg) were coadministered with the last dose of voriconazole (400 mg q12h on Day 1, followed by 200 mg q12h on Day 2). Voriconazole increased the mean AUC of diclofenac by 78% and increased the AUC of the active isomer of ibuprofen by 100%.(9-11) Coadministration of diosmin increased diclofenac levels by 63%.(2) Coadministration of flurbiprofen or ibuprofen with fluconazole increased the AUC of flurbiprofen by 81% and of the active ibuprofen by 82% compared with either agent alone.(4) Concurrent voriconazole increased meloxicam AUC by 47%.(12,13) The concurrent administration of fluconazole and parecoxib resulted in increases in the area-under-curve (AUC) and maximum concentration (Cmax) of valdecoxib (the active metabolite of parecoxib) by 62% and 19%, respectively.(6) In a study, single dose diclofenac (50mg) given concurrently with the last dose of voriconazole (400 mg every 12 hours on Day 1, 200 mg every 12 hours on Day 2) increased Cmax and AUC by 2.1-fold and 1.8-fold, respectively. (5) Inhibitors of CYP2C9 include: amiodarone, asciminib, camizestrant, diosmin, fluconazole, ketoconazole, miconazole, nitisinone, oxandrolone, piperine, voriconazole, and zafirlukast.(1,2)

Selected Cyp3a4 Inhibitors/Alfentanil

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

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of alfentanil.(1)

CLINICAL EFFECTS: The concurrent administration of a CYP3A4 inhibitor may result in elevated levels of and toxicity from alfentanil, including somnolence and potentially fatal respiratory depression.

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Use caution when initiating or discontinuing concurrent treatment. Monitor patients receiving CYP3A4 inhibitors for increased adverse effects such as sedation or respiratory suppression at frequent intervals and for an extended period of time. Dosage adjustments should be made if warranted. Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(4) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(5)

DISCUSSION: In a randomized study of coronary artery bypass patients, concurrent diltiazem (60 mg orally 2 hours before induction of anesthesia then 0.1 mg/kg/hr infusion) increased the area-under-curve (AUC) and half-life of alfentanil by 40% and 50%, respectively, when compared to placebo. Patients who received diltiazem were extubated an average of 2.5 hours later than in patients who received placebo.(6) In a clinical study, coadministration of single-dose midazolam 2 mg (a sensitive CYP3A4 substrate) with gepotidacin (3,000 mg every 12 hours for 2 doses) increased the area-under-curve (AUC) of midazolam by 1.9-fold.(2) In a clinical study, coadministration of midazolam (a sensitive CYP3A4 substrate) with sevabertinib (20 mg twice daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 2-fold and 1.8-fold.(3) Selected inhibitors of CYP3A4 linked to this monograph include: camizestrant, gepotidacin, oral lefamulin, nirogacestat, sevabertinib, and voxelotor.(2-3)

Selected Cyp3a4 Inhibitors/Fentanyl

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

MECHANISM OF ACTION: CYP3A4 inhibitors may inhibit the metabolism of fentanyl.(1)

CLINICAL EFFECTS: The concurrent administration of a CYP3A4 inhibitor may result in elevated levels of and toxicity from fentanyl,(1) including profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects.

PATIENT MANAGEMENT: Use caution when initiating or discontinuing concurrent treatment, particularly if the patient is also receiving treatment with other CYP3A4 inhibitors (e.g. systemic azole antifungals, clarithromycin, protease inhibitors).(1) Monitor patients receiving CYP3A4 inhibitors at frequent intervals and for an extended period of time. Dosage adjustments should be made if warranted. Monitor for increased adverse effects such as respiratory suppression or increased sedation.(1) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with agents that may increase opioid drug levels.(4) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(5) Avoid exposing the fentanyl patch application site and surrounding area to direct external heat sources as there have been reports of overdose and death as a result of exposure to heat.(1)

DISCUSSION: In a randomized, cross-over study in 12 healthy subjects, voriconazole (400 mg twice daily, Day 1; 200 mg twice daily, Day 2) and fluconazole (400 mg daily, Day 1; 200 mg daily, Day 2) decreased the clearance of a single dose of intravenous fentanyl (5 mcg/kg) by 23% and 16%, respectively.(6) In a clinical study, coadministration of single-dose midazolam 2 mg (a sensitive CYP3A4 substrate) with gepotidacin (3,000 mg every 12 hours for 2 doses) increased the area-under-curve (AUC) of midazolam by 1.9-fold.(2) In a clinical study, coadministration of midazolam (a sensitive CYP3A4 substrate) with sevabertinib (20 mg twice daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 2-fold and 1.8-fold.(3) Selected CYP3A4 inhibitors linked to this monograph include: camizestrant, gepotidacin, and sevabertinib.(2-3)

Selected Strong Cyp2c19 Inhibitors/Flibanserin

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

MECHANISM OF ACTION: Flibanserin is partially metabolized by the CYP2C19 isoenzyme.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP2C19 may result in elevated levels of and toxicity from flibanserin.(1)

PREDISPOSING FACTORS: Patients with any degree of hepatic impairment are expected to have increased systemic concentrations of flibanserin, adding to the risk for hypotension or syncopal episodes.(1) Hypotensive or syncopal episodes are more common when flibanserin is taken during waking hours.(1)

PATIENT MANAGEMENT: Increase monitoring for adverse reactions, e.g. hypotension or syncope, in patients who receive concurrent therapy with a strong CYP2C19 inhibitor.(1) Advise patients who experience pre-syncope or lightheadedness to lie down and to call for help if symptoms persist. Prompt medical attention should be obtained for patients who experience syncope.(1)

DISCUSSION: In a drug interaction study with 15 healthy subjects, the combination of flibanserin (100 mg on day 6) and fluconazole (a moderate CYP3A4 and strong CYP2C19 inhibitor, 400 mg once then 200 mg daily for 5 days) resulted in an increased flibanserin exposure of 7-fold. Hypotension or syncope requiring supine placement with leg elevation occurred in 3 subjects (20%). One patient became unresponsive with a blood pressure of 64/41 mm Hg and required emergency room treatment where she required intravenous saline.(1) In clinical trials, syncope occurred in one subject who was a CYP2C19 poor metabolizer.(1) Selected strong inhibitors of CYP2C19 include: camizestrant and ticlopidine.(2)

Slt Moderate And Weak Cyp3a4 Inhibit/Sirolimus Protein-Bound

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

MECHANISM OF ACTION: Moderate and weak CYP3A4 inhibitors may inhibit the metabolism of sirolimus by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of moderate or weak CYP3A4 inhibitors may result in elevated levels of and side effects from sirolimus.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(1)

DISCUSSION: In an open, randomized, cross-over trial in 18 healthy subjects, concurrent single doses of diltiazem (120 mg) and sirolimus (10 mg) increased sirolimus area-under-curve (AUC) and maximum concentration (Cmax) by 60% and by 43%, respectively. Sirolimus apparent oral clearance and volume of distribution decreased by 38% and 45%, respectively. There were no effects on diltiazem pharmacokinetics or pharmacodynamics.(2) In a study in 26 healthy subjects, concurrent sirolimus (2 mg daily) with verapamil (180 mg twice daily) increased sirolimus AUC and Cmax by 2.2-fold and 2.3-fold, respectively. The AUC and Cmax of the active S-enantiomer of verapamil each increased by 1.5-fold. Verapamil time to Cmax (Tmax) was increased by 1.2 hours.(2) Moderate and weak CYP3A4 inhibitors linked to this monograph include: amlodipine, anamorelin, aprepitant, avacopan, azithromycin, berberine, berotralstat, bicalutamide, blueberry, brodalumab, camizestrant, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clofazimine, conivaptan, crizotinib, daclatasvir, daridorexant, delavirdine, diltiazem, diosmin, elinzanetant, estrogen, flibanserin, fluvoxamine, fosaprepitant, fosnetupitant, fostamatinib, ginkgo, givinostat, glecaprevir/pibrentasvir, gepotidacin, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lazertinib, oral lefamulin, lenacapavir, levamlodipine, linagliptin, lomitapide, lumateperone, lurasidone, mavorixafor, netupitant, nicardipine, omeprazole, osilodrostat, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, rimegepant, roxithromycin, scutellarin, sevabertinib, simeprevir, sitaxsentan, stiripentol, ticagrelor, tofisopam, tolvaptan, trofinetide, vonoprazan, and voxelotor.(3,4)

Slt Strong & Moderate 2C19 Inhibitor/Cilostazol (<=50Mg Bid)

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

MECHANISM OF ACTION: Strong and moderate inhibitors of CYP2C19 may inhibit the metabolism of cilostazol.(1-4)

CLINICAL EFFECTS: Concurrent use of strong or moderate inhibitors of CYP2C19 may result in elevated levels of 3,4-dehydro-cilostazol, a metabolite of cilostazol that is 4-7 times as active as cilostazol.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The dose of cilostazol should be limited to 50 mg twice daily in patients receiving concurrent therapy with strong and moderate inhibitors of CYP2C19.(1) The Australian manufacturer of esomeprazole states concomitant use with cilostazol is contraindicated.(5)

DISCUSSION: In a study in 20 subjects examined the effects of omeprazole (40 mg daily) on a single dose of cilostazol (100 mg). Concurrent omeprazole increased the cilostazol maximum concentration (Cmax) and area-under-curve (AUC) by 18% and 26%, respectively. The Cmax and AUC of the 3,4-dehydro-cilostazol metabolite of cilostazol increased 29% and 69%, respectively. The Cmax and AUC of the OPC-13213 metabolite of cilostazol decreased by 22% and 31%, respectively.(4)

Strong Cyp2c9 Inhibitors/Aficamten

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

MECHANISM OF ACTION: Aficamten is a CYP3A4, CYP2C19, and CYP2C9 substrate. Strong CYP2C9 inhibitors may decrease the metabolism of aficamten.(1)

CLINICAL EFFECTS: Concurrent use of a strong CYP2C9 inhibitor increases plasma exposure of aficamten, which may increase the incidence and severity of adverse reactions of aficamten, including heart failure due to systolic dysfunction.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: In patients on stable therapy with a strong CYP2C9 inhibitor, initiate aficamten at the usual 5 mg starting dose.(1) In patients currently on aficamten and starting a strong CYP2C9 inhibitor: - If the patient is taking 5 mg of aficamten daily, continue 5 mg daily. - If the patient is taking 10 mg or 15 mg of aficamten daily, reduce the dose of aficamten to 5 mg daily. - If the patient is taking 20 mg of aficamten daily, reduce the dose of aficamten to 10 mg daily.(1) Schedule clinical and echocardiographic assessment 2-8 weeks after inhibitor initiation, and titrate aficamten dose based on prescribing information.(1)

DISCUSSION: Concomitant use of aficamten with sulfaphenazole (2000 mg), a strong CYP2C9 inhibitor, once daily increased aficamten area-under-curve (AUC) by 113%.(1) Strong CYP2C9 inhibitors linked to this monograph include: camizestrant and sulfaphenazole.(2,3)

Weak Cyp3a4 Inhibitors/Lemborexant (<= 5 Mg)

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

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of lemborexant.(1)

CLINICAL EFFECTS: Concurrent use of an inhibitor of CYP3A4 may result in increased levels of and effects from lemborexant, including somnolence, fatigue, CNS depressant effects, daytime impairment, headache, and nightmare or abnormal dreams.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The maximum recommended dose of lemborexant with concurrent use of a weak CYP3A4 inhibitors should not exceed 5 mg per dose.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

DISCUSSION: Lemborexant is a CYP3A4 substrate. In a PKPB model, concurrent use of lemborexant with itraconazole increased area-under-curve (AUC) and concentration maximum (Cmax) by 3.75-fold and 1.5-fold, respectively. Concurrent use of lemborexant with fluconazole increased AUC and Cmax by 4.25-fold and 1.75-fold, respectively.(1) Weak inhibitors of CYP3A4 include: amiodarone, amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, belumosudil, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, delavirdine, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, rucaparib, selpercatinib, simeprevir, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, and ziftomenib.(1,3)

Weak Cyp3a4 Inhibitors/Ubrogepant (<= 50 Mg)

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

MECHANISM OF ACTION: Weak inhibitors of CYP3A4 may inhibit the metabolism of ubrogepant.(1)

CLINICAL EFFECTS: Concurrent use of ubrogepant with weak CYP3A4 inhibitors may result in an increase in exposure of ubrogepant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when used concomitantly with weak CYP3A4 inhibitors. Initial dose of ubrogepant should not exceed 50 mg when used concomitantly with weak inhibitors of CYP3A4. A second dose may be given within 24 hours but should not exceed 50 mg when used concurrently with weak CYP3A4 inhibitors.(1) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

DISCUSSION: Coadministration of ubrogepant with verapamil, a moderate CYP3A4 inhibitor, resulted in a 3.5-fold and 2.8-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively. No dedicated drug interaction study was conducted to assess concomitant use with weak CYP3A4 inhibitors. The conservative prediction of the maximal potential increase in ubrogepant exposure with weak CYP3A4 inhibitors is not expected to be more than 2-fold.(1) Weak inhibitors of CYP3A4 include: amiodarone, amlodipine, anamorelin, asciminib, avapritinib, azithromycin, Baikal skullcap, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, capivasertib, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, cranberry, cyclosporine, daclatasvir, delavirdine, deutivacaftor, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fosaprepitant, fostamatinib, gepotidacin, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lapatinib, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, maribavir, mavorixafor, olaparib, osilodrostat, palbociclib, pazopanib, peppermint oil, piperine, pirtobrutinib, propiverine, propofol, ranitidine, ranolazine, resveratrol, roxithromycin, simeprevir, sitaxsentan, skullcap, teriflunomide, ticagrelor, tolvaptan, trofinetide, vepdegestrant, viloxazine, vonoprazan, and ziftomenib.(3,4)

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• Lactation

• Bradycardia
• Congenital long QT syndrome
• Hypocalcemia
• Hypokalemia
• Hypomagnesemia
• Pregnancy
• Torsades de pointes

• Child-pugh class B hepatic impairment
• Child-pugh class C hepatic impairment
• Disease of liver

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More Frequent

• Leukopenia
• Neutropenic disorder
• Visual changes

Less Frequent

• Aseptic necrosis of jaw bone
• Bradycardia
• Pneumonia
• Prolonged QT interval
• Urinary tract infection

Rare or Very Rare

• Acute respiratory distress syndrome
• Cholestasis
• Gastroesophageal reflux disease

More Frequent

• Abnormal hepatic function tests
• Anemia
• Arthralgia
• Dry eye
• Fatigue
• Gamma-glutamyl transferase raised
• Hypocalcemia
• Increased alanine transaminase
• Increased aspartate transaminase
• Increased creatine kinase level
• Lymphopenia
• Thrombocytopenic disorder

Less Frequent

• Back pain
• Increased alkaline phosphatase
• Nausea

Rare or Very Rare

• Hepatocellular damage

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No enhanced messaging available.

No enhanced messaging available.

No enhanced messaging available.

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