Wayrilz (rilzabrutinib)

If drug-induced liver injury (DILI) is suspected, withhold rilzabrutinib. Upon confirmation of DILI, discontinue therapy.

No dosing information is available for this tab.

No dosing information is available for this tab.

In vitro studies indicate that rilzabrutinib is a substrate, an inhibitor, and an inducer of cytochrome P-450 (CYP) isoenzyme 3A.

Rilzabrutinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but not a substrate for organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, or bile salt export pump (BSEP).

Rilzabrutinib inhibits P-gp, BCRP, OATP1B1, OATP1B3, and BSEP at clinically relevant concentrations.

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

Dual Moderate Cyp3a4 Inhibitors 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 inhibitors of CYP3A4 may inhibit 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 inhibitors and substrates may result in decreased levels of fexinidazole's active metabolites and the CYP3A4 substrate, resulting in decreased effectiveness of both drugs.(1)

PREDISPOSING FACTORS: 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. The manufacturer of fexinidazole advises avoiding the concurrent use of moderate CYP3A4 inhibitors. If coadministration cannot be avoided, monitor for lack of efficacy of fexinidazole.(1) The manufacturers of fedratinib and rilzabrutinib also advise avoiding the concurrent use of moderate CYP3A4 inducers.(2,3)

DISCUSSION: Although no clinical drug interaction studies were performed with CYP3A4 inhibitors, the formation of fexinidazole's M1 and M2 metabolites may be decreased.(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 inhibitors and CYP3A4 substrates linked to this monograph include: fedratinib and rilzabrutinib.(4)

Immunosuppressive Cyp3a4 Inhibitors/Etrasimod

SEVERITY LEVEL: 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 CYP3A4 may impair the CYP3A4-mediated metabolism of etrasimod. Etrasimod is metabolized by CYP2C8, CYP2C9, and CYP3A4.(1) Etrasimod causes reversible sequestration of lymphocytes in lymphoid tissues, resulting in a mean 55% decrease in peripheral blood lymphocyte count at 52 weeks.(1) Other immunosuppressives and immune-modulators also suppress the immune system.

CLINICAL EFFECTS: In patients who are poor metabolizers of CYP2C9, concurrent use of a strong or moderate inhibitor of CYP3A4 may result in elevated levels of and clinical effects from etrasimod including immunosuppression, decreased lung function, bradycardia, and AV conduction delays. Concurrent use of etrasimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious and fatal infections, such as disseminated herpetic infection, cryptococcal infection, or progressive multifocal leukoencephalopathy (PML).(1)

PREDISPOSING FACTORS: CYP2C9 poor metabolizers (e.g., *2/*3, *3/*3) may have decreased clearance of etrasimod when etrasimod is used concomitantly with strong or moderate inhibitors of CYP3A4.(1) Additionally, incomplete washout of previously prescribed immunosuppressive or immune-modulating medications increases the risk of adverse events.

PATIENT MANAGEMENT: The etrasimod US prescribing information states etrasimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Concomitant administration of these therapies with etrasimod should be avoided because of the risk of additive immune effects during therapy and in the weeks following administration. Etrasimod's effect on peripheral lymphocytes may persist for up to 5 weeks after discontinuation.(1) When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects.(1) In addition, concomitant use with strong or moderate CYP3A4 inhibitors in patients who are CYP2C9 poor metabolizers is not recommended.(1)

DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections, cryptococcal meningitis, disseminated cryptococcal infections, and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients treated with other sphingosine-1 phosphate receptor modulators.(1) CYP2C9 activity is decreased in individuals with genetic variants such as CYP2C9*2 and CYP2C9*3 alleles. The impact of CYP2C9 genetic variants on the pharmacokinetics of etrasimod has not been directly evaluated. Increased exposure of etrasimod in patients who are CYP2C9 poor metabolizers is expected with concomitant use of strong or moderate inhibitors of CYP3A4.(1) Concomitant use of etrasimod with steady-state fluconazole (a moderate CYP2C9 and CYP3A4 inhibitor) increased etrasimod area-under-curve (AUC) by 84%.(1) CYP3A4 inhibitors linked to this monograph include: duvelisib, fedratinib, idelalisib, imatinib, rilzabrutinib, and treosulfan.(3)

Immunosuppressive; Immunomod/Cladribine Onc Inj (10 Mg/5 Ml)

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

MECHANISM OF ACTION: Cladribine in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-2)

CLINICAL EFFECTS: Concurrent use of cladribine with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections.(1-2)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: Recommendations for cladribine regarding this interaction differ between regulatory approving agencies. The UK and AU manufacturers of Litak state that concomitant use of other myelosuppressive medicinal products with cladribine is contraindicated.(1-2) The Israeli manufacturer of Litak states that cladribine should not be used concomitantly with other myelosuppressive medicinal products.(3)

DISCUSSION: The risk of severe myelotoxicity and long-lasting immunosuppression is increased in patients with a disease-related bone marrow infiltration or a previous myelosuppressive treatment.(1-3)

Immunosuppressives; Immunomodulators/Efalizumab; Natalizumab

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

MECHANISM OF ACTION: Natalizumab,(1-3) efalizumab,(4) immunosuppressives, and immunomodulators all suppress the immune system.

CLINICAL EFFECTS: Concurrent use of natalizumab(1-3) or efalizumab(4) with immunosuppressives or immunomodulators may result in an increased risk of infections, including progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).

PREDISPOSING FACTORS: Previous JCV infection, longer duration of natalizumab treatment - especially if greater than 2 years, and prior or concomitant treatment with immunosuppressant medication are all independent risk factors which increase the risk for PML.(1,5) The FDA has estimated PML incidence stratified by risk factors: If anti-JCV antibody positive, no prior immunosuppressant use and natalizumab treatment less than 25 months, incidence <1/1,000. If anti-JCV antibody positive, history of prior immunosuppressant use and natalizumab treatment less than 25 months, incidence 2/1,000 If anti-JCV antibody positive, no prior immunosuppressant use and natalizumab treatment 25-48 months, incidence 4/1,000 If anti-JCV antibody positive, history of prior immunosuppressant use and natalizumab treatment 25-48 months, incidence 11/1,000.

PATIENT MANAGEMENT: The US manufacturer of natalizumab states patients with Crohn's disease should not receive concurrent immunosuppressants, with the exception of limited overlap of corticosteroids, due to the increased risk for PML. For new natalizumab patients currently receiving chronic oral corticosteroids for Crohn's Disease, begin corticosteroid taper when therapeutic response to natalizumab has occurred. If corticosteroids cannot be discontinued within six months of starting natalizumab, discontinue natalizumab.(3) The US manufacturer of natalizumab states that natalizumab should not ordinarily be used in multiple sclerosis patients receiving immunosuppressants or immunomodulators due to the increased risk for PML. Immunosuppressives include, but are not limited to azathioprine, cyclophosphamide, cyclosporine, mercaptopurine, methotrexate, mitoxantrone, mycophenolate, and corticosteroids.(3,6) The UK manufacturer of natalizumab states that concurrent use with immunosuppressives or antineoplastic agents is contraindicated.(1) The Canadian manufacturer of natalizumab states that natalizumab should not be used with immunosuppressive or immunomodulatory agents.(2) The US manufacturer of certolizumab states that concurrent therapy with natalizumab is not recommended.(7)

DISCUSSION: Progressive multifocal leukoencephalopathy has been reported in patients receiving concurrent natalizumab were recently or concomitantly taking immunomodulators or immunosuppressants.(1-5,8,9) In a retrospective cohort study of multiple sclerosis patients newly initiated on a disease-modifying therapy, use of high-efficacy agents (alemtuzumab, natalizumab, or ocrelizumab) resulted in the same risk of overall infections as moderate-efficacy agents, but there was an elevated risk of serious infections (adjusted hazard ratio [aHR] = 1.24, 95% confidence interval (CI) = 1.06-1.44) and UTIs (aHR = 1.21, 95% CI = 1.14-1.30).(10)

Moderate Cyp3a4 Inhibitors/Aumolertinib

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

MECHANISM OF ACTION: Aumolertinib is metabolized via CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of aumolertinib.(1)

CLINICAL EFFECTS: Concurrent use of aumolertinib with moderate CYP3A4 inhibitors may increase the levels and toxicities of aumolertinib, including cardiac failure, rhabdomyolysis, thrombosis, elevated LFTs, hyponatremia hematologic toxicity, and QT prolongation, which may lead to potentially life-threatening arrhythmias like torsades the pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Patients with risk factors for thrombosis may be at higher risk of adverse events, including those with advanced age, obesity (BMI >30), smoking, prolonged immobilization, heart failure, hypercoagulable state, history of venous thromboembolism, malignancy, and major surgery. The risk for rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of rhabdomyolysis.

PATIENT MANAGEMENT: The manufacturer of aumolertinib states that concurrent use with moderate CYP3A4 inhibitors should be avoided.(1) Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: The impact of moderate CYP3A4 inhibitors on the pharmacokinetics of aumolertinib has not been investigated in clinical studies. In a clinical study, itraconazole (strong CYP3A inhibitor) increased aumolertinib area-under-curve (AUC) by 3.7-fold.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, darunavir, duvelisib, fedratinib, fosamprenavir, fosnetupitant, imatinib, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and voxelotor.(2,3)

Moderate Cyp3a4 Inhibitors/Avanafil (> 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: Moderate inhibitors of CYP3A4 may inhibit the metabolism of avanafil.(1)

CLINICAL EFFECTS: The concurrent administration of a moderate CYP3A4 inhibitor may result in elevated levels of avanafil, which may result in increased adverse effects such as hypotension, visual changes, and priapism.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of avanafil states that in patients receiving moderate inhibitors of CYP3A4, the dose of avanafil should be limited to 50 mg in 24 hours.(1)

DISCUSSION: Ketoconazole (400 mg daily), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of avanafil (50 mg) by 3-fold and 13-fold, respectively. The half-life of avanafil increased from 5 hours to 9 hours.(1) Ritonavir (600 mg BID), a strong inhibitor of CYP3A4 and an inhibitor of 2C19, increased the Cmax and AUC of a single dose of avanafil (50 mg) by 2-fold and 13-fold, respectively. The half-life of avanafil increased from 5 hours to 9 hours.(1) Erythromycin (500 mg BID), a moderate inhibitor of CYP3A4, increased the Cmax and AUC of a single dose of avanafil (200 mg) by 2-fold and 3-fold, respectively. The half-life of avanafil increased from 5 hours to 8 hours.(1) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, grapefruit juice, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(1-3)

Moderate Cyp3a4 Inhibitors/Avutometinib-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: Avutometinib and defactinib are both CYP3A4 substrates. Strong CYP3A4 inhibitors may inhibit the metabolism of defactinib. Avutometinib also undergoes non-enzymatic degradation is not affected by CYP3A4 inhibitors.(1)

CLINICAL EFFECTS: The concurrent administration of a moderate CYP3A4 inhibitor may result in elevated levels of defactinib and toxicity from avutometinib-defactinib, including hepatotoxicity, rhabdomyolysis, ocular toxicities, and skin toxicities.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of avutometinib-defactinib and moderate CYP3A4 inhibitors should be avoided.(1)

DISCUSSION: The impact of moderate CYP3A4 inhibitors on the pharmacokinetics of defactinib has not been investigated in clinical studies. Defactinib maximum concentration (Cmax) increased by 2.2-fold and area-under-curve (AUC) by 3.9-fold following concomitant use with itraconazole (strong CYP3A4 inhibitor) 200 mg daily for 10 days. The AUC of M4, a major active metabolite of defactinib, increased by 2.2-fold and Cmax decreased by 6.8%.(1) No clinically significant differences in avutometinib pharmacokinetics were observed when used concomitantly with itraconazole.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2-3)

Moderate Cyp3a4 Inhibitors/Bosutinib

SEVERITY LEVEL: 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 inhibit CYP3A4 may inhibit the metabolism of bosutinib.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase levels of and effects from bosutinib.(1) Elevated levels of bosutinib may result in QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP). Other toxicities include nausea, vomiting, diarrhea, abdominal pain, myelosuppression, transaminitis, renal toxicity, and cardiac failure.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of moderate CYP3A4 inhibitors in patients undergoing therapy with bosutinib.(1)

DISCUSSION: In a study in 24 healthy subjects, ketoconazole (400 mg daily for 5 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of bosutinib (100 mg) by 5.2-fold and 8.6-fold, respectively.(1) In a cross-over study in 18 healthy subjects, aprepitant (125 mg) increased the Cmax and AUC of bosutinib (single dose 500 mg) by 1.5-fold and 2.0-fold, respectively.(1) A study using PKPB modeling found concurrent use of bosutinib and schisandra would result in an increase in bosutinib exposure with an increased AUC by 3.0-fold.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, boceprevir, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(3-4)

Moderate Cyp3a4 Inhibitors/Dapoxetine (>30 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 inhibitors may inhibit the metabolism of dapoxetine.(1-3)

CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in elevated levels and increased effects of dapoxetine.(1-3)

PREDISPOSING FACTORS: If the patient is a CYP2D6 poor metabolizer, dapoxetine metabolism can be further inhibited.(1-3)

PATIENT MANAGEMENT: The manufacturers of dapoxetine state that the dose of dapoxetine should not exceed 30 mg daily if coadministered with moderate CYP3A4 inhibitors.(1-3)

DISCUSSION: The impact of moderate CYP3A4 inhibitors on the pharmacokinetics of dapoxetine has not been investigated in clinical studies.(1-3) Ketoconazole (200 mg twice daily for 7 days), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of dapoxetine (30 mg) by 35% and 99%, respectively. The Cmax and AUC of the active fraction are expected to increase by 25% and 2-fold, respectively, with strong inhibitors of CYP3A4.(1-3) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(4,5)

Moderate Cyp3a4 Inhibitors/Daraxonrasib (> 200 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 substrate of CYP3A4. Moderate CYP3A4 inhibitors may inhibit the metabolism of daraxonrasib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase the levels and toxicities of daraxonrasib, including dermatologic toxicity, stomatitis, GI perforation, and interstitial lung disease/pneumonitis.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: For patients taking agents that are moderate CYP3A4 inhibitors, reduce the dose of daraxonrasib to 200 mg once daily. If the inhibitor is discontinued, resume the previous dose of daraxonrasib after 3 to 5 half-lives of the inhibitor.(1)

DISCUSSION: In a pharmacokinetic model, fluconazole 200 mg twice daily (a moderate CYP3A inhibitor) increased the area under curve (AUC) of daraxonrasib by 1.5-fold.(1) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, crizotinib, darunavir, duvelisib, fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, stiripentol, tofisopam, treosulfan, and voxelotor.(2-3)

Moderate Cyp3a4 Inhibitors/Daridorexant (>25 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 inhibitors of CYP3A4 may inhibit the metabolism of daridorexant.(1)

CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels of and effects from daridorexant including somnolence, fatigue, CNS depressant effects, daytime impairment, or headache.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The dose of daridorexant should be limited to 25 mg daily when used with a moderate CYP3A4 inhibitor.(1)

DISCUSSION: Daridorexant is a CYP3A4 substrate. In a PKPB model, concurrent use of daridorexant with diltiazem, a moderate CYP3A4 inhibitor, increased daridorexant area-under-curve (AUC) and maximum concentration (Cmax) by 2.4-fold and 1.4-fold, respectively.(1) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan and verapamil.(2)

Moderate Cyp3a4 Inhibitors/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: Moderate CYP3A4 inhibitors may inhibit the metabolism of dordaviprone.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase the levels and effects of dordaviprone, including QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)

PREDISPOSING FACTORS: This interaction may be more severe in patients with renal or hepatic impairment.(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 US manufacturer of dordaviprone states that concomitant use with moderate CYP3A4 inhibitors should be avoided.(1). If concomitant use with a moderate CYP3A4 inhibitor cannot be avoided in adult and pediatric patients who weigh at least 52.5 kg, reduce the dordaviprone dosage from 625 mg to 500 mg once weekly. Recommended doses for patients weighing less than 52.5 kg receiving moderate CYP3A4 inhibitors has not been established.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study, concomitant use of dordaviprone with itraconazole 200 mg daily for 8 days (a strong CYP3A4 inhibitor) increased dordaviprone maximum concentration (Cmax) and area-under-curve (AUC) by 2-fold and 4-fold, respectively.(1) Moderate CYP3A4 inhibitors (fluconazole or erythromycin) are predicted to increase dordaviprone Cmax and AUC by 1.5-fold and 2.5-fold.(1) Dordaviprone causes concentration-dependent QTc interval prolongation. In a QT study, the estimated change in QTcF was 11.8 msec (90% CI: 9.8, 13.7) with dordaviprone at 1.2 times the maximum recommended dose.(1) In a pooled safety analysis, out of 82 patients with a post-baseline ECG, 6% of patients had an increase in QTc of >60 msec from baseline and 1.2% had an increase in QTc >500 msec.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)

Moderate Cyp3a4 Inhibitors/Lumateperone (>21 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 inhibitors of CYP3A4 may inhibit the metabolism of lumateperone.(1)

CLINICAL EFFECTS: Concurrent use of lumateperone with moderate CYP3A4 inhibitors increases lumateperone exposure, which may increase the risk of adverse reactions.(1)

PREDISPOSING FACTORS: Patients with moderate or severe hepatic impairment (Child-Pugh class B or C) may be at higher risk of increased lumateperone exposure.(1)

PATIENT MANAGEMENT: The manufacturer of lumateperone recommends decreasing the dosage of lumateperone to 21 mg once daily in patients receiving moderate CYP3A4 inhibitors.(1)

DISCUSSION: Coadministration of lumateperone with itraconazole, a strong CYP3A4 inhibitor, resulted in a 4-fold and 3.5-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively.(1) Coadministration of lumateperone with diltiazem, a moderate CYP3A4 inhibitor, resulted in a 2.5-fold and 2-fold increase AUC and Cmax, respectively.(1) Moderate inhibitors of CYP3A4 include: aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, verapamil, treosulfan, and voxelotor.(2,3)

Moderate Cyp3a4 Inhibitors/Naloxegol (> 12.5 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 naloxegol.(1)

CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 without a dosage adjustment of naloxegol may result in increased levels of naloxegol, which may precipitate opioid withdrawal symptoms.(1)

PREDISPOSING FACTORS: Patients taking methadone may be more likely to experience gastrointestinal side effects such as abdominal pain and diarrhea as a result of opioid withdrawal.(1)

PATIENT MANAGEMENT: The daily dose of naloxegol should be limited to 12.5 mg daily in patients taking moderate inhibitors of CYP3A4.(1) If concurrent use is deemed medically necessary, monitor patients for signs of opioid withdrawal such as sweating, chills, diarrhea, stomach pain, anxiety, irritability, yawning, restlessness, muscle/joint aches, increased lacrimation, running nose, and piloerection. Monitor patients taking methadone for abdominal pain and diarrhea as well.(1)

DISCUSSION: Ketoconazole (400 mg daily for 5 days), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of naloxegol by 9.58-fold and 12.85-fold, respectively.(2) Diltiazem (240 mg XR daily), a moderate inhibitor of CYP3A4, increased the Cmax and AUC of a single dose of naloxegol by 2.85 and 3.41, respectively.(2) According to Physiologically-based-Pharmacokinetic (PBPK) models, erythromycin, a moderate inhibitor of CYP3A4, at a dose of 250 mg QID is expected to increase the Cmax and AUC of naloxegol by 2.77-fold and 3.47-fold, respectively.(2) According to PBPK models, erythromycin at a dose of 400 mg QID is expected to increase the Cmax and AUC of naloxegol by 3.42-fold and 4.63-fold, respectively.(2) According to PBPK models, fluconazole, a moderate inhibitor of CYP3A4, at a dose of 200 mg daily is expected to increase the Cmax and AUC of naloxegol by 2.4-fold and 2.81-fold, respectively.(2) According to PBPK models, verapamil moderate inhibitor of CYP3A4, at a dose of 120 mg daily is expected to increase the Cmax and AUC of naloxegol by 1.97-fold and 2.21-fold, respectively.(2) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(1,3,4)

Moderate Cyp3a4 Inhibitors/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 metabolized via CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of olverembatinib.(1)

CLINICAL EFFECTS: Concurrent use of olverembatinib with moderate CYP3A4 inhibitors may increase the levels and toxicities of olverembatinib, including myelosuppression, bleeding, and hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of olverembatinib states coadministration with moderate CYP3A4 inhibitors should be avoided.(1)

DISCUSSION: In a clinical study of 16 healthy subjects, coadministration of olverembatinib 20 mg with itraconazole 200 mg daily, a strong CYP3A4 inhibitor, resulted in a 2.59-fold increase in olverembatinib's area-under-curve (AUC) and a 1.76-fold increase in olverembatinib's maximum concentration (Cmax).(2) In a PBPK model, the moderate CYP3A4 inhibitors verapamil 80 mg three times daily, fluconazole 200 mg daily, and erythromycin 500 mg every 6 hours increased the AUC of olverembatinib 40 mg by 2.25-, 1.8-, and 2.39-fold, respectively. Olverembatinib Cmax was increased by 1.55-, 1.42-, and 1.6-fold, respectively.(3) Moderate inhibitors of CYP3A4 linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(4-5)

Moderate Cyp3a4 Inhibitors/Oveporexton (>0.5 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: Oveporexton is metabolized by CYP3A4. Moderate CYP3A4 inhibitors may inhibit the metabolism of oveporexton.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase the levels and toxicities of oveporexton, including insomnia, urinary frequency and urgency, and CPK elevation.(1)

PREDISPOSING FACTORS: Adverse reactions from oveporexton may be more likely in patients with Child-Pugh class C hepatic impairment and in patients with severe renal impairment on dialysis.

PATIENT MANAGEMENT: In patients on concomitant moderate CYP3A4 inhibitors with oveporexton, reduce the dosage of oveporexton to 0.5 mg after awakening and then 0.5 mg three to five hours later (maximum recommended dosage is 1 mg per day).(1)

DISCUSSION: In a study, fluconazole (a moderate CYP3A inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of oveporexton by 2.9-fold and 1.5-fold, respectively. Oveporexton half-life was increased by about 2-fold.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2-3)

Moderate Cyp3a4 Inhibitors/Pyrotinib (> 80 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: Pyrotinib is metabolized via CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of pyrotinib.(1)

CLINICAL EFFECTS: Concurrent use of pyrotinib with moderate CYP3A4 inhibitors may increase the levels and toxicities of pyrotinib, including hepatotoxicity, decreased left ventricular ejection fraction, bone marrow suppression and gastrointestinal adverse effects.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of pyrotinib states coadministration with moderate CYP3A4 inhibitors requires a dose adjustment. Reduce the dose of pyrotinib to 80 mg daily with moderate CYP3A4 inhibitors.(1)

DISCUSSION: In a clinical study of healthy subjects, coadministration of pyrotinib with fluconazole, a moderate CYP3A4 inhibitor, resulted in a 3.6-fold increase in area-under-curve (AUC) and a 2.16-fold increase in maximum concentration (Cmax).(1) Moderate inhibitors of CYP3A4 linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)

Moderate Cyp3a4 Inhibitors/Ranolazine (> 500 Mg 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: Moderate inhibitors of CYP3A4 may inhibit the metabolism of ranolazine. Verapamil may also increase the absorption of ranolazine by inhibiting P-glycoprotein.(1)

CLINICAL EFFECTS: Concurrent use of moderate inhibitors of CYP3A4 may result in elevated levels of and clinical effects from ranolazine. Elevated ranolazine levels may result in QTc prolongation, which may result in life-threatening cardiac arrhythmia, including torsades de pointes.(1)

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

PATIENT MANAGEMENT: The US manufacturer of ranolazine states that the dosage of ranolazine should be limited to 500 mg twice daily in patients receiving moderate inhibitors of CYP3A4.(1) If concurrent therapy is deemed medically necessary, obtain serum calcium, magnesium, and potassium levels and monitor ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Concurrent use of diltiazem, a moderate inhibitor of CYP3A4, at daily doses of 180 mg to 360 mg increased plasma levels of ranolazine (1000 mg twice daily) by 50% and 130%, respectively.(1,4) In healthy subjects, concurrent ranolazine (1000 mg twice daily) had no effects on the pharmacokinetics of diltiazem (60 mg three times daily).(1) Concurrent use of verapamil (120 mg three times daily) increased plasma levels of ranolazine (750 mg twice daily) by 100%.(1) In a study in 12 healthy males, ranolazine immediate release (IR, 240 mg three times daily) had no effect on diltiazem (60 mg three times daily) pharmacokinetics. However, at ranolazine IR steady state, diltiazem increased ranolazine IR area under the curve (AUC) by 85%, on average, and increased maximum concentration (Cmax) by 1.9-fold and minimum concentration (Cmin) by 2.1-fold.(4) In a study in 12 subjects, ranolazine sustained release (SR, 500 mg twice daily) had no effect on diltiazem (60 mg three times daily) pharmacokinetics. However, at ranolazine steady state, diltiazem increased ranolazine SR Cmax, concentration minimum (Cmin), AUC by 80%, 216%, and 90%, on average, respectively.(4) In a study in 8 healthy males, diltiazem modified release (MR, 180 mg, or 240 mg, or 360 mg, once daily) increased ranolazine sustained release (SR, 1000 mg twice daily) AUC by 52%, 93%, and 139%, respectively. Ranolazine half-lives did not show any consistent trend of changes with increasing doses of diltiazem.(4) In a study of patients with severe chronic angina, the addition of ranolazine 750 mg twice daily or 1,000 mg twice daily along with their standard dose of diltiazem (180 mg once daily) provided additional antianginal relief, without evident adverse, long-term survival consequences over 1 to 2 years of therapy.(5) Ranolazine-induced QTc prolongation is dose and concentration-related.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, treosulfan and verapamil.(1,3,6,7)

Moderate Cyp3a4 Inhibitors/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: Remibrutinib is metabolized via CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of remibrutinib.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase levels of and effects from remibrutinib, including bleeding.(1)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in older patients (65 years and over) and 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: Avoid the use of moderate CYP3A4 inhibitors in patients taking remibrutinib.(1)

DISCUSSION: Remibrutinib maximum concentration (Cmax) is predicted to increase by approximately 1.9-fold and area-under-curve (AUC) is predicted to increase by approximately 2.3-fold following concomitant administration with erythromycin (a moderate CYP3A4 inhibitor) 500 mg four times a day for 7 days. Moderate inhibitors of CYP3A4 linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2-3)

Moderate Cyp3a4 Inhibitors/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: Taletrectinib is a substrate of CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of taletrectinib.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in increased levels and toxicity from taletrectinib including hepatotoxicity, myalgia, and prolongation of the QT interval, which may result in life-threatening arrhythmia and death.(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) Taletrectinib should be taken on an empty stomach. Administration with food may increase the risk of QT prolongation or torsade de pointes.

PATIENT MANAGEMENT: The manufacturer of taletrectinib recommends avoiding concurrent administration with moderate CYP3A4 inhibitors.(1) If concurrent therapy cannot be avoided, adjust the frequency of monitoring as recommended in the prescribing information. Withhold taletrectinib if the QTc interval is >500 msec or the change from baseline is >60 msec.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Concomitant administration with moderate inhibitors of CYP3A4 (fluconazole, erythromycin, or verapamil) is predicted to increase taletrectinib area under the curve (AUC) up to 2.6-fold and maximum concentration (Cmax) up to 1.5-fold.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, schisandra, tofisopam, treosulfan, verapamil, and voxelotor.(3)

Moderate Cyp3a4 Inhibitors/Tolvaptan

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

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

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in elevated levels of and toxicity from tolvaptan.(1) Elevated levels of tolvaptan may lead to increased clinical effects such as hypotension, hypovolemia, and thirst, as well as toxicity in the form of neurologic sequelae such as osmotic demyelination syndrome (ODS). ODS can lead to coma and death. Symptoms of ODS include dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, and coma.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of Samsca for the treatment of clinically significant hypervolemic and euvolemic hyponatremia states that concurrent administration with moderate CYP3A4 inhibitors should be avoided.(1) The US manufacturer of Jynarque for the management to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease states concurrent administration with moderate CYP3A4 inhibitors warrants a dose reduction of Jynarque as follows: - Standard morning and evening dose: 90 mg and 30 mg should be dose adjusted to 45 mg and 15 mg, respectively - Standard morning and evening dose: 60 mg and 30 mg should be dose adjusted to 30 mg and 15 mg, respectively - Standard morning and evening dose: 45 mg and 15 mg should be dose adjusted to 15 mg and 15 mg, respectively Interrupt Jynarque temporarily for short term therapy with moderate CYP3A4 inhibitors if the recommended reduced doses are not available.(2)

DISCUSSION: Fluconazole 400 mg (moderate inhibitor of CYP3A4) given one day prior and 200 mg given concomitantly produced an 80% and 200% increase in tolvaptan maximum concentration (Cmax) and area-under-curve (AUC), respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, crizotinib, darunavir, diltiazem, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(1-4)

Moderate 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: Moderate inhibitors of CYP3A4 may inhibit the metabolism of ubrogepant.(1)

CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor may result in elevated levels of ubrogepant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when used concomitantly with moderate CYP3A4 inhibitors. Initial dose of ubrogepant should not exceed 50 mg. A second dose should be avoided within 24 hours of the first dose when used concurrently with moderate CYP3A4 inhibitors.(1)

DISCUSSION: Co-administration 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.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2-4)

Moderate Cyp3a4 Inhibitors/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: Moderate CYP3A4 inhibitors may inhibit the metabolism of zidesamtinib.(1)

CLINICAL EFFECTS: Concurrent use of zidesamtinib with moderate CYP3A4 inhibitors may result in elevated zidesamtinib levels and toxicities, including interstitial lung disease, pneumonitis, pancreatitis, myalgias, and QT prolongation, which may lead to potentially life-threatening cardiac arrhythmias like 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, and advanced age.(1,2) 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, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of zidesamtinib states that concurrent use of moderate CYP3A4 inhibitors should be avoided.(1) If concurrent use is warranted, monitor ECG and electrolytes when initiating zidesamtinib, during concurrent use, and as clinically indicated. Consider increasing the frequency of ECG and electrolyte monitoring. Withhold, then resume at same or reduced dose, or permanently discontinue zidesamtinib based on severity.(1) Consider obtaining serum calcium, magnesium, and potassium levels and correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Zidesamtinib is a CYP3A4 substrate. In a study, itraconazole 200 mg daily (a strong CYP3A4 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of zidesamtinib by 2.6-fold and 1.8-fold, respectively.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)

Rilzabrutinib/Dipyrone

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

MECHANISM OF ACTION: Dipyrone, a moderate CYP3A4 inducer, may induce the metabolism of rilzabrutinib.(1) Concurrent use of dipyrone with other drugs known to be associated with neutropenia or agranulocytosis such as rilzabrutinib may increase the frequency or risk for severe toxicity.(2)

CLINICAL EFFECTS: Concurrent or recent use of dipyrone, a moderate CYP3A4 inducer, may result in decreased levels and effectiveness of rilzabrutinib.(1) Concurrent use of dipyrone with agents such as rilzabrutinib that cause bone marrow depression, including myelosuppressives, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding. Undetected severe neutropenia or agranulocytosis may be fatal.(2)

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

PATIENT MANAGEMENT: The manufacturer of rilzabrutinib states that concomitant use of moderate CYP3A4 inducers should be avoided.(1) Concurrent use of dipyrone and myelosuppressive agents should be avoided.(2) The European Medicines Agency states dipyrone is contraindicated in patients with a prior medical history of dipyrone-induced agranulocytosis (or from other pyrazolones/pyrazolidines), impaired bone marrow function or diseases of the hematopoietic system.(4) The European Medicines Agency advises if agranulocytosis is suspected with dipyrone, a complete blood count (including differential blood count) should be performed immediately, and treatment must be stopped while waiting for the results. If confirmed, treatment must not be reintroduced.(2,4)

DISCUSSION: Rilzabrutinib is primarily metabolized by CYP3A4.(1) Concomitant administration of rilzabrutinib with efavirenz or rifabutin (moderate CYP3A4 inducers) is predicted to decrease rilzabrutinib area under the curve (AUC) and maximum concentration (Cmax) by up to 70% at steady state.(1) In the LUNA-3 study, Grade 1 or 2 neutropenia occurred in 11% of patients in the rilzabrutinib group.(2) A retrospective cohort study analyzed new users of dipyrone (n=444,972), non-steroidal anti-inflammatory drugs (n=3,814,367) which served as a reference cohort, and opioids-paracetamol (n=3,129,221) which was the negative control. During continuous treatment over a median of 37-40 days, 26 cases of hospitalized agranulocytosis occurred. With the assumption that agranulocytosis onset was 7 days prior to admission, the hazard ratio of agranulocytosis associated with dipyrone was 4.40 [0.90-21.57] compared to NSAIDs and 2.45 [0.68-8.83] compared to opioid-paracetamol. HR of neutropenia from dipyrone was 2.98 [1.57-5.65] compared to NSAIDs and not statistically significant compared to opioids-paracetamol. In a sensitivity analysis assuming that the onset of agranulocytosis was the date of hospitalization, the HR of dipyrone-induced agranulocytosis was 7.20 [95% confidence interval: 1.92-26.99] compared to NSAIDs and 3.31 [1.17-9.34] compared to opioids-paracetamol. Agranulocytosis was very rare but more than 4 times more common with dipyrone than other analgesics.(5)

Rilzabrutinib/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: Rilzabrutinib and lonafarnib are both substrates of CYP3A4. Lonafarnib is also a strong CYP3A4 inhibitor and rilzabrutinib is a moderate CYP3A4 inhibitor. Inhibitors of CYP3A4 may inhibit the metabolism of both drugs.(1-2)

CLINICAL EFFECTS: Concurrent use of rilzabrutinib and lonafarnib may increase levels and effects of both drugs, including hepatotoxicity, immunosuppression, hypertension, and QT prolongation, which may lead to potentially life-threatening cardiac arrhythmias like torsades de pointes.(1-2)

PREDISPOSING FACTORS: Patients with moderate to severe hepatic impairment (Child-Pugh class B-C) may be more susceptible to the effects of this drug interaction due to the potential for increased rilzabrutinib exposure.(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.(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 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).(3)

PATIENT MANAGEMENT: Avoid concurrent use of rilzabrutinib and lonafarnib.(1-2)

DISCUSSION: In a clinical study, ritonavir (a strong CYP3A4 inhibitor) increased the maximum concentration (Cmax) of rilzabrutinib by 5-fold and the area-under-curve (AUC) by 8-fold at steady state.(1) With coadministration of a single oral dose of 50 mg lonafarnib following 200 mg ketoconazole (a strong CYP3A4 inhibitor) once daily for 5 days, the AUC and Cmax were increased by 425% and 270%, respectively.(2)

Rilzabrutinib/Moderate Cyp3a4 Inducers

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

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

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

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

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

DISCUSSION: Rilzabrutinib is primarily metabolized by CYP3A4.(1) Concomitant administration of rilzabrutinib with efavirenz or rifabutin (moderate CYP3A4 inducers) is predicted to decrease rilzabrutinib area under the curve (AUC) and maximum concentration (Cmax) by up to 70% at steady state.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, lesinurad, lorlatinib, modafinil, nafcillin, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2)

Rilzabrutinib/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: Rilzabrutinib is metabolized via CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of rilzabrutinib.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase levels of and effects from rilzabrutinib, including hepatotoxicity and immunosuppression.(1)

PREDISPOSING FACTORS: Patients with moderate to severe hepatic impairment (Child-Pugh class B-C) may be more susceptible to the effects of this drug interaction due to the potential for increased rilzabrutinib exposure.(1)

PATIENT MANAGEMENT: Avoid the use of moderate CYP3A4 inhibitors in patients taking rilzabrutinib. If concurrent use cannot be avoided and the CYP3A4 inhibitor will be used short term (i.e., less than 7 days), interrupt treatment with rilzabrutinib.(1)

DISCUSSION: Concurrent use of rilzabrutinib with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, verapamil) is predicted to increase rilzabrutinib Cmax and AUC by 3-fold at steady state.(1) Moderate inhibitors of CYP3A4 linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, lenacapavir, letermovir, netupitant, nilotinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2-3)

Rilzabrutinib/Nirogacestat

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

MECHANISM OF ACTION: Rilzabrutinib and nirogacestat are both moderate inhibitors and substrates of CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of both drugs.(1-2)

CLINICAL EFFECTS: Concurrent use of rilzabrutinib and nirogacestat may increase levels and effects of both drugs, including hepatotoxicity, immunosuppression, hypokalemia, and hypophosphatemia.(1-2)

PREDISPOSING FACTORS: Patients with moderate to severe hepatic impairment (Child-Pugh class B-C) may be more susceptible to the effects of this drug interaction due to the potential for increased rilzabrutinib exposure.(1)

PATIENT MANAGEMENT: Avoid concurrent use of rilzabrutinib and nirogacestat.(1-2)

DISCUSSION: Concurrent use of rilzabrutinib with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, verapamil) is predicted to increase rilzabrutinib concentration maximum (Cmax) and area-under-curve (AUC) by 3-fold at steady state.(1) In a PKPB model, nirogacestat AUC was predicted to increase 2.73-and 3.18-fold following coadministration of multiple doses of nirogacestat (150 mg BID) with erythromycin (moderate CYP3A inhibitor) and fluconazole (moderate CYP3A inhibitor), respectively.(2)

Rilzabrutinib/Pacritinib

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

MECHANISM OF ACTION: Rilzabrutinib is a substrate and moderate inhibitor of CYP3A4.(1) Pacritinib is a substrate and moderate inducer of CYP3A4.(2) Agents that induce the CYP3A4 isoenzyme may induce the metabolism of rilzabrutinib.(1) Moderate CYP3A4 inhibitors may inhibit the CYP3A4 mediated metabolism of pacritinib.(2)

CLINICAL EFFECTS: Concurrent use of rilzabrutinib and pacritinib may decrease the levels and effectiveness of rilzabrutinib(1) while increasing levels and toxicity of pacritinib.(2) Elevated levels of pacritinib may result in QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(2) Other toxicities of pacritinib include bleeding, diarrhea, thrombocytopenia, major adverse cardiovascular events, thrombosis, and infection.(2)

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 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).(3) Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The concurrent use of rilzabrutinib and pacritinib should be avoided.(1,2) If concurrent use cannot be avoided, monitor patients for increased adverse reactions from pacritinib and consider pacritinib dose modifications based on safety.(2) If coadministration is unavoidable, monitor for prolongation of the QTc interval.(1,2) When concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If patients develop QTc prolongation >500 msec or >60 msec from baseline, hold pacritinib. If QTc prolongation resolves to <=480 msec or to baseline within 1 week, resume pacritinib at the same dose. If time to resolution of the QTc interval takes greater than 1 week to resolve, reduce the pacritinib dose according to labeling.(2)

DISCUSSION: Concomitant administration of rilzabrutinib with efavirenz or rifabutin (moderate CYP3A4 inducers) is predicted to decrease rilzabrutinib area under the curve (AUC) and maximum concentration (Cmax) by up to 70% at steady state.(1) Clarithromycin (500 mg twice daily for 5 days, a strong CYP3A4 inhibitor) increased the Cmax and AUC of a single dose of pacritinib (400 mg) by 30% and 80%, respectively.(2) In a 24 week clinical study, patients treated with pacritinib 200 mg twice daily had a change in QTc from baseline of 11 msec (90% CI: 5-17).(2) Pacritinib has been associated with QTc interval prolongation. In clinical trials, patients with QTc prolongation >500 msec occurred in 1.4% of patients in the treatment arm compared to 1% in the control arm. The treatment arm had a greater incidence of an increase in QTc > 60 msec from baseline than the control arm (1.9% vs 1%, respectively). QTc prolongation adverse reactions were higher in the treatment arm than the control group (3.8% vs 2%, respectively).(2)

Rilzabrutinib/Proton Pump 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: The aqueous solubility of rilzabrutinib is pH dependent. Higher gastric pH leads to lower solubility which may reduce rilzabrutinib absorption.(1)

CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) may reduce the bioavailability of rilzabrutinib, leading to decreased systemic levels and effectiveness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of rilzabrutinib states that concurrent use with proton pump inhibitors should be avoided.(1) If the PPI is replaced with an H2 antagonist, administer rilzabrutinib at least 2 hours before taking the H2 antagonist.(1) If the PPI is replaced with an antacid, administer rilzabrutinib at least 2 hours before taking the antacid.(1)

DISCUSSION: In an interaction study, coadministration of esomeprazole decreased rilzabrutinib maximum concentration (Cmax) by 55% and area-under-the-curve (AUC) by 51%.(1) In an interaction study, coadministration of famotidine decreased rilzabrutinib Cmax by 35% and AUC by 28%.(1)

Rilzabrutinib/Strong Cyp3a4 Inducers

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

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

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

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

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

DISCUSSION: Rilzabrutinib is primarily metabolized by CYP3A4.(1) Concomitant administration of rilzabrutinib with rifampin (a strong CYP3A4 inducer) resulted in a decrease in rilzabrutinib area under the curve (AUC) and maximum concentration (Cmax) by 80% and 80%, respectively.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2)

Rilzabrutinib/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: Rilzabrutinib is metabolized via CYP3A4. Strong inhibitors of CYP3A4 may inhibit the metabolism of rilzabrutinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from rilzabrutinib, including hepatotoxicity and immunosuppression.(1)

PREDISPOSING FACTORS: Patients with moderate to severe hepatic impairment (Child-Pugh class B-C) may be more susceptible to the effects of this drug interaction due to the potential for increased rilzabrutinib exposure.(1)

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients taking rilzabrutinib. If concurrent use cannot be avoided and the CYP3A4 inhibitor will be used short term (i.e., less than 7 days), interrupt treatment with rilzabrutinib.(1)

DISCUSSION: In a clinical study, ritonavir (a strong CYP3A4 inhibitor) increased the maximum concentration (Cmax) of rilzabrutinib by 5-fold and the area-under-curve (AUC) by 8-fold at steady state.(1) Strong inhibitors of CYP3A4 linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2,3)

Selected Cyp3a4 Inhibitors/Vardenafil (> 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: CYP3A4 inhibitors may inhibit the metabolism of vardenafil by CYP3A4.(1-4)

CLINICAL EFFECTS: Concurrent use of CYP3A4 inhibitors may result in increased levels of and adverse effects from vardenafil, including hypotension, visual changes, and sustained erections.(1-4)

PREDISPOSING FACTORS: The interaction may be more severe in men older than 75 years.(4)

PATIENT MANAGEMENT: The US manufacturer of vardenafil states that a maximum dose of 2.5 mg of vardenafil every 24 hours should not be exceeded in patients taking 400 mg of itraconazole or ketoconazole and that a maximum dose of 5 mg of vardenafil every 24 hours should not be exceeded in patients taking 200 mg of itraconazole or ketoconazole.(1) For moderate CYP3A4 inhibitors, do not exceed a maximum dose of 5 mg of vardenafil every 24 hours.(1) Note that other countries have stricter warnings. The Australian manufacturer of vardenafil states that vardenafil must not be taken with dosages of itraconazole or ketoconazole greater than 200 mg. A maximum dose of 5 mg of vardenafil should not be exceeded if used with lower dosages of itraconazole and ketoconazole.(2) The Canadian manufacturer of vardenafil states that the concurrent use of vardenafil with itraconazole or ketoconazole is contraindicated and that the dosage should not exceed 5 mg in patients taking erythromycin.(3) The UK manufacturer of vardenafil states that the concurrent use of vardenafil with either oral itraconazole or oral ketoconazole is contraindicated in men older than 75 years and should be avoided in all patients. The dosage of vardenafil should not exceed 5 mg in patients taking erythromycin.(4)

DISCUSSION: Concurrent use of ketoconazole (200 mg) with vardenafil (5 mg) increased the vardenafil area-under-curve (AUC) and maximum concentration (Cmax) by 10-fold and 4-fold, respectively.(1-4) Concurrent administration of erythromycin (500 mg three times daily) with vardenafil (5 mg) increased the AUC and Cmax of vardenafil by 4-fold and 3-fold, respectively.(1-4)

Selected Cyp3a4 Moderate Inhibitors/Lurasidone (> 80 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 inhibitors may inhibit the metabolism of lurasidone.(1)

CLINICAL EFFECTS: Concomitant use of lurasidone with inhibitors of CYP3A4 may lead to orthostatic hypotension, akathisia, acute dystonia, Parkinsonism or other lurasidone toxicities.(1)

PREDISPOSING FACTORS: Elderly patients, particularly those with a history of falls or swallowing disorders, and patients with Parkinson Disease, Lewy Body Disease, or other dementias are more sensitive to antipsychotics and have a greater risk for adverse effects.(1)

PATIENT MANAGEMENT: The US manufacturer of lurasidone states that the dose of lurasidone should not exceed 80 mg daily if coadministered with moderate CYP3A4 inhibitors.(1) If a patient is currently on lurasidone and a moderate CYP3A4 inhibitor is added to therapy, the dose of lurasidone should be decreased by 50% of the original dose.(1) If a patient is currently on a moderate CYP3A4 inhibitor and lurasidone is added to therapy, the recommended starting dose of lurasidone is 20 mg per day.(1)

DISCUSSION: Pretreatment with diltiazem (240 mg daily for 5 days), another moderate inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of lurasidone (20 mg) by 2.1-fold, and 2.2-fold, respectively.(1) Agents linked to this monograph include berotralstat, clofazimine, conivaptan, crizotinib, dronedarone, duvelisib, fedratinib, fluvoxamine, imatinib, isavuconazole, letermovir, nilotinib, nirogacestat, rilzabrutinib, stiripentol, and tofisopam.(2,3)

Selected Immunosuppressants/Nadofaragene Firadenovec

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

MECHANISM OF ACTION: Nadofaragene firadenovec may contain low levels of replication-competent adenovirus.(1)

CLINICAL EFFECTS: Concurrent use of nadofaragene firadenovec in patients receiving immunosuppressive therapy may cause disseminated adenovirus infection.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Individuals who are immunosuppressed or immune-deficient should not receive nadofaragene firadenovec.(1)

DISCUSSION: Nadofaragene firadenovec is a non-replicating adenoviral vector-based gene therapy but may contain low levels of replication-competent adenovirus. Immunocompromised persons, including those receiving immunosuppressant therapy, may be at risk for disseminated adenovirus infection.(1)

Selected Immunosuppressants/Talimogene Laherparepvec

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

MECHANISM OF ACTION: Talimogene laherparepvec is a live, attenuated herpes simplex virus.(1)

CLINICAL EFFECTS: Concurrent use of talimogene laherparepvec in patients receiving immunosuppressive therapy may cause a life-threatening disseminated herpetic infection.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Talimogene laherparepvec is contraindicated in immunosuppressed patients.(1) The magnitude of immunocompromise and associated risks due to immunosuppressant drugs should be determined by a physician.

DISCUSSION: Concurrent use of talimogene laherparepvec in patients receiving immunosuppressive therapy may cause a life-threatening disseminated herpetic infection.(1)

Selected Immunosuppressive Agents/Live Vaccines; Live Bcg

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

MECHANISM OF ACTION: A variety of disease modifying agents suppress the immune system. Immunocompromised patients may be at increased risk for uninhibited replication after administration of live, attenuated vaccines or intravesicular BCG. Immune response to vaccines may be decreased during periods of immunocompromise.(1)

CLINICAL EFFECTS: The expected serum antibody response may not be obtained and/or the vaccine may result in illness.(1) After instillation of intravesicular BCG, immunosuppression may interfere with local immune response, or increase the severity of mycobacterial infection following inadvertent systemic exposure.(2)

PREDISPOSING FACTORS: Immunosuppressive diseases (e.g. hematologic malignancies, HIV disease), treatments (e.g. radiation) and drugs may all increase the magnitude of immunodeficiency.

PATIENT MANAGEMENT: The Centers for Disease Control(CDC) Advisory Committee on Immunization Practices (ACIP) states that live-virus and live, attenuated vaccines should not be administered to patients who are immunocompromised. The magnitude of immunocompromise and associated risks should be determined by a physician.(1) For patients scheduled to receive chemotherapy, vaccination should ideally precede the initiation of chemotherapy by 14 days. Patients vaccinated while on immunosuppressive therapy or in the 2 weeks prior to starting therapy should be considered unimmunized and should be revaccinated at least 3 months after discontinuation of therapy.(1) Patients who receive anti-B cell therapies should not receive live vaccines for at least 6 months after such therapies due to a prolonged duration of immunosuppression. An exception is the Zoster vaccine, which can be given at least 1 month after receipt of anti-B cell therapies.(1) The US manufacturer of abatacept states live vaccines should not be given during or for up to 3 months after discontinuation of abatacept.(2) The US manufacturer of live BCG for intravesicular treatment of bladder cancer states use is contraindicated in immunosuppressed patients.(3) The US manufacturer of daclizumab states live vaccines are not recommended during and for up to 4 months after discontinuation of treatment.(4) The US manufacturer of guselkumab states that live vaccines should be avoided during treatment with guselkumab.(5) The US manufacturer of inebilizumab-cdon states that live vaccines are not recommended during treatment and after discontinuation until B-cell repletion. Administer all live vaccinations at least 4 weeks prior to initiation of inebilizumab-cdon.(6) The US manufacturer of ocrelizumab states that live vaccines are not recommended during treatment and until B-cell repletion occurs after discontinuation of therapy. Administer all live vaccines at least 4 weeks prior to initiation of ocrelizumab.(7) The US manufacturer of ozanimod states that live vaccines should be avoided during and for up to 3 months after discontinuation of ozanimod.(8) The US manufacturer of siponimod states that live vaccines are not recommended during treatment and for up to 4 weeks after discontinuation of treatment.(9) The US manufacturer of ustekinumab states BCG vaccines should not be given in the year prior to, during, or the year after ustekinumab therapy.(10) The US manufacturer of satralizumab-mwge states that live vaccines are not recommended during treatment and should be administered at least four weeks prior to initiation of satralizumab-mwge.(11) The US manufacturer of ublituximab-xiiy states that live vaccines are not recommended during treatment and until B-cell recovery. Live vaccines should be administered at least 4 weeks prior to initiation of ublituximab-xiiy.(12) The US manufacturer of etrasimod states that live vaccines should be avoided during and for 5 weeks after treatment. Live vaccines should be administered at least 4 weeks prior to initiation of etrasimod.(13) The US manufacturer of emapalumab-lzsg states that live vaccines should not be administered to patients receiving emapalumab-lzsg and for at least 4 weeks after the last dose of emapalumab-lzsg. The safety of immunization with live vaccines during or following emapalumab-lzsg therapy has not been studied.(14) The US manufacturer of sibeprenlimab-szsi states live vaccines should not be given within 30 days prior to initiation or during treatment with sibeprenlimab-szsi.(15)

DISCUSSION: Killed or inactivated vaccines do not pose a danger to immunocompromised patients.(1) Patients with a history of leukemia who are in remission and have not received chemotherapy for at least 3 months are not considered to be immunocompromised.(1)

Selected Moderate Cyp3a4 Inhibitors/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: Ensartinib is primarily metabolized by CYP3A4. Ensartinib metabolism may be inhibited by moderate CYP3A4 inhibitors.(1)

CLINICAL EFFECTS: The concurrent administration of a moderate CYP3A4 inhibitor may result in elevated levels of and toxicity from ensartinib.(1)

PREDISPOSING FACTORS: None determined.

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

DISCUSSION: Ensartinib is predominately metabolized by CYP3A4.(1) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, crizotinib, darunavir, duvelisib, fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, stiripentol, tofisopam, treosulfan, and voxelotor.(2,3)

Selected Strong And Moderate Cyp3a4 Inhibitors/Cisapride

SEVERITY LEVEL: 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 inhibitors impair the CYP3A4 mediated metabolism of cisapride.(1)

CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inhibitors may result in elevated levels of and toxicity from cisapride, including life-threatening cardiac arrhythmias such as torsades de pointes.(1-2)

PREDISPOSING FACTORS: In general, 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 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).(3)

PATIENT MANAGEMENT: Concurrent use of strong or moderate CYP3A4 inhibitors with cisapride is contraindicated. Use alternative antiemetics, or an alternative to the strong or moderate CYP3A4 inhibitor, whichever is more clinically appropriate. The US manufacturer of itraconazole states that concurrent administration with cisapride is contraindicated during and two weeks after itraconazole treatment.(4) If concurrent therapy is deemed medically necessary, 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: Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(5) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, atazanavir, avacopan, ciprofloxacin, clofazimine, conivaptan, darunavir, erythromycin, fosamprenavir, rilzabrutinib, and treosulfan.(5)

Slt Sensitive 3A4 Substrates That Inhibit 3A4/Oral Lefamulin

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

MECHANISM OF ACTION: Lefamulin is considered a moderate inhibitor of CYP3A4. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,2) Moderate inhibitors of CYP3A4 may inhibit the metabolism of oral lefamulin.(1,2)

CLINICAL EFFECTS: Concurrent use of oral lefamulin with a sensitive CYP3A4 substrate that also inhibits CYP3A4 may lead to increased serum levels and adverse effects of lefamulin and the sensitive substrate, including QT prolongation.(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, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)

PATIENT MANAGEMENT: If oral lefamulin must be coadministered with a sensitive CYP3A4 substrate, it is recommended to closely monitor for adverse effects of the CYP3A4 substrate and of lefamulin.(1) During concomitant therapy with a moderate CYP3A4 inhibitor, monitor patients closely for prolongation of the QT interval. Obtain serum calcium, magnesium, and potassium levels and monitor ECG at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: 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) Coadministration of ketoconazole (strong CYP3A4 inhibitor) with lefamulin tablets increased lefamulin area-under-the-curve (AUC) and maximum concentration (Cmax) by 165% and 58%.(1) Sensitive CYP3A4 substrates linked to this monograph include: aprepitant, atazanavir, darunavir, diltiazem, isavuconazonium, rilzabrutinib, and verapamil.(1,3)

Slt Strong & Moderate 3A4 Inhibitors/Cilostazol (>50 Mg 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 CYP3A4 may inhibit the metabolism of cilostazol.(1)

CLINICAL EFFECTS: The concurrent use of cilostazol and strong and moderate inhibitors of CYP3A4 may result in elevated levels of cilostazol, which may produce increased effects of cilostazol and adverse effects.(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 CYP3A4.(1)

DISCUSSION: In a study in 16 healthy males, the administration of a single dose of cilostazol (10 mg) with erythromycin (500 mg every eight hours) increased the maximum concentration (Cmax) and area-under-curve (AUC) of cilostazol by 47% and 73%, respectively. The Cmax and AUC of 4'-trans-hydroxy-cilostazol were increased by 29% and 141%, respectively.(2) Analysis of population pharmacokinetics indicated that the concurrent administration of diltiazem with cilostazol increased cilostazol concentrations by 53%. Concurrent administration of diltiazem and cilostazol decreased cilostazol clearance by 30%, increased the Cmax by 30%, and increased AUC by 40%.(1) In a study, the administration of a single dose of cilostazol (10 mg) with erythromycin (500 mg every eight hours) increased the Cmax and AUC of cilostazol by 47% and 73%, respectively. The AUC of 4'-trans-hydroxy-cilostazol was increased by 141%.(1) In an vitro study in human liver microsomes, ketoconazole inhibited the metabolism of cilostazol.(3)

Strong And Moderate Cyp3a4 Inhibitors/Asunaprevir

SEVERITY LEVEL: 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 asunaprevir.(1)

CLINICAL EFFECTS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may result in increased levels of and effects from asunaprevir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use strong or moderate CYP3A4 inhibitors with asunaprevir is contraindicated.(1)

DISCUSSION: Asunaprevir is a sensitive CYP3A4 substrate. Sensitive substrates would be expected to have an area-under-curve (AUC) ratio of at least 5-fold.(1,2) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, clarithromycin, ceritinib, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir/ritonavir, lonafarnib, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(2)

Strong And Moderate Cyp3a4 Inhibitors/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: Inhibitors of CYP3A4 may inhibit the metabolism of elacestrant.(1)

CLINICAL EFFECTS: Concomitant use of a strong or moderate CYP3A4 inhibitor increases elacestrant plasma concentrations, which may increase the incidence and severity of adverse reactions.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of elacestrant states avoid concomitant use of strong or moderate CYP3A4 inhibitors with elacestrant.(1) The US manufacturer of elacestrant does not provide dose modification recommendations with strong and moderate CYP3A4 inhibitors. The Australian and UK manufacturers state concomitant use of strong or moderate CYP3A4 inhibitors should be avoided and an alternative concomitant medicinal product with no or minimal potential to inhibit CYP3A4 should be considered. If concomitant use of a strong CYP3A4 inhibitor is unavoidable, the elacestrant dose should be reduced to 172 mg once daily with careful monitoring of tolerability. Subsequent dose reduction to 86 mg once daily may be considered with moderate CYP3A4 inhibitors based on tolerability. If the CYP3A4 inhibitor is discontinued, the elacestrant dose should be increased to the dose used prior to the initiation of the CYP3A4 inhibitor (after 5 half-lives of the CYP3A4 inhibitor).(2,3)

DISCUSSION: Coadministration of itraconazole (a strong CYP3A4 inhibitor) increased elacestrant area-under-curve (AUC) and maximum concentration (Cmax) by 5.3-fold and 4.4-fold, respectively.(1) Coadministration of fluconazole (a moderate CYP3A4 inhibitor) is predicted to increase elacestrant AUC and Cmax by 2.3-fold and 1.6-fold, respectively.(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.(4,5) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(4,5)

Strong And Moderate Cyp3a4 Inhibitors/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: Inhibitors of CYP3A4 may inhibit the metabolism of infigratinib.(1)

CLINICAL EFFECTS: Concomitant use of a strong or moderate CYP3A4 inhibitor increases infigratinib plasma concentrations, which may increase the incidence and severity of adverse reactions.(1)

PREDISPOSING FACTORS: None determined.

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

DISCUSSION: Coadministration of multiple doses of itraconazole (a strong CYP3A4 inhibitor) increased infigratinib area-under-curve (AUC) and maximum concentration (Cmax) by 622% and 164%, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2)

Strong And Moderate Cyp3a4 Inhibitors/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: Inhibitors of CYP3A4 may inhibit the metabolism of lemborexant.(1)

CLINICAL EFFECTS: Concurrent use of a strong or moderate 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 concurrent use of strong or moderate CYP3A4 inhibitors with lemborexant should be avoided.(1)

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) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(2)

Strong Or Moderate Cyp3a4 Inhibitors/Flibanserin

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

MECHANISM OF ACTION: Flibanserin is primarily metabolized by CYP3A4, though CYP2C19 also plays a role in metabolism.(1)

CLINICAL EFFECTS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may result in high to very high levels of and toxicity from flibanserin, including severe hypotension or syncope.(1)

PREDISPOSING FACTORS: Patients with any degree of hepatic impairment, who are poor CYP2C19 metabolizers, or who also receive concomitant therapy with strong CYP2C19 inhibitors 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: The concomitant use of flibanserin with moderate or strong CYP3A4 inhibitors significantly increases flibanserin concentrations which may lead to hypotension and syncope. The manufacturer of flibanserin states moderate or strong CYP3A4 inhibitors are contraindicated.(1) If the benefit of initiating a CYP3A4 inhibitor within 2 days of stopping flibanserin clearly outweighs the risk flibanserin-associated hypotension or syncope, monitor and counsel the patient regarding symptoms of hypotension or syncope. Discontinue moderate or strong CYP3A4 inhibitors for 2 weeks before initiating or restarting flibanserin therapy.(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) Though the combination has not been studied, a similar result is plausible with voriconazole, a strong CYP3A4 inhibitor and moderate CYP2C19 inhibitor.(1) In a drug interaction study with flibanserin 50 mg (one-half of the recommended dose) and ketoconazole 400 mg, flibanserin exposure increased 4.5-fold. One of 24 patients(4%) developed syncope.(1) A study of 12 healthy men and women on itraconazole (400 mg once then 200 mg daily for 4 days) with flibanserin 50 mg given 2 hours after itraconazole found that flibanserin exposure was increased 2.6-fold.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(1-3) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir/ritonavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole (also a CYP2C19 inhibitor), fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, ledipasvir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(1-3)

Strong Or Moderate Cyp3a4 Inhibitors/Lomitapide

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

MECHANISM OF ACTION: Lomitapide is primarily metabolized via CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may result in high to very high levels of and toxicity from lomitapide.(1)

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

PATIENT MANAGEMENT: Given the magnitude of this interaction and the potential toxicity of lomitapide, moderate and strong CYP3A4 inhibitors are contraindicated.(1) When possible use an alternative to the CYP3A4 inhibitor. If a moderate or strong CYP3A4 inhibitor is required, discontinue lomitapide. Due to its long half-life, it will take 1 to 2 weeks for remaining lomitapide to be eliminated; thus lomitapide adverse effects could occur after discontinuation. The US manufacturer of itraconazole states that concurrent use with lomitapide is contraindicated during and two weeks after itraconazole treatment.(4)

DISCUSSION: Concurrent administration with ketoconazole (a strong inhibitor of CYP3A4) increased lomitapide area-under-curve (AUC) by 27-fold.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, tucatinib, and voriconazole.(1-3,5) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir/ritonavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole (also a CYP2C19 inhibitor), fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, lefamulin, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(1-3)

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

Cyp3a4 Inhibitors And Substrates/Encorafenib

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

MECHANISM OF ACTION: Encorafenib is a CYP3A4 substrate and a strong CYP3A4 inducer. Strong and moderate inhibitors of CYP3A4 may inhibit the metabolism of encorafenib. Also, the metabolism of sensitive substrates of CYP3A4 may be induced by encorafenib.(1)

CLINICAL EFFECTS: Concomitant use of encorafenib with agents that are both strong or moderate CYP3A4 inhibitors and CYP3A4 substrates may result in increased levels and effects from encorafenib including QT prolongation. Concomitant use may also result in decreased 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: Avoid concomitant use of encorafenib with strong or moderate CYP3A4 inhibitors that are also CYP3A4 substrates.(1) The US manufacturer of encorafenib states that it should be avoided with CYP3A4 substrates for which decreased plasma concentrations may result in decreased therapeutic efficacy. If coadministration cannot be avoided, refer to the CYP3A4 substrate prescribing information for recommendations.(1) In addition, concurrent use of strong or moderate CYP3A4 inhibitors with encorafenib should be avoided.(1) The net effect of this two-way interaction is unknown and optimal doses of the drugs when used concurrently have not been determined. The manufacturer provides recommendations for dose modification when encorafenib is used with a CYP3A4 inhibitor, but the recommendations may not apply when there is a two-way interaction. Dose modifications mentioned below are informational only. If concurrent use of strong or moderate CYP3A4 inhibitors with encorafenib is unavoidable, reduce the encorafenib dose as follows: - If the current daily dose of encorafenib is 450 mg, reduce encorafenib to 150 mg with strong CYP3A4 inhibitors, and 225 mg with moderate CYP3A4 inhibitors. - If the current daily dose of encorafenib is 300 mg, reduce encorafenib to 75 mg with strong CYP3A4 inhibitors, and 150 mg with moderate CYP3A4 inhibitors. - If the current daily dose of encorafenib is 225 mg or 150 mg, reduce encorafenib to 75 mg with both strong and moderate CYP3A4 inhibitors. - After the inhibitor has been discontinued for 3 to 5 half-lives, resume encorafenib dose that was taken prior to initiating the CYP3A4 inhibitor.(1) When concurrent therapy cannot be avoided, monitor patients closely for prolongation of the QT interval. Obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. Recommended dosage modifications for encorafenib and QTc prolongation adverse reactions include: - QTcF greater than 500 ms and less than or equal to 60 ms increase from baseline: Withhold encorafenib until QTcF less than or equal to 500 ms. Resume at reduced dose. If more than one recurrence, permanently discontinue encorafenib. - QTcF greater than 500 ms and greater than 60 ms increase from baseline: Permanently discontinue encorafenib.(1) See encorafenib prescribing information for additional information regarding dose reductions.(1)

DISCUSSION: Coadministration of posaconazole (strong CYP3A4 inhibitor) or diltiazem (moderate CYP3A4 inhibitor) increased the area-under-curve (AUC) of encorafenib by 3-fold and 2-fold, respectively, and increased the maximum concentration (Cmax) by 68% and 45%, respectively, after a single dose of encorafenib 50 mg (0.1 times the recommended dose).(1) Encorafenib 450 mg daily with binimetinib 45 mg twice daily decreased the AUC and Cmax of single dose of midazolam 2 mg, a sensitive CYP3A4 substrate, by 82% and 74%, respectively, relative to midazolam 2 mg alone.(1) Encorafenib has been associated with a dose-dependent QTc interval prolongation. Following administration of encorafenib in combination with binimetinib, the largest mean (90% CI) QTcF change from baseline was 18 ms (14-22 ms), based on central tendency analysis. Following administration of encorafenib in combination with cetuximab and mFOLFOX6, an increase of QTcF >500 ms was measured in 4% (9/226) of patients. Following administration of encorafenib with cetuximab and FOLFIRI, an increase of QTcF >500 ms was measured in 1.5% (1/65) of patients.(1) Agents that are both strong CYP3A4 inhibitors and CYP3A4 substrates linked to this monograph include: idelalisib, itraconazole, mifepristone, and tucatinib.(3) Agents that are both moderate CYP3A4 inhibitors and CYP3A4 substrates linked to this monograph include: aprepitant, darunavir, diltiazem, duvelisib, fedratinib, fosnetupitant, imatinib, netupitant, rilzabrutinib, verapamil and voxelotor.(3)

Cyp3a4 Inhibitors And Substrates/Ivosidenib

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

MECHANISM OF ACTION: Ivosidenib is a CYP3A4 substrate and a strong CYP3A4 inducer. Strong and moderate inhibitors of CYP3A4 may inhibit the metabolism of ivosidenib. Also, the metabolism of sensitive substrates of CYP3A4 may be induced by ivosidenib.(1)

CLINICAL EFFECTS: Concomitant use of ivosidenib with agents that are both strong or moderate CYP3A4 inhibitors and CYP3A4 substrates may result in increased levels and effects from ivosidenib including QT prolongation. Concomitant use may also result in decreased 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: Avoid concomitant use of ivosidenib with strong or moderate CYP3A4 inhibitors that are also CYP3A4 substrates. Consider an alternative concomitant medication with less potential for CYP3A4 interaction.(1) The US manufacturer of ivosidenib states that if coadministration with a sensitive CYP3A4 substrate cannot be avoided, monitor patients for loss of therapeutic effect of these drugs.(1) The net effect of this two-way interaction is unknown and optimal doses of the drugs when used concurrently have not been determined. The manufacturer provides recommendations for dose modification when ivosidenib is used with a CYP3A4 inhibitor, but the recommendations may not apply when there is a two-way interaction. Dose modifications mentioned below are informational only. If coadministration of a strong CYP3A4 inhibitor cannot be avoided, reduce ivosidenib dose to 250 mg once daily. After the inhibitor has been discontinued for at least 5 half-lives, resume the ivosidenib dose that was taken prior initiating the CYP3A4 inhibitor (500 mg once daily).(1) No dose adjustment is recommended for ivosidenib when coadministered with moderate CYP3A4 inhibitors.(1) When concurrent therapy cannot be avoided, monitor patients closely for prolongation of the QT interval. Obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. Recommended dosage modifications for ivosidenib and QTc interval prolongation adverse reactions include: - QTc interval greater than 480 msec (millisecond) and less than 500 msec: Monitor and supplement electrolyte levels as clinically indicated. Review and adjust concomitant medications with known QTc interval-prolonging effects. Withhold ivosidenib until after the QT interval returns to less than or equal to 480 msec. Resume ivosidenib at a dose of 500 mg once daily. Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation. - QTc interval greater than 500 msec: Monitor and supplement electrolyte levels as clinically indicated. Review and adjust concomitant medications with known QTc interval-prolonging effects. Withhold ivosidenib until after the QT interval returns to within 30 msec of baseline or less than or equal to 480 msec. Resume ivosidenib at a reduced dose of 250 mg once daily. Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation. Consider re-escalating the dose of ivosidenib to 500 mg daily if an alternative etiology for QTc prolongation can be identified. - QTc interval prolongation with signs/symptoms of life-threatening arrhythmia: Permanently discontinue ivosidenib.(1) See ivosidenib prescribing information for additional information regarding dose reductions.(1)

DISCUSSION: In a drug interaction study in healthy subjects, coadministration of itraconazole (200 mg once daily for 18 days) with a single dose of ivosidenib (250 mg) increased ivosidenib area-under-the-curve (AUC) by 269%. No change was seen in ivosidenib's maximum concentration (Cmax).(1) Data from a pharmacokinetic simulation suggests that fluconazole, a moderate CYP3A4 inhibitor, may increase ivosidenib (500 mg) single-dose AUC by 173%. In regards to multiple-dosing, coadministration of ivosidenib with fluconazole is predicted to increase ivosidenib Cmax and AUC by 152% and 190%, respectively.(1) In a PBPK model, ivosidenib 500 mg for 15 days was predicted to decrease the AUC and Cmax of midazolam 5 mg by 82% and 73%, respectively.(3) In clinical trials of ivosidenib, 9% of patients experienced a QTc interval greater than 500 msec and 14% of patients had an increased from baseline QTc interval of greater than 60 msec. Patients with a baseline QTc of equal to or greater than 450 msec without pre-existing bundle branch block, or with a history of long QT syndrome were excluded from this trial.(1) Agents that are both strong CYP3A4 inhibitors and CYP3A4 substrates linked to this monograph include: mifepristone.(4) Agents that are both moderate CYP3A4 inhibitors and CYP3A4 substrates linked to this monograph include: aprepitant, darunavir, diltiazem, duvelisib, fosnetupitant, netupitant, rilzabrutinib, stiripentol, and verapamil.(4)

Cyp3a4 Inhibitors And Substrates/Repotrectinib

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

MECHANISM OF ACTION: Inhibitors of CYP3A4 may inhibit the metabolism of repotrectinib.(1) Clarithromycin(2) and idelalisib(3) are strong CYP3A4 inhibitors, and crizotinib,(4) duvelisib,(5) fedratinib,(6) oral lefamulin,(7) lenacapavir,(8) and voxelotor(9) are moderate CYP3A4 inhibitors. Moderate inducers of CYP3A4 may induce the metabolism of crizotinib,(4) duvelisib,(5) fedratinib,(6) idelalisib,(3) oral lefamulin,(7) lenacapavir,(8) vonoprazan,(2) and voxelotor.(9) Repotrectinib is a moderate CYP3A4 inducer.(1)

CLINICAL EFFECTS: Concomitant use of a strong or moderate CYP3A4 inhibitor increases repotrectinib plasma concentrations, which may increase the incidence and severity of adverse reactions, including CNS effects (dizziness, ataxia, cognitive disorders), interstitial lung disease/pneumonitis, hepatotoxicity, and myalgia.(1) The concurrent use of a moderate CYP3A4 inducer may result in decreased levels and effectiveness of crizotinib,(4) duvelisib,(5) fedratinib,(6) idelalisib,(3) oral lefamulin,(7) lenacapavir,(8) vonoprazan,(2) and voxelotor.(9)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant use of strong or moderate CYP3A4 inhibitors that are also CYP3A4 substrates with repotrectinib.(1)

DISCUSSION: In a study, itraconazole (a strong CYP3A4 and P-gp inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of repotrectinib by 5.9-fold and 1.7-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) 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.(5) 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.(3) In a study, concurrent administration of rifampin (a strong inducer) with oral lefamulin (tablets) decreased lefamulin AUC and Cmax by 72% and 57%.(7) In a study, efavirenz 600 mg once daily (inducer of CYP3A4 [moderate] and P-glycoprotein) decreased the Cmax and AUC of lenacapavir by 36% and 56%, respectively.(8) Strong CYP3A4 inducers like rifampin are predicted to decrease the AUC of vonoprazan by 80%, and moderate CYP3A4 inducers like efavirenz are predicted to decrease vonoprazan AUC by 50%.(2) Co-administration of efavirenz, a moderate CYP3A4 inducer, is predicted to decrease the AUC of voxelotor by 24%.(9) Agents linked to this monograph include: crizotinib, duvelisib, fedratinib, idelalisib, oral lefamulin, lenacapavir, rilzabrutinib, vonoprazan-amoxicillin-clarithromycin, and voxelotor.

Immunosuppres;Immunomodul/Selected Multiple Sclerosis Agents

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

MECHANISM OF ACTION: Ocrelizumab or ofatumumab in combination with immunosuppressives and immune-modulators all suppress the immune system.(1,2)

CLINICAL EFFECTS: Concurrent use of ocrelizumab or ofatumumab with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1,2)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: The ocrelizumab US prescribing information states: - Ocrelizumab and other immune-modulating or immunosuppressive therapies, (including immunosuppressant doses of corticosteroids) are expected to increase the risk of immunosuppression, and the risk of additive immune system effects must be considered if these therapies are coadministered with ocrelizumab. When switching from drugs with prolonged immune effects, such as daclizumab, fingolimod, natalizumab, teriflunomide, or mitoxantrone, the duration and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects when initiating ocrelizumab.(1) The ofatumumab US prescribing information states: - Ofatumumab and other immunosuppressive therapies (including systemic corticosteroids) may have the potential for increased immunosuppressive effects and increase the risk of infection. When switching between therapies, the duration and mechanism of action of each therapy should be considered due to the potential for additive immunosuppressive effects. Ofatumumab for MS therapy has not been studied in combination with other MS agents that suppress the immune system.(2)

DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1,2) In a retrospective cohort study of multiple sclerosis patients newly initiated on a disease-modifying therapy, use of high-efficacy agents (alemtuzumab, natalizumab, or ocrelizumab) resulted in the same risk of overall infections as moderate-efficacy agents, but there was an elevated risk of serious infections (adjusted hazard ratio [aHR] = 1.24, 95% confidence interval (CI) = 1.06-1.44) and UTIs (aHR = 1.21, 95% CI = 1.14-1.30).(3)

Immunosuppressive Moderate Cyp3a4 Inhibitors/Tofacitinib

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

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of tofacitinib.(1) Concurrent use of tofacitinib and potent immunosuppressants may result in additive or synergistic effects on the immune system.(1)

CLINICAL EFFECTS: Concurrent use of immunosuppressive moderate CYP3A4 inhibitors may increase levels of and effects from tofacitinib, including serious infections, thrombosis, gastrointestinal perforation, neutropenia, anemia, elevated liver enzymes, or lipid elevations.(1)

PREDISPOSING FACTORS: Patients who are also on a drug that is a strong inhibitor of CYP2C19 are at higher risk of increased tofacitinib levels and effects.

PATIENT MANAGEMENT: The manufacturer of tofacitinib states that concurrent use with immunosuppressive drugs is not recommended.(1) If concurrent use is clinically indicated, patients should be monitored for decreases in lymphocytes and neutrophils. If lymphopenia or neutropenia occurs, therapy should be adjusted based on the indication as recommended in the prescribing information. If concurrent use is clinically indicated in patients taking a moderate CYP3A4 inhibitor but not also a strong CYP2C19 inhibitor, no dosage modification of tofacitinib is recommended. Concurrent therapy with tofacitinib should be approached with caution as an interaction is likely.(1) In patients taking a strong CYP2C19 inhibitor in addition to a moderate CYP3A4 inhibitor, the dose of tofacitinib should be reduced as follows: - Xeljanz for rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: reduce to 5 mg once daily. - Xeljanz XR for rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: switch to Xeljanz 5 mg once daily. - Xeljanz for ulcerative colitis: - Induction: 5 mg twice daily for 8 weeks. If needed continue for maximum of 16 weeks. - Maintenance: 5 mg once daily. May consider 5 mg twice daily if loss of response. Use the lowest effective dosage for the shortest possible duration needed to maintain response. - Xeljanz XR for ulcerative colitis: - Induction: 11 mg once daily for 8 weeks. If needed continue for maximum of 16 weeks. - Maintenance: Not recommended. Switch to Xeljanz and follow recommendations with Xeljanz. - Xeljanz oral solution for polyarticular course juvenile idiopathic arthritis (pcJIA) or psoriatic arthritis (patients 2 years or older): - >= 10 kg to <20 kg: 3.2 mg once daily - >= 20 kg to <40 kg: 4 mg once daily - >= 40 kg: 5 mg once daily.(1)

DISCUSSION: In a study, administration of ketoconazole (a strong CYP3A4 inhibitor), increased the area-under-curve (AUC) of tofacitinib by more than 2-fold. Fluconazole (a moderate CYP3A4 and strong CYP2C19 inhibitor) increased tofacitinib AUC by about 1.75-fold.(1) Concurrent use of tofacitinib and azathioprine, other biologic DMARDs, or potent immunosuppressants may increase the risk of infection.(1) Serious infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving tofacitinib. Some patients presented with disseminated disease and were often taking concomitant immunomodulating agents. In the ulcerative colitis population, a greater risk of serious infections was seen with a higher tofacitinib dose. In 7 placebo-controlled rheumatoid arthritis trials (0-3 months exposure), the overall frequency of infections was 20% in the tofacitinib 5 mg twice daily group and 22% in the tofacitinib 10 mg twice daily group compared to 18% in the placebo group. Serious infections were reported in 11 patients (1.7 events per 100 patient-years) with a rate difference between treatment groups of 1.1 (-0.4, 2.5) events per 100 patient-years for both tofacitinib 5 mg twice daily and 10 mg twice daily. During 0-12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient years) in the tofacitinib 5 mg twice daily group and 33 patients (2.7 events per 100 patient years) in the tofacitinib 10 mg twice daily group.(1) Immunosuppressive moderate inhibitors of CYP3A4 include: crizotinib, duvelisib, fedratinib, imatinib, nilotinib, rilzabrutinib, and treosulfan.(3-4)

Immunosuppressives; Immunomodulators/Baricitinib

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

MECHANISM OF ACTION: Concurrent use of baricitinib with other biologic disease-modifying antirheumatic drugs (DMARDs) or potent immunosuppressants such as azathioprine or cyclosporine may result in additive or synergistic effects on the immune system.

CLINICAL EFFECTS: Concurrent use of baricitinib with other biologic DMARDs or potent immunosuppressants such as azathioprine or cyclosporine may increase the risk of serious infections.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of baricitinib states that concurrent use of baricitinib with biologic DMARDs or potent immunosuppressants is not recommended.(1)

DISCUSSION: Most patients who developed serious infections while being treated with baricitinib were on concomitant immunosuppressants like methotrexate and corticosteroids. The combination of baricitinib with other biologic DMARDs has not been studied.(1)

Immunosuppressives; Immunomodulators/Cladribine Oral

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

MECHANISM OF ACTION: Cladribine in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-2)

CLINICAL EFFECTS: Concurrent use of cladribine with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1-2)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: Recommendations for cladribine regarding this interaction differ between regulatory approving agencies. The cladribine US prescribing information states: -Concomitant use with myelosuppressive or other immunosuppressive drugs is not recommended. Acute short-term therapy with corticosteroids can be administered. In patients who have previously been treated with immunomodulatory or immunosuppressive drugs, consider potential additive effect, the mode of action, and duration of effect of the other drugs prior to initiation of cladribine.(1) The cladribine Canadian prescribing information states: -Use of cladribine in immunocompromised patients is contraindicated because of a risk of additive effects on the immune system. Acute short-term therapy with corticosteroids can be administered during cladribine treatment.(2)

DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1-2)

Immunosuppressives; Immunomodulators/Deuruxolitinib

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

MECHANISM OF ACTION: Deuruxolitinib, immunosuppressives, and immunomodulators all suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of deuruxolitinib and potent immunosuppressants may increase the risk of serious infections.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of deuruxolitinib states that concurrent use of deuruxolitinib with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants is not recommended.(1) If concurrent use cannot be avoided, patients should be monitored for signs and symptoms of infection. If a patient develops a serious or opportunistic infection, interrupt deuruxolitinib treatment until the infection is controlled.

DISCUSSION: Serious infections have been reported in patients receiving treatment with deuruxolitinib.(1)

Immunosuppressives; Immunomodulators/Filgotinib

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

MECHANISM OF ACTION: Concurrent use of filgotinib with other immunosuppressants or immunomodulators including azathioprine, cyclosporine, tacrolimus, biologic disease-modifying antirheumatic drugs (DMARDs), or other Janus kinase (JAK) inhibitors may result in additive or synergistic effects on the immune system.(1)

CLINICAL EFFECTS: Concurrent use of filgotinib with other immunosuppressants or immunomodulators including azathioprine, cyclosporine, tacrolimus, biologic DMARDs, or other JAK inhibitors may increase the risk of serious infections.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The UK manufacturer of filgotinib states that concurrent use of filgotinib with other immunosuppressants or immunomodulators including azathioprine, cyclosporine, tacrolimus, biologic DMARDs, or other JAK inhibitors is not recommended.(1)

DISCUSSION: Serious infections have been reported in patients receiving filgotinib. Caution should be used in patients with a higher incidence of serious infection, including elderly patients aged 75 years and older.(1)

Immunosuppressives; Immunomodulators/Fingolimod

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

MECHANISM OF ACTION: Fingolimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-3)

CLINICAL EFFECTS: Concurrent use of fingolimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1-3)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: Recommendations for fingolimod regarding this interaction differ between regulatory approving agencies. The fingolimod US prescribing information states: - Antineoplastic, immune-modulating, or immunosuppressive therapies, (including corticosteroids) are expected to increase the risk of immunosuppression, and the risk of additive immune system effects must be considered if these therapies are coadministered with fingolimod. When switching from drugs with prolonged immune effects, such as natalizumab, teriflunomide or mitoxantrone, the duration and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects when initiating fingolimod.(1) The fingolimod Canadian prescribing information states: - Concurrent use with immunosuppressive or immunomodulatory agents is contraindicated due to the risk of additive immune system effects. However, co-administration of a short course of corticosteroids (up to 5 days) did not increase the overall rate of infection in patients participating Phase III clinical trials.(2) The fingolimod UK specific product characteristics states: - Fingolimod is contraindicated in patients currently receiving immunosuppressive therapies or those immunocompromised by prior therapies. When switching patients from another disease modifying therapy to Gilenya, the half-life and mode of action of the other therapy must be considered in order to avoid an additive immune effect whilst at the same time minimizing the risk of disease activation.(3)

DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1-3)

Immunosuppressives; Immunomodulators/Inebilizumab

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

MECHANISM OF ACTION: Inebilizumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of inebilizumab with immunosuppressive or immunomodulating agents may result in myelosuppression including neutropenia resulting in an increased risk for serious infections.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of inebilizumab states that the concurrent use of inebilizumab with immunosuppressive agents, including systemic corticosteroids, may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)

DISCUSSION: Inebilizumab has not been studied in combination with other immunosuppressants. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents. The most common infections reported by inebilizumab treated patients in the randomized and open-label clinical trial periods included urinary tract infections (20%), nasopharyngitis (13%), upper respiratory tract infections (8%), and influenza (7%). Although there been no cases of Hepatitis B virus reactivation or progressive multifocal leukoencephalopathy reported in patients taking inebilizumab, these infections have been observed in patients taking other B-cell-depleting antibodies.(1)

Immunosuppressives; Immunomodulators/Ozanimod

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

MECHANISM OF ACTION: Ozanimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of ozanimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: The ozanimod US prescribing information state this information regarding this interaction: -Ozanimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the week following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with ozanimod after alemtuzumab is not recommended. However, ozanimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1)

DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1)

Immunosuppressives; Immunomodulators/Ponesimod

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

MECHANISM OF ACTION: Ponesimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of ponesimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection, cryptococcal infection, or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: The ponesimod US prescribing information states ponesimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with ponesimod after alemtuzumab is not recommended. However, ponesimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1)

DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections, cryptococcal meningitis, disseminated cryptococcal infections, and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1)

Immunosuppressives; Immunomodulators/Ritlecitinib

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

MECHANISM OF ACTION: Ritlecitinib, immunosuppressives, and immunomodulators all suppress the immune system.

CLINICAL EFFECTS: Concurrent use of ritlecitinib with immunosuppressives or immunomodulators may result in an increased risk of serious infections.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of ritlecitinib states that concurrent use of ritlecitinib with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants is not recommended.(1)

DISCUSSION: Serious infections have been reported in patients receiving ritlecitinib. Reported infections included appendicitis, COVID-19 infection (including pneumonia), and sepsis. Reports of viral reactivation, including herpes virus reactivation was reported in clinical studies with ritlecitinib.(1)

Immunosuppressives; Immunomodulators/Siponimod

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

MECHANISM OF ACTION: Siponimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of siponimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: The siponimod US prescribing information state this information regarding this interaction: -Siponimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the week following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with siponimod after alemtuzumab is not recommended. However, siponimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1)

DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1)

Immunosuppressives; Immunomodulators/Upadacitinib

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

MECHANISM OF ACTION: Upadacitinib, immunosuppressives, and immunomodulators all suppress the immune system.

CLINICAL EFFECTS: Concurrent use of upadacitinib with immunosuppressives or immunomodulators may result in an increased risk of serious infections.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of upadacitinib states that concurrent use of upadacitinib with immunosuppressives or immunomodulators is not recommended.

DISCUSSION: Serious infections have been reported in patients receiving upadacitinib. Reported infections included pneumonia, cellulitis, tuberculosis, multidermatomal herpes zoster, oral/esophageal candidiasis, cryptococcosis. Reports of viral reactivation, including herpes virus reactivation and hepatitis B reactivation, were reported in clinical studies with upadacitinib.(1)

Moderate Cyp3a4 Inhibitors & Substrates/Pexidartinib

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 pexidartinib.(1,2) Fedratinib,(2) oral lefamulin,(3) rilzabrutinib,(4)and voxelotor(5) are moderate CYP3A4 inhibitors. Moderate inducers of CYP3A4 may induce the metabolism of fedratinib,(2) lefamulin,(3) rilzabrutinib,(4) and voxelotor.(5) Pexidartinib is a moderate CYP3A4 inducer.(1)

CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in elevated levels and increased effects of pexidartinib, such as hepatotoxicity.(1,2) Symptoms can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue. The concurrent use of a moderate CYP3A4 inducer may result in decreased levels and effectiveness of fedratinib,(2) lefamulin,(3) rilzabrutinib,(4) and voxelotor.(5)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of pexidartinib states that pexidartinib coadministration with moderate inhibitors of CYP3A4 should be avoided.(1) The US manufacturers of fedratinib states that concurrent use with moderate CYP3A4 inducers should be avoided.(2) The US manufacturers of lefamulin states that concurrent use with moderate CYP3A4 inducers should be avoided.(3) The US manufacturer of rilzabrutinib states that concurrent use with moderate CYP3A4 inducers should be avoided.(4) The US manufacturers of voxelotor states that concurrent use with moderate CYP3A4 inducers should be avoided.(5)

DISCUSSION: Coadministration of fluconazole (a moderate CYP3A4 inhibitor) increased pexidartinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 41% and 67%.(1) The effect of CYP3A4 inducers has not been studied. Fedratinib is metabolized by CYP3A4.(2) In a study, concurrent administration of rifampin (a strong inducer) with lefamulin injection decreased lefamulin AUC and Cmax by 28% and 8%.(3) In a study, concurrent administration of rifampin (a strong inducer) with oral lefamulin (tablets) decreased lefamulin AUC and Cmax by 72% and 57%.(3) In a study, oral lefamulin tablets administered concomitantly with and at 2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the AUC and Cmax of midazolam by 200% and 100%, respectively. No clinically significant effect on midazolam pharmacokinetics was observed when co-administered with lefamulin injection.(3) Concomitant administration of rilzabrutinib with efavirenz or rifabutin (moderate CYP3A4 inducers) is predicted to decrease rilzabrutinib AUC and Cmax by up to 70% at steady state.(4) A pharmacokinetic model predicted that co-administration of rifampin, a strong CYP3A4 inducer, would decrease the area-under-curve (AUC) of voxelotor by 40%.(5) Co-administration of efavirenz, a moderate CYP3A4 inducer, is predicted to decrease the AUC of voxelotor by 24%.(5) Drugs that are both moderate inhibitors and substrates of CYP3A4 include: fedratinib, oral lefamulin, rilzabrutinib, and voxelotor.(2-7)

Moderate Cyp3a4 Inhibitors/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 inhibitors of CYP3A4 may inhibit the metabolism of brigatinib.(1)

CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels and toxicity from brigatinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of brigatinib states to avoid concurrent administration with moderate CYP3A4 inhibitors. If concurrent therapy cannot be avoided, reduce the once daily dose of brigatinib by approximately 40% (i.e. from 180 mg to 120 mg, 120 mg to 90 mg). Upon discontinuation of a moderate CYP3A4 inhibitor, resume the brigatinib dose that was tolerated prior to initiating the moderate CYP3A4 inhibitor.(1) Monitor patient for signs of brigatinib toxicity with concurrent use.

DISCUSSION: Brigatinib is a substrate of CYP3A4.(1) Concurrent administration of itraconazole (200 mg twice daily, a strong CYP3A4 inhibitor) with a single 90 mg dose of brigatinib increased the brigatinib maximum concentration (Cmax) by 21% and area-under-curve (AUC) by 101% compared to brigatinib alone. Moderate CYP3A4 inhibitors are expected to increase the AUC of brigatinib by approximately 40%.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2,3)

Moderate Cyp3a4 Inhibitors/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.(1-4)

CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor may result in elevated levels of and toxicity from cariprazine.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When possible, avoid the use of moderate CYP3A4 inhibitors with cariprazine. The US manufacturer of cariprazine states that concurrent use of moderate CYP3A4 inhibitors requires a dose adjustment. If a moderate CYP3A4 inhibitor is initiated in a patient on a stable dose of cariprazine, the following dose adjustments are recommended: -If current cariprazine dose is 1.5 or 3 mg daily: Decrease cariprazine dose to 0.75 mg daily. -If current cariprazine dose is 4.5 or 6 mg daily: Decrease cariprazine dose to 1.5 mg daily. In adult patients taking a moderate CYP3A4 inhibitor when cariprazine is started, the following dose adjustments are recommended: -For schizophrenia or bipolar mania: Start cariprazine dose at 0.75 mg daily; increase to 1.5 mg daily, if needed. -For bipolar depression or adjunctive therapy for treatment of Major Depressive Disorder (MDD): Start cariprazine dose at 0.75 mg daily.(1) -Initiating cariprazine is not recommended in pediatric patients while taking a moderate CYP3A4 inhibitor.(1) Cariprazine has two active metabolites, DCAR and DDCAR which have similar in vitro activity and potency. However, DDCAR has a longer half-life (1-3 weeks) than cariprazine (2-4 days), resulting in systemic DDCAR concentrations that are about 4-fold higher than cariprazine. Thus although interaction onset may begin within a few days, the full effect of inhibition may not be seen for 4 or more weeks. When the inhibitor is discontinued, cariprazine, DCAR and DDCAR will begin to fall and the dosage may need be increased. Monitor for decreased effectiveness for 4 or more weeks. The Australian, and Canadian manufacturers of cariprazine state that concurrent use of moderate CYP3A4 inhibitors is contraindicated.(2,3) The UK manufacturer of cariprazine states that concurrent use of moderate CYP3A4 inhibitors may require a dose adjustment.(4) The Canadian manufacturer of cariprazine states that concurrent use of moderate CYP3A4 inhibitors is also contraindicated for at least 2 weeks after cariprazine discontinuation.(3)

DISCUSSION: In an interaction study, coadministration of ketoconazole 400 mg/day with cariprazine 0.5 mg/day increased cariprazine exposure (AUC, area-under-curve) 4-fold and increased DDCAR AUC about 1.5-fold.(1) In a PKPB model, coadministration of ketoconazole 400 mg/day with cariprazine 0.5 mg/day is predicted to increase cariprazine concentration maximum (Cmax) and AUC by 5.5-fold and 6-fold, respectively. Coadministration of fluconazole 200 mg/day with cariprazine 0.5 mg/day is predicted to increased cariprazine Cmax and AUC by up to 3-fold.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(5,6)

Moderate Cyp3a4 Inhibitors/Cobimetinib; Olaparib; Sonidegib

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

MECHANISM OF ACTION: Agents which inhibit the CYP3A4 enzyme may inhibit the metabolism of cobimetinib, olaparib, and sonidegib.(1-4)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase systemic exposure and the risk for adverse effects from cobimetinib, olaparib, or sonidegib.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When possible, avoid the use of moderate CYP3A4 inhibitors in patients receiving cobimetinib, olaparib, or sonidegib.(1-4) For patients taking cobimetinib 60 mg daily, if concurrent short term use (14 days or less) of a moderate CYP3A4 inhibitor cannot be avoided, reduce cobimetinib dose to 20 mg daily. After discontinuation of the moderate CYP3A4 inhibitor resume the previous 60 mg dose. Patients who are taking cobimetinib 40 mg or 20 mg daily should not receive a moderate or strong CYP3A4 inhibitor.(1) If concomitant use with olaparib cannot be avoided, reduce the olaparib dose. Dosage adjustments are specific to the formulation of olaparib.(2,3) Reduce the dosage of the CAPsule formulation to 200 mg (four 50 mg CAPsules) taken twice daily.(2) Reduce the dosage of the TABlet formulation to 150 mg (one 150 mg TABlet) twice daily). If the CYP3A4 inhibitor is discontinued, resume the dose of olaparib taken prior to initiation of the CYP3A4 inhibitor after 3 to 5 half-lives.(3) If sonidegib and a moderate CYP3A4 inhibitor must be used, administer the moderate CYP3A4 inhibitor for less than 14 days and monitor closely for adverse effects, particularly musculoskeletal adverse reactions.(4)

DISCUSSION: In an interaction study, itraconazole (a strong CYP3A4 inhibitor) given 200 mg once daily for 14 days followed by a single dose of cobimetinib 10 mg increased mean cobimetinib AUC 6.7-fold (90% CI 5.6, 8.0). Subsequent simulations showed that predicted steady-state concentrations of cobimetinib at a reduced daily dose of 20 mg given with short term use of a moderate CYP3A4 inhibitor were similar to observed steady-state concentrations at the 60 mg dose without an inhibitor.(1) In simulations using physiologically-based pharmacokinetic (PBPK) models, concurrent use of fluconazole, a moderate CYP3A4 inhibitor, may increase the area-under-curve (AUC) of olaparib by 2.2-fold.(2,3) Based upon PBPK simulations, sonidegib mean steady-state AUC would increase 1.8-fold if administered with a moderate CYP3A4 inhibitor for 14 days and would further increase to 2.8-fold if the moderate CYP3A4 inhibitor is coadministered with sonidegib for 4 months.(4) Moderate CYP3A4 inhibitors linked to this monograph include: aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, schisandra, rilzabrutinib, stiripentol, tofisopam, treosulfan, and verapamil.(5)

Moderate Cyp3a4 Inhibitors/Colchicine (For Cardioprotection)

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

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

CLINICAL EFFECTS: Concurrent use of moderate 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.(1,2)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with renal and/or hepatic impairment.(1,2)

PATIENT MANAGEMENT: Monitor patients receiving moderate CYP3A4 inhibitors for signs of colchicine toxicity. Avoid concurrent use in patients with existing renal or hepatic impairment.(1) 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: There is one case report of colchicine toxicity with concurrent erythromycin.(4) In a study in 20 subjects, pretreatment with diltiazem (240 mg daily for 7 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by 44.2% (range -46.6% to 318.3%) and by 93.4% (range -30.2% to 338.6%), respectively.(1) In a study in 18 subjects, pretreatment with ritonavir (100 mg twice daily for 5 days) increased the Cmax and AUC of a single dose of colchicine (0.6 mg) by 184.4% (range 79.2% to 447.4%) and by 296% (range 53.8% to 924.4%), respectively.(1) In a study in 24 subjects, pretreatment with verapamil (240 mg twice daily for 7 days) increased the Cmax and AUC of a single dose of colchicine (0.6 mg) by 40.1% (range -47.1% to 149.5%) and by 103.3% (range -9.8% to 217.2%), respectively.(1) Colchicine toxicity has been reported with concurrent use of CYP3A4 inhibitors such as clarithromycin, cyclosporine, diltiazem, erythromycin, and verapamil.(1,2) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, avacopan, clofazimine, conivaptan, crizotinib, duvelisib, fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, stiripentol, and treosulfan.(1,5,6)

Moderate Cyp3a4 Inhibitors/Colchicine (For Gout & Fmf)

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

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

CLINICAL EFFECTS: Concurrent use of moderate 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: Avoid use of colchicine concurrently with or within 14 days of taking moderate CYP3A4 inhibitors (without ritonavir). If concurrent use is unavoidable, the dosage of colchicine should be reduced.(1-3) For gout flares, the recommended dosage is 1.2 mg (2 tablets) for one dose. This dose should be repeated no earlier than in 3 days.(1-4) For gout prophylaxis, if the original dosage was 0.6 mg twice daily, use 0.3 mg twice daily or 0.6 mg daily. If the original dosage was 0.6 mg daily, use 0.3 mg daily.(1-4) For Familial Mediterranean fever (FMF), the recommended maximum daily dose is 1.2 mg (may be given as 0.6 mg twice a day).(1-4) 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: Fluconazole (400 mg loading dose followed by 200 mg daily for 4 days) increased the area-under-curve (AUC) of colchicine by 40%.(2) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, avacopan, clofazimine, conivaptan, crizotinib, duvelisib, fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, stiripentol, and treosulfan.(1,5,6)

Moderate Cyp3a4 Inhibitors/Elexacaftor-Tezacaftor-Ivacaftor

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 CYP3A4-mediated metabolism of elexacaftor, tezacaftor, and ivacaftor.(1)

CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in elevated levels of and toxicity from elexacaftor, tezacaftor, and ivacaftor.(1)

PREDISPOSING FACTORS: This interaction may be more severe in patients with hepatic impairment.(1)

PATIENT MANAGEMENT: The dosage of elexacaftor-tezacaftor-ivacaftor should be reduced when co-administered with moderate CYP3A4 inhibitors as follows: - In patients 12 years and older and patients 6 to 12 years old weighing at least 30 kg who are receiving concurrent moderate CYP3A4 inhibitors, the evening dose of ivacaftor should not be taken. The morning dose of therapy should be modified to the following alternate daily dosing schedule: Day 1 - two tablets of elexacaftor 100 mg-tezacaftor 50 mg-ivacaftor 75 mg (total dose of elexacaftor 200 mg-tezacaftor 100 mg-ivacaftor 150 mg); Day 2 - one tablet of ivacaftor 150 mg. - In patients 6 to 12 years old weighing less than 30 kg who are receiving concurrent moderate CYP3A4 inhibitors, the evening dose of ivacaftor should not be taken. The morning dose of therapy should be modified to the following alternate daily dosing schedule: Day 1 - two tablets of elexacaftor 50 mg-tezacaftor 25 mg-ivacaftor 37.5 mg (total daily dose of elexacaftor 100 mg-tezacaftor 50 mg-ivacaftor 75 mg); Day 2 - one tablet of ivacaftor 75 mg. - In patients 2 to less than 6 years old weighing at least 14 kg who are receiving concurrent moderate CYP3A4 inhibitors, the evening dose of ivacaftor should not be taken. The morning dose of therapy should be modified to the following alternate daily dosing schedule: Day 1 - one packet of oral granules containing elexacaftor 100 mg-tezacaftor 50 mg-ivacaftor 75 mg; Day 2 - one packet of oral granules containing ivacaftor 75 mg.(1) - In patients 2 to less than 6 years old weighing less than 14 kg who are receiving concurrent moderate CYP3A4 inhibitors, the evening dose of ivacaftor should not be taken. The morning dose of therapy should be modified to the following alternate daily dosing schedule: Day 1 - one packet of oral granules containing elexacaftor 80 mg-tezacaftor 40 mg-ivacaftor 60 mg; Day 2 - one packet of oral granules containing ivacaftor 59.5 mg.(1)

DISCUSSION: In a study, fluconazole (400 mg on day 1 then 200 mg daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of ivacaftor (150 mg every 12 hours) by 2.95-fold and 2.45-fold, respectively.(1) Simulations suggest that moderate CYP3A inhibitors may increase the AUC of elexacaftor and tezacaftor by approximately 1.9 to 2.3-fold and 2.1-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2-4)

Moderate Cyp3a4 Inhibitors/Entrectinib

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 entrectinib.(1,2)

CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in elevated levels and increased effects of entrectinib, such as QT prolongation, hepatotoxicity, CNS effects, hyperuricemia, anemia, or neutropenia.(1,2) Symptoms of hepatotoxicity can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue.

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, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The US manufacturer of entrectinib states that entrectinib coadministration with moderate inhibitors of CYP3A4 should be avoided.(1) If concurrent therapy cannot be avoided, reduce the entrectinib dose as follows for adult and pediatric patients 2 years and older: -If the starting dose is 600 mg, reduce the entrectinib dose to 200 mg daily. -If the starting dose is 400 mg, reduce the entrectinib dose to 200 mg daily. -If the starting dose is 300 mg, reduce the entrectinib dose to 100 mg daily. -If the starting dose is 200 mg, reduce the entrectinib dose to 50 mg daily.(1) For pediatric patients less than 2 years old, avoid coadministration with moderate CYP3A4 inhibitors.(1) If concomitant use of a moderate CYP3A4 inhibitor is discontinued, increase the entrectinib dose to the dose that was used before starting the inhibitor after three to five plasma half-lives of the moderate CYP3A4 inhibitor. Monitor liver tests, including AST and ALT. Advise patients to immediately report any symptoms of hepatotoxicity. During concomitant therapy with a moderate CYP3A4 inhibitor, monitor patients closely for prolongation of the QT interval. Obtain serum calcium, magnesium, and potassium levels and monitor ECG at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. The Australian manufacturer of entrectinib states that entrectinib coadministration with moderate inhibitors of CYP3A4 should be avoided. If concurrent therapy with a moderate CYP3A4 inhibitor cannot be avoided, reduce the dose of entrectinib to 200 mg once daily.(4) If concomitant use of a moderate CYP3A4 inhibitor is discontinued, increase the entrectinib dose to the dose that was used before starting the inhibitor after three to five plasma half-lives of the moderate CYP3A4 inhibitor.(4)

DISCUSSION: Coadministration of itraconazole (strong CYP3A4 inhibitor) with a single 100 mg entrectinib dose increased entrectinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 1.7-fold and 6-fold.(1) Coadministration of a moderate CYP3A4 inhibitor with entrectinib is predicted to increase entrectinib Cmax and AUC by 2.9-fold and 3-fold.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, ciprofloxacin, conivaptan, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(1,5)

Moderate Cyp3a4 Inhibitors/Ergot Alkaloids

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

MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of ergot alkaloids.

CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor may result in increased levels of the ergot alkaloid, which may result in clinical signs of ergotism, including vasospasm, dysesthesia, renal ischemia, and peripheral ischemia.

PREDISPOSING FACTORS: Patients receiving the maximum recommended (or higher than recommended) dosages of ergot alkaloids may be at a higher risk of adverse effects from this combination.

PATIENT MANAGEMENT: When possible, avoid the concurrent use of moderate CYP3A4 inhibitors in patients taking ergot alkaloids. If concurrent use is warranted, consider reducing the dose of the ergot alkaloid during concurrent therapy. Patients receiving concurrent therapy should be monitored for and instructed to report any signs of ergotism.

DISCUSSION: Coadministration of dihydroergotamine and ergotamine with potent inhibitors of CYP3A4 such as clarithromycin, erythromycin, indinavir, nelfinavir, ritonavir, and troleandomycin has resulted in ergotism, characterized by vasospasm and ischemia of the extremities. Inhibition of ergot alkaloid metabolism by moderate inhibitors would also be expected, but to a lesser degree. Moderate CYP3A4 inhibitors linked to this monograph are aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lenacapavir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, tofisopam, treosulfan and verapamil.

Moderate Cyp3a4 Inhibitors/Gepotidacin

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

MECHANISM OF ACTION: Gepotidacin is a substrate of CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of gepotidacin.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in increased levels and toxicity from gepotidacin,(1) including diarrhea, nausea, abdominal pain and prolongation of the QT interval, which may result in life-threatening arrhythmia and death.

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)

PATIENT MANAGEMENT: The manufacturer of gepotidacin states that concomitant use of moderate CYP3A4 inhibitors 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 inhibitors.(1)

DISCUSSION: Gepotidacin is primarily metabolized by CYP3A4.(1) Concomitant administration of fluconazole (moderate CYP3A4 inhibitor) and single 1,500 mg dose of gepotidacin is predicted to increase gepotidacin maximum concentration (Cmax) by 1.3-fold and area-under-curve (AUC) by 1.5-fold.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)

Moderate Cyp3a4 Inhibitors/Iberdomide

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

MECHANISM OF ACTION: Iberdomide is primarily metabolized by CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of iberdomide.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase the levels and effects of iberdomide, including thromboembolic events and hematologic abnormalities (neutropenia, thrombocytopenia).(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of iberdomide states that concomitant use of moderate CYP3A4 inhibitors should be avoided. If concomitant use with moderate CYP3A4 inhibitors cannot be avoided, reduce iberdomide dose to 0.75 mg once daily on Days 1 to 21 of a 28-day cycle.(1)

DISCUSSION: In a PBPK model in patients with cancer, iberdomide area-under-curve (AUC) was predicted to be increased by 1.7-fold and maximum concentration (Cmax) by 1.5-fold following concomitant use with fluconazole or diltiazem (moderate CYP3A4 inhibitors).(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)

Moderate Cyp3a4 Inhibitors/Ivabradine

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 ivabradine. Increased levels of ivabradine may cause ivabradine-induced reduction in heart rate which can contribute to increased QT prolongation risk.(1-3)

CLINICAL EFFECTS: Concurrent use of moderate inhibitors may result in elevated levels of and toxicity from ivabradine including a reduction in heart rate which can contribute to QT prolongation or torsades de pointes.(1-3)

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: The US manufacturer of ivabradine states that concurrent use of moderate inhibitors of CYP3A4, including diltiazem and verapamil, should be avoided.(1) The Australian and UK manufacturers of ivabradine state that concurrent use of diltiazem or verapamil is contraindicated but that other moderate inhibitors of CYP3A4 may be considered with monitoring of heart rate and with a starting dose of 2.5 mg ivabradine twice daily if resting heart rate is above 70 bpm.(2-3) Monitor patients receiving concurrent therapy for bradycardia (heart rate less than 50 bpm), dizziness, fatigue, hypotension, and/or symptoms of atrial fibrillation (heart palpitations, chest pressure, shortness of breath).

DISCUSSION: Concurrent use of potent CYP3A4 inhibitors ketoconazole (200 mg daily) and josamycin (1000 mg twice daily) increased mean ivabradine plasma exposure by 7- to 8-fold. Concurrent use of moderate CYP3A4 inhibitors diltiazem and verapamil increased ivabradine area-under-curve (AUC) by 2- to 3-fold and reduced heart rate by an additional 5 bpm.(2) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, avacopan, berotralstat, conivaptan, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(5)

Moderate Cyp3a4 Inhibitors/Lirafugratinib

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

MECHANISM OF ACTION: Lirafugratinib is primarily metabolized by CYP3A4. Moderate CYP3A4 inhibitors may inhibit the metabolism of lirafugratinib.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase the levels and toxicities of lirafugratinib, including ocular toxicities (retinal pigment epithelial detachment, blurred vision, corneal keratitis) and hyperphosphatemia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant use of moderate CYP3A4 inhibitors with lirafugratinib. If concomitant use cannot be avoided, reduce the dosage of lirafugratinib to 50 mg once daily. If the CYP3A4 inhibitor is discontinued, resume the prior dosage of lirafugratinib after 3 elimination half-lives of the inhibitor.(1)

DISCUSSION: In a pharmacokinetic model, erythromycin 500 mg four times daily for 15 days was predicted to increase the area-under-curve (AUC) and maximum concentration (Cmax) of lirafugratinib by 1.7-fold and 1.1-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2-3)

Moderate Cyp3a4 Inhibitors/Lurbinectedin

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

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

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors with lurbinectedin may increase systemic exposure and the risk for toxicities such as myelosuppression, hepatotoxicity, neuropathy, fatigue, nausea, and musculoskeletal pain.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of lurbinectedin states that the concurrent use of lurbinectedin with moderate CYP3A4 inhibitors should be avoided. If the use of a moderate CYP3A4 inhibitor cannot be avoided, reduce the dose of lurbinectedin by 50%. After discontinuation of the moderate CYP3A4 inhibitor for 5 half-lives of the inhibitor, resume the lurbinectedin dose used before starting the inhibitor.(1)

DISCUSSION: Itraconazole (a strong CYP3A4 inhibitor) increased the area-under-curve (AUC) of total lurbinectedin by 2.7-fold and unbound lurbinectedin by 2.4-fold.(1) In a study including data from 443 patients with solid and hematologic malignancies treated in six phase I and three phase II trials with lurbinectedin as a single agent or combined with other agents, lurbinectedin clearance decreased by 30%, area-under-curve (AUC) increased by 42%, and concentration maximum (Cmax) increased by 7% when coadministered with a CYP3A inhibitor.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)

Moderate Cyp3a4 Inhibitors/Mobocertinib

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 mobocertinib.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase levels of and effects from mobocertinib.(1) Elevated levels of mobocertinib may result in QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(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)

PATIENT MANAGEMENT: Avoid the use of moderate CYP3A4 inhibitors in patients undergoing therapy with mobocertinib.(1) If concurrent therapy with a moderate CYP3A4 inhibitor is warranted, reduce the dose of mobocertinib by approximately 50% (ie, 160 to 80 mg, 120 to 40 mg, or 80 to 40 mg) and monitor the QTc interval more frequently. After the moderate CYP3A4 inhibitor has been discontinued for 3 to 5 elimination half-lives, resume mobocertinib at the dose taken prior to initiating the moderate CYP3A4 inhibitor. Consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Increase the frequency of ECG monitoring in patients with risk factors for QTc prolongation, including congenital long QT syndrome, heart disease, or electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If patients develop QTc prolongation during mobocertinib therapy, dose modifications are recommended: - If Grade 2 (QTc interval 481-500 msec) and first occurrence: hold mobocertinib until QTc returns to <= Grade 1 or baseline. Upon recovery, resume mobocertinib at the same dose. - If Grade 2 and recurrence: hold mobocertinib until QTc returns to <= Grade 1 or baseline. Upon recovery, resume mobocertinib at the next lower dose or permanently discontinue. - If Grade 3 (QTc interval >= 501 msec or QTc interval increase of > 60 msec from baseline) and first occurrence: hold mobocertinib until QTc returns to <= Grade 1 or baseline. Upon recovery, resume mobocertinib at the next lower dose or permanently discontinue. - If Grade 3 and recurrence: permanently discontinue mobocertinib. - If Grade 4 (Torsades de pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrhythmia): permanently discontinue mobocertinib.

DISCUSSION: Coadministration of mobocertinib with multiple doses of a moderate CYP3A inhibitor is predicted to increase the steady-state combined molar area-under curve (AUC) of mobocertinib and its active metabolites by approximately 100 to 200%.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)

Moderate Cyp3a4 Inhibitors/Naloxegol (<= 12.5 Mg)

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

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

CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 without a dosage adjustment of naloxegol may result in increased levels of naloxegol, which may precipitate opioid withdrawal symptoms.(1)

PREDISPOSING FACTORS: Patients taking methadone may be more likely to experience gastrointestinal side effects such as abdominal pain and diarrhea as a result of opioid withdrawal.(1)

PATIENT MANAGEMENT: Avoid the use of moderate inhibitors of CYP3A4 in patients who require therapy with naloxegol. If concurrent use cannot be avoided, the daily dose of naloxegol should be limited to 12.5 mg daily in patients taking moderate inhibitors of CYP3A4.(1) Monitor patients for signs of opioid withdrawal such as sweating, chills, diarrhea, stomach pain, anxiety, irritability, yawning, restlessness, muscle/joint aches, increased lacrimation, running nose, and piloerection. Monitor patients taking methadone for abdominal pain and diarrhea as well.(1)

DISCUSSION: Ketoconazole (400 mg daily for 5 days), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of naloxegol by 9.58-fold and 12.85-fold, respectively.(2) Diltiazem (240 mg XR daily), a moderate inhibitor of CYP3A4, increased the Cmax and AUC of a single dose of naloxegol by 2.85 and 3.41, respectively.(2) According to Physiologically-based-Pharmacokinetic (PBPK) models, erythromycin, a moderate inhibitor of CYP3A4, at a dose of 250 mg QID is expected to increase the Cmax and AUC of naloxegol by 2.77-fold and 3.47-fold, respectively.(2) According to PBPK models, erythromycin at a dose of 400 mg QID is expected to increase the Cmax and AUC of naloxegol by 3.42-fold and 4.63-fold, respectively.(2) According to PBPK models, fluconazole, a moderate inhibitor of CYP3A4, at a dose of 200 mg daily is expected to increase the Cmax and AUC of naloxegol by 2.4-fold and 2.81-fold, respectively.(2) According to PBPK models, verapamil moderate inhibitor of CYP3A4, at a dose of 120 mg daily is expected to increase the Cmax and AUC of naloxegol by 1.97-fold and 2.21-fold, respectively.(2) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(1,3,4)

Moderate Cyp3a4 Inhibitors/Omaveloxolone

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

MECHANISM OF ACTION: Agents which inhibit the CYP3A4 enzyme may inhibit the metabolism of omaveloxolone.(1)

CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels of and effects from omaveloxolone including hepatotoxicity and hyperlipidemia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of moderate CYP3A4 inhibitors with omaveloxolone should be avoided. If concurrent use cannot be avoided, reduce the omaveloxolone dosage to 100 mg daily and monitor closely. If adverse reactions emerge, reduce the dose to 50 mg once daily.(1)

DISCUSSION: Coadministration of omaveloxolone with verapamil (a moderate CYP3A4 inhibitor) increased both the concentration maximum (Cmax) and area-under-curve (AUC) of omaveloxolone by 1.25-fold.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)

Moderate Cyp3a4 Inhibitors/Selpercatinib

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

MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of selpercatinib.(1) Cimetidine increases gastric pH and may decrease pH-dependent solubility and absorption of selpercatinib.(1)

CLINICAL EFFECTS: Concurrent administration of a moderate CYP3A4 inhibitor may result in elevated levels of and toxicity from selpercatinib.(1) Elevated levels of selpercatinib may increase the risk of QTc prolongation and potentially life-threatening arrhythmias, including torsades de pointes, hepatotoxicity, hypertension, and severe or life-threatening hemorrhagic events.(1) Conversely, concurrent use of cimetidine may result in decreased levels and effectiveness of selpercatinib. The overall effect of cimetidine on selpercatinib pharmacokinetics is unknown.(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)

PATIENT MANAGEMENT: The US manufacturer of selpercatinib recommends avoiding concomitant use of moderate CYP3A4 inhibitors with selpercatinib. If concomitant use cannot be avoided, reduce the dose of selpercatinib as follows: - If the current dose of selpercatinib is 160 mg twice daily, decrease the dose to 120 mg twice daily. - If the current dose of selpercatinib is 120 mg twice daily, decrease the dose to 80 mg twice daily. - If the current dose of selpercatinib is 80 mg twice daily, decrease the dose to 40 mg twice daily. - If the current dose of selpercatinib is 40 mg three times daily, decrease the dose to 40 mg once daily. If concomitant use of cimetidine is unavoidable, take selpercatinib at least 2 hours before or 10 hours after cimetidine. When 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. If grade 3 QT interval prolongation occurs, withhold selpercatinib until recovery to baseline or Grades 0 or 1, then resume selpercatinib at a reduced dose. If grade 4 QT interval prolongation occurs, discontinue selpercatinib.(1) After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume selpercatinib at the dose taken prior to initiating the CYP3A inhibitor.(1)

DISCUSSION: Coadministration of diltiazem, fluconazole, or verapamil (moderate CYP3A inhibitors) is predicted to increase the area-under-curve (AUC) and maximum concentration (Cmax) of selpercatinib by 60-99% and 46-76%, respectively.(1) In a thorough QT study, selpercatinib 160 mg twice daily increased QTc by a mean of 10.6 msec (upper 90% confidence interval: 12.1 msec). An increase in QTcF interval to greater than 500 msec was measured in 6% of patients and an increase in the QTcF interval of at least 60 msec over baseline was measured in 15% of patients.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3)

Moderate Cyp3a4 Inhibitors/Sonrotoclax

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

MECHANISM OF ACTION: Moderate CYP3A4 inhibitors inhibit the metabolism of sonrotoclax.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in elevated levels of sonrotoclax, increasing the risk for tumor lysis syndrome and other toxicities.(1)

PREDISPOSING FACTORS: Risk factors for tumor lysis syndrome include higher tumor burden such as bulky lymphadenopathy or lymphocytosis and reduced renal function.(1)

PATIENT MANAGEMENT: Recommendations vary depending the stage of therapy. During sonrotoclax initiation and at the 1 mg and 2 mg dose of sonrotoclax ramp-up therapy, avoid moderate CYP3A4 inhibitors. Reduce all other ramp-up doses of sonrotoclax by at least 4-fold as follows: - If original sonrotoclax dose is 5 mg, reduce sonrotoclax dose to 1 mg. - If original sonrotoclax dose is 10 mg, reduce sonrotoclax dose to 2 mg. - If original sonrotoclax dose is 20 mg, reduce sonrotoclax dose to 5 mg. - If original sonrotoclax dose is 40 mg, reduce sonrotoclax dose to 10 mg. - If original sonrotoclax dose is 80 mg, reduce sonrotoclax dose to 20 mg. - If original sonrotoclax dose is 160 mg, reduce sonrotoclax dose to 40 mg. - If original sonrotoclax dose is 320 mg, reduce sonrotoclax dose to 80 mg. In patients taking the target daily dose of sonrotoclax after the ramp-up phase who start a moderate CYP3A4 inhibitor, decrease sonrotoclax daily dose to 80 mg. Monitor for tumor lysis syndrome, hematologic and non-hematologic toxicity and adjust dosage as directed in prescribing information. If the moderate CYP3A4 inhibitor is discontinued, resume the prior (i.e., pre-inhibitor) sonrotoclax dose at least 5 days after discontinuation of the inhibitor.(1)

DISCUSSION: In a study, itraconazole (a strong CYP3A inhibitor and P-gp inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of sonrotoclax by 11-fold and 4-fold, respectively. Posaconazole (a strong CYP3A inhibitor) increased sonrotoclax AUC and Cmax by 13-fold and 7-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3-4)

Moderate Cyp3a4 Inhibitors/Suvorexant (> 10 Mg)

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

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

CLINICAL EFFECTS: Concurrent use of an agent that is a moderate or strong inhibitor of CYP3A4 may result in elevated levels of and clinical effects of suvorexant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of suvorexant recommends a starting dose of 5 mg daily and a maximum dose of 10 mg daily in patients receiving concomitant therapy with a moderate inhibitor of CYP3A4.(1) Concurrent use with strong inhibitors of CYP3A4 is not recommended.(1)

DISCUSSION: Diltiazem, a moderate inhibitor of CYP3A4, increased suvorexant AUC and Cmax by approximately 2-fold and 1.25-fold, respectively.(1) Ketoconazole, a strong inhibitor of CYP3A4, increased suvorexant area-under-curve (AUC) and maximum concentration (Cmax) by approximately 2.75-fold and 1.25-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(1-3)

Moderate Cyp3a4 Inhibitors/Tavapadon

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

MECHANISM OF ACTION: Tavapadon is primarily metabolized by CYP3A4. Moderate CYP3A4 inhibitors may inhibit the metabolism of tavapadon.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase the levels and toxicities of tavapadon, including hypotension, altered impulse control, hallucinations, and dyskinesias.(1)

PREDISPOSING FACTORS: The risk of hallucinations appears to be increased in patients 65 years of age and older.

PATIENT MANAGEMENT: During tavapadon titration, concomitant use with moderate CYP3A4 inhibitors should be avoided. During tavapadon maintenance, if moderate CYP3A4 inhibitors are initiated, decrease the dosing frequency from once daily to every 3 days: - If the current dose of tavapadon is 5 mg daily, lower dosage to 5 mg every 3 days. - If the current dose of tavapadon is 10 mg daily, lower dosage to 10 mg every 3 days. - If the current dose of tavapadon is 15 mg daily, lower dosage to 15 mg every 3 days. If the CYP3A4 inhibitor is discontinued, resume the prior maintenance dosage of tavapadon and monitor patients for clinical response and tolerability.(1)

DISCUSSION: In a clinical study, fluconazole 200 mg daily was predicted to increase the area-under-curve (AUC) and maximum concentration (Cmax) of tavapadon 15 mg by approximately 2.6-fold and 2.3-fold, respectively. When fluconazole is given with tavapadon once every 3 days, steady-state AUC and Cmax are predicted to fluctuate between +14% to -40% and +1 to -43%, respectively from Day 1 to Day 3 of the dosing interval, compared to tavapadon once daily alone.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2-3)

Moderate Cyp3a4 Inhibitors/Tazemetostat

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 tazemetostat.(1)

CLINICAL EFFECTS: Coadministration of tazemetostat with a moderate CYP3A4 inhibitor may increase tazemetostat plasma concentrations and increase the frequency or severity of adverse reactions.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of tazemetostat states to avoid coadministration of moderate CYP3A4 inhibitors with tazemetostat.(1) If coadministration of moderate CYP3A4 inhibitors cannot be avoided, reduce the tazemetostat dose as follows: If the current tazemetostat dose is 800 mg twice daily, reduce the dose to 400 mg twice daily. If the current tazemetostat dose is 600 mg twice daily, reduce the dose to 400 mg for the first dose and 200 mg for the second dose. If the current tazemetostat dose is 400 mg twice daily, reduce the dose to 200 mg twice daily.(1) After discontinuation of the moderate CYP3A4 inhibitor for 3 elimination half-lives, resume the prior tazemetostat dose.(1)

DISCUSSION: Coadministration of fluconazole, a moderate CYP3A4 inhibitor, with tazemetostat 400 mg twice daily in patients increased tazemetostat area-under-curve (AUC) by 3.1-fold and maximum concentration (Cmax) by 2.3-fold.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2-4)

Moderate Cyp3a4 Inhibitors/Venetoclax

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

MECHANISM OF ACTION: Moderate CYP3A4 inhibitors inhibit the metabolism of venetoclax.(1)

CLINICAL EFFECTS: Concurrent use of moderate inhibitors of CYP3A4 may result in elevated levels of venetoclax, increasing the risk for tumor lysis syndrome and other toxicities.(1)

PREDISPOSING FACTORS: Risk factors for tumor lysis syndrome include (1): - the ramp-up phase of venetoclax therapy when tumor burden is highest - initial magnitude of tumor burden - renal impairment The risk of venetoclax toxicities may be increased in patients with severe hepatic impairment.(1)

PATIENT MANAGEMENT: Avoid moderate CYP3A4 inhibitors and consider alternative treatments when possible. If a moderate CYP3A4 inhibitor must be used, reduce venetoclax dose by at least 50%. Monitor more closely for signs of toxicity such as tumor lysis syndrome, hematologic and non-hematologic toxicities.(1) Canadian labeling for atazanavir contraindicates concurrent use of atazanavir/ritonavir with venetoclax at venetoclax dose initiation and during the ramp-up phase.(2) If the moderate CYP3A4 inhibitor is discontinued, the manufacturer of venetoclax recommends resuming the prior (i.e. pre-inhibitor) dose of venetoclax 2 to 3 days after discontinuation of the moderate CYP3A4 inhibitor.

DISCUSSION: In 11 previously treated NHL subjects, ketoconazole (a strong CYP3A4 inhibitor which also inhibits P-gp and BCRP) 400 mg daily for 7 days increased the maximum concentration (Cmax) and area-under-curve (AUC) of venetoclax 2.3-fold and 6.4-fold respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(3-4)

Moderate Cyp3a4 Inhibitors/Voclosporin

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

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

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase levels of and effects from voclosporin, including infection, neurotoxicity, nephrotoxicity, hypertension, or hyperkalemia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The prescribing information for voclosporin states the use of moderate CYP3A4 inhibitors in patients undergoing therapy with voclosporin requires a dose adjustment. Voclosporin dose should be reduced to 15.8 mg in the morning and 7.9 mg in the evening.(1) Consider alternatives with no or minimal enzyme inhibition.

DISCUSSION: Concurrent use of voclosporin and ketoconazole 400 mg daily (strong CYP3A4 inhibitor) for 9 days increased the concentration maximum (Cmax) and area-under-curve (AUC) by 6.45-fold and 18.55-fold, respectively.(1) Concurrent use of voclosporin and verapamil 80 mg three times a day for 10 days (moderate CYP3A4 inhibitor and P-gp inhibitor) increased Cmax and AUC by 2.08-fold and 2.71-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)

Myelosuppressive Mod-Weak 3A4 Inh/Sirolimus Protein-Bound

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

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

CLINICAL EFFECTS: Concurrent use of moderate or weak CYP3A4 inhibitors may result in elevated levels of and side effects from sirolimus including immunosuppression.(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) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(2)

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.(3) 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.(3) Moderate CYP3A4 inhibitors linked to this monograph include: duvelisib, fedratinib, imatinib, rilzabrutinib, and treosulfan.(3,4) Weak CYP3A4 inhibitors linked to this monograph include: asciminib, avapritinib, belumosudil, capivasertib, everolimus, lapatinib, larotrectinib, leflunomide, olaparib, palbociclib, teriflunomide, vepdegestrant, and ziftomenib.(4,5)

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Rilzabrutinib/Bosentan

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

MECHANISM OF ACTION: Bosentan is metabolized by CYP2C9 and CYP3A4. It is also an inducer of these enzymes. With regular dosing bosentan auto-induces its own metabolism.(1) Moderate CYP3A4 inhibitors such as rilzabrutinib may inhibit the CYP3A4 mediated metabolism of bosentan.(1,2) Rilzabrutinib is a substrate of CYP3A4. Moderate CYP3A4 inducers such as bosentan may induce the metabolism of rilzabrutinib.(2)

CLINICAL EFFECTS: Concurrent use of bosentan with an inhibitor of CYP3A4 such as rilzabrutinib may result in elevated levels of and toxicity from bosentan.(1) The concurrent use of rilzabrutinib with a moderate CYP3A4 inducer such as bosentan may result in decreased levels and effectiveness of rilzabrutinib.(2)

PREDISPOSING FACTORS: Concurrent use of bosentan, a CYP3A4 inhibitor and a CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone, sulfinpyrazone, or phenylbutazone)(3) could lead to blockade of both major metabolic pathways for bosentan, resulting in large increases in bosentan plasma concentrations.(1,3)

PATIENT MANAGEMENT: The effect of the two-way inhibition and induction of rilzabrutinib and bosentan metabolism is unknown. The optimal doses of rilzabrutinib and bosentan when used concurrently have not been determined. Concurrent use should be avoided. Dose modifications mentioned below are informational only. The manufacturer of rilzabrutinib states that concurrent use with moderate CYP3A4 inducers should be avoided.(2) In patients receiving bosentan, review medication list to see if patient is also receiving a CYP2C9 inhibitor (e.g. amiodarone, fluconazole, miconazole, oxandrolone, sulfinpyrazone, or phenylbutazone). Concomitant use of both a CYP2C9 and CYP3A4 inhibitor is not recommended by the manufacturer of bosentan as the combination may lead to large increases in bosentan plasma concentrations.(1) For patients stabilized on bosentan when a CYP3A4 inhibitor is initiated, monitor tolerance to concomitant therapy and adjust bosentan dose if needed.

DISCUSSION: In a study in healthy subjects, concurrent bosentan and ketoconazole (a strong CYP3A4 inhibitor) administration increased bosentan steady-state maximum concentrations (Cmax) and area-under-curve (AUC) by 2.1-fold and 2.3-fold, respectively.(1) Concomitant administration of rilzabrutinib with efavirenz or rifabutin (moderate CYP3A4 inducers) is predicted to decrease rilzabrutinib AUC and Cmax by up to 70% at steady state.(2)

Rilzabrutinib/Mavacamten

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

MECHANISM OF ACTION: Rilzabrutinib and mavacamten are both metabolized by CYP3A4. Mavacamten is a moderate CYP3A4 inducer while rilzabrutinib is a moderate CYP3A4 inhibitor.(1-2)

CLINICAL EFFECTS: The net effect of coadministration of rilzabrutinib and mavacamten on CYP3A4 enzyme activity is unknown. Concurrent use may either decrease the clinical effectiveness of rilzabrutinib(1) or increase the levels and toxicities of mavacamten.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: There are no recommendations for concurrent use of rilzabrutinib with mavacamten. Concurrent therapy should be avoided. If use of this combination is necessary, the patient should be closely monitored for rilzabrutinib efficacy and mavacamten toxicity. The manufacturer of rilzabrutinib states that concomitant use of moderate CYP3A4 inducers should be avoided.(1) The manufacturer of mavacamten makes the recommendations below for concurrent use with CYP3A4 inhibitors: Initiate mavacamten at the recommended starting dosage in patients who are on stable therapy with a moderate CYP3A4 inhibitor. Reduce dose by one level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients who are on mavacamten treatment and intend to initiate a moderate CYP3A4 inhibitor. Schedule clinical and echocardiographic assessment 4 weeks after inhibitor initiation, and do not up-titrate mavacamten until 12 weeks after inhibitor initiation.(2) Avoid initiation of concomitant moderate CYP3A4 inhibitors in patients who are on stable treatment with the lowest recommended dose of mavacamten because a lower dose is not available.(2) For short-term use (e.g. 1 week), interrupt mavacamten therapy for the duration of the moderate CYP3A4 inhibitor. After therapy with the moderate CYP3A4 inhibitor is discontinued, mavacamten may be reinitiated at the previous dose immediately upon discontinuation.(2)

DISCUSSION: Concomitant administration of rilzabrutinib with efavirenz or rifabutin (moderate CYP3A4 inducers) is predicted to decrease rilzabrutinib area under the curve (AUC) and maximum concentration (Cmax) by up to 70% at steady state.(1) Concomitant use of mavacamten (25 mg) with verapamil sustained release (240 mg), a moderate CYP3A4 inhibitor, increased mavacamten AUC by 15% and Cmax by 52% in intermediate metabolizers and normal metabolizers of CYP2C19.(2) Concomitant use of mavacamten with diltiazem, a moderate CYP3A4 inhibitor, in CYP2C19 poor metabolizers is predicted to increase mavacamten AUC and Cmax up to 55% and 42%, respectively.(2)

Rilzabrutinib/Mitapivat

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)

Selected Immunosuppressants/Leflunomide; Teriflunomide

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

MECHANISM OF ACTION: Concurrent use of leflunomide or teriflunomide and potent immunosuppressants may result in additive or synergistic effects on the immune system.(1,2) Leflunomide is a prodrug and is converted to its active metabolite teriflunomide.(1)

CLINICAL EFFECTS: Concurrent use of leflunomide or teriflunomide with immunosuppressants may result in an increased risk of serious infections, including opportunistic infections, especially Pneumocystis jiroveci pneumonia, tuberculosis (including extra-pulmonary tuberculosis), and aspergillosis.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If leflunomide or teriflunomide is used concurrently with immunosuppressive agents, chronic CBC monitoring should be performed more frequently, every month instead of every 6 to 8 weeks. If bone marrow suppression or a serious infection occurs, leflunomide or teriflunomide should be stopped and rapid drug elimination procedure should be performed.(1,2)

DISCUSSION: Pancytopenia, agranulocytosis and thrombocytopenia have been reported in patients receiving leflunomide or teriflunomide alone, but most frequently in patients taking concurrent immunosuppressants.(1,2) Severe and potentially fatal infections, including sepsis, have been reported in patients receiving leflunomide or teriflunomide, especially Pneumocystis jiroveci pneumonia and aspergillosis. Tuberculosis has also been reported.(1,2)

Selected Moderate Cyp3a4 Inhibitors/Alprazolam

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 alprazolam.(1)

CLINICAL EFFECTS: Concurrent use may result in increased pharmacologic or toxic effects of alprazolam. Toxic effects include profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant use with moderate CYP3A4 inhibitors. Consider reducing the dose of alprazolam when coadministered with a moderate CYP3A4 inhibitor. If fluvoxamine is concurrently administered with alprazolam, the manufacturer of fluvoxamine recommends that the initial dose of alprazolam be reduced by 50%, followed by titration to the lowest effective dose.(2) If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: Coadministration of cimetidine, a moderate CYP3A4 inhibitor, increased the maximum concentration (Cmax) of alprazolam by 82%.(1) Coadministration with erythromycin, a moderate CYP3A4 inhibitor, increased the area-under-curve (AUC) of alprazolam by 1.61-fold.(1) Coadministration of fluvoxamine 100 mg daily and alprazolam 1 mg given 4 times per day resulted in a 2-fold increase of AUC, Cmax, and half-life of alprazolam.(2) Selected moderate CYP3A4 inhibitors linked to this monograph include: aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(3,4)

Selected Moderate Cyp3a4 Inhibitors/Domperidone

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

MECHANISM OF ACTION: Moderate CYP3A4 inhibitors impair the CYP3A4 mediated metabolism of domperidone.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in elevated levels of and toxicity from domperidone, including life-threatening cardiac arrhythmias such as torsades de pointes.(1)

PREDISPOSING FACTORS: In epidemiologic studies and post-market safety data, domperidone was associated with an increased risk for serious ventricular arrhythmias in patients > 60 years of age, using more than 30 mg of domperidone daily, and having other risk factors for QT prolongation.(1) In general, 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: Concurrent use of moderate CYP3A4 inhibitors with domperidone is not recommended. Use alternative antiemetics, or an alternative to the moderate CYP3A4 inhibitor, whichever is more clinically appropriate. If concurrent therapy is deemed medically necessary, 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 in 24 healthy subjects, ketoconazole (200 mg twice daily) tripled plasma levels of domperidone (10 mg four times daily). In male subjects, the combination significantly increased QTc interval greater than either agent alone. In females, there were no significant changes in QTc intervals, but QTc intervals were correlated with domperidone levels.(3) Moderate CYP3A4 inhibitors linked to this monograph include: aprepitant, avacopan, berotralstat, conivaptan, crizotinib, diltiazem, duvelisib, fedratinib, fluvoxamine, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(4-5)

Selected Moderate Cyp3a4 Inhibitors/Eplerenone

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 eplerenone.(1)

CLINICAL EFFECTS: Concurrent use of moderate inhibitors of CYP3A4 may result in a 2-fold increase in eplerenone concentration and toxicity (e.g. hyperkalemia, hypotension).(1)

PREDISPOSING FACTORS: Severe renal disease increases the risk for hyperkalemia.

PATIENT MANAGEMENT: The starting dose of eplerenone for hypertension should be reduced to 25 mg in patients receiving moderate CYP3A4 inhibitors. For inadequate blood pressure response, dosing may be increased to a maximum of 25 mg twice daily. Do not exceed 25 mg once daily in post-MI CHF patients receiving a moderate CYP3A4 inhibitor.(1) In all patients taking eplerenone who start taking a moderate CYP3A4 inhibitor, check serum potassium and creatinine levels after 3-7 days of concurrent therapy.(1)

DISCUSSION: Ketoconazole (200 mg BID) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of eplerenone (100 mg) by 1.7-fold and 5.4-fold, respectively.(1) The concurrent use of eplerenone with less potent CYP3A4 inhibitors (erythromycin 500 mg BID, fluconazole 200 mg daily, saquinavir 1200 mg TID, and verapamil 240 mg daily) increased the Cmax of eplerenone by 1.4-fold to 1.6-fold and the AUC of eplerenone by 2.0-fold and 2.9-fold.(1) Moderate inhibitors of CYP3A4 include: aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(1-3)

Selected Moderate Cyp3a4 Inhibitors/Pimozide

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 pimozide.(1)

CLINICAL EFFECTS: Concurrent administration of a moderate inhibitor of CYP3A4 may result in elevated levels of pimozide, which may result in prolongation of the QTc interval and potentially life-threatening ventricular arrhythmias.(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) 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.(3)

PATIENT MANAGEMENT: Avoid concurrent use, especially when other risk factors for QT prolongation are present. The 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) If concurrent use cannot be avoided, then correct or minimize QT prolonging risk factors, e.g. correct electrolyte disturbances, use the lowest effective dose of pimozide, and discontinue other concurrent QT prolonging agents or CYP3A4 inhibitors if possible. Consider ECG to evaluate baseline and/or concurrent QT prolongation risk. Monitor patients on the combination and counsel patients accordingly.

DISCUSSION: Pimozide is metabolized at CYP3A.(1,4) Elevated levels of pimozide may prolong the QTc interval resulting in life-threatening ventricular arrhythmias.(1) Moderate inhibitors of CYP3A4 include: avacopan, berotralstat, conivaptan, diltiazem, duvelisib, fedratinib, fosnetupitant, imatinib, isavuconazonium, lenacapavir, netupitant, rilzabrutinib, schisandra, tofisopam, treosulfan and verapamil.(5,6)

Selected Myelosuppressive Agents/Clozapine

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

MECHANISM OF ACTION: Clozapine and other myelosuppressive agents may be associated with neutropenia or agranulocytosis.(2)

CLINICAL EFFECTS: Moderate neutropenia, even if due to combination therapy, may require abrupt discontinuation of clozapine resulting in decompensation of the patient's psychiatric disorder (e.g. schizophrenia). The disease treated by the myelosuppressive agent may be compromised if myelosuppression requires dose reduction, delay, or discontinuation of the myelosuppressive agent. Undetected severe neutropenia or agranulocytosis may be fatal.

PREDISPOSING FACTORS: Low white blood counts prior to initiation of the myelosuppressive agent may increase risk for clinically significant neutropenia.

PATIENT MANAGEMENT: If a patient stabilized on clozapine therapy requires treatment with a myelosuppressive agent, the clozapine prescriber should consult with prescriber of the myelosuppressive agent (e.g. oncologist) to discuss treatment and monitoring options.(2) More frequent absolute neutrophil count (ANC) monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. The U.S. Food and Drug Administration (FDA) recommends that prescribers monitor patients' ANC according to the monitoring frequencies described in the prescribing information. Severe neutropenia remains a serious, potentially fatal risk that is greatest in the first several months of clozapine treatment. ANC monitoring can help identify neutropenia early to allow for timely intervention.(1-2) Australia, Canada, and U.K.: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing. For most clozapine patients, clozapine treatment must be interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter. For patients with benign ethnic neutropenia (BEN), treatment must be interrupted for suspected clozapine-induced neutropenia < 500 cells/microliter.(2)

DISCUSSION: Concurrent use of clozapine and selected myelosuppressive agents may require more frequent ANC monitoring or consideration of treatment alternatives secondary to neutropenic episodes. Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(3-26)

Selected Myelosuppressive Agents/Deferiprone

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

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

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

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

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

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

Slt Immunosuppress; Immunomodulator/Ropeginterferon Alfa-2B

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

MECHANISM OF ACTION: Ropeginterferon alfa-2b and immunosuppressives both suppress the immune system.

CLINICAL EFFECTS: Concurrent use of ropeginterferon alfa-2b with immunosuppressives may result in an increased risk of serious infections.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concurrent use of myelosuppressive agents.(1-2) If concurrent use cannot be avoided, monitor for effects of excessive immunosuppression.

DISCUSSION: In clinical trials, 20% of patients experienced leukopenia. Interferon alfa products may cause fatal or life-threatening infections.(1-2)

Strong & Moderate Cyp3a4 Inhibitors/Eliglustat

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

MECHANISM OF ACTION: Strong or moderate 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 strong or moderate 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 has liver disease, is also taking an inhibitor of CYP2D6 and/or is an intermediate or poor metabolizer of CYP2D6, 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 strong or moderate inhibitors of CYP3A4 concomitantly with strong or moderate inhibitors of CYP2D6 in both extensive and intermediate metabolizers of CYP2D6 is contraindicated.(1) The concurrent use of eliglustat with strong inhibitors of CYP3A4 in intermediate and poor metabolizers of CYP2D6 is contraindicated.(1) The concurrent use of eliglustat with moderate inhibitors of CYP3A4 in intermediate and poor metabolizers of CYP2D6 should be avoided.(1) The dosage of eliglustat with strong or moderate inhibitors of CYP3A4 in extensive metabolizers of CYP2D6 should be limited to 84 mg daily.(1) The concurrent use of eliglustat with strong inhibitors of CYP3A4 concomitantly with strong or moderate inhibitors of CYP2D6 is contraindicated.(1) The concurrent use of eliglustat with moderate inhibitors of CYP3A4 concomitantly with strong or moderate inhibitors of CYP2D6 in poor metabolizers of CYP2D6 should be avoided and is contraindicated in extensive and intermediate metabolizers of CYP2D6.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: 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) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, ensitrelvir, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tucatinib, and voriconazole.(1,3,4) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, casopitant, clofazimine, conivaptan, crizotinib, darunavir, duvelisib, erythromycin, fluconazole, fosamprenavir, fosnetupitant, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, and treosulfan.(1,3,4)

Strong & Moderate Cyp3a4 Inhibitors/Guanfacine

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

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

CLINICAL EFFECTS: The concurrent administration of a strong or moderate CYP3A4 inhibitor may result in elevated levels of guanfacine, which may result in increased adverse effects such as hypotension, bradycardia, loss of consciousness, and drowsiness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients maintained on guanfacine may need dosage adjustments if strong or moderate inhibitors of CYP3A4 are initiated or discontinued. The manufacturer of extended-release guanfacine recommends a starting dose of extended-release guanfacine initiated at half the recommended level of the weight based dosing in patients receiving strong or moderate inhibitors of CYP3A4. If a patient has been maintained on extended-release guanfacine and is started on a strong or moderate CYP3A4 inhibitor, the dose of extended-release guanfacine should be decreased to half the recommended weight based dose. If a patient has been maintained on extended-release guanfacine and a strong or moderate CYP3A4 inhibitor and the strong or moderate CYP3A4 inhibitor is discontinued, the dose of extended-release guanfacine may need to be increased to the recommended weight based dose based upon patient response. 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: Ketoconazole (dosage not stated), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of guanfacine (dosage not stated) by approximately 1.75-fold and 3-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(1-3) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(1-3)

Strong And Moderate Cyp3a4 Inhibitors/Deflazacort

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

MECHANISM OF ACTION: Deflazacort is a prodrug and is rapidly metabolized to the active metabolite, 21-desDFZ, by esterases. The metabolite 21-desDFZ is metabolized by CYP3A4 to inactive metabolites.(1) Inhibitors of CYP3A4 may inhibit the metabolism of the active metabolite of deflazacort metabolized by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inhibitors may result in increased systemic exposure to and effects from deflazacort.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer recommends decreasing the dose to one-third of the recommended dose of deflazacort when used concurrently with strong or moderate CYP3A4 inhibitors. For example, if the recommended dose of deflazacort is 36 mg per day, the reduced dose would be 12 mg per day when administered with strong or moderate CYP3A4 inhibitors.(1)

DISCUSSION: Deflazacort is a prodrug and is rapidly metabolized to the active metabolite, 21-desDFZ. The metabolite 21-desDFZ is metabolized by CYP3A4.(1) Coadministration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total geometric mean exposure (maximum concentration (Cmax) and area-under-curve (AUC)) to the active metabolite 21-desDFZ by 2.3- to 3.4-fold.(1)

Strong And Moderate Cyp3a4 Inhibitors/Ivacaftor

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

MECHANISM OF ACTION: Strong and moderate inhibitors of CYP3A4 may inhibit the metabolism of ivacaftor.(1)

CLINICAL EFFECTS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may result in elevated levels of and toxicity from ivacaftor.(1)

PREDISPOSING FACTORS: This interaction may be more severe in patients with hepatic impairment.(1)

PATIENT MANAGEMENT: In patients receiving concurrent strong CYP3A4 inhibitors such as boceprevir, ceritinib, clarithromycin, cobicistat, conivaptan, idelalisib, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib, or voriconazole, the dose of ivacaftor should be reduced to one 150 mg tablet or one packet (25 mg if body weight 5 kg to < 7 kg, 50 mg if body weight < 14 kg, 75 mg if weight equal or > 14 kg) two times a week.(1) In patients receiving concurrent moderate CYP3A4 inhibitors such as amprenavir, aprepitant, atazanavir, berotralstat, crizotinib, cyclosporine, darunavir/ritonavir, diltiazem, dronedarone, erythromycin, fluconazole, fosamprenavir, fosaprepitant, imatinib, isavuconazonium, ledipasvir, netupitant, schisandra or verapamil, the dose of ivacaftor should be reduced to one 150 mg tablet or one packet (25 mg if body weight 5 kg to < 7 kg, 50 mg if body weight < 14 kg, 75 mg if weight equal or > 14 kg) daily.(1) In patients who are less than 6 months of age, concurrent use of ivacaftor with strong or moderate CYP3A4 inhibitors is not recommended.(1)

DISCUSSION: Concurrent administration with ketoconazole (a strong inhibitor of CYP3A4) increased ivacaftor area-under-curve (AUC) by 8.5-fold.(1) Concurrent administration with fluconazole (a moderate inhibitor of CYP3A4) increased ivacaftor area-under-curve (AUC) by 3-fold.(1) A study in 12 subjects compared ivacaftor alone (study A), ivacaftor with ritonavir (a strong inhibitor of CYP3A4) 50 mg daily on days 1-4 (study B), and ivacaftor with ritonavir 50 mg daily for two weeks prior and on days 1-4 of ivacaftor administration (study C). In study A, B, and C, ivacaftor AUC increased from 10.94 mcg/hr to 215.6 mcg/hr and 216 mcg/hr, respectively, with the addition of ritonavir. Ivacaftor concentration maximum (Cmax) was 0.9944 mcg, 1.812 mcg, and 2.267 mcg in study A, B, and C, respectively.(2) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(3-5) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir/ritonavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, ledipasvir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan and verapamil.(3-5)

Strong And Moderate Cyp3a4 Inhibitors/Pemigatinib

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

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

CLINICAL EFFECTS: Concomitant use of a strong or moderate CYP3A4 inhibitor increases pemigatinib plasma concentrations, which may increase the incidence and severity of adverse reactions.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of pemigatinib states that coadministration with strong or moderate CYP3A4 inhibitors should be avoided. If coadministration cannot be avoided, the dosage of pemigatinib should be reduced as follows: -Reduce dose from 13.5 mg to 9 mg. -Reduce dose from 9 mg to 4.5 mg. If the strong or moderate CYP3A4 inhibitor is discontinued, resume the pemigatinib dose that was taken prior to the initiation of the inhibitor after 3 half-lives of the CYP3A4 inhibitor have elapsed.(1)

DISCUSSION: Itraconazole, a strong CYP3A4 inhibitor, increased the maximum concentration (Cmax) by 17% and area-under-curve (AUC) by 88% following a single oral pemigatinib dose of 4.5 mg. Concomitant use of moderate CYP3A4 inhibitors is predicted to increase pemigatinib exposure by approximately 50-80%.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2)

Strong And Moderate Cyp3a4 Inhibitors/Pralsetinib

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

MECHANISM OF ACTION: Strong and moderate CYP3A4 inhibitors (including combined moderate CYP3A4 and P-glycoprotein (P-gp) inhibitors) may inhibit the metabolism of pralsetinib.(1)

CLINICAL EFFECTS: Concurrent administration of a strong or moderate CYP3A4 inhibitor (including combined moderate CYP3A4 and P-gp inhibitors) may result in elevated levels of and toxicity from pralsetinib, including QTc prolongation which may lead to potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP). Other toxicities include hemorrhagic events, pneumonitis, hepatotoxicity, and hypertension.(1-3)

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.(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 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).(4)

PATIENT MANAGEMENT: Coadministration of pralsetinib with strong or moderate CYP3A4 inhibitors (including combined moderate CYP3A4 and P-gp inhibitors) should be avoided.(1) If coadministration with a strong or moderate CYP3A4 inhibitor cannot be avoided, use with caution and reduce the dose of pralsetinib as follows: -If the current dose is 400 mg once daily, decrease the dose to 300 mg daily. -If the current dose is 300 mg once daily, decrease the dose to 200 mg daily. -If the current dose is 200 mg once daily, decrease the dose to 100 mg daily. After the inhibitor is discontinued for three to five half-lives, resume the dose of pralsetinib at the dose taken prior to initiation of the inhibitor.(1) When concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If the QTc interval exceeds 500 ms, interrupt pralsetinib therapy until QTc is <470 ms. Resume pralsetinib at the same dose if risk factors that cause QT prolongation an are identified and corrected. If risk factors that cause QT prolongation are not identified, resume pralsetinib at a reduced dose. Permanently discontinue pralsetinib if the patient develops life-threatening arrhythmia.(3)

DISCUSSION: Coadministration of voriconazole 400 mg twice daily for 1 day then 200 mg twice daily (a strong CYP3A inhibitor) resulted in 122% and 20% increase in pralsetinib area-under-curve (AUC) and maximum concentration (Cmax), respectively.(1) Fluconazole 400 mg daily (a moderate CYP3A4 inhibitor) increased pralsetinib AUC and Cmax by 71% and 15%, respectively.(1) Verapamil 80 mg three times daily (a moderate CYP3A4 and P-glycoprotein inhibitor) increased pralsetinib AUC and Cmax by 108% and 60%, respectively.(1) Strong CYP3A4 inhibitors linked to this monograph include: boceprevir, ensitrelvir, idelalisib, nelfinavir, relacorilant, and troleandomycin.(5,6) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, clofazimine, conivaptan, darunavir, duvelisib, fedratinib, fosamprenavir, fosnetupitant, imatinib, letermovir, netupitant, nilotinib, rilzabrutinib, stiripentol, tofisopam, treosulfan, and voxelotor.(5,6) Dual moderate CYP3A4 and P-gp inhibitors include: berotralstat, diltiazem, fluvoxamine, isavuconazonium, lenacapavir, schisandra, and verapamil.(5,6)

Strong And Moderate Cyp3a4 Inhibitors/Selumetinib

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

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

CLINICAL EFFECTS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may result in increased levels of and effects from selumetinib, including vomiting, diarrhea, skin rashes, ocular toxicity (e.g., blurred vision, visual loss), cardiomyopathy, and rhabdomyolysis.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of selumetinib states that the coadministration of selumetinib with strong or moderate CYP3A4 inhibitors should be avoided. If coadministration cannot be avoided, the dosage of selumetinib should be reduced as follows: -If the current dose is 25 mg/m2 twice daily, reduce to 20 mg/m2 twice daily. -If the current dosage is 20 mg/m2 twice daily, reduce to 15 mg/m2 twice daily. If the strong or moderate CYP3A4 inhibitor is discontinued, resume the selumetinib dose that was taken prior to the initiation of the inhibitor after 3 half-lives of the CYP3A4 inhibitor have elapsed.(1)

DISCUSSION: In a study of 26 healthy subjects, itraconazole 200 mg twice daily (a strong CYP3A4 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of selumetinib 25 mg by 49% and 19%, respectively. Fluconazole 400 mg loading dose then 200 mg daily (a moderate CYP3A4 inhibitor and strong CYP2C19 inhibitor) increased AUC and Cmax of selumetinib (25 mg) by 53% and 26%.(1,2) In a pharmacokinetic model, erythromycin (a moderate CYP3A4 inhibitor) was predicted to increase selumetinib AUC and Cmax by 41% and 23%, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib and voriconazole.(3) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(3)

Strong And Moderate Cyp3a4 Inhibitors/Tezacaftor-Ivacaftor

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

MECHANISM OF ACTION: Strong and moderate inhibitors of CYP3A4 may inhibit the metabolism of tezacaftor-ivacaftor.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may result in elevated levels of and toxicity from tezacaftor-ivacaftor.(1,2)

PREDISPOSING FACTORS: This interaction may be more severe in patients with hepatic impairment.(1,2)

PATIENT MANAGEMENT: Refer to current prescribing information for tezacaftor-ivacaftor for dose adjustment recommendations with strong and moderate CYP3A4 inhibitors.(2) Dose modifications for concurrent use of strong CYP3A4 inhibitors: - In adults, patients 12 years and older, and patients 6 to 12 years old weighing at least 30 kg who are receiving concurrent strong CYP3A4 inhibitors, the morning dose of tezacaftor 100 mg/ivacaftor 150 mg should be given twice a week, approximately 3 to 4 days apart. The evening dose of ivacaftor 150 mg should not be taken. - In patients 6 to 12 years old weighing less than 30 kg who are receiving concurrent strong CYP3A4 inhibitors, the morning dose of tezacaftor 50 mg/ivacaftor 75 mg should be given twice a week, approximately 3 to 4 days apart. The evening dose of ivacaftor 75 mg should not be taken.(2) Dose modifications for concurrent use of moderate CYP3A4 inhibitors: - In adults, patients 12 years and older, and patients 6 to 12 years old weighing at least 30 kg who are receiving concurrent moderate CYP3A4 inhibitors, the morning dose of tezacaftor 100 mg/ivacaftor 150 mg should be given every other day alternating with ivacaftor 150 mg. The evening dose of ivacaftor 150 mg should not be taken. - In patients 6 to 12 years old weighing less than 30 kg who are receiving concurrent moderate CYP3A4 inhibitors, the morning dose of tezacaftor 50 mg/ivacaftor 75 mg should be given every other day alternating with ivacaftor 75 mg. The evening dose of ivacaftor 75 mg should not be taken.(2)

DISCUSSION: Concurrent administration with ketoconazole (a strong inhibitor of CYP3A4) increased ivacaftor area-under-curve (AUC) by 8.5-fold.(1) Concurrent administration with fluconazole (a moderate inhibitor of CYP3A4) increased ivacaftor AUC by 3-fold.(1) Concurrent administration with itraconazole (a strong inhibitor of CYP3A4) increased tezacaftor AUC by 4-fold and ivacaftor by 15.6-fold.(2) Concurrent administration with fluconazole (a moderate inhibitor of CYP3A4) increased tezacaftor AUC by 2-fold.(2) A study in 12 subjects compared ivacaftor alone (study A), ivacaftor with ritonavir (a strong inhibitor of CYP3A4) 50 mg daily on days 1-4 (study B), and ivacaftor with ritonavir 50 mg daily for two weeks prior and on days 1-4 of ivacaftor administration (study C). In study A, B, and C, ivacaftor AUC increased from 10.94 mcg/hr to 215.6 mcg/hr and 216 mcg/hr, respectively, with the addition of ritonavir. Ivacaftor concentration maximum (Cmax) was 0.9944 mcg, 1.812 mcg, and 2.267 mcg in study A, B, and C, respectively.(3) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(4-6) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir/ritonavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(4-6)

Strong Or Moderate Cyp3a4 Inhibitors/Simeprevir

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

MECHANISM OF ACTION: Strong or moderate inhibitors of CYP3A4 may slow down the metabolism of simeprevir.(1) Simeprevir may inhibit the metabolism of darunavir, diltiazem, erythromycin, and verapamil.(1)

CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inhibitors may result in elevated levels of and toxicity from simeprevir.(1) Simeprevir may increase levels and toxicity of darunavir, diltiazem, erythromycin, and verapamil.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of simeprevir states that concurrent administration of strong or moderate inhibitors of CYP3A4 is not recommended due to risk of toxicity.(1) The American Society of Transplantation guidelines state that the combination of cyclosporine and simeprevir is contraindicated.(7) The US manufacturer of itraconazole states that concurrent administration with simeprevir is not recommended during and two weeks after itraconazole treatment (6).

DISCUSSION: In a study in 24 subjects, erythromycin (500 mg TID for 7 days) increased the maximum concentration (Cmax), area-under-curve (AUC) and Cmin of simeprevir (150 mg daily for 7 days) by 4.53-fold, 7.47-fold, and 12.74-fold, respectively. The Cmax and AUC of erythromycin increased by 1.59-fold and 1.39-fold, respectively.(1) In a study in 9 subjects, an individualized dose of cyclosporine increased the Cmax and AUC of simeprevir (150 mg daily for 14 days) by 4.74 fold and 5.81-fold.(1) In a study in 25 subjects, simeprevir (50 mg once daily) increased the Cmax, AUC, and Cmin of darunavir (800 mg once daily) by 4%, 18%, and 31%.(4) In a study in 25 subjects, darunavir-ritonavir (800 mg-100 mg once daily) increased the Cmax, AUC, and Cmin of simeprevir (50 mg once daily) by 1.79-fold, 2.59-fold, and 4.58-fold.(4) In a study in 12 subjects, ritonavir (100 mg twice daily, 15 days) increased the AUC, Cmax, and Cmin of simeprevir (200 mg daily, 7 days) by 618% (463-815%), 370% (284-476%), and 1335% (929-1901%).(5) Strong and moderate inhibitors of CYP3A4 linked to this monograph include adagrasib, amprenavir, aprepitant, atazanavir, avacopan, berotralstat, boceprevir, ceritinib, clarithromycin, clofazimine, cobicistat, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, ensitrelvir, erythromycin, fedratinib, fosamprenavir, fluconazole, fluvoxamine, fosnetupitant, idelalisib, imatinib, indinavir, isavuconazonium, itraconazole, josamycin, ketoconazole, lefamulin, lenacapavir, lonafarnib, lopinavir, mibefradil, mifepristone, milk thistle, nefazodone, nelfinavir, netupitant, nilotinib, nirmatrelvir/ritonavir, nirogacestat, posaconazole, relacorilant, ribociclib, rilzabrutinib, ritonavir, saquinavir, schisandra, silibinin, stiripentol, telaprevir, telithromycin, tipranavir, treosulfan, troleandomycin, tucatinib, verapamil, and voriconazole.(1-3)

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

Cyp3a4; Cyp2c8; P-Glycoprotein (P-Gp) Inhibitors/Loperamide

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

MECHANISM OF ACTION: Inhibitors of CYP3A4, CYP2C8, and/or P-gp may increase loperamide systemic absorption and facilitate entry into central nervous system (CNS).(1)

CLINICAL EFFECTS: Concurrent use of inhibitors of CYP3A4, CYP2C8, and/or P-gp may increase levels of loperamide, resulting in respiratory depression.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Use loperamide with caution in patients receiving inhibitors of CYP3A4, CYP2C8, and/or P-gp. Consider lower doses of loperamide in these patients and monitor for adverse effects. The manufacturer of lonafarnib recommends starting loperamide at a dose of 1 mg and slowly increasing the dose as needed.(2)

DISCUSSION: In a randomized, cross-over study in 12 healthy subjects, itraconazole (100 mg twice daily for 5 days - first dose 200 mg), gemfibrozil (600 mg twice daily), and the combination of itraconazole and gemfibrozil (same dosages) increased the area-under-curve (AUC) of single doses of loperamide (4 mg) by 2.9-fold, 1.6-fold, and 4.2-fold, respectively.(3) In a study of healthy subjects, lonafarnib (100 mg twice daily for 5 days) increased the AUC and maximum concentration (Cmax) of single dose loperamide (2 mg) by 299% and 214%, respectively.(3) In a study in 18 healthy males, quinidine increased the AUC of a single dose of loperamide by 2.2-fold and markedly decreased pupil size.(4) In a study in 8 healthy subjects, subjects experienced respiratory depression when a single dose of loperamide (16 mg) was administered with a single dose of quinidine (600 mg) but not when loperamide was administered alone.(6) Loperamide plasma levels increased 2-fold to 3-fold.(5) Coadministration of trofinetide 12,000 mg twice daily with 4 mg of loperamide increased the AUC of loperamide by 1.73-fold and the Cmax by 1.95-fold. Administration of trofinetide 2 hours prior to loperamide increased the AUC of loperamide by 1.22-fold and the Cmax by 1.44-fold.(7)

Dual P-Gp And Moderate Cyp3a4 Inhibitors/Everolimus

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

MECHANISM OF ACTION: Dual P-glycoprotein (P-gp) and moderate CYP3A4 inhibitors may increase absorption and decrease elimination of everolimus.(1-2)

CLINICAL EFFECTS: Concurrent use of dual P-gp and moderate CYP3A4 inhibitors may result in elevated levels of and toxicity from everolimus.(1-2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If concurrent therapy with everolimus and dual P-gp and moderate CYP3A4 inhibitors is warranted, reduce the dosage of everolimus.(1) In patients with advanced hormone receptor-positive, HER2-negative breast cancer (HR+BC); advanced pancreatic neuroendocrine tumors (PNET); advanced renal cell carcinoma; or renal angiomyolipoma with TSC, decrease the dose of everolimus to 2.5 mg daily. An increase to 5 mg daily may be considered based on patient tolerance. If the inhibitor is discontinued, allow an elimination period of 3 days before increasing the dose to that used prior to the inhibitor.(1) In patients with subependymal giant cell astrocytoma with TSC and TSC-associated partial-onset seizures, reduce the dosage of everolimus by 50% to maintain trough concentrations of 5 ng/ml to 15 ng/ml. If the patient is already receiving 2.5 mg daily, consider a dose of 2.5 mg every other day. Assess everolimus levels 2 weeks after the addition of the inhibitor. Resume the everolimus dose used prior to initiation of the inhibitor after the inhibitor has been discontinued for 3 days, and assess everolimus trough levels 2 weeks later.(1) In patients taking everolimus for prophylaxis of organ rejection, monitor everolimus blood concentration and adjust dose as needed.(2) Guidelines from the American Society of Transplantation state that protease inhibitors are contraindicated, and recommend avoiding the use of erythromycin with everolimus. If the combination must be used, lower the dose of everolimus by up to 50% upon initiation of the antibiotic and monitor levels daily.(3)

DISCUSSION: In a study in healthy subjects, concurrent use of erythromycin, a moderate CYP3A4 inhibitor and a P-gp inhibitor, increased everolimus AUC and Cmax by 2.0-fold and 4.4-fold, respectively.(1) 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.(1) In a study in healthy subjects, concurrent use of verapamil, a moderate CYP3A4 inhibitor and a P-gp inhibitor, increased everolimus AUC and Cmax by 2.3-fold and 3.5-fold, respectively.(1) In a study in 16 healthy subjects, concurrent use of verapamil increased everolimus Cmax and AUC by 130% and 250%, respectively.(4) Moderate CYP3A4 and/or P-gp inhibitors include: conivaptan, diltiazem, dronedarone, erythromycin, fluvoxamine, isavuconazonium, lenacapavir, rilzabrutinib, and verapamil.(5-7)

Immunosuppressives; Immunomodulators/Cladribine Oncology Inj

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

MECHANISM OF ACTION: Cladribine in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-4)

CLINICAL EFFECTS: Concurrent use of cladribine with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections.(1-4)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: Recommendations for cladribine regarding this interaction differ between regulatory approving agencies. The cladribine US, UK, and Australian prescribing information state: -Caution should be exercised if cladribine injection is administered before, after, or in conjunction with other drugs known to cause immunosuppression or myelosuppression.(1-3) The cladribine Canadian prescribing information states: -Proceed carefully in patients with severe bone marrow impairment of any etiology since further suppression of bone marrow function should be anticipated.(4)

DISCUSSION: Severe bone marrow suppression, including neutropenia, anemia and thrombocytopenia, has been commonly observed in patients treated with cladribine injection, especially at high doses.(1-4)

Immunosuppressives; Immunomodulators/Covid-19 Vaccines

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

MECHANISM OF ACTION: Immunosuppressants and immunomodulators may prevent the immune system from properly responding to the COVID-19 vaccine.(1-3)

CLINICAL EFFECTS: Administration of a COVID-19 vaccine with immunosuppressants or immunomodulators may interfere with vaccine-induced immune response and impair the efficacy of the vaccine. However, patients should be offered and given a COVID-19 vaccine even if the use and timing of immunosuppressive agents cannot be adjusted.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Centers for Disease Control and Prevention (CDC),(1) Infectious Diseases Society of America (IDSA),(2) and the American College of Rheumatology (ACR)(3) have published guidances for COVID-19 vaccination in patients on immunosuppressants. The CDC states that all immunocompromised patients over 6 months of age should receive at least 1 dose of COVID-19 vaccine if eligible. See the CDC's Interim Clinical Considerations for Use of COVID-19 Vaccines for specific recommendations based on age, vaccination history, and vaccine manufacturer.(1) The CDC advises planning for vaccination at least 2 weeks before starting or resuming immunosuppressive therapy.(1) IDSA recommends timing COVID-19 vaccination at least 2 weeks before starting or at least 3 months after completing immunosuppressive therapy.(2) The ACR states that in general, immunosuppressants and immunomodulators should be held for 1-2 weeks after each vaccine dose.(3) Patients should be offered and given a COVID-19 vaccine even if the use and timing of immunosuppressive agents cannot be adjusted, though the immune response will likely be blunted. COVID-19 vaccines should not be delayed in patients taking immunosuppressive therapies.(1-2) See below for specific recommendations for certain agents. B-cell depleting agents, including rituximab: The CDC states that the utility of B-cell quantification to guide clinical care is not known and is not recommended. Patients who receive B-cell depleting therapy on a continuing basis should receive COVID-19 vaccines about 4 weeks before the next scheduled dose. For patients who received 1 or more doses of COVID-19 vaccine during treatment with B-cell-depleting therapies that were administered over a limited period (e.g., as part of a treatment regimen for certain malignancies), revaccination may be considered according to the current CDC recommendations for unvaccinated patients. The suggested interval to start revaccination is about 6 months after completion of the B-cell-depleting therapy.(1) IDSA recommends waiting for at least 3-6 months after the last infusion of B-cell depleting therapy before administering COVID-19 vaccines.(2) The ACR recommends consulting with the rheumatologist to determine optimal timing of COVID-19 vaccination. Measuring CD19 B cells may be considered to determine need for a booster vaccine dose. If B cell levels are not measured, a supplemental vaccine dose 2-4 weeks before the next scheduled dose of rituximab is recommended.(3) Recipients of hematopoietic cell transplant or CAR-T-cell therapy who received one or more doses of COVID-19 vaccine prior to or during treatment should undergo revaccination following the current CDC recommendations for unvaccinated patients. Revaccination should start at least 3 months (12 weeks) after transplant or CAR-T-cell therapy.(1,2) The CDC includes abatacept, cyclophosphamide, and TNF-alpha and cytokine inhibitors in their general recommendation to hold therapy for at least 2 weeks following vaccination (1) while the ACR provides different recommendations:(3) *Abatacept: - Subcutaneous abatacept should be withheld for 1-2 weeks after each vaccine dose, as disease activity allows. - For intravenous abatacept, time administration so that vaccination will occur 1 week before the next abatacept infusion. *Cyclophosphamide: When feasible, administer cyclophosphamide 1 week after each COVID-19 vaccine dose. *TNF-alpha inhibitors and cytokine inhibitors: The ACR was not able to reach consensus on whether to modify dosing or timing of these agents with COVID-19 vaccination.

DISCUSSION: IDSA recommendations are based on cohort and case control studies in immunocompromised patients that found low to modest vaccine effectiveness (37-61%) but lower risks of COVID-19 association hospitalization, COVID-19 related mortality, and critical illness.(2) The ACR convened a COVID-19 Vaccine Guidance Task Force to provide guidance on optimal use of COVID-19 vaccines in rheumatology patients. These recommendations are based on limited clinical evidence of COVID-19 vaccines in patients without rheumatic and musculoskeletal disorders and evidence of other vaccines in this patient population.(3) The ACR recommendation for rituximab is based on studies of humoral immunity following receipt of other vaccines. These studies have uncertain generalizability to vaccination against COVID-19, as it is unknown if efficacy is attributable to induction of host T cells versus B cell (antibody-based) immunity.(3) The ACR recommendation for mycophenolate is based on preexisting data of mycophenolate on non-COVID-19 vaccine immunogenicity. Emerging data suggests that mycophenolate may impair SARS-CoV-2 vaccine response in rheumatic and musculoskeletal disease and transplant patients.(3) The ACR recommendation for methotrexate is based on data from influenza vaccines and pneumococcal vaccines with methotrexate.(3) The ACR recommendation for JAK inhibitors is based on concerns related to the effects of JAK inhibitors on interferon signaling that may result in a diminished vaccine response.(3) The ACR recommendation for subcutaneous abatacept is based on several studies suggesting a negative effect of abatacept on vaccine immunogenicity. The first vaccine dose primes naive T cells, naive T cell priming is inhibited by CTLA-4, and abatacept is a CTLA-4Ig construct. CTLA-4 should not inhibit boosts of already primed T cells at the time of the second vaccine dose.(3)

Immunosuppressives; Immunomodulators/Sarilumab

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

MECHANISM OF ACTION: Sarilumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of sarilumab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sarilumab recommends caution because the concurrent use of sarilumab with immunosuppressive agents may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)

DISCUSSION: Sarilumab was studied as monotherapy and in combination with methotrexate or conventional disease modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis studies. Sarilumab has not been studied with biological DMARDs and concurrent use should be avoided. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents.(1) The most common infections reported by sarilumab treated patients in the clinical trial periods included pneumonia and cellulitis. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving sarilumab. Cases of tuberculosis, candidiasis, and pneumocystis with sarilumab have been reported.(1)

Immunosuppressives; Immunomodulators/Tocilizumab

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

MECHANISM OF ACTION: Tocilizumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of tocilizumab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of tocilizumab recommends caution because the concurrent use of tocilizumab with immunosuppressive agents may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)

DISCUSSION: Tocilizumab was studied as monotherapy and in combination with methotrexate, non-biologic DMARDs or corticosteroids, depending on the indication. Tocilizumab has not been studied with biological DMARDs and concurrent use should be avoided. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents.(1) The most common infections reported by tocilizumab treated patients in the clinical trial periods included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving tocilizumab. Cases of tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis have been reported.(1)

Immunosuppressives; Immunomodulators/Ublituximab

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

MECHANISM OF ACTION: Ublituximab, immunosuppressives, and immunomodulators all suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of ublituximab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: The US manufacturer of ublituximab recommends caution because the concurrent use of ublituximab with immunomodulating or immunosuppressive agents, including immunosuppressant doses of corticosteroids, may increase the risk of infection.(1) If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents. When switching from agents with immune effects, the half-life and mechanism of action of these drugs must be taken into consideration in order to prevent additive immunosuppressive effects.(1)

DISCUSSION: The most common infections reported by ublituximab-treated patients in the clinical trial periods included upper respiratory tract infections and urinary tract infections. Serious, including life-threatening or fatal, bacterial and viral infections were observed in patients receiving ublituximab.(1) Serious and/or fatal bacterial, fungal, and new or reactivated viral infections have been associated with other anti-CD20 B-cell depleting therapies. There were no cases of progressive multifocal leukoencephalopathy (PML) reported during the clinical trials; however, there have been reports of PML during or following completion of other anti-CD20 B-cell depleting therapies.(1)

Immunosuppressives; Immunomodulators/Ustekinumab

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

MECHANISM OF ACTION: Ustekinumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of ustekinumab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of ustekinumab recommends caution because the concurrent use of ustekinumab with immunosuppressive agents may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)

DISCUSSION: Ustekinumab has not been studied in combination with other immunosuppressants in psoriasis studies. In psoriatic arthritis studies, concomitant methotrexate use did not appear to influence the safety or efficacy of ustekinumab. In Crohn's disease and ulcerative colitis studies, concomitant use of immunosuppressants or corticosteroids did not appear to influence the safety or efficacy of ustekinumab. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents.(1) The most common infections reported by ustekinumab treated patients in the clinical trial periods included nasopharyngitis(8%) and upper respiratory tract infection(5%). Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving ustekinumab. Cases of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia resulting in respiratory failure or prolonged hospitalization have been reported in patients receiving ustekinumab.(1)

Moderat Cyp3a4 Inhibitor/Vanzacaftor-Tezacaftor-Deutivacafto

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 vanzacaftor-tezacaftor-deutivacaftor. Vanzacaftor, tezacaftor, and deutivacaftor are CYP3A substrates.(1)

CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor may result in elevated levels of and toxicity from vanzacaftor-tezacaftor-deutivacaftor, such as hepatotoxicity.(1)

PREDISPOSING FACTORS: This interaction may be more severe in patients with hepatic impairment.(1)

PATIENT MANAGEMENT: The US manufacturer of vanzacaftor-tezacaftor-deutivacaftor states that concurrent use with moderate CYP3A4 inhibitors requires a dose adjustment. If concurrent use is warranted, the following dose adjustments are recommended: -For age 6 to less than 12 years old AND less than 40 kg - Two tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg every other day; -For age 6 to less than 12 years old AND greater than or equal to 40 kg - One tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every other day; -For age 12 years and older AND any weight - One tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every other day.(1)

DISCUSSION: Concurrent administration with itraconazole (200 mg every 12 hours on Day 1, followed by 200 mg daily, a strong inhibitor of CYP3A4) with tezacaftor (25 mg daily)-ivacaftor (50 mg daily) increased tezacaftor area-under-curve (AUC) and concentration maximum (Cmax) by 4-fold and 2.83-fold, respectively.(1) Concurrent administration with itraconazole (200 mg daily, a strong inhibitor of CYP3A4) with single-dose elexacaftor 20 mg-tezacaftor 50 mg-deutivacaftor 50 mg increased tezacaftor AUC and Cmax by 4.51-fold and 1.48-fold and deutivacaftor AUC and Cmax by 11.1-fold and 1.96-fold.(1) Concurrent administration with itraconazole (200 mg daily, a strong inhibitor of CYP3A4) with vanzacaftor (5 mg single dose) increased vanzacaftor AUC and Cmax by 6.37-fold and 1.55-fold, respectively.(1) Concurrent administration with fluconazole (200 mg daily, a moderate inhibitor of CYP3A4) with vanzacaftor (20 mg daily)-tezacaftor (100 mg daily)-deutivacaftor (250 mg daily) is predicted to increase vanzacaftor AUC and Cmax by 2.55-fold and 2.48-fold and deutivacaftor by 3.13-fold and 2.27-fold, respectively.(1) Concurrent administration with erythromycin (500 mg four times daily, a moderate inhibitor of CYP3A4) with vanzacaftor (20 mg daily)-tezacaftor (100 mg daily)-deutivacaftor (250 mg daily) is predicted to increase vanzacaftor AUC and Cmax by 3.29-fold and 3.19-fold and deutivacaftor by 4.13-fold and 2.89-fold, respectively.(1) Concurrent administration with verapamil (80 mg three times daily, a moderate inhibitor of CYP3A4) with vanzacaftor (20 mg daily)-tezacaftor (100 mg daily)-deutivacaftor (250 mg daily) is predicted to increase vanzacaftor AUC and Cmax by 3.93-fold and 3.8-fold and deutivacaftor by 5.11-fold and 3.43-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2-4)

Moderate Cyp3a4 Inhibitors/Abemaciclib

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

MECHANISM OF ACTION: Abemaciclib is a substrate of CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of abemaciclib.(1)

CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels and toxicity from abemaciclib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of abemaciclib recommends monitoring for adverse reactions and consider a dose reduction of abemaciclib dose in 50 mg decrements as detailed in prescribing information (based on starting dose, previous dose reductions, and combination or monotherapy use) with concurrent use of moderate CYP3A4 inhibitors.(1) Monitor patient for signs and symptoms of abemaciclib toxicity with concurrent use.

DISCUSSION: Abemaciclib is a substrate of CYP3A4.(1) Concurrent administration of verapamil and diltiazem (moderate CYP3A4 inhibitors) are predicted to increase the relative adjusted unbound area-under-curve (AUC) of abemaciclib and its active metabolites (M2, M18, and M20) by approximately 1.6-fold and 2.4-fold, respectively.(1) Concurrent administration of ketoconazole (a strong CYP3A4 inhibitor) is predicted to increase the AUC of abemaciclib up to 16-fold.(1) Concurrent administration of itraconazole (a strong CYP3A4 inhibitor) is predicted to increase the relative potency adjusted unbound AUC of abemaciclib and its active metabolites (M2, M18, and M20) by 2.2-fold.(1) Concurrent administration of clarithromycin (500 mg twice daily, a strong CYP3A4 inhibitor) with a single dose of 50 mg of abemaciclib increased the relative potency adjusted unbound AUC of abemaciclib and its active metabolites (M2, M18, and M20) by 2.5-fold.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, avacopan, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2,3)

Moderate Cyp3a4 Inhibitors/Avanafil (<= 50 Mg)

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 avanafil.(1)

CLINICAL EFFECTS: The concurrent administration of a moderate CYP3A4 inhibitor may result in elevated levels of avanafil, which may result in increased adverse effects such as hypotension, visual changes, and priapism.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of avanafil states that in patients receiving moderate inhibitors of CYP3A4, the dose of avanafil should be limited to 50 mg in 24 hours.(1)

DISCUSSION: Ketoconazole (400 mg daily), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of avanafil (50 mg) by 3-fold and 13-fold, respectively. The half-life of avanafil increased from 5 hours to 9 hours.(1) Ritonavir (600 mg BID), a strong inhibitor of CYP3A4 and an inhibitor of 2C19, increased the Cmax and AUC of a single dose of avanafil (50 mg) by 2-fold and 13-fold, respectively. The half-life of avanafil increased from 5 hours to 9 hours.(1) Erythromycin (500 mg BID), a moderate inhibitor of CYP3A4, increased the Cmax and AUC of a single dose of avanafil (200 mg) by 2-fold and 3-fold, respectively. The half-life of avanafil increased from 5 hours to 8 hours.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, grapefruit juice, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(1-3)

Moderate Cyp3a4 Inhibitors/Avapritinib

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 avapritinib.(1)

CLINICAL EFFECTS: Concurrent use of avapritinib with a moderate CYP3A4 inhibitor increases avapritinib plasma concentrations, which may increase the incidence and severity of adverse reactions of avapritinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant use of avapritinib with strong or moderate CYP3A4 inhibitors. If coadministration of avapritinib with a moderate CYP3A4 inhibitor cannot be avoided, reduce the dose of avapritinib to 100 mg once daily for treatment of gastrointestinal stromal tumors or 50 mg once daily for treatment of advanced systemic mastocytosis.(1)

DISCUSSION: Coadministration of avapritinib 300 mg once daily with fluconazole 200 mg once daily, a moderate CYP3A4 inhibitor, is predicted to increase avapritinib AUC by 210% at steady state.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2,3)

Moderate Cyp3a4 Inhibitors/Brexpiprazole

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

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

CLINICAL EFFECTS: Concurrent administration of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from brexpiprazole.(1)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients who are CYP2D6 poor metabolizers, or who receive concomitant treatment with a strong or moderate CYP2D6 inhibitor (e.g. bupropion, fluoxetine, paroxetine, quinidine) in addition to treatment with a moderate CYP3A4 inhibitor.

PATIENT MANAGEMENT: The US manufacturer of brexpiprazole recommends the following dose adjustments for patients who are receiving a moderate CYP3A4 inhibitor: - in patients taking a moderate CYP3A4 inhibitor who are poor CYP2D6 metabolizers or are receiving a strong or moderate inhibitor of CYP2D6, decrease the dose to one-fourth the usual dose. The dose of brexpiprazole should be adjusted to its original level if the CYP3A4 inhibitor is discontinued.(1) No empiric dosage adjustment is recommended in other patients.

DISCUSSION: Coadministration of ketoconazole, a strong inhibitor of CYP3A4, increased the area-under-curve (AUC) of brexpiprazole approximately 2-fold.(1) Moderate CYP3A4 inhibitors linked to this monograph include aprepitant, avacopan, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.

Moderate Cyp3a4 Inhibitors/Bromocriptine

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

MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of bromocriptine.

CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor may result in increased levels of bromocriptine, which may result in increased side effects of these agents.

PREDISPOSING FACTORS: Patients receiving the maximum recommended (or higher than recommended) dosages of ergotamine derivatives may be at a higher risk of adverse effects from this combination.

PATIENT MANAGEMENT: Use caution with concurrent therapy with bromocriptine with azole antifungals. The US manufacturer of bromocriptine states use caution when co-administering drugs that are inhibitors of CYP3A4. Bromocriptine dose should not exceed 1.6 mg per day when used with a moderate CYP3A4 inhibitor. Concomitant use of strong CYP3A4 inhibitors should be avoided. Ensure adequate washout of strong CYP3A4 inhibitor drug before initiating bromocriptine.(1)

DISCUSSION: A study in five healthy subjects found that concurrent administration of erythromycin and bromocriptine resulted in a 268% increase in area-under-curve (AUC) for bromocriptine and a 4.6-fold increase in bromocriptine maximum concentration (Cmax).(2) Inhibition of ergotamine derivative metabolism by moderate inhibitors would also be expected, but to a lesser degree. Moderate CYP3A4 inhibitors linked to this monograph are aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(3,4)

Moderate Cyp3a4 Inhibitors/Cabergoline

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

MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of cabergoline.

CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor may result in increased levels of cabergoline, which may result in increased side effects of cabergoline.

PREDISPOSING FACTORS: Patients receiving the maximum recommended (or higher than recommended) dosages of cabergoline may be at a higher risk of adverse effects from this combination.

PATIENT MANAGEMENT: Use caution with concurrent therapy with cabergoline and moderate CYP3A4 inhibitors.

DISCUSSION: Cabergoline metabolism has been shown to be inhibited by strong CYP3A4 inhibitors, including macrolides and itraconazole.(1,2) Inhibition of cabergoline metabolism by moderate inhibitors would also be expected, but to a lesser degree. Moderate CYP3A4 inhibitors linked to this monograph are aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(3,4)

Moderate Cyp3a4 Inhibitors/Capivasertib

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

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

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in increased systemic exposure to and effects from capivasertib, hyperglycemia, severe diarrhea, and cutaneous adverse reactions.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concomitant use of capivasertib with moderate CYP3A4 inhibitors requires a dose reduction of capivasertib. Reduce the capivasertib dose to 320 mg twice daily for 4 days followed by 3 days off.(1) After discontinuation of the strong CYP3A4 inhibitor for 3 to 5 half-lives of the inhibitor, resume the capivasertib dosage that was taken prior to initiating the strong CYP3A4 inhibitor.(1)

DISCUSSION: Itraconazole (strong CYP3A4 inhibitor) is predicted to increase capivasertib area-under-curve (AUC) by up to 1.7-fold and maximum concentration (Cmax) by up to 1.4-fold.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)

Moderate Cyp3a4 Inhibitors/Dapoxetine (<= 30 Mg)

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

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

CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in elevated levels and increased effects of dapoxetine.(1-3)

PREDISPOSING FACTORS: If the patient is a CYP2D6 poor metabolizer, dapoxetine metabolism can be further inhibited.(1-3)

PATIENT MANAGEMENT: The manufacturers of dapoxetine state that the dose of dapoxetine should not exceed 30 mg daily if coadministered with moderate CYP3A4 inhibitors.(1-3)

DISCUSSION: The impact of moderate CYP3A4 inhibitors on the pharmacokinetics of dapoxetine has not been investigated in clinical studies.(1-3) Ketoconazole (200 mg twice daily for 7 days), a strong inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of dapoxetine (30 mg) by 35% and 99%, respectively. The Cmax and AUC of the active fraction are expected to increase by 25% and 2-fold, respectively, with strong inhibitors of CYP3A4.(1-3) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(4,5)

Moderate Cyp3a4 Inhibitors/Daraxonrasib (<=200 Mg)

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

MECHANISM OF ACTION: Daraxonrasib is a substrate of CYP3A4. Moderate CYP3A4 inhibitors may inhibit the metabolism of daraxonrasib.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase the levels and toxicities of daraxonrasib, including dermatologic toxicity, stomatitis, GI perforation, and interstitial lung disease/pneumonitis.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: For patients taking agents that are moderate CYP3A4 inhibitors, reduce the dose of daraxonrasib to 200 mg once daily. If the inhibitor is discontinued, resume the previous dose of daraxonrasib after 3 to 5 half-lives of the inhibitor.(1)

DISCUSSION: In a pharmacokinetic model, fluconazole 200 mg twice daily (a moderate CYP3A inhibitor) increased the area under curve (AUC) of daraxonrasib by 1.5-fold.(1) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, crizotinib, darunavir, duvelisib, fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, stiripentol, tofisopam, treosulfan, and voxelotor.(2-3)

Moderate Cyp3a4 Inhibitors/Daridorexant (<=25 Mg)

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 daridorexant.(1)

CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels of and effects from daridorexant including somnolence, fatigue, CNS depressant effects, daytime impairment, or headache.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The dose of daridorexant should be limited to 25 mg daily when used with a moderate CYP3A4 inhibitor.(1)

DISCUSSION: Daridorexant is a CYP3A4 substrate. In a PKPB model, concurrent use of daridorexant with diltiazem, a moderate CYP3A4 inhibitor, increased daridorexant area-under-curve (AUC) and maximum concentration (Cmax) by 2.4-fold and 1.4-fold, respectively.(1) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(2)

Moderate Cyp3a4 Inhibitors/Elinzanetant

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

MECHANISM OF ACTION: Elinzanetant is metabolized via CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of elinzanetant.(1,2)

CLINICAL EFFECTS: Concurrent use of elinzanetant with moderate CYP3A4 inhibitors may result in an increase in exposure of elinzanetant.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Canadian(1) and US(2) manufacturers of elinzanetant recommends reducing the dose of elinzanetant to 60 mg once daily at bedtime when coadministered with moderate CYP3A4 inhibitors. After discontinuation of the moderate inhibitor (after 3 to 5 half lives of the inhibitor), elinzanetant should be used at the usual dose of 120 mg once daily.(1,2)

DISCUSSION: Concomitant use of erythromycin (moderate CYP3A4 inhibitor) increased elinzanetant 120 mg area-under-curve (AUC) and maximum concentration (Cmax) by 3-fold and 2-fold, respectively. Concomitant use of erythromycin with elinzanetant 60 mg increased elinzanetant AUC by 1.4-fold.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)

Moderate Cyp3a4 Inhibitors/Finerenone

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 finerenone.(1)

CLINICAL EFFECTS: Concurrent use of finerenone with a moderate inhibitor of CYP3A4 increases finerenone concentrations and may increase the risk of toxicity (e.g., hyperkalemia, hypotension).(1)

PREDISPOSING FACTORS: Severe renal disease and concurrent use of potassium supplements increase the risk for hyperkalemia.

PATIENT MANAGEMENT: The manufacturer of finerenone states that use with moderate CYP3A4 inhibitors should be closely monitored. Check serum potassium during drug initiation or dosage adjustment of either finerenone or the moderate CYP3A4 inhibitor. Dose adjustment of finerenone may be necessary.(1)

DISCUSSION: Concurrent use of finerenone with erythromycin, a moderate CYP3A4 inhibitor, increased finerenone area-under-curve (AUC) by 248% and maximum concentration (Cmax) by 88%.(1) Concurrent use of finerenone with verapamil, a moderate CYP3A4 inhibitor, increased finerenone AUC by 170% and Cmax by 122%.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)

Moderate Cyp3a4 Inhibitors/Gepirone

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

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

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase the levels of and effects from gepirone, including QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP). Serotonin syndrome may also result. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(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)

PATIENT MANAGEMENT: If gepirone is used concurrently with a moderate CYP3A4 inhibitor, reduce the dose of gepirone by 50%.(1) Monitor for prolongation of the QTc interval.(1) When concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If QTcF is > 450 msec at baseline, do not initiate gepirone. If QTc increases to > 450 msec during treatment, monitor ECGs more frequently and do not increase the dose of gepirone.(1)

DISCUSSION: In a study, verapamil (80 mg 3 times daily), a moderate CYP3A4 inhibitor, increased both the maximum concentration (Cmax) and area-under-curve (AUC) of gepirone 18.2 mg by about 2.75-fold.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)

Moderate Cyp3a4 Inhibitors/Ibrutinib

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

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

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase levels of and effects from ibrutinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of moderate CYP3A4 inhibitors in patients undergoing therapy with ibrutinib requires a dose adjustment.(1) If a moderate CYP3A4 inhibitor is required for B-cell malignancies treatment, reduce the dose of ibrutinib to 280 mg daily.(1) If a moderate CYP3A4 inhibitor is required for chronic graft versus host disease treatment, reduce the dose of ibrutinib in patients 12 years and older to 420 mg once daily, and in patients 1 year to 12 years old to 240 mg/m2 once daily.(1) After discontinuation of a CYP3A4 inhibitor, resume previous dose of ibrutinib.(1)

DISCUSSION: The coadministration of multiple doses of erythromycin (moderate CYP3A inhibitor) increased ibrutinib's concentration maximum (Cmax) and area-under-curve (AUC) by 3.4-fold and 3-fold.(1) In a case report, concomitant administration of ibrutinib and verapamil/trandolapril resulted in ibrutinib toxicity consisting of nausea, dizziness, malaise, and severe diarrhea.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, casopitant, clofazimine, clotrimazole, conivaptan, crizotinib, darunavir, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, grapefruit juice, imatinib, isavuconazonium, ledipasvir, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(1,3,4)

Moderate Cyp3a4 Inhibitors/Larotrectinib

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

MECHANISM OF ACTION: Agents which inhibit the CYP3A4 enzyme may inhibit the metabolism of larotrectinib.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase systemic exposure and the risk for larotrectinib toxicities such as neurotoxicity or hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving a moderate CYP3A4 inhibitor concurrently with larotrectinib should be monitored for adverse effects more frequently. A dose reduction may be needed based on the severity of adverse effects. Refer to prescribing information for dosage modifications.

DISCUSSION: In a drug interaction study in healthy subjects, coadministration of itraconazole (a strong CYP3A4 inhibitor) with a single dose of larotrectinib (100 mg) increased larotrectinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 2.8 and 4.3-fold, respectively.(1) Fluconazole (a moderate CYP3A4 inhibitor) is predicted to increase the AUC and Cmax of larotrectinib by 2.7-fold and 1.9-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)

Moderate Cyp3a4 Inhibitors/Lumateperone (<=21 Mg)

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 lumateperone.(1)

CLINICAL EFFECTS: Concurrent use of lumateperone with moderate CYP3A4 inhibitors increases lumateperone exposure, which may increase the risk of adverse reactions.(1)

PREDISPOSING FACTORS: Patients with moderate or severe hepatic impairment (Child-Pugh class B or C) may be at higher risk of increased lumateperone exposure.(1)

PATIENT MANAGEMENT: The manufacturer of lumateperone recommends decreasing the dosage of lumateperone to 21 mg once daily in patients receiving moderate CYP3A4 inhibitors.(1)

DISCUSSION: Coadministration of lumateperone with itraconazole, a strong CYP3A4 inhibitor, resulted in a 4-fold and 3.5-fold increase in area-under-curve (AUC) and concentration maximum (Cmax), respectively.(1) Coadministration of lumateperone with diltiazem, a moderate CYP3A4 inhibitor, resulted in a 2.5-fold and 2-fold increase AUC and Cmax, respectively.(1) Moderate inhibitors of CYP3A4 include: aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)

Moderate Cyp3a4 Inhibitors/Macitentan

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

MECHANISM OF ACTION: Macitentan is primarily metabolized by CYP3A4, with minor contributions from CYP2C8, CYP2C9, and CYP2C19. Moderate inhibitors of CYP3A4 may inhibit the metabolism of macitentan.(1)

CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in elevated levels and increased effects of macitentan, including hepatotoxicity and fluid retention.(1)

PREDISPOSING FACTORS: Concomitant use of a moderate CYP2C9 inhibitor increases the magnitude of this interaction and the risk of adverse events.

PATIENT MANAGEMENT: The US manufacturer of macitentan states that concurrent use of both a moderate CYP2C9 inhibitor and a moderate CYP3A4 inhibitor should be avoided.(1) The Australian and Canadian manufacturers of macitentan state caution should be exercised when macitentan is administered concomitantly with a moderate CYP3A4 inhibitor.(2,3) While the manufacturer does not provide recommendations for concurrent use of a moderate CYP3A4 inhibitor alone, it would be prudent to use caution and monitor for adverse effects.

DISCUSSION: Based on pharmacokinetic (PBPK) modeling, dual moderate inhibitors of CYP2C9 and CYP3A4 such as fluconazole are predicted to increase macitentan exposure by 4-fold.(1) Pretreatment with ketoconazole increased the area-under-curve (AUC) and maximum concentration (Cmax) of macitentan by approximately 2.3 and 1.3-fold, respectively.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(4)

Moderate Cyp3a4 Inhibitors/Mavorixafor

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

MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of mavorixafor.(1) Mavorixafor is also a substrate of P-glycoprotein (P-gp). P-gp inhibitors may increase mavorixafor exposure.(1) Many CYP3A4 inhibitors also inhibit P-glycoprotein (P-gp), including cimetidine, diltiazem, fluvoxamine, isavuconazonium, schisandra, and verapamil.(2)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase the levels and effects of mavorixafor, including thrombocytopenia and QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)

PREDISPOSING FACTORS: The risk of QT prolongation or 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 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).(3)

PATIENT MANAGEMENT: When used concomitantly with moderate CYP3A4 inhibitors, monitor more frequently for mavorixafor adverse effects and reduce the dose in 100 mg increments, if necessary, but not to a dose less than 200 mg.(1) When concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: There are no clinical studies for the combination of mavorixafor and moderate CYP3A4 inhibitors. In a study with healthy subjects, itraconazole 200 mg daily (a strong CYP3A4 and P-gp inhibitor) increased the exposure to single-dose mavorixafor 200 mg similar to that from single-dose mavorixafor 400 mg alone. This suggests that itraconazole increased mavorixafor exposure by about 2-fold.(1) A study in healthy volunteers found that ritonavir 100 mg twice daily (a strong CYP3A4 inhibitor and P-gp inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose mavorixafor 200 mg by 60% and 39%, respectively.(4) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, cimetidine, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil and voxelotor.(2,5)

Moderate Cyp3a4 Inhibitors/Oliceridine

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

MECHANISM OF ACTION: Oliceridine is metabolized equally by CYP2D6 and CYP3A4. Oliceridine metabolism may be inhibited by inhibitors of CYP2D6 or CYP3A4.(1)

CLINICAL EFFECTS: The concurrent administration of a strong or moderate CYP2D6 or strong or moderate CYP3A4 inhibitor may result in elevated levels of and toxicity from oliceridine including profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: Patients with CYP2D6 poor metabolizer phenotype may be affected to a greater extent by CYP3A4 inhibitors. Inhibition of both CYP2D6 and CYP3A4 pathways may result in a greater increase in the levels of and toxcity of oliceridine.(1)

PATIENT MANAGEMENT: Caution should be used when administering oliceridine to patients taking strong or moderate inhibitors of CYP2D6 or CYP3A4. Dosage adjustments should be made if warranted. Closely monitor these patients for respiratory depression and sedation at frequent intervals and evaluate subsequent doses based on response. If concomitant use of a strong or moderate CYP2D6 or CYP3A4 inhibitor is necessary, less frequent dosing of oliceridine may be required. If a strong or moderate CYP2D6 or CYP3A4 inhibitor is discontinued, increase of the oliceridine dosage may be necessary. Monitor for signs of opioid withdrawal. Patients receiving concurrent therapy with both a strong or moderate CYP3A4 inhibitor and CYP2D6 inhibitors may be at greater risk of adverse effects. Patient who are CYP2D6 normal metabolizers taking a CYP2D6 inhibitor and a strong CYP3A4 inhibitor may require less frequent dosing of oliceridine.(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 other agents that may cause CNS depression.(2) 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).(3)

DISCUSSION: In a study of four healthy subjects who are CYP2D6 poor metabolizers, itraconazole (200 mg daily for 5 days) increased the area-under-curve (AUC) of single-dose oliceridine (0.25 mg) by 80%.(1) In a study of subjects who were not CYP2D6 poor metabolizers, ketoconazole (200 mg for 2 doses 10 hours apart) did not affect the pharmacokinetics of oliceridine.(1) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(4)

Moderate Cyp3a4 Inhibitors/Oveporexton (<=0.5 Mg)

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

MECHANISM OF ACTION: Oveporexton is metabolized by CYP3A4. Moderate CYP3A4 inhibitors may inhibit the metabolism of oveporexton.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase the levels and toxicities of oveporexton, including insomnia, urinary frequency and urgency, and CPK elevation.(1)

PREDISPOSING FACTORS: Adverse reactions from oveporexton may be more likely in patients with Child-Pugh class C hepatic impairment and in patients with severe renal impairment on dialysis.

PATIENT MANAGEMENT: In patients on concomitant moderate CYP3A4 inhibitors with oveporexton, reduce the dosage of oveporexton to 0.5 mg after awakening and then 0.5 mg three to five hours later (maximum recommended dosage is 1 mg per day).(1)

DISCUSSION: In a study, fluconazole (a moderate CYP3A inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of oveporexton by 2.9-fold and 1.5-fold, respectively. Oveporexton half-life was increased by about 2-fold.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2-3)

Moderate Cyp3a4 Inhibitors/Palovarotene

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

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

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in elevated levels of and toxicity from palovarotene, including rash, alopecia, skin exfoliation, photosensitivity, reduction in bone mass, hyperostosis, and night blindness.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of moderate CYP3A4 inhibitors with palovarotene should be avoided. If concurrent use cannot be avoided, reduce the dose of palovarotene by half, according to the US prescribing information.(1)

DISCUSSION: In a clinical trial, erythromycin, a moderate CYP3A4 inhibitor, increased the maximum concentration (Cmax) and area-under-curve (AUC) of palovarotene by 1.6- and 2.5-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)

Moderate Cyp3a4 Inhibitors/Pyrotinib (<= 80 Mg)

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

MECHANISM OF ACTION: Pyrotinib is metabolized via CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of pyrotinib.(1)

CLINICAL EFFECTS: Concurrent use of pyrotinib with moderate CYP3A4 inhibitors may increase the levels and toxicities of pyrotinib, including hepatotoxicity, decreased left ventricular ejection fraction, bone marrow suppression and gastrointestinal adverse effects.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of pyrotinib states coadministration with moderate CYP3A4 inhibitors requires a dose adjustment. Reduce the dose of pyrotinib to 80 mg daily with moderate CYP3A4 inhibitors.(1)

DISCUSSION: In a clinical study of healthy subjects, coadministration of pyrotinib with fluconazole, a moderate CYP3A4 inhibitor, resulted in a 3.6-fold increase in area-under-curve (AUC) and a 2.16-fold increase in maximum concentration (Cmax).(1) Moderate inhibitors of CYP3A4 linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2,3)

Moderate Cyp3a4 Inhibitors/Quetiapine

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

MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of quetiapine. Quetiapine is a sensitive substrate for CYP3A4 and so an approximately 2-fold or higher increase in exposure (AUC, area-under-curve) is possible when quetiapine is given with a moderate CYP3A4 inhibitor.(1-4)

CLINICAL EFFECTS: Concurrent use of a strong or moderate CYP3A4 inhibitor may result in elevated levels of and toxicity from quetiapine, including potentially life-threatening cardiac arrhythmias such as torsades de pointes.(2,3)

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.(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 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).(4)

PATIENT MANAGEMENT: Monitor patients when moderate inhibitors of CYP3A4 are co-prescribed with quetiapine as the magnitude of the interaction is highly variable between patients.(6) Use of higher doses of either the CYP3A4 inhibitor or quetiapine are other factors which may affect the magnitude of this interaction. Decrease the quetiapine dose if needed. 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, fainting, excessive drowsiness, rapid pulse/hypotension, weakness, fatigue, dizziness, or muscle stiffness/tremors (EPS).

DISCUSSION: In a study in 19 Chinese patients with schizophrenia, patients received quetiapine (200 mg twice daily) alone and with erythromycin (500 mg 3 times daily, a moderate inhibitor of CYP3A4). Erythromycin increased the quetiapine maximum concentration (Cmax)by 68%(range approximately 20-130%), area-under-curve (AUC) 129% (range approximately 20-300%), and half-life by 92% (range approximately 0-250%). Quetiapine clearance decreased 52% (range approximately -15 to -80%).(6) Moderate inhibitors of CYP3A4 include: aprepitant, avacopan, berotralstat, conivaptan, diltiazem, duvelisib, fedratinib, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(4)

Moderate Cyp3a4 Inhibitors/Ranolazine (<=500 Mg Bid)

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 ranolazine. Verapamil may also increase the absorption of ranolazine by inhibiting P-glycoprotein.(1)

CLINICAL EFFECTS: Concurrent use of moderate inhibitors of CYP3A4 may result in elevated levels of and clinical effects from ranolazine. Elevated ranolazine levels may result in QTc prolongation, which may result in life-threatening cardiac arrhythmia, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(5) 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 US manufacturer of ranolazine states that the dosage of ranolazine should be limited to 500 mg twice daily in patients receiving moderate inhibitors of CYP3A4.(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: Concurrent use of diltiazem, a moderate inhibitor of CYP3A4, at daily doses of 180 mg to 360 mg increased plasma levels of ranolazine (1000 mg twice daily) by 50% and 130%, respectively.(1,3) In healthy subjects, concurrent ranolazine (1000 mg twice daily) had no effects on the pharmacokinetics of diltiazem (60 mg three times daily).(1) Concurrent use of verapamil (120 mg three times daily) increased plasma levels of ranolazine (750 mg twice daily) by 100%.(1) In a study in 12 healthy males, ranolazine immediate release (IR, 240 mg three times daily) had no effect on diltiazem (60 mg three times daily) pharmacokinetics. However, at ranolazine IR steady state, diltiazem increased ranolazine IR area under the curve (AUC) by 85%, on average, and increased maximum concentration (Cmax) by 1.9-fold and minimum concentration (Cmin) by 2.1-fold.(4) In a study in 12 subjects, ranolazine sustained release (SR, 500 mg twice daily) had no effect on diltiazem (60 mg three times daily) pharmacokinetics. However, at ranolazine steady state, diltiazem increased ranolazine SR Cmax, concentration minimum (Cmin), AUC by 80%, 216%, and 90%, on average, respectively.(4) In a study in 8 healthy males, diltiazem modified release (MR, 180 mg, or 240 mg, or 360 mg, once daily) increased ranolazine sustained release (SR, 1000 mg twice daily) AUC by 52%, 93%, and 139%, respectively. Ranolazine half-lives did not show any consistent trend of changes with increasing doses of diltiazem.(4) In a study of patients with severe chronic angina, the addition of ranolazine 750 mg twice daily or 1,000 mg twice daily along with their standard dose of diltiazem (180 mg once daily) provided additional antianginal relief, without evident adverse, long-term survival consequences over 1 to 2 years of therapy.(5) Ranolazine-induced QTc prolongation is dose and concentration-related.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, erythromycin, dronedarone, duvelisib, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, treosulfan and verapamil.(1,3,6,7)

Moderate Cyp3a4 Inhibitors/Rimegepant

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

MECHANISM OF ACTION: Rimegepant is primarily metabolized by CYP3A4. Moderate inhibitors of CYP3A4 may decrease the metabolism of rimegepant.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in increased levels of and toxicity from rimegepant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of rimegepant recommends avoiding a second dose of rimegepant within 48 hours of a first dose when used concomitantly with moderate CYP3A4 inhibitors.(1)

DISCUSSION: In a drug interaction study (n=23), fluconazole, a moderate CYP3A4 inhibitor, increased rimegepant mean area-under-curve from time 0 to infinity (AUC 0-inf) by 1.8-fold (90% confidence interval 1.68-1.93), with no impact on the maximum concentration (Cmax) (1.04-fold; 90% CI 0.94-1.15). (2) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, and treosulfan.(3-4)

Moderate Cyp3a4 Inhibitors/Sebetralstat

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

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

CLINICAL EFFECTS: Concurrent use of CYP3A4 inhibitors may increase the levels and effects of sebetralstat including QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)

PREDISPOSING FACTORS: Child-Pugh class B or C hepatic impairment may increase the risk for increased exposure to sebetralstat. Sebetralstat should be avoided in patients with severe hepatic impairment (Child-Pugh class C).(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 manufacturer of sebetralstat states when used concomitantly with moderate CYP3A4 inhibitors, reduce the dose of sebetralstat to one dose of 300 mg (one tablet) orally at the earliest recognition of a hereditary angioedema attack. A second dose of 300 mg (one tablet) may be taken at least 3 hours after the first dose if response is inadequate, or if symptoms worsen or recur.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Concomitant use of sebetralstat with verapamil (240 mg once daily for 6 days), a moderate CYP3A4 inhibitor, increased sebetralstat maximum concentration (Cmax) and area-under-curve (AUC) by 1.8-fold and 2-fold, respectively.(1) In a study in healthy subjects, the largest mean increase in QTc interval was 10.4 msec (upper confidence interval = 15.3 msec) after administration of sebetralstat (2.5 times the maximum recommended dose). The increase in the QTc interval was concentration dependent.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, rilzabrutinib, schisandra, tofisopam, treosulfan, verapamil, voxelotor.(3-4)

Moderate Cyp3a4 Inhibitors/Suvorexant (<= 10 Mg)

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 suvorexant.(1)

CLINICAL EFFECTS: Concurrent use of an agent that is a moderate inhibitor of CYP3A4 may result in elevated levels of and clinical effects of suvorexant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of suvorexant recommends a starting dose of 5 mg daily and a maximum dose of 10 mg daily in patients receiving concurrent therapy with a moderate CYP3A4 inhibitor.(1)

DISCUSSION: Diltiazem, a moderate inhibitor of CYP3A4, increased suvorexant AUC and Cmax by approximately 2-fold and 1.25-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, diltiazem, dronedarone, erythromycin, duvelisib, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan and verapamil.(1-3)

Moderate Cyp3a4 Inhibitors/Suzetrigine

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

MECHANISM OF ACTION: Suzetrigine and M6-SUZ (active metabolite of suzetrigine) are CYP3A4 substrates. Moderate CYP3A4 inhibitors increase suzetrigine and M6-SUZ exposures, which may cause suzetrigine adverse reactions.(1)

CLINICAL EFFECTS: The concurrent administration of a moderate CYP3A4 inhibitor may result in elevated levels of and toxicity from suzetrigine including pruritis, muscle spasms, increased blood creatine phosphokinase, and rash.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When possible, avoid the use of moderate CYP3A4 inhibitors with suzetrigine. The US manufacturer of suzetrigine states when suzetrigine is administered to patients taking moderate CYP3A4 inhibitors reduce the suzetrigine dose as follows: -Dose 1: The recommended starting dose of suzetrigine is 100 mg orally. -Dose 2, 3, and 4: Starting 12 hours after the initial dose, take 50 mg of suzetrigine orally every 12 hours. -Dose 5 and Subsequent Doses: Starting 12 hours after Dose 4, take 50 mg of suzetrigine orally every 24 hours.(1)

DISCUSSION: In a PKPB model, concomitant administration of fluconazole (a moderate CYP3A4 inhibitor) with suzetrigine with the recommended dosage modification is predicted to increase the area-under-curve (AUC) of suzetrigine and active metabolite M6-SUZ by 1.5-fold and 1.2-fold, respectively, while the maximum concentration (Cmax) of suzetrigine and M6-SUZ by 1.4-fold and 1.1-fold, respectively, when compared to the regular recommended dosage in the absence of fluconazole.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2-3)

Moderate Cyp3a4 Inhibitors/Tretinoin

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 tretinoin.(1)

CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor may result in increased levels of and effects from tretinoin including hepatotoxicity and hyperlipidemia.(1) Retinoids, including tretinoin, have been associated with intracranial hypertension, especially in pediatric patients. Early signs and symptoms include papilledema, headache, nausea, vomiting, and visual disturbances.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of tretinoin recommends monitoring patients taking a moderate CYP3A4 inhibitor in combination with tretinoin more frequently for adverse reactions.(1) Evaluate patients with symptoms for intracranial hypertension (such as papilledema, headache, nausea, vomiting, and visual disturbances), and, if present, institute care in concert with neurological assessment. Consider interruption, dose reduction, or discontinuation of tretinoin as appropriate.(1)

DISCUSSION: In 13 patients on tretinoin for 4 weeks, single-dose ketoconazole (400 to 1200 mg) (strong CYP3A4 inhibitor) increased tretinoin area-under-curve (AUC) by 72%.(1) There are no clinical pharmacokinetic studies on the combination of tretinoin with a moderate CYP3A4 inhibitor. The US manufacturer of tretinoin states increased tretinoin toxicity following concomitant use of tretinoin with certain antimycotics that are moderate CYP3A4 inhibitors has been reported post-marketing.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, and treosulfan.(2-3)

Moderate Cyp3a4 Inhibitors/Ubrogepant (<= 50 Mg)

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 ubrogepant.(1)

CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor may result in elevated levels of ubrogepant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when used concomitantly with moderate CYP3A4 inhibitors. Initial dose of ubrogepant should not exceed 50 mg. A second dose should be avoided within 24 hours of the first dose when used concurrently with moderate CYP3A4 inhibitors.(1)

DISCUSSION: Co-administration 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.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2-4)

Moderate Cyp3a4 Inhibitors/Zanubrutinib

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 zanubrutinib.(1)

CLINICAL EFFECTS: Concurrent use of a moderate CYP3A4 inhibitor may result in elevated levels of and toxicity from zanubrutinib.(1)

PREDISPOSING FACTORS: Patients with severe hepatic impairment (Child-Pugh class C) have elevated zanubrutinib plasma concentrations and may be more susceptible to the effects of this interaction.(1)

PATIENT MANAGEMENT: The dosage of zanubrutinib should be reduced to 80 mg twice daily when co-administered with moderate CYP3A4 inhibitors. Modify the dose as recommended by prescribing information for adverse reactions.(1)

DISCUSSION: Co-administration with itraconazole 200 mg once daily, a strong CYP3A4 inhibitor, increased zanubrutinib concentration maximum (Cmax) and area-under-curve (AUC) by 157% and 278%, respectively. It is predicted co-administration with fluconazole 200 mg daily, a moderate CYP3A4 inhibitor, would increase zanubrutinib Cmax and AUC by 179% and 177%, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2-4)

Moderate Cyp3a4 Inhibitors/Ziftomenib

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

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

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase the levels and effects of ziftomenib, including differentiation syndrome, neutropenia, and QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1)

PREDISPOSING FACTORS: The risk of QT prolongation or 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 US manufacturer of ziftomenib states that concomitant use with moderate CYP3A4 inhibitors should be monitored more closely for adverse reactions.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Concomitant use of ziftomenib with itraconazole, voriconazole, and posaconazole (strong CYP3A4 inhibitors) is predicted to increase ziftomenib area-under-curve (AUC) and maximum concentration (Cmax) by 3-fold and 2-fold, respectively.(1) Moderate CYP3A4 inhibitors (fluconazole, erythromycin, and isavuconazole) are predicted to increase ziftomenib AUC and Cmax by 2-fold and 2-fold, respectively.(1) Weak CYP3A4 inhibitors (cimetidine) are predicted to increase ziftomenib AUC and Cmax by 1.4-fold and 1.4-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, Schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)

Myelosuppressive Mod-Weak Cyp3a4 Inh/Tacrolimus

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

MECHANISM OF ACTION: Moderate and weak immunosuppressive inhibitors of CYP3A4 may inhibit the metabolism of tacrolimus and increase the risk of additive immunosuppression.(1)

CLINICAL EFFECTS: Concurrent use of an immunosuppressive CYP3A4 inhibitor may result in elevated levels of and toxicity from tacrolimus, including nephrotoxicity, neurotoxicity, immunosuppression, 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) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(3) 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%.(4) 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.(5) 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%.(6) An analysis of FAERS data from 2004-2017, found a significant association between transplant rejection and concurrent use of tacrolimus and clotrimazole (reporting odds ration 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) Moderate CYP3A4 inhibitors linked to this monograph include: duvelisib, fedratinib, imatinib, rilzabrutinib, and treosulfan.(6) Weak CYP3A4 inhibitors linked to this monograph include: asciminib, avapritinib, belumosudil, capivasertib, everolimus, larotrectinib, leflunomide, olaparib, palbociclib, and teriflunomide.(6)

Rilzabrutinib/Antacids

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

MECHANISM OF ACTION: Rilzabrutinib solubility decreases with increasing pH. Antacid induced increase in gastric pH may result in a decrease in rilzabrutinib absorption.(1)

CLINICAL EFFECTS: Simultaneous administration of an antacid may result in decreased levels and effectiveness of rilzabrutinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Administer rilzabrutinib at least 2 hours before taking antacids.(1) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.

DISCUSSION: The impact of antacids on the pharmacokinetics of rilzabrutinib has not been investigated in clinical studies. In an interaction study, administration of famotidine (H2 receptor antagonist) two hours after the evening dose of rilzabrutinib decreased the next morning dose of rilzabrutinib maximum concentration (Cmax) by 35% and area-under-curve (AUC) by 28%.(1) In another interaction study, coadministration of esomeprazole decreased rilzabrutinib Cmax by 55% and AUC by 51%.(1)

Rilzabrutinib/H2 Antagonists

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

MECHANISM OF ACTION: Rilzabrutinib solubility decreases with increasing pH. H2 antagonist induced increase in gastric pH may result in a decrease in rilzabrutinib absorption.(1)

CLINICAL EFFECTS: Simultaneous administration of a H2 antagonist may result in decreased levels and effectiveness of rilzabrutinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Administer rilzabrutinib at least 2 hours before taking H2 antagonists.(1) Concurrent use of rilzabrutinib with proton pump inhibitors should be avoided.(1)

DISCUSSION: In an interaction study, administration of famotidine (H2 receptor antagonist) two hours after the evening dose of rilzabrutinib decreased the next morning dose of rilzabrutinib maximum concentration (Cmax) by 35% and area-under-curve (AUC) by 28%.(1)

Selected Cyp3a4 Inhibitors/Vardenafil (<= 5 Mg)

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 vardenafil by CYP3A4.(1-4)

CLINICAL EFFECTS: Concurrent use of CYP3A4 inhibitors may result in increased levels of and adverse effects from vardenafil, including hypotension, visual changes, and sustained erections.(1-4)

PREDISPOSING FACTORS: The interaction may be more severe in men older than 75 years.(4)

PATIENT MANAGEMENT: The US manufacturer of vardenafil states that a maximum dose of 2.5 mg of vardenafil every 24 hours should not be exceeded in patients taking 400 mg of itraconazole or ketoconazole and that a maximum dose of 5 mg of vardenafil every 24 hours should not be exceeded in patients taking 200 mg of itraconazole or ketoconazole.(1) For moderate CYP3A4 inhibitors, do not exceed a maximum dose of 5 mg of vardenafil every 24 hours.(1) Patients receiving concurrent therapy should be monitored for increased vardenafil effects. Note that other countries have stricter warnings. The Australian manufacturer of vardenafil states that vardenafil must not be taken with dosages of itraconazole or ketoconazole greater than 200 mg. A maximum dose of 5 mg of vardenafil should not be exceeded if used with lower dosages of itraconazole and ketoconazole.(2) The Canadian manufacturer of vardenafil states that the concurrent use of vardenafil with itraconazole or ketoconazole is contraindicated and that the dosage should not exceed 5 mg in patients taking erythromycin.(3) The UK manufacturer of vardenafil states that the concurrent use of vardenafil with either oral itraconazole or oral ketoconazole is contraindicated in men older than 75 years and should be avoided in all patients. The dosage of vardenafil should not exceed 5 mg in patients taking erythromycin.(4))

DISCUSSION: Concurrent use of ketoconazole (200 mg) with vardenafil (5 mg) increased the vardenafil area-under-curve (AUC) and maximum concentration (Cmax) by 10-fold and 4-fold, respectively.(1-4) Concurrent administration of erythromycin (500 mg three times daily) with vardenafil (5 mg) increased the AUC and Cmax of vardenafil by 4-fold and 3-fold, respectively.(1-4)

Selected Cyp3a4 Moderate Inhibitors/Lurasidone (<= 80 Mg)

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

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

CLINICAL EFFECTS: Concomitant use of lurasidone with inhibitors of CYP3A4 may lead to orthostatic hypotension, akathisia, acute dystonia, Parkinsonism or other lurasidone toxicities.(1)

PREDISPOSING FACTORS: Elderly patients, particularly those with a history of falls or swallowing disorders, and patients with Parkinson Disease, Lewy Body Disease, or other dementias are more sensitive to antipsychotics and have a greater risk for adverse effects.(1)

PATIENT MANAGEMENT: The US manufacturer of lurasidone states that the dose of lurasidone should not exceed 80 mg daily if coadministered with moderate CYP3A4 inhibitors.(1) If a patient is currently on lurasidone and a moderate CYP3A4 inhibitor is added to therapy, the dose of lurasidone should be decreased by 50% of the original dose.(1) If a patient is currently on a moderate CYP3A4 inhibitor and lurasidone is added to therapy, the recommended starting dose of lurasidone is 20 mg per day.(1)

DISCUSSION: Pretreatment with diltiazem (240 mg daily for 5 days), another moderate inhibitor of CYP3A4, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of lurasidone (20 mg) by 2.1-fold, and 2.2-fold, respectively.(1) Agents linked to this monograph include berotralstat, clofazimine, conivaptan, crizotinib, dronedarone, duvelisib, fedratinib, fluvoxamine, imatinib, isavuconazonium, letermovir, nilotinib, nirogacestat, rilzabrutinib, stiripentol, and tofisopam.(2,3)

Selected Moderate Cyp3a4 Inhibitors/Acalabrutinib

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

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

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase levels of and effects from acalabrutinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Recommendations for management of this interaction vary in different regions. The US and Australian manufacturers of acalabrutinib state that the concurrent chronic use of moderate CYP3A4 inhibitors should be approached with caution. If a moderate CYP3A4 inhibitor is required, reduce the dose of acalabrutinib to 100 mg once daily.(1,2) The UK manufacturer of acalabrutinib states no dose adjustment is needed for concurrent use of acalabrutinib with moderate CYP3A4 inhibitors. Patients should be monitored closely for adverse effects.(3)

DISCUSSION: In a study with healthy volunteers, single-dose fluconazole 400 mg and isavuconazole 200 mg daily for 5 days (both moderate CYP3A4 inhibitors) increased the maximum concentration (Cmax) and area-under-curve (AUC) of acalabrutinib by 1.4- to 2-fold. The Cmax and AUC of the active metabolite ACP-5862 was decreased by 0.65- to 0.88-fold.(2) A physiologically based pharmacokinetic simulation with acalabrutinib and moderate CYP3A inhibitors (erythromycin, fluconazole, diltiazem) predicted that coadministration increases acalabrutinib Cmax and AUC by 2- to almost 3-fold.(1) In a study in healthy subjects, itraconazole (200mg once daily for 5 days, a strong inhibitor) increased the Cmax and AUC of acalabrutinib by 3.9-fold and 5.1-fold, respectively.(1) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, grapefruit juice, imatinib, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(4,5)

Selected Moderate Cyp3a4 Inhibitors/Atorvastatin

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

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

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in elevated levels of atorvastatin and increase the risk of myopathy and rhabdomyolysis.(1)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis.

PATIENT MANAGEMENT: Concurrent use of moderate CYP3A4 inhibitors with atorvastatin may require a dose reduction. Use the lowest dose possible of atorvastatin and monitor for adverse reactions, especially with higher atorvastatin doses. Patients should be instructed to report any signs of myopathy.(1) Fluvastatin, pitavastatin and pravastatin, HMG-CoA reductase inhibitors that are not metabolized by CYP3A4, may be alternatives to atorvastatin in patients receiving strong CYP3A4 inhibitors.

DISCUSSION: Atorvastatin is a CYP3A4 substrate.(1) In a study, itraconazole (200 mg daily for 4 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of atorvastatin (40 mg single dose) by 3.3-fold and 20%, respectively.(4) Concurrent administration of atorvastatin (40 mg for 4 days) with ritonavir-saquinavir (400 mg twice daily) increased atorvastatin AUC and Cmax by 3.9-fold and 4.3-fold, respectively.(1) Concurrent administration of atorvastatin (20 mg) with lopinavir-ritonavir (400-100 mg twice daily) increased atorvastatin by 5.9-fold.(1) In a study, concurrent clarithromycin (500 mg BID for 9 days) increased the AUC and maximum concentration (Cmax) of atorvastatin (80 mg daily for 8 days) by 4.4-fold and 5.4-fold, respectively.(1) Moderate CYP3A4 inhibitors linked to this monograph include: berotralstat, clofazimine, conivaptan, crizotinib, duvelisib, fedratinib, grapefruit, imatinib, isavuconazole, lenacapavir, netupitant, nilotinib, nirogacestat, rilzabrutinib, ritlecitinib, tofisopam, treosulfan, and voxelotor.(2,3)

Selected Moderate Cyp3a4 Inhibitors/Cyclosporine

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

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

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in elevated levels of and toxicity from cyclosporine, including serious infections, nephrotoxicity, and hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If cyclosporine is used with a moderate CYP3A4 inhibitor, dose adjustment of cyclosporine may be necessary to achieve the desired cyclosporine concentration.(1)

DISCUSSION: In a study, renal and cardiac patients required a cyclosporine dose reduction of 15% to 48% when diltiazem was co-administered to maintain a cyclosporine trough similar to cyclosporine alone.(2) In a study, cyclosporine required a 25% dose reduction when co-administered with fluconazole to maintain a goal serum concentration similar to cyclosporine alone.(3) Moderate inhibitors of CYP3A4 include: avacopan, berotralstat, clofazimine, duvelisib, fedratinib, fluvoxamine, oral lefamulin, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, and treosulfan.(4,5)

Selected Moderate Cyp3a4 Inhibitors/Selected Opioids

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, benzhydrocodone, fentanyl,(1) hydrocodone, meperidine,(2) oxycodone,(3) and sufentanil.(4)

CLINICAL EFFECTS: The concurrent administration of a CYP3A4 inhibitor may result in elevated levels of and toxicity from alfentanil, benzhydrocodone, fentanyl,(1,5) hydrocodone, meperidine,(2) oxycodone(3) and sufentanil(4), including somnolence and potentially fatal respiratory depression.

PREDISPOSING FACTORS: Heat.

PATIENT MANAGEMENT: Monitor patients receiving moderate CYP3A4 inhibitors for an extended period of time. Dosage adjustments should be made if warranted. The manufacturer of sufentanil sublingual tablets states that if concomitant use with CYP3A4 inhibitors is necessary, consider use of an alternate agent that allows dose adjustment.(4) 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.(6) 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).(7) 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: Fentanyl(1) and oxycodone(3) are metabolized by the CYP3A4 isoenzyme. Moderate and strong inhibitors of this isoenzyme are expected to increase fentanyl(1) and oxycodone(3) levels. In a single dose study of sufentanil sublingual tablet 15 mcg with a strong CYP3A4 inhibitor, ketoconazole, resulted in 77% and 19% greater AUC and Cmax values of sufentanil, respectively, compared to its administration alone.(4) In a randomized study in 30 patients, continuous diltiazem (1 mcg/kg/min) infusion had no effect on epidural fentanyl consumption when compared to placebo. There were no significant differences in Visual Analogue Scores (VAS), Verbal Rating Scores (VRS), or incidence of side effects, although there was a trend towards increased nausea with concurrent diltiazem.(5) 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.(8) In a study in 13 patients, administration of a single dose of verapamil (75mcg/kg to 150mcg/kg) had no significant effects on the pharmacodynamic effects of a single dose of fentanyl; however, individual patients had modest decreases in blood pressure.(9) In a case report, concurrent diltiazem and fentanyl produced delirium.(10) A study in healthy subjects shown that the application of heat over the fentanyl patch system increased mean overall fentanyl exposure by 120% and average maximum fentanyl level by 61%.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, duvelisib, fedratinib, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, treosulfan, and verapamil.(11,12)

Slt Strong & Moderate 3A4 Inhibitors/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 CYP3A4 may inhibit the metabolism of cilostazol.(1)

CLINICAL EFFECTS: The concurrent use of cilostazol and strong and moderate inhibitors of CYP3A4 may result in elevated levels of cilostazol, which may produce increased effects of cilostazol and adverse effects.(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 CYP3A4.(1)

DISCUSSION: In a study in 16 healthy males, the administration of a single dose of cilostazol (10 mg) with erythromycin (500 mg every eight hours) increased the maximum concentration (Cmax) and area-under-curve (AUC) of cilostazol by 47% and 73%, respectively. The Cmax and AUC of 4'-trans-hydroxy-cilostazol were increased by 29% and 141%, respectively.(2) Analysis of population pharmacokinetics indicated that the concurrent administration of diltiazem with cilostazol increased cilostazol concentrations by 53%. Concurrent administration of diltiazem and cilostazol decreased cilostazol clearance by 30%, increased the Cmax by 30%, and increased AUC by 40%.(1) In a study, the administration of a single dose of cilostazol (10 mg) with erythromycin (500 mg every eight hours) increased the Cmax and AUC of cilostazol by 47% and 73%, respectively. The AUC of 4'-trans-hydroxy-cilostazol was increased by 141%.(1) In an vitro study in human liver microsomes, ketoconazole inhibited the metabolism of cilostazol.(3)

Strong And Moderate Cyp3a4 Inhibitors/Apixaban

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

MECHANISM OF ACTION: Apixaban is a substrate of CYP3A4 and P-glycoprotein (P-gp). It is about 20% metabolized, mainly by CYP3A4.(1-4) Strong and moderate CYP3A4 inhibitors may inhibit the metabolism of apixaban by CYP3A4.

CLINICAL EFFECTS: Concurrent use of a CYP3A4 inhibitor may result in elevated levels of and clinical effects of apixaban, including an increased risk of bleeding, especially in the setting of concurrent therapy with an agent that inhibits P-gp.(1-4)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug-associated risk factors include concurrent use of P-gp inhibitors and concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The US manufacturer of apixaban provides recommendations regarding concurrent use with strong inhibitors of both CYP3A4 and P-gp, but does not provide guidance for concurrent use with agents that inhibit CYP3A4 alone.(1) The Australian, Canadian, and UK labels for apixaban state that no dose adjustment for apixaban is required when co-administered with agents that are not strong inhibitors of both CYP3A4 and P-gp.(2-4) Expert opinion on the clinical significance of this interaction is varied and depends on the inhibitor. Some experts state that specific agents (i.e., voriconazole, imatinib, and crizotinib) should be contraindicated.(5) Others state that concurrent use is acceptable if there are no other pharmacokinetic interactions; otherwise, a 50% dose reduction of apixaban is suggested.(6) In patients who are also on concurrent P-gp inhibitors, consider the manufacturer recommendations for use with dual CYP3A4 and P-gp inhibitors. The US manufacturer of apixaban states that if concurrent use of strong CYP3A4 and P-gp inhibitors cannot be avoided, the dosage of apixaban should be reduced by 50%. In patients already receiving apixaban 2.5 mg twice daily, avoid the concurrent use of strong inhibitors of both P-gp and CYP3A4.(1) The Australian(2) and Canadian(3) manufacturers of apixaban states that the concurrent use of agents that are strong inhibitors of both P-gp and CYP3A4 with apixaban is contraindicated. The UK manufacturer of apixaban states that concurrent use of these agents is not recommended.(4) Concurrent use of agents that are dual P-gp and moderate CYP3A4 inhibitors are expected to increase apixaban levels to a lesser extent than agents that are P-gp and strong CYP3A4 inhibitors. No dose adjustment of apixaban is necessary. Use caution when administering apixaban with moderate inhibitors of CYP3A4. 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 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%.(7) In a microdose cocktail study using apixaban 25 mcg, voriconazole 400 mg every 12 hours for 2 doses then 200 mg every 12 hours (strong CYP3A4 inhibitor) had "only a minor interaction," increasing the AUC of apixaban by 1.33-fold (95% CI 1.01-1.75) while the Cmax and half-life remained unchanged.(8) Another microdose cocktail study with apixaban 25 mcg and voriconazole 400 mg twice daily found that apixaban AUC increased by 1.24-fold with a non-significant change in Cmax.(9) A retrospective cohort study of 50 oncology patients on apixaban identified 14 patients on concurrent voriconazole, with 3 of those patients receiving reduced-dose apixaban. No bleeding or thrombosis occurred in any of the patients on concurrent voriconazole.(10) 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.(11) A review article on DOAC drug-drug interactions suggests that the combination of voriconazole, crizotinib or imatinib with apixaban or rivaroxaban is contraindicated due to the potential for significant increases in DOAC AUC. The authors state that data with voriconazole is missing and thus the interactions are unpredictable.(5) Another review article states that apixaban may be used with voriconazole if no other pharmacokinetic inhibitor is present; otherwise, concurrent use requires a 50% apixaban dose reduction. No dose adjustment is recommended with moderate CYP3A4 inhibitors.(6) Strong CYP3A4 inhibitors linked to this monograph include: boceprevir, ceritinib, ensitrelvir, idelalisib, mibefradil, nefazodone, relacorilant, ribociclib, troleandomycin, and voriconazole.(12,13) Moderate CYP3A4 inhibitors linked to this monograph include: aprepitant, avacopan, berotralstat, clofazimine, crizotinib, duvelisib, fedratinib, fosnetupitant, imatinib, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and voxelotor.(12,13)

Strong And Moderate Cyp3a4 Inhibitors/Rivaroxaban

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

MECHANISM OF ACTION: Rivaroxaban is a substrate of CYP3A4 and P-glycoprotein (P-gp). It is about 18% metabolized, mainly by CYP3A4.(1-4) Strong and moderate CYP3A4 inhibitors may inhibit the metabolism of rivaroxaban by CYP3A4.

CLINICAL EFFECTS: Concurrent use of a CYP3A4 inhibitor may result in elevated levels of and clinical effects of rivaroxaban, including an increased risk of bleeding, especially in the setting of concurrent therapy with an agent that inhibits P-gp.(1-4)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Patients with renal impairment may be at higher risk of elevated rivaroxaban levels. Drug-associated risk factors include concurrent use of P-gp inhibitors and concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The US manufacturer of rivaroxaban provides recommendations regarding concurrent use with strong and moderate inhibitors of both CYP3A4 and P-gp, but does not provide guidance for concurrent use with agents that inhibit CYP3A4 alone.(1) The Canadian manufacturer of rivaroxaban states that increases in rivaroxaban levels by drugs inhibiting only CYP3A4 are expected to be less clinically relevant compared to drugs inhibiting both CYP3A4 and P-gp.(2) The UK manufacturer of rivaroxaban states that drug interactions with agents that inhibit only CYP3A4 are likely not clinically relevant in most patients but may be significant in high-risk patients (e.g., renal impairment).(3) The Australian manufacturer of rivaroxaban states that drug interactions with drugs that inhibit only CYP3A4 are not clinically relevant.(4) Expert opinion on the clinical significance of this interaction is varied and depends on the inhibitor. Some experts state that specific agents (i.e., voriconazole, imatinib, and crizotinib) should be contraindicated.(5) Others state that concurrent use is acceptable if there are no other pharmacokinetic interactions; otherwise, the combination should be avoided.(6) In patients who are also on concurrent P-gp inhibitors, consider the manufacturer recommendations for use with dual CYP3A4 and P-gp inhibitors. The Australian and Canadian manufacturers of rivaroxaban state that the concurrent use of agents that are both an inhibitor of P-gp and a strong inhibitor of CYP3A4 with rivaroxaban is contraindicated.(2,4) The US manufacturer states that concurrent use of strong CYP3A4 and P-gp inhibitors should be avoided(1) while the UK manufacturer states that concurrent use is not recommended.(3) Agents that are not strong inhibitors of both CYP3A4 and P-gp, including fluconazole, are expected to increase rivaroxaban levels to a lesser extent and can be used with rivaroxaban with caution in patients with normal renal function; however, in patients with decreased renal function (CrCL of 15 ml/min to 80 ml/min) these agents should only be used if the benefits of concurrent therapy outweigh the increased risk of bleeding.(1-4) 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: In a microdose cocktail study using rivaroxaban 25 mcg, voriconazole 400 mg every 12 hours for 2 doses then 200 mg every 12 hours (strong CYP3A4 inhibitor) had "only a minor interaction," increasing the AUC of rivaroxaban by 1.33-fold (p<0.05) while the Cmax and half-life remained unchanged.(7) Another microdose cocktail study with rivaroxaban 25 mcg and voriconazole 400 mg twice daily found that rivaroxaban AUC increased by 1.16-fold with a non-significant change in Cmax.(8) A review article on DOAC drug-drug interactions suggests that the combination of voriconazole, crizotinib or imatinib with apixaban or rivaroxaban is contraindicated due to the potential for significant increases in DOAC AUC. The authors state that data with voriconazole is missing and thus the interactions are unpredictable.(5) Another review article states that rivaroxaban may be used with voriconazole if no other pharmacokinetic inhibitor is present; otherwise, concurrent use should be avoided. No dose adjustment is recommended with moderate CYP3A4 inhibitors.(6) Strong CYP3A4 inhibitors linked to this monograph include: boceprevir, ceritinib, ensitrelvir, idelalisib, mibefradil, nefazodone, relacorilant, ribociclib, troleandomycin, and voriconazole.(9,10) Moderate CYP3A4 inhibitors linked to this monograph include: aprepitant, avacopan, berotralstat, clofazimine, crizotinib, duvelisib, fedratinib, fosnetupitant, imatinib, oral lefamulin, lenacapavir, letermovir, netupitant, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and voxelotor.(9,10)

*None.

• Child-pugh class B hepatic impairment
• Lactation

• Disease of liver
• Infection

There are no moderate contraindications for this drug.

The most common adverse reactions (incidence >=10%) reported with rilzabrutinib in clinical studies were diarrhea, nausea, headache, abdominal pain, and COVID-19.

More Frequent

• COVId-19

Less Frequent

• Pneumonia

Rare or Very Rare

• Urinary tract infection

More Frequent

• Acute abdominal pain
• Diarrhea
• Headache disorder
• Nausea
• Neutropenic disorder

Less Frequent

• Abnormal hepatic function tests
• Arthralgia
• Cough
• Dizziness
• Dyspepsia
• Erythema nodosum
• Pain in extremities
• Pharyngitis
• Vomiting

No enhanced messaging available.

Safety and effectiveness have not been established in pediatric patients.

There are no adequate data regarding use of rilzabrutinib in pregnant women. Based on findings from preliminary animal data, rilzabrutinib may cause fetal harm when administered to pregnant females.

Advise pregnant women of the potential risk to a fetus.

It is not known whether rilzabrutinib is distributed into human milk, or if the drug has any effects on the breastfed infant or on milk production. Due to the potential for adverse reactions in a breastfed child from rilzabrutinib, advise lactating women not to breastfeed while taking rilzabrutinib and for at least 1 week after the final dose.

The manufacturer makes no specific dosage recommendations for geriatric patients.

In the LUNA-3 study involving 202 patients, 36 (18%) patients were >=65 years of age and 9 (5%) patients were >=75 years of age. No overall differences in efficacy or safety were observed between patients >=65 years of age and younger adult patients.