Fluvoxamine Maleate (fluvoxamine maleate)

Fluvoxamine maleate dosage is expressed in terms of the salt.

Fluvoxamine maleate is administered orally either as immediate-release tablets or extended-release capsules. Since food does not appear to substantially affect GI absorption of fluvoxamine maleate from either formulation, the drug generally can be administered without regard to meals.

Fluvoxamine maleate immediate-release tablets are administered orally once or twice daily. Dosages of 100 mg daily or less in adults or 50 mg daily or less in pediatric patients generally are given as a single daily dose at bedtime; higher dosages generally are given as 2 divided doses, either as equally divided doses or as unequal doses with the larger dose given at bedtime.

Fluvoxamine maleate extended-release capsules are administered once daily at bedtime. The extended-release capsules should not be crushed or chewed.

Commercially available fluvoxamine maleate tablets should be protected from high humidity and stored at 20-25degreesC, but may be exposed to temperatures ranging from 15-30degreesC.

Fluvoxamine maleate extended-release capsules should be protected from high humidity and stored at 25degreesC, but may be exposed to temperature ranging from 15-30degreesC. Avoid exposure to temperatures above 30degreesC.

Although the optimum duration of fluvoxamine therapy has not been established, obsessive-compulsive disorder requires several months or longer of sustained drug therapy. If therapy with the drug is prolonged, the lowest possible dosage should be used and the need for continued therapy should be reassessed periodically.

Symptoms associated with discontinuation of other selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) have been reported. Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

There is no enhanced messaging for this drug.

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

Cyp1a2 Inhibitors/Fezolinetant

SEVERITY LEVEL: 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 CYP1A2 may inhibit the metabolism of fezolinetant.(1-4)

CLINICAL EFFECTS: Concurrent use of a CYP1A2 inhibitor may increase levels of and adverse effects from fezolinetant.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Recommendations for concurrent use of fezolinetant with CYP1A2 inhibitors differ in different regions. The US manufacturer of fezolinetant states that concurrent use with strong, moderate, and weak CYP1A2 inhibitors is contraindicated.(1) The Australian, Canadian, and UK manufacturers of fezolinetant state that concurrent use with strong and moderate CYP1A2 inhibitors is contraindicated, while weak CYP1A2 inhibitors are not predicted to cause clinically relevant changes in fezolinetant exposure.(2-4)

DISCUSSION: In a study, fluvoxamine, a strong CYP1A2 inhibitor, increased fezolinetant maximum concentration (Cmax) and area-under-curve (AUC) by 80% and 840%, respectively. Mexiletine (400 mg every 8 hours), a moderate CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 40% and 360%, respectively. Cimetidine (300 mg every 6 hours), a weak CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 30% and 100%, respectively.(1) Strong CYP1A2 inhibitors linked to this monograph include angelica root, ciprofloxacin, enasidenib, enoxacin, fluvoxamine, and rofecoxib. Moderate CYP1A2 inhibitors linked to this monograph include capmatinib, centanafadine, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine. Weak CYP1A2 inhibitors linked to this monograph include acyclovir, allopurinol, artemisinin, belumosudil, caffeine, cannabidiol, cimetidine, curcumin, dan-shen, deferasirox, disulfiram, Echinacea, famotidine, ginseng, norfloxacin, obeticholic acid, parsley, piperine, propafenone, propranolol, ribociclib, simeprevir, thiabendazole, ticlopidine, triclabendazole, valacyclovir, verapamil, and zileuton.(5-7)

Dual Moderate Cyp3a4 & P-Gp 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 and is transported by P-glycoprotein (P-gp).(1) Inhibitors of CYP3A4 and P-gp may inhibit the absorption and metabolism of ensartinib.(1)

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

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of ensartinib states concurrent use with both P-gp and moderate CYP3A4 inhibitors should be avoided.(1)

DISCUSSION: Ensartinib is predominately metabolized by CYP3A4 and is a P-gp substrate.(1) Dual P-gp and moderate CYP3A4 inhibitors linked to this monograph include: conivaptan, diltiazem, dronedarone, erythromycin, fluvoxamine, isavuconazonium, Schisandra, and verapamil.(2,3)

Dual Moderate Cyp3a4 And P-Gp Inhib/Daraxonrasib (>100 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 and P-glycoprotein (P-gp). Moderate CYP3A4 and P-gp inhibitors may inhibit the metabolism of daraxonrasib.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 and P-gp 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 both moderate CYP3A4 inhibitors and P-gp inhibitors, reduce the dose of daraxonrasib to 100 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 study, diltiazem 80 mg three times daily (a moderate CYP3A and P-gp inhibitor) increased the area under curve (AUC) of daraxonrasib by 2.6-fold.(1) Dual moderate CYP3A4 and P-gp inhibitors include: conivaptan, diltiazem, dronedarone, erythromycin, fluvoxamine, isavuconazole, schisandra, and verapamil.(2-3)

Dual Strong Or Moderate Cyp2c19 & 3A4 Inhibitors/Mavacamten

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

MECHANISM OF ACTION: Strong or moderate inhibitors of CYP2C19 or CYP3A4 may decrease the metabolism of mavacamten.(1-3)

CLINICAL EFFECTS: Concurrent use of strong or moderate CYP2C19 or CYP3A4 inhibitors increases plasma exposure of mavacamten, which may increase the incidence and severity of adverse reactions of mavacamten.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US and Canadian manufacturer of mavacamten state concomitant use of strong or moderate inhibitors of CYP2C19 or CYP3A4 is contraindicated.(1,2) The UK manufacturer of mavacamten states combined use of a strong CYP2C19 inhibitor and a strong CYP3A4 inhibitor (e.g., fluconazole, voriconazole) is contraindicated. The UK manufacturer does not provide recommendations for combined use of a dual moderate CYP2C9 inhibitor and CYP3A4 inhibitor (e.g., fedratinib).(3)

DISCUSSION: Concomitant use of mavacamten (15 mg) with omeprazole (20 mg), a weak CYP2C19 inhibitor, once daily increased mavacamten area-under-curve (AUC) by 48% with no effect on maximum concentration (Cmax) in healthy CYP2C19 normal metabolizers and rapid metabolizers.(1) Concomitant use of mavacamten (15 mg) with ketoconazole 400 mg, a strong CYP3A4 inhibitor, once daily is predicted to increase mavacamten AUC and Cmax up to 130% and 90%, respectively.(1) Drugs that inhibit both CYP2C19 and CYP3A4 linked to this monograph include: fedratinib, fluconazole, fluvoxamine, and voriconazole.(4,5)

Fluvoxamine/Agomelatine

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

MECHANISM OF ACTION: Fluvoxamine inhibits the metabolism of agomelatine by CYP P-450-1A2 and by CYP P-450-2C9.(1)

CLINICAL EFFECTS: Concurrent use of fluvoxamine results in dramatic increases in agomelatine levels, which can produce toxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The UK manufacturer of agomelatine states that concurrent use of fluvoxamine is contraindicated.(1)

DISCUSSION: Concurrent use of fluvoxamine increased agomelatine exposure by 60-fold (range: 12-fold to 412-fold).(1)

Fluvoxamine/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: Fluvoxamine may inhibit the metabolism of cisapride, resulting in elevated cisapride levels.(1,2)

CLINICAL EFFECTS: Concurrent administration may result in increased serum cisapride levels resulting in possible life-threatening cardiotoxicity including QT prolongation or torsades de pointes.

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: Concurrent administration of fluvoxamine(2) with cisapride is contraindicated. If alternatives are not available and 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: It has not been demonstrated that fluvoxamine is a potent inhibitor of CYP3A4; however, fluvoxamine is suspected to be. In vitro studies have shown fluvoxamine to be an inhibitor of CYP3A4.(2) Therefore the manufacturer of fluvoxamine contraindicates concurrent therapy with cisapride.(2) In a study, concurrent administration of fluoxetine with a single dose of terfenadine resulted in no changes in terfenadine levels. The manufacturer of fluoxetine states that fluoxetine inhibition of CYP3A4 is unlikely to be of clinical significance.(4) In a study, concurrent administration of paroxetine with terfenadine at steady state resulted in no changes in terfenadine levels. The manufacturer of paroxetine states that paroxetine inhibition of CYP3A4 is unlikely to be of clinical significance.(5,6) In a study, concurrent administration of sertraline with cisapride at steady state resulted in no changes in cisapride levels. The manufacturer of sertraline states that sertraline inhibition of CYP3A4 is unlikely to be of clinical significance.(6,7)

Fluvoxamine/Ramelteon

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

MECHANISM OF ACTION: Fluvoxamine may inhibit the metabolism of ramelteon by CYP1A2.(1)

CLINICAL EFFECTS: Concurrent use of fluvoxamine may result in elevated levels of and toxicity from ramelteon.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of ramelteon states that concurrent use of fluvoxamine is contraindicated.(1) The US manufacturer of fluvoxamine states that ramelteon should not be used with fluvoxamine.(2)

DISCUSSION: Pretreatment for 3 days with fluvoxamine (100 mg twice daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of ramelteon (16 mg) by 190-fold and 70-fold, respectively.(1,2) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

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/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/Mitapivat (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: Moderate inhibitors of CYP3A4 may inhibit the metabolism of mitapivat.(1)

CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels of and effects from mitapivat including decreased estrone and estradiol levels in males, increased urate, back pain, and arthralgias.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of moderate CYP3A4 inhibitors with mitapivat should be monitored closely for increased risk of adverse reactions. Mitapivat dose should not exceed 20 mg twice daily with concurrent moderate CYP3A4 inhibitors.(1)

DISCUSSION: Mitapivat is a CYP3A4 substrate. In a pharmacokinetic study with mitapivat 5, 20, or 50 mg twice daily dosing, fluconazole increased mitapivat area-under-curve (AUC) and concentration maximum (Cmax) by 2.6-fold and 1.6-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, letermovir, netupitant, nilotinib, schisandra, stiripentol, treosulfan, tofisopam, and verapamil.(2)

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/Rilzabrutinib

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

MECHANISM OF ACTION: 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)

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)

P-Glycoprotein (P-Gp) Inh/Colchicine (For Cardioprotection)

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

MECHANISM OF ACTION: P-glycoprotein (P-gp) inhibitors may affect the transport of colchicine, a P-gp substrate.(1,2)

CLINICAL EFFECTS: Concurrent use of a P-gp inhibitor may result in elevated levels of and toxicity from colchicine. Symptoms of colchicine toxicity include abdominal pain; nausea or vomiting; severe diarrhea; muscle weakness or pain; numbness or tingling in the fingers or toes; myelosuppression; 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 or hepatic impairment.(1,2)

PATIENT MANAGEMENT: The manufacturer of colchicine used for cardiovascular risk reduction states that concurrent use of colchicine with P-gp inhibitors is contraindicated.(1)

DISCUSSION: There are several reports of colchicine toxicity(3-5) and death(6,7) following the addition of clarithromycin to therapy. In a retrospective review of 116 patients who received clarithromycin and colchicine during the same hospitalization, 10.2% (9/88) of patients who received simultaneous therapy died, compared to 3.6% (1/28) of patients who received sequential therapy.(8) An FDA review of 117 colchicine-related deaths that were not attributable to overdose found that 60 deaths (51%) involved concurrent use of clarithromycin.(2) There is one case report of colchicine toxicity with concurrent erythromycin.(9) 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 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 and P-gp inhibitors such as clarithromycin, cyclosporine, diltiazem, erythromycin, and verapamil.(1,2) P-gp inhibitors include abrocitinib, amiodarone, asciminib, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, cyclosporine, danicopan, daraxonrasib, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, erythromycin, flibanserin, fluvoxamine, fostamatinib, glecaprevir/pibrentasvir, imlunestrant, ivacaftor, lapatinib, ledipasvir, mavorixafor, neratinib, osimertinib, pirtobrutinib, propafenone, quinidine, ranolazine, schisandra, selpercatinib, sotorasib, tepotinib, valbenazine, velpatasvir, vemurafenib, venetoclax, vepdegestrant, verapamil, vimseltinib, and voclosporin.(1,10,11)

P-Glycoprotein (P-Gp) Inhibitors/Doxorubicin

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

MECHANISM OF ACTION: P-glycoprotein (P-gp) inhibition may increase doxorubicin cellular concentration, as well as decrease biliary or renal elimination.(1)

CLINICAL EFFECTS: Increased cellular or systemic levels of doxorubicin may result in doxorubicin toxicity, including cardiomyopathy, myelosuppression, or hepatic impairment.(1)

PREDISPOSING FACTORS: The interaction magnitude may be greater in patients with impaired renal or hepatic function.

PATIENT MANAGEMENT: Avoid the concurrent use of P-gp inhibitors in patients undergoing therapy with doxorubicin.(1) Consider alternatives with no or minimal inhibition. If concurrent therapy is warranted, monitor the patient closely for signs and symptoms of doxorubicin toxicity. For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(2)

DISCUSSION: Doxorubicin is a substrate of P-gp.(1) Clinical studies have identified and evaluated the concurrent use of doxorubicin and P-gp inhibitors as a target to overcome P-gp mediated multidrug resistance.(3,4) P-gp inhibitors linked to this monograph include: amiodarone, asciminib, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, cimetidine, cyclosporine, daclatasvir, danicopan, daraxonrasib, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, eliglustat, erythromycin, flibanserin, fluvoxamine, fostamatinib, ginkgo, ginseng, glecaprevir/pibrentasvir, hydroquinidine, imlunestrant, istradefylline, ivacaftor, lapatinib, ledipasvir, mavorixafor, neratinib, osimertinib, paroxetine, pirtobrutinib, propafenone, quercetin, quinidine, quinine, ranolazine, sarecycline, schisandra, selpercatinib, simeprevir, sofosbuvir/velpatasvir/voxilaprevir, sotorasib, tepotinib, valbenazine, vemurafenib, vepdegestrant, verapamil, vimseltinib, and voclosporin.(5,6)

P-Glycoprotein (P-Gp) Inhibitors/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: Inhibitors of P-glycoprotein (P-gp) may increase the absorption of lefamulin.(1) Oral lefamulin tablets may inhibit the metabolism of P-gp inhibitors that are also sensitive CYP3A4 substrates (i.e., asunaprevir, felodipine, ivacaftor, and neratinib).(1-3)

CLINICAL EFFECTS: The concurrent administration of lefamulin with an inhibitor of P-gp may result in elevated levels of lefamulin and signs of toxicity, such as QT prolongation. Coadministration of oral lefamulin with agents that are also sensitive CYP3A4 substrates (i.e., asunaprevir, felodipine, ivacaftor, and neratinib) may result in elevated levels and toxicities of the sensitive CYP3A4 substrate.

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 lefamulin states that oral lefamulin tablet coadministration with P-gp inhibitors should be avoided.(1) If concomitant therapy with a P-gp inhibitor is necessary, 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. Concomitant use of asunaprevir, felodipine, ivacaftor, or neratinib requires close monitoring for adverse effects of these drugs.(1) The manufacturer of venetoclax states that if concurrent use with a P-gp substrate cannot be avoided, take lefamulin at least 6 hours before venetoclax.(5)

DISCUSSION: Coadministration of ketoconazole (a strong CYP3A4 and P-gp inhibitor) with lefamulin tablets increased lefamulin area-under-the-curve (AUC) and maximum concentration (Cmax) by 165% and 58%.(1) In a study, oral lefamulin tablets administered concomitantly with and at 2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200% and 100%, respectively. No clinically significant effect on midazolam pharmacokinetics was observed when co-administered with lefamulin injection.(1) P-gp inhibitors include: asunaprevir, belumosudil, capmatinib, carvedilol, cimetidine, danicopan, daridorexant, diosmin, flibanserin, fluvoxamine, fostamatinib, ginseng, glecaprevir/pibrentasvir, hydroquinidine, ivacaftor, ledipasvir, neratinib, pirtobrutinib, propafenone, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, valbenazine, vimseltinib, and voclosporin.(1-3)

Select P-Gp 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 a substrate for P-glycoprotein (P-gp). Inhibitors of P-gp may increase intestinal absorption and decrease elimination of aumolertinib.(1)

CLINICAL EFFECTS: Concurrent use with selected P-gp inhibitors may result in higher systemic concentrations of aumolertinib which may increase the risk for cardiac failure, rhabdomyolysis, thrombosis, elevated LFTs, hyponatremia, hematologic toxicity, and QT prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsade 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) 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 concomitant administration of aumolertinib should be avoided with P-gp inhibitors.(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: Based on in vitro data, aumolertinib is a substrate of P-gp.(1) P-gp inhibitors linked to this interaction are: abrocitinib, asunaprevir, belumosudil, capmatinib, carvedilol, cimetidine, cobicistat, conivaptan, curcumin, cyclosporine, danicopan, daridorexant, diltiazem, diosmin, flibanserin, fluvoxamine, fostamatinib, ginseng, glecaprevir/pibrentasvir, grapefruit, imlunestrant, indinavir, isavuconazole, itraconazole, ivacaftor, josamycin, ketoconazole, mifepristone, neratinib, nirmatrelvir, pirtobrutinib, ritonavir, telaprevir, tepotinib, tezacaftor, tipranavir, tucatinib, valbenazine, velpatasvir, verapamil, vimseltinib, voclosporin, and voxilaprevir.(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 Dual Cyp1a2 And Cyp3a4 Inhibitors/Alosetron

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

MECHANISM OF ACTION: Dual inhibitors of CYP1A2 and CYP3A4 may inhibit the metabolism of alosetron.(1,2)

CLINICAL EFFECTS: Concurrent administration with dual CYP1A2 and CYP3A4 inhibitors may result in 6-fold increases in alosetron levels and toxicity.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of alosetron states that concurrent use is contraindicated.(1)

DISCUSSION: In a study in 40 healthy females, pretreatment with fluvoxamine (escalating doses from 50 mg to 200 mg daily for 16 days) increased the area-under-curve (AUC) and half-life of alosetron by 6-fold and 3-fold, respectively.(1,2) Selected dual CYP1A2 and CYP3A4 inhibitors linked include: enasidenib and fluvoxamine.(3,4)

Selected Ssris; Duloxetine/Thioridazine

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

MECHANISM OF ACTION: Dapoxetine,(1) duloxetine,(2) fluoxetine,(3-7) and paroxetine(3,4) may inhibit the metabolism of thioridazine by CYP2D6. Fluvoxamine may inhibit the metabolism of thioridazine by CYP2C19 and/or CYP1A2.(8)

CLINICAL EFFECTS: The concurrent administration of dapoxetine, duloxetine, fluoxetine, fluvoxamine, or paroxetine with thioridazine may result in elevated levels of thioridazine. Elevated levels of thioridazine may augment thioridazine-induced prolongation of the QTc interval, which may increase the risk of serious, potentially fatal, cardiac arrhythmias such as torsades de pointes.(3,4)

PREDISPOSING FACTORS: Patients who are CYP2D6 ultrarapid metabolizers may be affected to a greater extent by CYP2D6 inhibitors. Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition. 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.(15) 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. co-administration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(15)

PATIENT MANAGEMENT: Use an alternative antipsychotic agent. The concurrent use of thioridazine with dapoxetine,(1) duloxetine,(2) fluoxetine,(3-5,7) fluvoxamine,(3,4,8) or paroxetine(3,4,9,10) is contraindicated. If thioridazine cannot be discontinued, use an alternative to the interacting SSRI or duloxetine and evaluate patient for predisposing risk factors for QT prolongation. Correct modifiable risk factors and monitor for QT prolongation as appropriate throughout treatment with thioridazine. If alternative treatment is not possible and concurrent therapy is deemed medically necessary, strongly 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. At least 7 days should elapse following the discontinuation of dapoxetine before thioridazine is initiated and at least 14 days should elapse following the discontinuation of thioridazine before dapoxetine is initiated.(1) At least five weeks should elapse following the discontinuation of fluoxetine before thioridazine is initiated.(5-7)

DISCUSSION: In a study, pretreatment with duloxetine (60 mg twice daily) increased the area-under-curve (AUC) of a single dose of desipramine (50 mg) by 3-fold. Desipramine is metabolized by CYP2D6.(2) In a study in 10 patients, concurrent fluvoxamine (25 mg twice daily) resulted in a 3-fold increase in the levels of thioridazine and its two active metabolites, mesoridazine and sulforidazine.(11) A study in six slow and 13 rapid metabolizers of debrisoquin showed that slow metabolizers of debrisoquin had 2.4-fold and 4.5-fold higher thioridazine maximum concentration (Cmax) and AUC, respectively, than rapid metabolizers.(5,6,12) Slow metabolizers of debrisoquin have a genetic defect that results in low levels of CYP2D6.(3) A study in healthy subjects showed a thioridazine dose-related prolongation of the QTc interval.(13) A study in schizophrenic patients found no changes in thioridazine levels following the addition of citalopram.(14)

Serotonergic Agents/Dapoxetine

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

MECHANISM OF ACTION: Concurrent administration of dapoxetine with other serotonergic agents may result in additive effects on serotonin, resulting in serotonin syndrome.(1,2)

CLINICAL EFFECTS: Concurrent use of dapoxetine with other serotonergic agents may result in serotonin syndrome, a potentially life-threatening syndrome which may include one or more of the following symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3)

PREDISPOSING FACTORS: Use of multiple drugs which increase serotonin levels is associated with an increased risk for this toxidrome.

PATIENT MANAGEMENT: Dapoxetine should not be administered with other serotonergic agents such as the selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), L-tryptophan, triptans, tramadol, lithium, and/or St. John's Wort.(1,2) Dapoxetine should not be initiated within 14 days of receiving other serotonergic agents. Other serotonergics should not be initiated within 7 days of receiving dapoxetine.(2)

DISCUSSION: This interaction is based on class labeling for these agents. Although there is no clinical documentation for an interaction between dapoxetine and either the elective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), L-tryptophan, triptans, tramadol, lithium, and/or St. John's Wort, caution is still warranted. This syndrome has been reported with the selective serotonin reuptake inhibitors and other serotonergic agents, including sumatriptan and dihydroergotamine.

Serotonergic Agents/Sibutramine

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

MECHANISM OF ACTION: Concurrent administration may result in additive effects on serotonin, resulting in serotonin syndrome.

CLINICAL EFFECTS: Concurrent use of sibutramine and agents which effect serotonin may result in serotonin syndrome, a serious and potentially fatal reaction. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity. (1-5)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Sibutramine has been removed from the market by the European Medicines Agency and by regulatory agencies in a number of countries including Australia, Canada, Hong Kong, India, Thailand, United Kingdom and the United States. The Canadian manufacturer of sibutramine formerly stated that concurrent use with antidepressants or serotonergic agents is contraindicated. At least 14 days should elapse between discontinuation of these agents and initiation of sibutramine. Five weeks is required following the discontinuation of fluoxetine.(1) The Australian(2) and UK(3) manufacturers of sibutramine stated that sibutramine is contraindicated within 2 weeks of antidepressant use and should not be used with other serotonergic agents. The US manufacturer of sibutramine stated that in general, sibutramine should not be administered with other serotonergic agents such as the selective serotonin reuptake inhibitors, sumatriptan or dihydroergotamine. However, if concurrent administration is clinically indicated, the patient should be appropriately observed.(4) If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. Patients in whom serotonin syndrome is suspected should receive immediate medical attention.

DISCUSSION: Sibutramine has been removed from the market by the European Medicines Agency and by regulatory agencies in a number of countries including Australia, Canada, Hong Kong, India, Thailand, United Kingdom and the United States. Sibutramine inhibits serotonin reuptake and serotonin syndrome has been reported during concomitant use of selective serotonin reuptake inhibitors and other selective serotonin reuptake inhibitors, sumatriptan, and dihydroergotamine(1-4)

Serotonin Reuptake Inhibitors; Snris/Selected Maois

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

MECHANISM OF ACTION: Serotonin reuptake inhibitors and MAOIs may act synergistically to increase blood pressure and evoke behavioral excitation.

CLINICAL EFFECTS: Concurrent use or switching between agents without a sufficient washout period may result in serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of the selective serotonin reuptake inhibitors, the selective serotonin and norepinephrine reuptake inhibitors, nefazodone, and venlafaxine state that concurrent use with MAOIs is contraindicated. A minimum 5 week washout period should separate the switch of fluoxetine to a MAOI. A washout period of at least 21 days is recommended for the switch from vortioxetine to a MAOI. A washout period of at least 2 weeks is recommended for the switch of citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, or vilazodone to a MAOI. A washout period of 7 days is recommended for the switch of dapoxetine, levomilnacipran, nefazodone, desvenlafaxine, and venlafaxine to a MAOI. A washout period of 5 days is recommended for the switch of duloxetine or milnacipran to a MAOI. Prior to starting any selective serotonin reuptake inhibitor, non-selective serotonin reuptake inhibitor, or duloxetine, allow a 2 week washout period after stopping MAOI therapy. These washout recommendations apply to the selective MAO-B inhibitors rasagiline and selegiline as well. If rasagiline is used in combination with fluvoxamine, patients should receive no more than 0.5mg of rasagiline daily. In emergency situations in patients maintained on SSRIs or SNRIs, weigh the availability and safety of alternatives to linezolid and methylene blue against the risk of serotonin syndrome. If linezolid or methylene blue therapy is required, the patient's SSRI or SNRI should be immediately discontinued. Patients should be monitored for serotonin syndrome for 2 weeks (5 weeks in the case of fluoxetine, 21 days in the case of vortioxetine, and 5 days in the case of duloxetine and milnacipran) or until 24 hours after the last dose of linezolid or methylene blue, whichever comes first. In non-emergency situations in patients maintained on SSRIs or SNRIs when linezolid or methylene blue therapy is planned, discontinue the patient's SSRI or SNRI at least 2 weeks (5 weeks in the case of fluoxetine, 21 days in the case of vortioxetine, and 5 days in the case of duloxetine and milnacipran) in advance of linezolid or methylene blue therapy. The patient's SSRI or SNRI therapy may be resumed 24 hours after the last dose of linezolid or methylene blue. Do not initiate SSRI or SNRI therapy in patients receiving linezolid or methylene blue until 24 hours after the last dose of these agents.

DISCUSSION: This serious interaction (serotonin syndrome) has been reported with fluoxetine, sertraline, and venlafaxine. Although this has been not been reported with the fluvoxamine, nefazodone, or paroxetine, current recommendations by their manufacturers indicate that the potential for this interaction should be assumed. Manufacturer's product information for fluoxetine, paroxetine, and venlafaxine state that concurrent administration of these agents with a MAOI is contraindicated. The other selective serotonin reuptake inhibitors and non-selective serotonin reuptake inhibitors have shorter half-lives than fluoxetine. Therefore, the time frame during which the interaction would be expected to occur with agents and MAOIs would not be expected to be as prolonged as with fluoxetine. In a case report, a patient had stopped taking paroxetine 10 days prior to initiating St. John's wort. The evening after initiating St. John's wort, the patient took a paroxetine. At noon the next day, the patient was able to be awakened, but was incoherent, groggy, slow-moving, and almost unable to get up. Two hours later during an examination, she was groggy and lethargic, but able to respond appropriately. She complained of nausea, weakness, and fatigue. Her vital signs and physical exam were normal, except for a slow response time and limp muscle tone. She did not take any additional paroxetine and was normal the next day. The metabolism of rasagiline has been shown to be inhibited by CYP P-450-1A2 inhibitors such as fluvoxamine. Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A. Serotonin syndrome has been reported following administration of methylene blue in patients receiving selective serotonin reuptake inhibitors (SSRIs). Metaxalone is a weak inhibitor of MAO. The FDA AERS contains reports of serotonin syndrome with the concurrent use of linezolid and citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine as well as reports of serotonin syndrome with concurrent injectable methylene blue and citalopram, clomipramine, escitalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine. One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Ssris; Nefazodone/Astemizole; Terfenadine

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

MECHANISM OF ACTION: Concurrent administration may result in the inhibition of the metabolism of astemizole and terfenadine by the SSRIs and nefazodone.

CLINICAL EFFECTS: Concurrent administration may result in increased serum levels of astemizole and terfenadine resulting in possible life-threatening cardiotoxicity including QT prolongation or torsades de pointes.

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.(9) 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).(9)

PATIENT MANAGEMENT: Concomitant administration of terfenadine with either fluvoxamine and nefazodone is contraindicated.(1-3) The manufacturer of terfenadine states that concurrent administration of terfenadine and sertraline is not recommended.(3) Concomitant administration of astemizole with fluvoxamine and nefazodone is contraindicated by the manufacturers of fluvoxamine and nefazodone.(1,2) Concomitant administration of astemizole and fluoxetine, fluvoxamine, nefazodone, paroxetine, or sertraline is not recommended by the manufacturer of astemizole.(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: Elevated plasma levels of the nonsedating antihistamines astemizole or terfenadine can cause QT prolongation and torsades de pointes-type ventricular tachycardia which may be fatal. Both astemizole and terfenadine are metabolized by CYP3A4. Drugs that block the metabolism of astemizole and terfenadine may produce an increase in plasma concentrations of these antihistamines. It has not been demonstrated that fluvoxamine is a potent inhibitor of CYP3A4: however, fluvoxamine is suspected to be. In vitro studies have shown nefazodone to be an inhibitor of CYP3A4. Therefore the manufacturers of fluvoxamine and nefazodone contraindicate concurrent use with either astemizole or or terfenadine.(1,2) The manufacturer of astemizole states that concurrent administration of astemizole and fluoxetine, fluvoxamine, nefazodone, paroxetine, or sertraline is not recommended.(4) In a study, concurrent administration of fluoxetine with a single dose of terfenadine resulted in no changes in terfenadine levels. The manufacturer of fluoxetine states that fluoxetine inhibition of CYP3A4 is unlikely to be of clinical significance.(5) In a study, concurrent administration of paroxetine with terfenadine at steady state resulted in no changes in terfenadine levels. The manufacturer of paroxetine states that paroxetine inhibition of CYP3A4 is unlikely to be of clinical significance.(6,7) In a study, concurrent administration of sertraline with terfenadine at steady state resulted in no changes in terfenadine levels. The manufacturer of sertraline states that sertraline inhibition of CYP3A4 is unlikely to be of clinical significance.(8)

Ssris; Nefazodone/Pimozide

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

MECHANISM OF ACTION: Fluvoxamine,(1) nefazodone,(2,3) may inhibit the metabolism of pimozide at CYP3A4. The mechanisms for the interactions between citalopram,(4) escitalopram,(5) and sertraline(6) and pimozide are unknown.

CLINICAL EFFECTS: Concurrent use may result in prolongation of the QTc interval and potentially life-threatening ventricular arrhythmias.(1-9) Concurrent use may also result in extrapyramidal symptoms such as akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, and oculogyric crisis.(7)

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.(8) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increased systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(8) 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.(9)

PATIENT MANAGEMENT: The concurrent use of pimozide with citalopram,(3-5) escitalopram,(3-5) fluvoxamine,(1,3) nefazodone,(2,3) or sertraline(3,6) is contraindicated. 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: An in vitro study indicates that pimozide is metabolized at CYP3A4.(7) In a controlled study, the administration of a single dose of pimozide (2 mg) with citalopram (40 mg daily for 11 days) increased mean QTc values by 10 msec compared to pimozide administered alone. There was no change in pimozide area-under-curve (AUC) or maximum concentration (Cmax).(4,5) In a controlled study, the administration of sertraline (200 mg daily) with a single dose of pimozide (2 mg) resulted in 40% increases in both the AUC and Cmax of pimozide, but was not associated with EKG changes. However, given the narrow therapeutic index of pimozide, their concurrent use is contraindicated by the manufacturer of sertraline.(6) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

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

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

PREDISPOSING FACTORS: None determined.

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

DISCUSSION: In a study, itraconazole (a strong CYP3A4 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of nirogacestat by 8.2-fold and 2.5-fold, respectively, following a single 100 mg dose of nirogacestat. In a PKPB model, nirogacestat AUC was predicted to increase by 6.33-, 5.19-, and 3.46-fold following coadministration of multiple doses of nirogacestat (150 mg BID) with itraconazole, ketoconazole and clarithromycin (strong CYP3A inhibitors), respectively.(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.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2) Moderate CYP3A4 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, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(2)

Strong And Moderate Cyp3a4 Inhibitors/Repotrectinib

SEVERITY LEVEL: 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 repotrectinib.(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)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant use of strong or moderate CYP3A4 inhibitors with repotrectinib. Discontinue CYP3A4 inhibitors for 3 to 5 half lives of the inhibitor prior to initiating 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) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, letermovir, netupitant, nilotinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2)

Strong Cyp1a2 Inhibitors/Duloxetine

SEVERITY LEVEL: 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 CYP1A2 may inhibit the metabolism of duloxetine.(1)

CLINICAL EFFECTS: Concurrent use of inhibitors of CYP1A2 may result in elevated levels of and toxicity from duloxetine.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of duloxetine states that concurrent use with strong inhibitors of CYP1A2 should be avoided.(1)

DISCUSSION: In a study in 14 male subjects, concurrent fluvoxamine increased duloxetine area-under-curve (AUC), maximum concentration (Cmax), and half-life by over 5-fold, about 2.5-fold, and approximately 3-fold, respectively.(1) In a study in 14 subjects who were poor metabolizers of CYP2D6, fluvoxamine (100 mg) increased the AUC and Cmax of duloxetine (40 mg BID) by 6-fold each.(1)

Strong Cyp1a2 Inhibitors/Tasimelteon

SEVERITY LEVEL: 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 CYP1A2 inhibitors may inhibit the metabolism of tasimelteon.(1)

CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP1A2 may result in elevated levels of and toxicity from tasimelteon.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP1A2 inhibitors and tasimelteon.(1)

DISCUSSION: Fluvoxamine (50 mg daily for 6 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of tasimelteon by 2-fold and 7-fold, respectively.(1) Strong inhibitors of CYP1A2 include angelica root (angelica dahurica radix), ciprofloxacin, enasidenib, enoxacin, fluvoxamine, and rofecoxib.(2,3)

Strong Cyp1a2 Inhibitors/Tizanidine

SEVERITY LEVEL: 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 CYP1A2 inhibitors may inhibit the metabolism of tizanidine.

CLINICAL EFFECTS: Concurrent use of strong CYP1A2 inhibitors may result in elevated levels of and effects from tizanidine, including hypotension (including decreases in both systolic and diastolic pressure), bradycardia, drowsiness, sedation, and decreased psychomotor function.(1-5)

PREDISPOSING FACTORS: 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.(6)

PATIENT MANAGEMENT: The US manufacturer for tizanidine states concurrent use with strong CYP1A2 inhibitors is contraindicated.(1,3)

DISCUSSION: In a double-blind, randomized, cross-over study in 10 healthy subjects, pretreatment with ciprofloxacin (500 mg twice daily) for 3 days increased the tizanidine area-under-curve (AUC) and maximum concentration (Cmax) by 10-fold (range 6-fold to 24-fold) and 7-fold (range 4-fold to 21-fold), respectively, when compared to administration with placebo. During the ciprofloxacin phase, tizanidine pharmacodynamic effects were also increased; the mean decreases in systolic and diastolic blood pressure were 35 mmHg and 24 mmHg, respectively, and there were significant increases in sedation as shown by the Digit Symbol Substitution Test, subjective drug effect, and subjective drowsiness. During the placebo phase, the mean decreases in systolic and diastolic blood pressure were 15 mmHg and 11mm Hg, respectively.(7) In a case report, a 45 year old woman on maintenance tizanidine therapy was given ciprofloxacin which reduced her systolic and diastolic blood pressure 22 and 14 mmHg, respectively, on the day of ciprofloxacin administration. On day three the patient's blood pressure was reported low at 92/54 mmHg. On days 5 and 6, her body temperature and urine volume decreased 1.1 C and 496 mL/dL, respectively. The patient's symptoms improved immediately after ciprofloxacin was discontinued.(8) A retrospective study looked at adverse reaction case reports in the WHO pharmacovigilance database with concurrent tizanidine and ciprofloxacin administration and found that 57.1% of the adverse reactions were qualified as serious because of hospitalization. The most frequently observed reactions included hypotension, somnolence, fatigue, and asthenia.(9) A retrospective cohort study assessed the impact of concurrent administration of tizanidine and ciprofloxacin on outpatient physician visits and hospitalizations and found a significant association between exposure to tizanidine and ciprofloxacin and outpatient physician visits at 14 and 30 days (odds ratio (OR) = 1.61, (95% CI = 1.17-2.24)(p = 0.004); OR = 1.59 (95% CI = 1.1-2.34)(p = 0.016)) and a trend for increased risk of hospitalization for all evaluated time periods (OR = 1.68 (95% CI = 0.84-3.17), OR = 1.52 (95% CI = 0.63-3.33), OR = 2.19 (95% CI = 0.88-5.02).(10) Following multiple doses of enasidenib 100 mg, the AUC and Cmax of a single dose of caffeine 100 mg (a sensitive CYP1A2 substrate) increased by 655% and 18%, respectively.(3) In a study in 10 healthy subjects, pretreatment with fluvoxamine (100 mg daily for 4 days) increased the AUC and Cmax of a single dose of tizanidine (4 mg) by 33-fold (range: 14-fold to 103-fold) and by 12-fold (range 5-fold to 33-fold), respectively. Tizanidine half-life increased from 1.5 hours to 4.3 hours. The mean decrease in systolic blood pressure was 35 mmHg. The mean decrease in diastolic blood pressure was 20 mmHg. Heart rate decreased by 4 beats/minute. There were also significant effects on the Digit Substitution Test, subjective drug effects, and drowsiness.(1,11) There is one case report of an interaction between tizanidine and fluvoxamine.(12) In a study in human liver microsomes, fluvoxamine inhibited the metabolism of tizanidine.(13) Concomitant use of viloxazine significantly increases the total exposure, but not peak exposure, of sensitive CYP1A2 substrates, which may increase the risk of adverse reactions associated with these CYP1A2 substrates. In a study, viloxazine increased the AUC of caffeine by almost 6-fold.(5) Strong CYP1A2 inhibitors linked to this monograph include: angelica root (angelica dahurica radix), ciprofloxacin, enasidenib, enoxacin, fluvoxamine, rofecoxib, and viloxazine.(3) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Strong Cyp1a2 Inhibitors/Vorasidenib

SEVERITY LEVEL: 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 CYP1A2 inhibitors may inhibit the metabolism of vorasidenib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP1A2 inhibitors may result in elevated levels of and effects from vorasidenib, including hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer for vorasidenib states concurrent use with strong CYP1A2 inhibitors should be avoided.(1)

DISCUSSION: Vorasidenib is primarily metabolized by CYP1A2.(1) Concurrent use of vorasidenib and fluvoxamine (a strong CYP1A2 inhibitor) is predicted to increase vorasidenib maximum concentration (Cmax) and area-under-curve (AUC) by greater than 5-fold.(1) In a study, concurrent use of vorasidenib and ciprofloxacin (a moderate CYP1A2 inhibitor) increased vorasidenib Cmax 1.3-fold and AUC 2.5-fold.(1) Strong CYP1A2 inhibitors linked to this monograph include: angelica root (angelica dahurica radix), enasidenib, enoxacin, fluvoxamine, and rofecoxib.(2)

Strong Cyp2c19 Inhib Cause Bleeding/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: Fluoxetine and fluvoxamine are strong CYP2C19 inhibitors. Strong CYP2C19 inhibitors may inhibit the metabolism of cilostazol.(1-3) In addition, serotonin release by platelets plays a role in hemostasis.(2,3) This may result in an increased risk of bleeding due to a decrease in serotonin reuptake by platelets.

CLINICAL EFFECTS: Concurrent use of cilostazol and strong CYP2C19 inhibitors may result in elevated levels and increased effects of cilostazol.(1) Concurrent use of a selective serotonin reuptake inhibitor(2,3) and cilostazol may result in bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(5) 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: The dose of cilostazol should be limited to 50 mg twice daily in patients receiving concurrent therapy with strong CYP2C19 inhibitors.(1) Selective serotonin reuptake inhibitors and agents that affect coagulation should be used concurrently with caution. 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: A study in 20 subjects examined the effects of omeprazole (40 mg daily) on a single dose of cilostazol (100 mg). Concurrent omeprazole increased the cilostazol maximum concentration (Cmax) and area-under-curve (AUC) by 18% and 26%, respectively. The Cmax and AUC of the 3,4-dehydro-cilostazol metabolite of cilostazol increased 29% and 69%, respectively. The Cmax and AUC of the OPC-13213 metabolite of cilostazol decreased by 22% and 31%, respectively.(4) In a retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ration was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a selective serotonin reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(5) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with selective serotonin reuptake inhibitors and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6, respectively.(6) In a case-control study conducted in users of acenocoumarol or phenprocoumon, 1848 patients who had been hospitalized with abnormal bleeding were each matched to 4 control patients. When patients took both a SSRI and a coumarin, an increased risk of hospitalization due to major non-gastrointestinal bleeding was observed (adjusted OR 1.7), but not due to gastrointestinal bleeding (adjusted OR 0.8).(7) A retrospective review examined patients discharged from a hospital with antiplatelet therapy following a myocardial infarction. When compared to aspirin therapy alone, both aspirin therapy with a SSRI and aspirin, clopidogrel, and SSRI therapy were associated with an increased risk of bleeding (hazard ratios 1.42 and 2.35, respectively.) Compared with dual antiplatelet therapy (aspirin and clopidogrel), use of aspirin and clopidogrel and a SSRI was also associated with increased risk of bleeding (hazard ration 1.57).(8) In The Rotterdam Study, fluvoxamine increased the risk of over anticoagulation (hazard ratio 2.63). Paroxetine was not associated with an increased risk. There were insufficient numbers of patients taking other SSRIs to assess increased risk.(9)

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.

Agents That Affect Catecholamines/Iobenguane I 123

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

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with imaging completed with iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores prior to imaging with iobenguane. Before imaging with iobenguane, discontinue agents that affect catecholamines for at least 5 biological half-lives, as clinically tolerated.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine)

Agents That Affect Catecholamines/Iobenguane I 131

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

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may impact the dosimetry calculations or effectiveness of iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores for at least 5 half-lives before administration of either the dosimetry or a therapeutic dose of iobenguane. Do not administer these drugs until at least 7 days after each iobenguane dose.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine) - calcium channel blockers

Dopamine Transporter Binders/Ioflupane I 123

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

MECHANISM OF ACTION: Ioflupane binds to the dopamine transporter. Agents that also bind to this transporter may affect the results of single photon emission computed tomography (SPECT) brain imaging using ioflupane.(1)

CLINICAL EFFECTS: SPECT imaging using ioflupane may not be accurate in patients taking other drugs that bind to the dopamine transporter binders.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: It is unknown if discontinuing other agents that bind to the dopamine transporter prior to a scan with ioflupane will decrease interference with the scan.(1) If use of these drugs can be safely suspended, consider discontinuing for at least 5 biological half-lives before administration of ioflupane.(1) Make sure the radiologist interpreting the scan knows the patient is taking another agent that binds to the dopamine transporter. Alternative diagnostic tools may need to be considered.

DISCUSSION: Ioflupane binds to the dopamine transporter. Agents that also bind to this transporter may affect the results of the scan. These agents include amoxapine, amphetamine, armodafinil, benztropine, bupropion, buspirone, citalopram, cocaine, dexmethylphenidate, escitalopram, fluoxetine, fluvoxamine, mazindol, methamphetamine, methylphenidate, modafinil, norephedrine, paroxetine, phentermine, phenylpropanolamine, selegiline, and sertraline.(1) In patients taking venlafaxine or desvenlafaxine, there have been cases of altered ioflupane uptake that impacted image interpretation. The mechanism of interference of these drugs with ioflupane is not known.(1)

Dual Cyp3a4 & Weak Cyp2d6 Inhibitors/Eliglustat

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

MECHANISM OF ACTION: Dual strong or moderate CYP3A4 and weak CYP2D6 inhibitors may inhibit the metabolism of eliglustat.(1)

CLINICAL EFFECTS: Concurrent use of an agent that is a dual strong or moderate CYP3A4 and weak CYP2D6 inhibitor 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: Prescribing information has no specific recommendation on the use of eliglustat with drugs that are dual strong or moderate CYP3A4 and weak CYP2D6 inhibitors. 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 CYP2D6 metabolizers is contraindicated.(1) The concurrent use of eliglustat with strong inhibitors of CYP3A4 in intermediate and poor CYP2D6 metabolizers is contraindicated.(1) The concurrent use of eliglustat with moderate inhibitors of CYP3A4 in intermediate and poor CYP2D6 metabolizers should be avoided.(1) The dosage of eliglustat with strong or moderate inhibitors of CYP3A4 in extensive CYP2D6 metabolizers 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 CYP2D6 metabolizers.(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) Dual strong CYP3A4 and weak CYP2D6 inhibitors include: cobicistat.(1,3,4) Dual moderate CYP3A4 and weak CYP2D6 inhibitors include: diltiazem, fedratinib, fluvoxamine, imatinib, and verapamil.(1,3,4)

Fluoxetine; Fluvoxamine/Clopidogrel

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

MECHANISM OF ACTION: Clopidogrel is a prodrug and is converted to its active metabolite via a 2 step process. The first conversion step is mediated by CYP2C19, CYP1A2 and CYP2B6, while the second step is mediated by CYP3A4, CYP2B6 and CYP2C19.(1,2) CYP2C19 contributes to both steps and is thought to be the more important enzyme involved in formation of the pharmacologically active metabolite.(1) Fluoxetine and fluvoxamine may inhibit the metabolism of clopidogrel to its active form by CYP2C19.(1)

CLINICAL EFFECTS: Concurrent use of fluoxetine and fluvoxamine may result in decreased clopidogrel effectiveness, resulting in increased risk of adverse cardiac events.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of clopidogrel states that alternatives to clopidogrel should be considered in patients who are poor metabolizers of CYP2C19.(1) It would be prudent to assume that patients taking strong inhibitors of CYP2C19, such as fluoxetine and fluvoxamine, are poor metabolizers of this isoenzyme. Consider alternatives to fluoxetine and fluvoxamine in patients stabilized on clopidogrel and alternatives to clopidogrel in patients stabilized on fluoxetine or fluvoxamine. If concurrent therapy is warranted, consider appropriate testing to assure adequate inhibition of platelet reactivity.

DISCUSSION: In an open-label, cross-over study in 8 health male volunteers, a loading dose of clopidogrel (600 mg) was administered alone and after 5 days of fluoxetine (20 mg). The maximum concentration (Cmax) and area-under-curve (AUC) of the active metabolite of clopidogrel were decreased by 25.3% and 20.6%, respectively. There was an average decrease of approximately 25% in the antiplatelet effects of clopidogrel when administered with fluoxetine.(2) However, it is likely that this study significantly underestimates the magnitude of this interaction. Both fluoxetine and its norfluoxetine metabolite inhibit CYP2C19 and have long half-lives of 4 to 9 days and so and is an irreversible inhibitor of CYP2C19. In a randomized, cross-over study in healthy subjects, ketoconazole (another CYP2C19 inhibitor, 400 mg daily) decreased the Cmax of the active metabolite of clopidogrel (300 mg loading dose, followed by 75 mg daily) by 61%. The AUC of the active metabolite of clopidogrel was decreased by 22% following the loading dose and by 29% during maintenance dosing. Clopidogrel-induced inhibition of platelet aggregation was decreased by 28% following the loading dose and by 33% during the maintenance dose.(4) In a cross-over study in 72 healthy subjects, simultaneous administration of omeprazole (another CYP2C19 inhibitor, 80 mg daily) and clopidogrel (300 mg loading dose, followed by 75 mg daily) decreased the AUC of the active metabolite of clopidogrel by 46% following the loading dose and by 42% during maintenance dosing. Clopidogrel-induced inhibition of platelet aggregation was decreased by 47% following the loading dose and by 30% during the maintenance dose. In a cross-over study in 72 healthy subjects, administration of omeprazole (another CYP2C19 inhibitor, 80 mg daily) 12 hours after clopidogrel (300 mg loading dose, followed by 75 mg daily) produced similar effects.(1)

Fluvoxamine/Hydantoins

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

MECHANISM OF ACTION: Phenytoin is metabolized by CYP2C9 and CYP2C19. Fluvoxamine inhibits both of these metabolic pathways.(1-3)

CLINICAL EFFECTS: The pharmacological and toxic effects of hydantoins may be increased when fluvoxamine is initiated. If fluvoxamine is stopped after long-term concomitant treatment seizure risk may be increased due to decreased hydantoin serum concentrations. Phenytoin has a narrow therapeutic range. Early symptoms of phenytoin toxicity may include nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting. Severe toxicity may produce organ dysfunction (e.g. coma, irreversible cerebellar dysfunction and atrophy, hypotension, bradycardia, seizures, and cardiac arrest) and may be fatal.(1)

PREDISPOSING FACTORS: Renal impairment, hepatic impairment, or hypoalbuminemia.

PATIENT MANAGEMENT: Serum hydantoin concentrations should be monitored and the patient should be observed for changes in seizure control if therapy with fluvoxamine is started, stopped or altered. Monitor patients for hydantoin toxicity if fluvoxamine treatment is started or if dose is increased (e.g. nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting). Adjust the hydantoin dose as indicated. If long term fluvoxamine therapy is discontinued, the hydantoin concentration may decrease.(1)

DISCUSSION: In one case report, a patient stabilized on phenytoin developed phenytoin intoxication after initiation of fluvoxamine. Phenytoin concentrations increased from 16.6 to 49.1 mcg/mL with symptoms of ataxia.(4) In another case report, a patient stabilized on phenytoin for two months developed elevated phenytoin serum concentrations (133% increase) as well as signs and symptoms of phenytoin toxicity within 5 days of starting fluoxetine (another CYP2C19 inhibitor).(5) In another case report, a patient stabilized on phenytoin for one year had a 309% increase in plasma phenytoin concentration and signs of phenytoin toxicity 10 days after initiation of treatment with fluoxetine. Similar cases have been reported to the FDA through the Spontaneous Reporting System.(6)

Fluvoxamine/Selected Benzodiazepines

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

MECHANISM OF ACTION: Fluvoxamine, a strong CYP2C19 inhibitor and moderate CYP3A4 inhibitor, may decrease the metabolism of Phase I hepatically metabolized benzodiazepines.

CLINICAL EFFECTS: Concurrent use of fluvoxamine and selected benzodiazepines may result in increased systemic levels and clinical effects of the benzodiazepine including profound sedation, respiratory depression, coma, and/or death. Benzodiazepines linked to this monograph are chlordiazepoxide, clorazepate, diazepam, flurazepam, halazepam, prazepam and quazepam.

PREDISPOSING FACTORS: The interaction may be more severe in patients receiving another CYP3A4 inhibitor.

PATIENT MANAGEMENT: Benzodiazepines that do not undergo extensive Phase I metabolism (lorazepam, oxazepam) may be an alternative in patients receiving fluvoxamine. The US manufacturer of fluvoxamine recommends that fluvoxamine and diazepam not be concurrently administered. If fluvoxamine is started in a patient already receiving a benzodiazepine, monitor closely and anticipate the need to reduce the benzodiazepine dose. Counsel patient to report excess drowsiness, confusion, memory problems including sleep-driving behaviors, loss of coordination, unusual dizziness of lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: In a study in healthy volunteers, administration of fluvoxamine (150 mg daily) decreased the clearance of a single dose of diazepam (10 mg) by 65%. The clearance of N-desmethyldiazepam was too low to measure. Benzodiazepines such as lorazepam or oxazepam, would not be expected to have a pharmacokinetic interaction with fluvoxamine.

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/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/Mitapivat (100 Mg)

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

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

CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels of and effects from mitapivat including decreased estrone and estradiol levels in males, increased urate, back pain, and arthralgias.(1-2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of mitapivat 100 mg tablets states that concurrent use with moderate CYP3A4 inhibitors should be avoided.(1) The Middle Eastern prescribing information for mitapivat states that alternative therapies that are not moderate CYP3A4 inhibitors should be considered during treatment with mitapivat. If concomitant use of a moderate CYP3A4 inhibitor is unavoidable, the dose of mitapivat should not exceed 100 mg once daily. Patients should be monitored for adverse reactions.(2)

DISCUSSION: Mitapivat is a CYP3A4 substrate. In a pharmacokinetic study with mitapivat 100 mg twice daily dosing, fluconazole increased mitapivat area-under-curve (AUC) and concentration maximum (Cmax) by 2.7-fold and 1.7-fold, respectively.(1) Moderate inhibitors of CYP3A4 linked to this monograph include: amprenavir, aprepitant, atazanavir, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, letermovir, netupitant, nilotinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(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/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)

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.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of pexidartinib states that pexidartinib coadministration with moderate inhibitors of CYP3A4 should be avoided.(1) If coadministration with a moderate CYP3A4 inhibitor cannot be avoided, reduce the pexidartinib dose according to the following recommendations. If the planned total daily dose is currently 500 mg, modify the total daily dose to 250 mg by administering 125 mg twice daily. If the planned total daily dose is currently 375 mg, modify the total daily dose to 250 mg by administering 125 mg twice daily. If the planned total daily dose is currently 250 mg, modify the total daily dose to 125 mg by administering 125 mg once daily. If concomitant use of a moderate CYP3A4 inhibitor is discontinued, increase the pexidartinib dose to the dose that was used before starting the inhibitor after three plasma half-lives of the moderate CYP3A4 inhibitor. Monitor liver tests, including AST, ALT, total bilirubin, direct bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the recommendations in the Turalio package insert. Advise patients to immediately report any symptoms of hepatotoxicity.

DISCUSSION: Coadministration of fluconazole (a moderate CYP3A4 inhibitor) increased pexidartinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 41% and 67%.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, erythromycin, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, letermovir, netupitant, nilotinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(1,3)

Moderate Cyp3a4 Inhibitors/Pexidartinib (200 Mg)

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)

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.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of pexidartinib states that pexidartinib coadministration with moderate inhibitors of CYP3A4 should be avoided.(1) If coadministration with a moderate CYP3A4 inhibitor cannot be avoided, reduce the pexidartinib dose according to the following recommendations. If the planned total daily dose is currently 800 mg, modify the total daily dose to 400 mg by administering 200 mg twice daily. If the planned total daily dose is currently 600 mg, modify the total daily dose to 400 mg by administering 200 mg twice daily. If the planned total daily dose is currently 400 mg, modify the total daily dose to 200 mg by administering 200 mg once daily. If concomitant use of a moderate CYP3A4 inhibitor is discontinued, increase the pexidartinib dose to the dose that was used before starting the inhibitor after three plasma half-lives of the moderate CYP3A4 inhibitor. Monitor liver tests, including AST, ALT, total bilirubin, direct bilirubin, ALP and gamma-glutamyltransferase (GGT) according to the recommendations in the Turalio package insert. Advise patients to immediately report any symptoms of hepatotoxicity.

DISCUSSION: Coadministration of fluconazole (a moderate CYP3A4 inhibitor) increased pexidartinib maximum concentration (Cmax) and area-under-the-curve (AUC) by 41% and 67%.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, erythromycin, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, letermovir, netupitant, nilotinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(1,3)

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)

P-Glycoprotein (P-Gp) Inhibitors/Bilastine

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

MECHANISM OF ACTION: P-glycoprotein (P-gp) inhibition may increase the absorption of bilastine.(1,2)

CLINICAL EFFECTS: Concurrent use of P-gp inhibitors may result in elevated levels and toxicities from bilastine, including headache and somnolence.(1,2)

PREDISPOSING FACTORS: The interaction magnitude may be greater in patients with moderate to severe renal impairment.

PATIENT MANAGEMENT: The Canadian manufacturer of bilastine states that concomitant use of P-gp inhibitors with bilastine is not recommended. Coadministration should be avoided in patients with moderate or severe renal impairment.(1) The UK manufacturer of bilastine states that coadministration of bilastine and P-gp inhibitors should be avoided in patients with moderate to severe renal impairment.(2) The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(5)

DISCUSSION: In a study, ketoconazole and erythromycin both increased bilastine area-under-curve (AUC) and maximum concentration (Cmax) by 2-fold and 2- to 3-fold, respectively.(1) The UK manufacturer of bilastine states that these changes do not appear to affect the safety of bilastine.(2) P-gp inhibitors linked to this monograph include: amiodarone, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, cyclosporine, daclatasvir, danicopan, daraxonrasib, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, eliglustat, erythromycin, flibanserin, fluvoxamine, fostamatinib, ginkgo, ginseng, glecaprevir/pibrentasvir, hydroquinidine, imlunestrant, istradefylline, ivacaftor, lapatinib, ledipasvir, mavorixafor, neratinib, osimertinib, paroxetine, pirtobrutinib, posaconazole, propafenone, quercetin, quinidine, quinine, ranolazine, sarecycline, schisandra, selpercatinib, simeprevir, sofosbuvir/velpatasvir/voxilaprevir, sotorasib, tepotinib, valbenazine, vemurafenib, vepdegestrant, verapamil, vimseltinib, and voclosporin.(4,5)

P-Glycoprotein (P-Gp) Inhibitors/Colchicine (For Gout & Fmf)

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

MECHANISM OF ACTION: P-glycoprotein (P-gp) inhibitors may affect the transport of colchicine, a P-gp substrate.(1,2)

CLINICAL EFFECTS: Concurrent use of a P-gp inhibitor may result in elevated levels of and toxicity from colchicine. Symptoms of colchicine toxicity include abdominal pain; nausea or vomiting; severe diarrhea; muscle weakness or pain; numbness or tingling in the fingers or toes; myelosuppression; 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) and in patients who receive concurrent therapy.

PATIENT MANAGEMENT: The concurrent use of colchicine with P-gp inhibitors is contraindicated in patients with renal or hepatic impairment.(1-3) Avoid concurrent use in other patients, if possible.(3) In patients without renal or hepatic impairment who are currently taking or have taken a P-gp inhibitor in the previous 14 days, the dosage of colchicine should be reduced. For gout flares, the recommended dosage is 0.6 mg (1 tablet) for one dose. This dose should be repeated no earlier than in 3 days.(1,2) For gout prophylaxis, if the original dosage was 0.6 mg twice daily, use 0.3 mg daily. If the original dosage was 0.6 mg daily, use 0.3 mg every other day.(3-12) For Familial Mediterranean fever (FMF), the recommended maximum daily dose is 0.6 mg (may be given as 0.3 mg twice a day).(1,2) Patients should be instructed to immediately report any signs of colchicine toxicity, such as abdominal pain, nausea/significant diarrhea, vomiting; muscle weakness/pain; numbness/tingling in fingers/toes; unusual bleeding or bruising, infections, weakness/tiredness, or pale/gray color of the lips/tongue/palms of hands. The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(13)

DISCUSSION: There are several reports of colchicine toxicity(4-6) and death(7,8) following the addition of clarithromycin to therapy. In a retrospective review of 116 patients who received clarithromycin and colchicine during the same hospitalization, 10.2% (9/88) of patients who received simultaneous therapy died, compared to 3.6% (1/28) of patients who received sequential therapy.(9) An FDA review of 117 colchicine-related deaths that were not attributable to overdose found that 60 deaths (51%) involved concurrent use of clarithromycin.(2) There is one case report of colchicine toxicity with concurrent erythromycin.(10) 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 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 and P-gp inhibitors such as clarithromycin, cyclosporine, diltiazem, erythromycin, and verapamil.(1,2) P-gp inhibitors include abrocitinib, amiodarone, asciminib, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, danicopan, daraxonrasib, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, erythromycin, flibanserin, fluvoxamine, fostamatinib, glecaprevir/pibrentasvir, imlunestrant, ivacaftor, lapatinib, ledipasvir, mavorixafor, neratinib, osimertinib, pirtobrutinib, propafenone, quinidine, ranolazine, schisandra, selpercatinib, sotorasib, tepotinib, valbenazine, velpatasvir, vemurafenib, venetoclax, vepdegestrant, verapamil, vimseltinib, and voclosporin.(1,11,12)

P-Glycoprotein (P-Gp) Inhibitors/Relugolix

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

MECHANISM OF ACTION: Relugolix is a substrate of the intestinal P-glycoprotein (P-gp) efflux transporter. Inhibitors of P-gp may increase the absorption of relugolix.(1)

CLINICAL EFFECTS: The concurrent administration of relugolix with an inhibitor of P-glycoprotein may result in elevated levels of relugolix and adverse effects, including hot flashes, skin flushing, musculoskeletal pain, hyperglycemia, acute renal injury, transaminitis, arrhythmias, and hemorrhage.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of relugolix states that the coadministration of relugolix with P-gp inhibitors should be avoided. If the P-gp inhibitor is to be used short-term, relugolix may be held for up to 2 weeks. If treatment with relugolix is interrupted for longer than 7 days, resume relugolix with a loading dose of 360 mg on the first day, followed by 120 mg once daily.(1) If coadministration with a P-gp inhibitor cannot be avoided, relugolix should be taken at least 6 hours before the P-gp inhibitor. Monitor the patient more frequently for adverse events.(1) For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(2)

DISCUSSION: Coadministration of relugolix with erythromycin (a P-gp and moderate CYP3A4 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of relugolix by 6.2-fold. Voriconazole (a strong CYP3A4 inhibitor) did not have a clinically significant effect on the pharmacokinetics of relugolix.(1) P-gp inhibitors linked to this monograph include: amiodarone, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan, curcumin, cyclosporine, daclatasvir, danicopan, daraxonrasib, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, eliglustat, erythromycin, flibanserin, fluvoxamine, fostamatinib, ginkgo, ginseng, glecaprevir/pibrentasvir, indinavir, itraconazole, ivacaftor, josamycin, ketoconazole, lapatinib, lonafarnib, mavorixafor, mibefradil, mifepristone, neratinib, osimertinib, paroxetine, pirtobrutinib, posaconazole, propafenone, quinidine, quinine, ranolazine, ritonavir, sarecycline, schisandra, selpercatinib, simeprevir, sotorasib, telaprevir, telithromycin, tepotinib, tucatinib, valbenazine, velpatasvir, vemurafenib, venetoclax, vepdegestrant, verapamil, vimseltinib, and voclosporin.(3,4)

P-Glycoprotein (P-Gp) Inhibitors/Vincristine

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

MECHANISM OF ACTION: P-glycoprotein (P-gp) inhibitors may inhibit cellular efflux of vincristine.(1)

CLINICAL EFFECTS: Concurrent administration of a P-gp inhibitor may result in elevated levels of and toxicity from vincristine including myelosuppression, neurologic toxicity, tumor lysis syndrome, hepatotoxicity, constipation, or bowel obstruction.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of P-gp inhibitors in patients undergoing therapy with vincristine.(1) Consider alternatives with no or minimal P-gp inhibition. The manufacturer of vincristine states that concomitant use of P-gp inhibitors should be avoided.(1) The manufacturer of lopinavir/ritonavir states that patients who develop significant hematological or gastrointestinal toxicity on concomitant vincristine should temporarily hold lopinavir/ritonavir, or use alternative medications that do not inhibit CYP3A4 or P-gp.(2) The manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(3)

DISCUSSION: Vincristine is a substrate of P-gp. Inhibitors of P-gp may increase toxicity of vincristine.(1) There are several case reports of neurotoxicity with concurrent administration of vincristine and itraconazole.(4-6) There is a case report of neurotoxicity with concurrent administration of lopinavir-ritonavir with vincristine.(7) In a prospective study in 22 children receiving various chemotherapy with prophylactic itraconazole oral solution (0.5 ml/kg per day), two children receiving vincristine developed non-alcoholic steatohepatitis (NASH) and one child developed syndrome of inappropriate anti-diuretic hormone secretion (SIADH).(8) Inhibitors of P-gp linked to this monograph include: abrocitinib, amiodarone, Asian ginseng (Panax ginseng), asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, cyclosporine, danicopan, daraxonrasib, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, elagolix, eliglustat, erythromycin, flibanserin, fluvoxamine, fostamatinib, ginkgo biloba, glecaprevir and pibrentasvir, imlunestrant, isavuconazonium, ivacaftor, lapatinib, mavorixafor, milk thistle (Silybum marianum), neratinib, osimertinib, pirtobrutinib, propafenone, quercetin, quinidine, ranolazine, rolapitant, Schisandra chinensis, selpercatinib, sofosbuvir, sotorasib, tepotinib, valbenazine, velpatasvir, vemurafenib, venetoclax, vepdegestrant, verapamil, vilazodone, vimseltinib, and voclosporin.(9-10)

P-Gp Inhibitors That Cause Bleeding/Betrixaban; Dabigatran

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

MECHANISM OF ACTION: This combination may interact via both a pharmacodynamic and a pharmacokinetic mechanism. Pharmacodynamically, serotonin release by platelets plays a role in hemostasis.(1) Fluvoxamine may cause a decrease in serotonin reuptake by platelets, resulting in an additive risk of bleeding with oral anticoagulants.(1) Mifepristone is an antagonist at the progesterone receptor which can result in endometrium thickening, cystic dilatation of endometrial glands, or excessive vaginal bleeding. Concurrent use with anticoagulants may further increase risk.(2) Pharmacokinetically, fluvoxamine and mifepristone are inhibitors of the P-glycoprotein (P-gp) transporter and may increase the absorption of betrixaban and dabigatran.(3)

CLINICAL EFFECTS: Concurrent use of P-gp inhibitors with betrixaban or dabigatran may result in bleeding. The concurrent use of mifepristone with anticoagulants may result in endometrium thickening, cystic dilatation of endometrial glands, or excessive vaginal bleeding.(2)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia, recent trauma). Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(4) Patient-associated risk factors include age greater than 74 years and weight less than 50 kg.(5,6) Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet transport or metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Concurrent therapy of P-gp inhibitors with betrixaban or dabigatran should be undertaken with caution. Assess renal function and evaluate the patient for other pre-existing risk factors for bleeding prior to initiating concurrent therapy. The concurrent use of betrixaban and P-gp inhibitors should be avoided in patients with severe renal impairment (CrCl less than 30 ml/min). The recommended dose of betrixaban for patients receiving or starting concomitant P-gp inhibitors is an initial single dose of 80 mg followed by 40 mg once daily. The recommended duration of treatment is 35 to 42 days.(5) The US manufacturer of dabigatran states that the concurrent use of dabigatran and P-gp inhibitors should be avoided in atrial fibrillation patients with severe renal impairment (CrCl less than 30 ml/min) and in patients being treated for or undergoing prophylaxis for deep vein thrombosis (DVT) or pulmonary embolism (PE) who have moderate renal impairment (CrCl less than 50 ml/min). The interaction with P-gp inhibitors can be minimized by taking dabigatran several hours apart from the P-gp inhibitor dose.(6) The manufacturer of mifepristone states that mifepristone should be used with caution in patients receiving concurrent anticoagulant therapy.(2) Women experiencing vaginal bleeding during concurrent use should be referred to a gynecologist for further evaluation. If concurrent therapy is warranted, monitor patients for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. 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 the APEX randomized, double-blind study the incidence of major or clinically relevant non-major bleeds (CRNM) in the betrixaban 40mg and 80 mg group was higher in patients taking concomitant P-gp inhibitors (2.8% vs. 4.1% vs. 4.7%).(7) In a study in 12 subjects, concomitant administration of betrixaban (40 mg) following a 5-day regimen of ketoconazole (200 mg twice daily) resulted in an increase in betrixaban's maximum concentration (Cmax) and area-under-the-curve (AUC) of 2.3-fold and 2.3-fold, respectively.(8) An open-label study, concomitant administration of a single dose of betrixaban with verapamil resulted in an increase in betrixaban's Cmax and AUC of approximately 4.7-fold and 3-fold, respectively.(8) Coadministration with amiodarone resulted in an increase in betrixaban's Cmax by 143%.(8) When dabigatran was co-administered with amiodarone, dabigatran AUC and Cmax were increased by about 60% and 50%, respectively.(9) Chronic administration of verapamil one hour prior to dabigatran increased dabigatran AUC by 154%.(11) Administration of dabigatran two hours before verapamil results in a negligible increase in dabigatran AUC.(9) A retrospective cohort study evaluated adverse bleeding rates with standard doses of oral anticoagulants with concurrent verapamil or diltiazem in patients with normal kidney function. Concomitant dabigatran use with verapamil or diltiazem was associated with increased overall bleeding (hazard ratio (HR) 1.52; HR 1.43) and increased overall GI bleeding (HR 2.16; HR 2.32) when compared to amlodipine and metoprolol, respectively. No association was found between increased bleeding of any kind and concurrent use of rivaroxaban or apixaban with verapamil or diltiazem.(14) A retrospective cohort study examined 24,943 patients with concurrent therapy of an anticoagulant, either rivaroxaban (40.0%), apixaban (31.9%), or dabigatran (28.1%), with either azithromycin or clarithromycin. The primary outcome of hospital admission with major hemorrhage within 30 days on concurrent therapy was higher in patients on clarithromycin (0.77%) compared to azithromycin (0.43%) with an adjusted HR of 1.71.(12) In a retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. Concurrent use of a selective serotonin reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(13) In a case-control study conducted in users of acenocoumarol or phenprocoumon, 1,848 patients who had been hospitalized with abnormal bleeding were each matched to 4 control patients. When patients took both a SSRI and a coumarin, an increased risk of hospitalization due to major non-gastrointestinal bleeding was observed (adjusted OR 1.7), but not due to gastrointestinal bleeding (adjusted OR 0.8).(15) A retrospective review examined patients discharged from a hospital with antiplatelet therapy following a myocardial infarction. When compared to aspirin therapy alone, both aspirin therapy with a SSRI and aspirin, clopidogrel, and SSRI therapy were associated with an increased risk of bleeding (HR 1.42 and 2.35, respectively). Compared with dual antiplatelet therapy (aspirin and clopidogrel), use of aspirin and clopidogrel and a SSRI was also associated with increased risk of bleeding (HR 1.57).(16) In The Rotterdam Study, fluvoxamine increased the risk of over anticoagulation (HR 2.63). Paroxetine was not associated with an increased risk. There were insufficient numbers of patients taking other SSRIs to assess increased risk.(17) A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of dabigatran and citalopram resulted in a ratio of rate ratios (95% CI) of 1.69 (1.11-2.57).(18)

Select Cyp2c19 Inhibitors/Citalopram (>20 Mg)

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

MECHANISM OF ACTION: Citalopram is primarily metabolized by the CYP2C19 isoenzyme.(1)

CLINICAL EFFECTS: Concurrent use of an agent that inhibits CYP2C19 may result in elevated levels of and toxicity from citalopram, including including risks for serotonin syndrome or prolongation of the QTc interval.(1-5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(5)

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, advanced age, poor metabolizer status at CYP2C19, or higher blood concentrations of citalopram.(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) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,5) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

PATIENT MANAGEMENT: The dose of citalopram should be limited to 20 mg in patients receiving concurrent therapy with an inhibitor of CYP2C19.(1,4) Evaluate the patient for other drugs, diseases and conditions which increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, discontinue other QT prolonging drugs) when possible.(1,2) Weigh the specific benefits versus risks for each patient. The US manufacturer recommends ECG monitoring for citalopram patients with congestive heart failure, bradyarrhythmias, taking concomitant QT prolonging medications or receiving concurrent therapy.(4) Citalopram should be discontinued in patients with persistent QTc measurements greater than 500 ms.(2) 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. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: Concurrent use of citalopram (40 mg daily) and cimetidine (400 mg twice daily) for 8 days increased the maximum concentration (Cmax) and area-under-curve (AUC) of citalopram by 39% and 43%, respectively.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), armodafinil, asciminib, berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, elagolix, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, tecovirimat, treosulfan, and vonoprazan.(7,8)

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)

Serotonergic Cyp3a4 Inhibitors/Meperidine

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

MECHANISM OF ACTION: CYP3A4 inhibitors such as fluvoxamine and nefazodone may inhibit the metabolism of meperidine.(1-3) Meperidine inhibits the reuptake of serotonin.(1) Fluvoxamine and nefazodone also inhibit the reuptake of serotonin.(2,3)

CLINICAL EFFECTS: Concurrent administration may result in elevated levels of and toxicity from meperidine.(1) Concurrent administration could also increase the risk for serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(4)

PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of meperidine would be predicted to increase risk for serotonin toxicity. Concomitant therapy with other agents which increase brain serotonin concentrations may also increase risk.(1-4) Renal dysfunction and chronic use of meperidine would be expected to increase the risk for serotonin toxicity due to meperidine.(1)

PATIENT MANAGEMENT: If concomitant use is necessary, consider dose reduction of meperidine until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.(1) If the CYP3A4 inhibitor is discontinued, consider increasing the meperidine dose until stable drug effects are achieved. Monitor for signs of opioid withdrawal.(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.(5) 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).(6) Assess patient for predisposing risk factors of serotonin syndrome and monitor accordingly. The manufacturer of meperidine recommends careful monitoring for signs and symptoms of serotonin syndrome when a metabolic inhibitor or another serotoninergic agent is started, or when the dose of either agent is increased.(1-4)

DISCUSSION: Plasma concentrations of the active metabolite normeperidine may be increased by ritonavir (strong CYP3A4 inhibitor).(1)

Serotonin Reuptake Inhibitors/Linezolid

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

MECHANISM OF ACTION: Serotonin reuptake inhibitors and linezolid, which inhibits MAO, may act synergistically to increase central nervous system (CNS) serotonin concentrations, leading to toxicity.

CLINICAL EFFECTS: Concurrent use or switching between agents without a sufficient washout period may result in serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(2) Serotonin syndrome may result in death.

PREDISPOSING FACTORS: High doses of serotonin reuptake inhibitors or concurrent use of multiple drugs which increase CNS serotonin levels may increase risk for serotonin syndrome.

PATIENT MANAGEMENT: If linezolid is required for urgent or life threatening treatment, the FDA states the interacting serotonergic drug should be stopped. The FDA has also released a statement that linezolid can be given with serotonergic agents if the "benefit is deemed to outweigh the risk" for conditions including but not limited to vancomycin-resistant Enterococcus (VRE) infections, nosocomial pneumonia, and complicated skin and skin structure infections, including cases caused by methicillin resistant Staphylococcus aureus (MRSA). In these instances, linezolid can be started with serotonergic agents under close monitoring.(1) Serotonergic medications should not preclude the use of linezolid if clinically warranted. If concurrent use of linezolid without a washout is warranted, the patient should be closely monitored.(24-29) If serotonergic agents are discontinued, serotonin toxicity due to the interaction is still possible. Patients should be monitored for CNS serotonin toxicity for two weeks (five weeks if fluoxetine, 3 weeks if vortioxetine, 7 days if desvenlafaxine or venlafaxine, or 5 days if duloxetine was taken) or until 24 hours after the last linezolid dose, whichever comes first. Therapy with the serotonergic agent may be resumed 24 hours after the last dose of linezolid.(1,3-13)

DISCUSSION: Serotonin syndrome has been reported with the use of linezolid and SSRIs including in: four patients receiving concurrent citalopram, one patient receiving concurrent fluoxetine, three patients receiving concurrent sertraline, one patient receiving concurrent venlafaxine, one patient in whom linezolid was initiated 18 days after fluoxetine discontinuation, and one patient in whom linezolid was initiated three days after the discontinuation of paroxetine.(14-23) Literature states that linezolid is a weak MAOI and rarely causes serotonin toxicity. Cases of serotonin toxicity were rapidly reversible with discontinuation of the offending agent(s) and supportive care. Some literature suggests that use of serotonergic medications should not preclude the use of linezolid but that the clinical situation should be assessed. If concurrent use or use of linezolid without a washout is warranted, the patient should be closely monitored.(24-29)

Slt Strong Cyp1a2 Inhibitors/Olanzapine Extended Release Im

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

MECHANISM OF ACTION: Inhibitors of CYP1A2 may inhibit the metabolism of olanzapine by this pathway.(1-5)

CLINICAL EFFECTS: Concurrent use of CYP1A2 inhibitors may result in elevated levels of and toxicity from olanzapine. This may be particularly problematic in patients receiving the intramuscular (IM) extended release suspension as this dose form as been associated with post-injection delirium sedation syndrome. Patients with this syndrome have unexpectedly high olanzapine concentrations after a therapeutic dose. Symptoms usually begin within 3 hours of an injection and if not managed may be fatal. Although the cause has not been identified, very high olanzapine blood levels were also found in two patients who died 3-4 days after a therapeutic dose of extended release olanzapine injection.(8)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Whenever possible, it would be prudent to use an alternative agent that does not inhibit CYP1A2. If concurrent therapy cannot be avoided, the dose of olanzapine may need to be adjusted when a CYP1A2 inhibitor is initiated or discontinued. Concurrent therapy should be closely monitored for olanzapine side effects as described in the REMS for this product. Assure that patient has received, read and understood possible serious side effects described in the Medication Guide for olanzapine extended release injection.

DISCUSSION: In a study in 10 male smokers with schizophrenia, pretreatment with fluvoxamine (100 mg daily for 10 days) increased olanzapine area-under-curve (AUC), maximum concentration (Cmax), and half-life by 30-50%, 12-64%, and by 25-32%, respectively. Olanzapine volume of distribution and clearance were decreased by 4-26% and 26-38%, respectively.(1) In a study in 8 schizophrenic patients, the addition of fluvoxamine (100 mg daily) to olanzapine (10-20 mg daily) increased olanzapine levels from 12-112%. N-desmethylolanzapine levels were not significantly affected.(2) In a retrospective review, 10 patients receiving concurrent fluvoxamine and olanzapine were compared to 134 patients receiving olanzapine alone. The ratio of olanzapine concentration/daily dose was 2.3-fold higher in patients receiving concurrent fluvoxamine.(3) Fluvoxamine has been shown to increase olanzapine Cmax and AUC by 54% and by 52%, respectively, in female nonsmokers. Fluvoxamine has been shown to increase olanzapine Cmax and AUC by 77% and by 108%, respectively, in male smokers.(4,5) Selected Strong CYP1A2 inhibitors linked include: ciprofloxacin, enasidenib, enoxacin, fluvoxamine, and rofecoxib.(6,7)

Ssris; Snris/Selected Anticoagulants (Vitamin K Antagonists)

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

MECHANISM OF ACTION: SSRI or SNRI inhibition of platelet serotonin uptake may result in impaired platelet aggregation.(1-11) This effect may be additive or synergistic when combined with other agents which impair hemostasis. Fluvoxamine is an inhibitor of CYP2C9 mediated metabolism of warfarin.(9)

CLINICAL EFFECTS: Concurrent use of selected anticoagulants and SSRIs or SNRIs may increase the risk for bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(11) 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: For the combination of fluvoxamine and warfarin: when possible change to a SSRI which does not inhibit warfarin metabolism (e.g. citalopram or paroxetine). For patients who require this combination, monitor for an increase in INR when fluvoxamine is started or the dose is increased. The warfarin dose may need to be reduced. For all anticoagulant/SSRI or SNRI combinations, if concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. 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. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: The manufacturer's product information for fluvoxamine reports a study in which the plasma warfarin concentrations increased 98% and prothrombin times were prolonged in patients who received concurrent fluvoxamine and warfarin.(9) In a single study in 24 healthy patients, concurrent administration of paroxetine and warfarin resulted in clinically significant bleeding in five patients. No changes in paroxetine or warfarin disposition were seen.(13) In a review describing the bleeding risk with SRIs, warfarin was associated with an increased rate of hemorrhage among SRI users (adjusted relative risk = 1.41).(14) In a cohort study of patients taking warfarin in combination with an SSRI versus warfarin treatment alone, an analysis including first bleedings revealed a hazard ratio of 3.49 for bleeding during treatment with a combination of SSRI and warfarin compared with warfarin only.(15) A retrospective study of warfarin-treated patients prescribed or not prescribed an antidepressant showed that use of an SSRI with warfarin was significantly associated with increased risk of any bleed (overall risk (OR)=2.6), major bleeding (OR=4.4), and hospitalization secondary to bleeding (OR=7.0) as compared to those not taking an SSRI.(16) A population based study of patient outcomes in 176 primary intracerebral hemorrhage patients showed that 19 patients taking SSRI/SNRIs together with warfarin had an increased 30-day case fatality rate of 78.9% compared to warfarin alone (50.7%).(17) In a study of the Anticoagulation and Risk factors in Atrial fibrillation (ATRIA) cohort, hemorrhage rates were higher during periods of SSRI exposure compared with periods on no antidepressants (2.32 per 100 person-years vs 1.35 per 100 person-years). After adjusting for bleeding risk and time in INR range > 3, SSRI exposure was associated with an increased rate of hemorrhage compared with no antidepressants (adjusted relative risk = 1.41).(18) Increased bleeding risk has been found when patients receive 3 agents which can affect bleeding risk: an anticoagulant, SSRI and NSAID.(19) In a retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ratio was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a SSRI with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(19) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with SSRIs and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, SSRIs, or both were 3.7, 2.6, or 15.6, respectively.(20) A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 10 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and antidepressants (OR=1.54; 95% CI 1.4-1.7). Increased bleeding risk was also seen in subgroup analyses with SSRIs (OR=1.62; 95% CI 1.42-1.85) but not SNRIs. There was an increased case fatality rate for intracerebral hemorrhage with SSRIs and SNRIs (OR=3.64; 95% CI 1.15-11.53).(21) There are two published case reports involving increased effects of warfarin following addition of fluoxetine. Another case report is inconclusive. In a study in seven healthy volunteers, neither single dose or eight days of consecutive therapy resulted in alteration of warfarin clearance.(22, 23) In a parallel group study involving 12 healthy volunteers, the prothrombin time and area-under-curve (AUC) were increased and the normalization of prothrombin time was decreased with concurrent warfarin and sertraline. There was also a clinically insignificant increase in warfarin protein binding.(24) There is one case report of increased INR during concurrent warfarin and duloxetine.(25)

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/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) Strong and moderate CYP3A4 inhibitors may inhibit the CYP3A4 mediated metabolism of bosentan.(1,2)

CLINICAL EFFECTS: Concurrent use of bosentan with an inhibitor of CYP3A4 may result in elevated levels of and toxicity from bosentan.(1)

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: 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 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. In patients who have been receiving a strong CYP3A4 inhibitor for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of a strong CYP3A4 inhibitor. After at least 10 days following the initiation of a strong CYP3A4 inhibitor, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

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.(2) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, itraconazole, josamycin, ketoconazole, levoketoconazole, mibefradil, mifepristone, nefazodone, posaconazole, relacorilant, ribociclib, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(3) Moderate CYP3A4 inhibitors linked to this monograph include: aprepitant, berotralstat, clofazimine, conivaptan, diltiazem, dronedarone, erythromycin, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, letermovir, netupitant, nilotinib, schisandra, stiripentol, treosulfan, and verapamil.(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/Encorafenib

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 encorafenib.(1)

CLINICAL EFFECTS: Concurrent use of a strong or moderate inhibitor of CYP3A4 may result in elevated levels of and toxicity from encorafenib, including QT prolongation.(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)

PATIENT MANAGEMENT: Concurrent use of strong or moderate CYP3A4 inhibitors with encorafenib should be avoided. 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 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 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) Strong inhibitors of CYP3A4 include: indinavir, josamycin, ketoconazole, mibefradil, nefazodone, nelfinavir, relacorilant, tipranavir, and troleandomycin.(4-6) Moderate inhibitors of CYP3A4 include: amprenavir, berotralstat, conivaptan, fluvoxamine, fosamprenavir, letermovir, schisandra, stiripentol, and treosulfan.(4-6)

Strong And Moderate Cyp3a4 Inhibitors/Fexinidazole

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 fexinidazole to its active metabolites.(1)

CLINICAL EFFECTS: The concurrent use of fexinidazole with inhibitors of CYP3A4 may result in decreased levels of its active metabolites, resulting in decreased efficacy.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the concurrent use of fexinidazole with strong and moderate CYP3A4 inhibitors. If coadministration cannot be avoided, monitor for lack of efficacy of fexinidazole.(1)

DISCUSSION: Although no clinical drug interaction studies were performed with CYP3A4 inhibitors, the formation of the M1 and M2 metabolites may be decreased.(1) Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, ensitrelvir, indinavir, itraconazole, josamycin, ketoconazole, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, relacorilant, telaprevir, tipranavir, troleandomycin, and tucatinib.(2,3) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, berotralstat, conivaptan, diltiazem, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, letermovir, netupitant, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2,3)

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 Cyp1a2 Inhibitors/Clozapine

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

MECHANISM OF ACTION: The metabolism of clozapine may be inhibited by CYP1A2 inhibitors.(1)

CLINICAL EFFECTS: The concurrent administration of clozapine with strong CYP1A2 inhibitors may result in elevated levels of clozapine and an increase in clozapine related side effects such as orthostatic hypotension, syncope, QT prolongation, profound sedation and seizures. This interaction may be noted with even low doses of CYP1A2 inhibitors and the onset of this interaction may be rapid.(1-7)

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.(8) 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).(8) 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.(9)

PATIENT MANAGEMENT: The manufacturer recommends reducing the clozapine dose to one-third the original dose with concurrent strong CYP1A2 inhibitors. Close monitoring is required to prevent clozapine toxicity. Clozapine levels should be monitored in patients receiving concurrent therapy with strong CYP1A2 inhibitors. Patients should be monitored for adverse clozapine effects and QT prolongation.(1) If concurrent therapy is warranted in patients receiving clozapine, 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. When the strong CYP1A2 inhibitor is discontinued, the clozapine dose should be increased based on clinical response. Serum clozapine measurements may be useful.

DISCUSSION: Several case reports have documented increased levels of clozapine when fluvoxamine was added to therapy.(2-5) The increases in clozapine levels ranged from 231% to 780%. Several case reports describe increased clozapine-related side effects following the addition of fluvoxamine to clozapine therapy.(3,6-7) In a study in 16 subjects(1,10), the addition of fluvoxamine to patients receiving clozapine resulted in 3-fold increases in clozapine, N-desmethylclozapine, and clozapine N-oxide. The half-life of clozapine increased from 17 hours to 50 hours. Another study (11) compared patients receiving clozapine monotherapy to patients receiving concurrent therapy with clozapine and fluvoxamine and found that the dose-normalized clozapine concentration increased by a factor of 5-10 when fluvoxamine was added. Strong CYP1A2 inhibitors linked include: enasidenib and fluvoxamine.(13)

Strong Cyp1a2 Inhibitors/Melatonin

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

MECHANISM OF ACTION: Strong CYP1A2 inhibitors may significantly increase the area-under-curve (AUC) of melatonin by inhibiting CYP1A2.(1,2) Fluvoxamine, a strong CYP1A2 inhibitor, has also been shown to increase endogenous melatonin levels.

CLINICAL EFFECTS: The concurrent administration of melatonin and strong CYP1A2 inhibitors may result in significantly increased melatonin levels and subsequent side effects.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The UK manufacturer of melatonin recommends against the concurrent use of melatonin and CYP1A2 inhibitors.(1) The Australian manufacturer of melatonin states concurrent use of melatonin and CYP1A2 inhibitors should be avoided.(2) Patients should be monitored for increased effects of melatonin when melatonin and CYP1A2 inhibitors are used concurrently.

DISCUSSION: In a study, fluvoxamine increased the area-under-curve (AUC) and concentration maximum (Cmax) of melatonin by 17-fold and 12-fold, respectively.(2) In a case report, a 51 year old female with chronic primary insomnia who received 5 mg melatonin at bedtime and 75 mg fluvoxamine in the afternoon experienced increased nocturnal sleep, from 2.5 hours (drug free) to 4.2 hours (melatonin alone) up to 5.5 hours per night (melatonin with fluvoxamine). Both melatonin and fluvoxamine alone increased melatonin levels; however administration of melatonin alone increased melatonin levels more than fluvoxamine alone. Concurrent use of melatonin and fluvoxamine increased melatonin levels 20-fold when compared to the administration of melatonin alone.(3) In a study involving five males, 5 mg of melatonin daily was given for one week, then 50 mg of fluvoxamine was added (administered three hours apart. The AUC of melatonin increased at least nine-fold (p<0.05). The Cmax increased at least six-fold in melatonin (p<0.01), versus the Cmax in patients who received melatonin alone.(4) Strong CYP1A2 inhibitors include: enasidenib, fluvoxamine, and viloxazine.(5)

Strong Cyp1a2 Inhibitors/Pirfenidone

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

MECHANISM OF ACTION: Pirfenidone is primarily metabolized by CYP1A2 which is responsible for about 50% of its conversion to inactive drug. CYP2C9, 2C19, 2D6 and 2E1 are additional minor contributors to pirfenidone metabolism.(1,2) Strong inhibitors of CYP1A2 may inhibit the metabolism of pirfenidone.(1,2) Fluvoxamine is a strong inhibitor of CYP1A2 and CYP2C19, and a weak inhibitor of CYP2C9 and so inhibits both primary and secondary pirfenidone metabolic pathways.(3,4)

CLINICAL EFFECTS: Concurrent pirfenidone use with strong inhibitors of CYP1A2 may lead to increased systemic concentrations and toxicity from pirfenidone, including serious liver injury.(1,2)

PREDISPOSING FACTORS: A greater risk of adverse events may result from concomitant treatment with fluvoxamine, which also inhibits CYP2C19, or with strong or moderate inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), CYP2C19 (e.g. fluconazole, fluoxetine, ticlopidine) and CYP2D6 (e.g. fluoxetine, paroxetine). The magnitude of this interaction may be reduced in cigarette smokers. Cigarette smoking induces production of CYP1A2 and, in the absence of a CYP1A2 inhibitor, leads to decreased systemic concentrations of pirfenidone.(1)

PATIENT MANAGEMENT: The US manufacturer of pirfenidone states that concurrent use with strong inhibitors of CYP1A2 is not recommended. Use of strong CYP1A2 inhibitors should be discontinued prior to administration of pirfenidone and avoided during treatment with pirfenidone. Combinations of strong or moderate CYP1A2 inhibitors with strong or moderate CYP2C9, CYP2C19, and/or CYP2D6 inhibitors should also be discontinued prior to and avoided during pirfenidone treatment. If concurrent therapy of pirfenidone and strong CYP1A2 inhibitors cannot be avoided, reduce pirfenidone to one-267 mg capsule three times a day (total daily dose of 801 mg/day).(2) The Canadian(1) and Indian(5) manufacturers of pirfenidone states that fluvoxamine is contraindicated with pirfenidone and fluvoxamine should be discontinued prior to initiation of pirfenidone therapy. The concurrent use of pirfenidone and other strong or moderate CYP1A2 inhibitors should be used with caution.

DISCUSSION: Pirfenidone is converted to inactive metabolites prior to elimination. CYP1A2 is responsible for approximately half of this metabolism. In an interaction study conducted in non-smokers and smokers, coadministration of pirfenidone with fluvoxamine (a strong CYP1A2 inhibitor), an agent which inhibits multiple pirfenidone elimination pathways (CYP1A2, CYP2C9, CYP2C19), led to an approximately 4-fold and 7-fold, respectively, increase in pirfenidone exposure.(2) Strong CYP1A2 inhibitors include: angelica root (angelica dahurica radix), enasidenib, enoxacin, fluvoxamine, and rofecoxib.(4)

Strong Cyp1a2 Inhibitors/Pomalidomide

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

MECHANISM OF ACTION: Pomalidomide is primarily metabolized by CYP1A2, which accounts for approximately 50% of pomalidomide hepatic clearance respectively.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP1A2 inhibitors may result in elevated levels of and toxicity from pomalidomide.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of pomalidomide states strong inhibitors of CYP1A2 should be avoided. Reduce the dose of pomalidomide to 2 mg if a strong CYP1A2 inhibitor must be administered concomitantly with pomalidomide. Closely monitor patients for hematologic and other toxicities and adjust pomalidomide dose accordingly.(2)

DISCUSSION: In a study in healthy volunteers, coadministration of fluvoxamine and pomalidomide resulted in an increase in pomalidomide's maximum concentration (Cmax) and area-under-the-curve (AUC) by 24% and 125% respectively.(2) In a study in healthy volunteers, coadministration of ketoconazole and fluvoxamine with pomalidomide resulted in an increase in pomalidomide's AUC by 146%.(2) Strong CYP1A2 inhibitors include angelica root, enasidenib, enoxacin, fluvoxamine, and rofecoxib.(3,4)

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)

Strong; Selected Moderate Cyp2c19 Inhibitors/Clobazam

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

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

Agents With Hyponatremia Risk/Desmopressin

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

MECHANISM OF ACTION: Carbamazepine, chlorpromazine, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants increase the risk of hyponatremia.(1-3)

CLINICAL EFFECTS: Concurrent use may increase the risk of hyponatremia with desmopressin.(1-3)

PREDISPOSING FACTORS: Predisposing factors for hyponatremia include: polydipsia, renal impairment (eGFR < 50 ml/min/1.73m2), illnesses that can cause fluid/electrolyte imbalances, age >=65, medications that cause water retention and/or increase the risk of hyponatremia (glucocorticoids, loop diuretics).

PATIENT MANAGEMENT: The concurrent use of agents with a risk of hyponatremia with desmopressin may increase the risk of hyponatremia. If concurrent use is deemed medically necessary, make sure serum sodium levels are normal before beginning therapy and consider using the desmopressin nasal 0.83 mcg dose. Consider measuring serum sodium levels more frequently than the recommended intervals of: within 7 days of concurrent therapy initiation, one month after concurrent therapy initiation and periodically during treatment. Counsel patients to report symptoms of hyponatremia, which may include: headache, nausea/vomiting, feeling restless, fatigue, drowsiness, dizziness, muscle cramps, changes in mental state (confusion, decreased awareness/alertness), seizures, coma, and trouble breathing. Counsel patients to limit the amount of fluids they drink in the evening and night-time and to stop taking desmopressin if they develop a stomach/intestinal virus with nausea/vomiting or any nose problems (blockage, stuffy/runny nose, drainage).(1)

DISCUSSION: In clinical trials of desmopressin for the treatment of nocturia, 4 of 5 patients who developed severe hyponatremia (serum sodium <= 125 mmol/L) were taking systemic or inhaled glucocorticoids. Three of these patients were also taking NSAIDs and one was receiving a thiazide diuretic.(2) Drugs associated with hyponatremia may increase the risk, including loop diuretics, carbamazepine, chlorpromazine, glucocorticoids, lamotrigine, NSAIDs, opioids, SSRIs, thiazide diuretics, and/or tricyclic antidepressants.(1,3-4)

Ciprofloxacin; Fluvoxamine/Zolpidem

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

MECHANISM OF ACTION: Ciprofloxacin, a weak CYP3A4 inhibitor and a moderate CYP1A2 inhibitor, may inhibit metabolism of zolpidem via these pathways.(1,2) Fluvoxamine, a weak CYP3A4 inhibitor and a strong CYP1A2 inhibitor, may inhibit metabolism of zolpidem via these pathways.(1,2)

CLINICAL EFFECTS: Concurrent use of zolpidem with ciprofloxacin or fluvoxamine may result in an increase in zolpidem systemic concentrations and clinical effects, including profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: Adult women clear zolpidem at lower rate than men resulting in approximately 50% higher exposure compared with men taking the same dose.(3) Elderly or debilitated patients are more likely to have impaired motor or cognitive performance when treated with zolpidem.(3)

PATIENT MANAGEMENT: Monitor for adverse effects or consider lowering the zolpidem dose, particularly in elderly patients or adult women on higher doses of zolpidem.(3) The US, UK, Australian, and Canadian manufacturers of ciprofloxacin state the concurrent use of zolpidem with ciprofloxacin is not recommended.(4-7) The UK and Australian manufacturers of zolpidem state the concurrent use of fluvoxamine is not recommended.(8,9) Patients should be counseled that concurrent use of ciprofloxacin or fluvoxamine and zolpidem may result in an increase in side effects such as confusion, amnesia, sleep-walking or sleep-driving behaviors, or daytime drowsiness.

DISCUSSION: An interaction study was conducted in 18 healthy, non-smoking men. The pharmacokinetics of zolpidem 5 mg was evaluated before and after ciprofloxacin 500 mg daily for 5 days. Zolpidem half-life increased from 2.39 to 3.34 hours and exposure (area-under-curve, AUC) was increased by 46%.(10) An interaction study was conducted in healthy volunteers. The pharmacokinetics of zolpidem 5 mg was evaluated before and after fluvoxamine 100 mg daily for 6 days. Zolpidem half-life increased from 2.24 +/- 0.81 to 4.99 +/- 2.92 hours after pretreatment with fluvoxamine and zolpidem exposure was increased by approximately 150%.(11)

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 Cyp3a4 & P-Gp Inhibitors/Nintedanib

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

MECHANISM OF ACTION: Nintedanib is a substrate for the P-glycoprotein (P-gp) transporter and is metabolized to a minor extent by CYP3A4.

CLINICAL EFFECTS: Concurrent use of an agent that is both an inhibitor of P-gp and CYP3A4 may result in elevated levels of and clinical effects of nintedanib.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of nintedanib recommends close monitoring for nintedanib patients receiving drugs which are both P-gp and CYP3A4 inhibitors. In an interaction study ketoconazole increased exposure to nintedanib by 60%. Nintedanib therapy may need to be interrupted or the dose may need to be reduced.(1)

DISCUSSION: In an interaction study coadministration with ketoconazole, a P-gp and CYP3A4 inhibitor, increased nintedanib exposure (area-under-curve, AUC) and maximum concentration (Cmax) by 1.61-fold and 1.83 fold respectively.(1) Strong CYP3A4 & P-gp inhibitors include: adagrasib, boceprevir, clarithromycin, cobicistat, grapefruit, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, and tucatinib. Moderate CYP3A4 & P-gp inhibitors include: conivaptan, diltiazem, dronedarone, erythromycin, fluvoxamine, isavuconazonium, schisandra, and verapamil. Weak CYP3A4 & P-gp inhibitors include: amiodarone, azithromycin, cimetidine, cyclosporine, daclatasvir, daridorexant, diosmin, flibanserin, fluvoxamine, fostamatinib, glecaprevir/pibrentasvir, ivacaftor, lapatinib, mavorixafor, ranolazine, and vepdegestrant.(2)

Dual Inhibitors Of Cyp2c19 & Cyp3a4/Fedratinib

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

MECHANISM OF ACTION: Agents that are both inhibitors of CYP2C19 and CYP3A4 may inhibit the metabolism of fedratinib.(1-2)

CLINICAL EFFECTS: Concurrent use of a dual inhibitor of CYP2C19 and CYP3A4 may result in elevated levels of and clinical effects of fedratinib, such as neutropenia, thrombocytopenia, hepatotoxicity, or gastrointestinal toxicity.(1-2) Symptoms of hepatotoxicity can include nausea, vomiting, jaundice, dark urine, abdominal pain, and unexplained fatigue.

PREDISPOSING FACTORS: Patients with hepatic impairment may be at greater risk of experiencing toxicity from fedratinib.

PATIENT MANAGEMENT: The manufacturer of fedratinib states that concurrent use of dual CYP3A4 and CYP2C19 inhibitors with fedratinib requires intensive monitoring for adverse reactions. Fedratinib dose may require adjustment based on adverse reactions.(1) If concurrent use is necessary, monitor liver tests, including AST, ALT, and bilirubin, renal function, complete blood count and thiamine levels. Advise patients to immediately report any symptoms of hepatotoxicity.

DISCUSSION: In a study, fluconazole 200 mg daily, a dual CYP3A4 and CYP2C19 inhibitor, increased the area-under-curve (AUC) of single-dose fedratinib 100 mg by 1.7-fold.(1) Fluconazole 200 mg daily is predicted to increase the AUC of fedratinib 400 mg daily by 1.5-fold.(1) Dual inhibitors of CYP2C19 and CYP3A4 linked to this monograph include fluconazole, fluvoxamine, and stiripentol.(2-3)

Dual Moderate Cyp3a4 And P-Gp Inhib/Daraxonrasib (<=100 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 and P-glycoprotein (P-gp). Moderate CYP3A4 and P-gp inhibitors may inhibit the metabolism of daraxonrasib.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 and P-gp 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 both moderate CYP3A4 inhibitors and P-gp inhibitors, reduce the dose of daraxonrasib to 100 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 study, diltiazem 80 mg three times daily (a moderate CYP3A and P-gp inhibitor) increased the area under curve (AUC) of daraxonrasib by 2.6-fold.(1) Dual moderate CYP3A4 and P-gp inhibitors include: conivaptan, diltiazem, dronedarone, erythromycin, fluvoxamine, isavuconazole, schisandra, and verapamil.(2-3)

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)

Duloxetine; Fluvoxamine/Selected Tricyclic Compounds

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

MECHANISM OF ACTION: Duloxetine or fluvoxamine may impair the oxidative hepatic metabolism of tricyclic compounds.

CLINICAL EFFECTS: Concurrent administration of duloxetine or fluvoxamine with a tricyclic compound may result in an increase in serum levels, toxicities (e.g. torsades de pointes), and/or clinical effects of the tricyclic compound.

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). 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.(9)

PATIENT MANAGEMENT: Patients should be observed for increased adverse effects and clinical effects of tricyclic compounds at the initiation of concurrent therapy with duloxetine or fluvoxamine. Plasma concentrations of the tricyclic compound should be monitored and the dosage adjusted accordingly. If duloxetine or fluvoxamine is discontinued in a patient receiving a tricyclic compound, the dosage of the tricyclic compound may need to be adjusted.

DISCUSSION: In a study, pretreatment with duloxetine (60 mg twice daily) increased the area-under-curve (AUC) of a single dose of desipramine (50 mg) by 3-fold. Fluvoxamine has been shown in an in vitro study to inhibit the metabolism of imipramine. Three case reports have shown increased serum levels of imipramine (32%, 198%, and 470% increases) and an increase in adverse effects (anticholinergic effects, confusion, and sedation) during concurrent administration with fluvoxamine. Two case reports of adverse effects (tonic-clonic seizure, tremors, dizziness, and confusion) and increased plasma desipramine levels (79% and 54% increases) with concurrent administration of fluvoxamine exist. Increased plasma levels of clomipramine (586%) and amitriptyline (100-150%) without signs of clinical toxicity were seen following the addition of fluvoxamine to a tricyclic compound therapy. The affinity of the different SSRIs, SNRIs, and tricyclics for CYP450 may vary.

Fluoxetine; Fluvoxamine/Haloperidol

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

MECHANISM OF ACTION: Haloperidol is metabolized via many metabolic pathways. The contributions of CYP2D6, CYP3A4 and possibly CYP1A2 pathways are most clearly defined. Concomitant use of haloperidol with inhibitors of one or more of these pathways may lead to clinically significant increases in haloperidol levels. Fluoxetine is a strong CYP2D6 inhibitor and a weak CYP3A4 inhibitor. Fluvoxamine is a strong inhibitor of CYP1A2 and CYP2C19 and is a weak inhibitor of CYP2C8, CYP2C9, and CYP3A4.

CLINICAL EFFECTS: The concurrent administration of fluoxetine or fluvoxamine may result in elevated levels of haloperidol and lead to toxicities such as orthostatic hypotension, akathisia, acute dystonia, or Parkinsonism.

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. Younger patients, patients on low doses of haloperidol, or on a dose targeted to lower-therapeutic serum levels, have a lower interaction risk.

PATIENT MANAGEMENT: Monitor patient for extrapyramidal side effects and orthostatic hypotension if fluoxetine or fluvoxamine is added to haloperidol therapy and lower haloperidol dose if needed. The onset and peak effects of an interaction with fluoxetine may be delayed 1 to 2 weeks due to its long 3 to 7 day half-life.

DISCUSSION: Although it is an older agent, the complex pharmacokinetics of haloperidol are not yet fully understood.

Fluoxetine; Fluvoxamine/Ticlopidine

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

MECHANISM OF ACTION: Serotonin release by platelets plays a role in hemostasis.(1,2) The increased risk of bleeding may be a result of a decrease in serotonin reuptake by platelets.

CLINICAL EFFECTS: Concurrent use of a selective serotonin reuptake inhibitor and ticlopidine may result in bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(3) 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: Selective serotonin reuptake inhibitors and agents that affect coagulation should be used concurrently with caution. 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 retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ration was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a selective serotonin reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(4) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with selective serotonin reuptake inhibitors and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6, respectively.(5) In a case-control study conducted in users of acenocoumarol or phenprocoumon, 1848 patients who had been hospitalized with abnormal bleeding were each matched to 4 control patients. When patients took both a SSRI and a coumarin, an increased risk of hospitalization due to major non-gastrointestinal bleeding was observed (adjusted OR 1.7), but not due to gastrointestinal bleeding (adjusted OR 0.8).(6) A retrospective review examined patients discharged from a hospital with antiplatelet therapy following a myocardial infarction. When compared to aspirin therapy alone, both aspirin therapy with a SSRI and aspirin, clopidogrel, and SSRI therapy were associated with an increased risk of bleeding (hazard ratios 1.42 and 2.35, respectively.) Compared with dual antiplatelet therapy (aspirin and clopidogrel), use of aspirin and clopidogrel and a SSRI was also associated with increased risk of bleeding (hazard ration 1.57).(7) In The Rotterdam Study, fluvoxamine increased the risk of over anticoagulation (hazard ratio 2.63). Paroxetine was not associated with an increased risk. There were insufficient numbers of patients taking other SSRIs to assess increased risk.(8)

Fluvoxamine/Aficamten

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

MECHANISM OF ACTION: Aficamten is a CYP3A4, CYP2C19, CYP2C9, and CYP2D6 substrate. Fluvoxamine is a strong CYP2C19 inhibitor, weak to moderate CYP3A inhibitor, weak CYP2C9 inhibitor, and weak CYP2D6 inhibitor. Fluvoxamine may decrease the metabolism of aficamten.(1)(1)

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

PREDISPOSING FACTORS: None determined.

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

DISCUSSION: Concomitant use of aficamten with fluvoxamine (150 mg), a strong CYP2C19 inhibitor, weak to moderate CYP3A inhibitor, weak CYP2C9 inhibitor, and weak CYP2D6 inhibitor, twice daily increased aficamten area-under-curve (AUC) by 116%.(1)

Fluvoxamine/Apixaban; Rivaroxaban

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

MECHANISM OF ACTION: Apixaban and rivaroxaban are substrates of CYP3A4. Apixaban is about 20% metabolized and rivaroxaban is about 18% metabolized, mainly by CYP3A4.(1-8) Fluvoxamine is a moderate CYP3A4 inhibitor and may inhibit the metabolism of apixaban and rivaroxaban by CYP3A4.(9) Serotonin release by platelets plays a role in hemostasis.(9) Fluvoxamine may cause a decrease in serotonin reuptake by platelets, resulting in an additive risk of bleeding with anticoagulants.

CLINICAL EFFECTS: Concurrent use of fluvoxamine and agents that affect coagulation may result in bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Renal impairment has been associated with a higher risk of rivaroxaban levels and an elevated risk of GI bleed in patients on SSRIs.(10) 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: Concurrent therapy of fluvoxamine with apixaban or rivaroxaban should be undertaken with caution. The manufacturers of apixaban and rivaroxaban do not provide guidance for concurrent use with agents that inhibit CYP3A4 alone, while international manufacturer recommendations vary but generally state that such interactions are of low to no clinical significance.(1-8) Use caution with concurrent use of moderate CYP3A4 inhibitors. 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, anti Factor Xa inhibition) 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: Fluvoxamine is a moderate CYP3A4 inhibitor and a serotonin reuptake inhibitor. Concurrent use with apixaban and rivaroxaban may increase levels of the anticoagulants and result in an additive risk of bleeding. There are no studies or reports on the combination of apixaban and rivaroxaban with moderate CYP3A4 inhibitors like fluvoxamine. In a microdose cocktail study using apixaban 25 mcg or 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 both apixaban and rivaroxaban by 1.33-fold (p<0.05) while the Cmax and half-life remained unchanged.(11) Another microdose cocktail study with apixaban 25 mcg or rivaroxaban 25 mcg and voriconazole 400 mg twice daily found that apixaban AUC increased by 1.24-fold and rivaroxaban AUC increased by 1.16-fold with a non-significant change in Cmax.(12) 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.(13) Another review article states that apixaban and rivaroxaban may be used with voriconazole if no other pharmacokinetic inhibitor is present. No dose adjustment is recommended with moderate CYP3A4 inhibitors.(14) A systemic review and meta-analysis evaluated the risk of bleeding associated with the combination of SSRIs or SNRIs and DOACs. Concurrent use had a significantly higher risk of major bleeding than use of DOACs alone (RR 1.25, 95% CI 1.07-1.47 among cohort studies; OR 1.4, 95% CI 1.24-1.66 for case-control studies).(15) In The Rotterdam Study, fluvoxamine increased the risk of over anticoagulation (hazard ratio 2.63). Paroxetine was not associated with an increased risk. There were insufficient numbers of patients taking other SSRIs to assess increased risk.(16) A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of dabigatran and citalopram resulted in a ratio of rate ratios (95% CI) of 1.69 (1.11-2.57).(17)

Fluvoxamine/Gepirone

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

MECHANISM OF ACTION: Fluvoxamine is a moderate CYP3A4 inhibitor and may inhibit the metabolism of gepirone.(1-2, 5-6) Both fluvoxamine and gepirone can increase serotonin effects, resulting in serotonin toxicity.

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).(1,2) Concurrent use of fluvoxamine and gepirone may also result in serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(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) Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity.(3) Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(3)

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) If concurrent use of gepirone with other serotonergic agents is clinically warranted, counsel the patient on the increased risk of serotonin syndrome and monitor for symptoms. If symptoms of serotonin syndrome develop, discontinue gepirone and/or the other serotonergic agents immediately and initiate supportive measures.(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) Gepirone and its 3'-OH metabolite act as agonists at 5HT1A receptors. Use with other agents that also increase serotonin in the body must be undertaken with caution and monitored closely due to the risk of serotonin syndrome.(1)

Fluvoxamine/Levomethadone; Methadone

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

MECHANISM OF ACTION: Fluvoxamine has been shown to inhibit the metabolism of methadone at CYP3A4 in vitro.(1,2) Levomethadone is an enantiomer of methadone.(3)

CLINICAL EFFECTS: Concurrent administration may result in increased levels and clinical effects of methadone, which may result in QTc prolongation and life-threatening arrhythmias. Elevated levels can also cause profound sedation, respiratory depression, coma, and/or death. The discontinuation of fluvoxamine in patients maintained on methadone may result in symptoms of methadone withdrawal. Methadone has been associated with serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.

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 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: Patients receiving methadone should be monitored closely when fluvoxamine is initiated or withdrawn. The dosage of methadone may need to be adjusted. 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. Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with agents that may increase opioid drug levels.(5) If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. 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).(6)

DISCUSSION: Five case reports of concurrent methadone and fluvoxamine were reported in a single article. In two patients, methadone levels increased 20% following the addition of fluvoxamine therapy. In the remaining three patients, methadone levels increased 40-100%. One patient experienced symptoms of methadone withdrawal following the discontinuation of fluvoxamine.(7) Severe cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have been reported in patients receiving concurrent therapy with itraconazole and levomethadyl(1) or methadone.(1,7) In vitro studies have shown that fluvoxamine inhibits the metabolism of methadone at CYP3A4.(1,2)

Fluvoxamine/Propranolol

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

MECHANISM OF ACTION: Fluvoxamine may inhibit the metabolism of propranolol by CYP1A2 and CYP2C19.(1,2)

CLINICAL EFFECTS: Concurrent use of fluvoxamine and propranolol may result in increased levels of and effects from propranolol.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The initial dose of propranolol in patients who are on fluvoxamine should be lower in the beginning and titrated more cautiously. Closely monitor patients for adverse effects in patients on concurrent therapy. The dosage of propranolol may need to be adjusted if fluvoxamine is discontinued.(1)

DISCUSSION: In a study of healthy volunteers, fluvoxamine 100 mg daily increased the minimum concentration (Cmin) of propranolol 160 mg daily by a mean of five-fold (range: 2-17). Subjects experienced a slight reduction in heart rate and in exercise diastolic pressure.(1)

Fluvoxamine/Selected Xanthine Derivatives

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

MECHANISM OF ACTION: Fluvoxamine may inhibit the metabolism of the xanthine derivatives by CYP1A2.(1,2)

CLINICAL EFFECTS: Concurrent use of fluvoxamine and xanthine derivatives may result in elevated levels of the xanthine derivative and toxicity.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of fluvoxamine recommends that the dose of theophylline be decreased to one-third of the usual daily dose in patients receiving concurrent therapy. Theophylline levels should be closely monitored and patients should be observed for signs of theophylline toxicity.(3) The dosage of theophylline may need to be adjusted if fluvoxamine is discontinued. Patients receiving fluvoxamine should be instructed to consume caffeine containing beverages and/or medications with caution.

DISCUSSION: In a study in 12 healthy subjects, the administration of a single dose of theophylline ethylenediamine (300 mg) on Day 4 of fluvoxamine (50 mg Day 1, 100 mg daily Days 2-6) decreased theophylline total clearance by 70%. The half-life of theophylline increased 2.3-fold (from 6.6 hours to 22 hours).(1) In a study in 12 healthy males, the administration of a single dose of theophylline (375 mg given as 442 mg aminophylline) with fluvoxamine (50 mg twice daily at steady state) decreased theophylline clearance by 3-fold.(3) Fluvoxamine has been shown to inhibit the metabolism of theophylline in vitro.(2) There are four case reports of theophylline toxicity during concurrent fluvoxamine therapy.(4-7) In a study in eight healthy subjects, the administration of a single dose of caffeine (200 mg) on Day 8 of fluvoxamine (50 mg daily Days 1-4, 100 mg daily Days 5-12) decreased caffeine clearance by 80%. The half-life of caffeine increased 5.2-fold (from 5 hours to 31 hours).(8) In a study, seven reports of impaired caffeine clearance were reported in patients whom received single 250mg doses of caffeine together with fluvoxamine (four doses of 100mg over two days). Fluvoxamine reduced the apparent oral clearance of caffeine by 91.3%, and prolonged its elimination half-life by 11.4-fold (from 4.9 hours to 56 hours). There were no changes in the pharmacodynamic effects of caffeine.(9)

Fluvoxamine/Slt Anticoagulants;Antiplatelets;Thrombolytics

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

MECHANISM OF ACTION: Serotonin release by platelets plays a role in hemostasis.(1) Fluvoxamine may cause a decrease in serotonin reuptake by platelets, resulting in an additive risk of bleeding with anticoagulants, antiplatelets, and thrombolytics.

CLINICAL EFFECTS: Concurrent use of fluvoxamine and agents that affect coagulation may result in bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(2) 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: Concurrent therapy of fluvoxamine and agents that affect coagulation should be undertaken with caution. 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, anti Factor Xa inhibition) 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 retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ration was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a selective serotonin reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(3) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with selective serotonin reuptake inhibitors and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6, respectively.(4) In a case-control study conducted in users of acenocoumarol or phenprocoumon, 1,848 patients who had been hospitalized with abnormal bleeding were each matched to 4 control patients. When patients took both a SSRI and a coumarin, an increased risk of hospitalization due to major non-gastrointestinal bleeding was observed (adjusted OR 1.7), but not due to gastrointestinal bleeding (adjusted OR 0.8).(5) A retrospective review examined patients discharged from a hospital with antiplatelet therapy following a myocardial infarction. When compared to aspirin therapy alone, both aspirin therapy with a SSRI and aspirin, clopidogrel, and SSRI therapy were associated with an increased risk of bleeding (hazard ratios 1.42 and 2.35, respectively.) Compared with dual antiplatelet therapy (aspirin and clopidogrel), use of aspirin and clopidogrel and a SSRI was also associated with increased risk of bleeding (hazard ratio 1.57).(6) In The Rotterdam Study, fluvoxamine increased the risk of over anticoagulation (hazard ratio 2.63). Paroxetine was not associated with an increased risk. There were insufficient numbers of patients taking other SSRIs to assess increased risk.(7) A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of dabigatran and citalopram resulted in a ratio of rate ratios (95% CI) of 1.69 (1.11-2.57).(8)

Fluvoxamine/Tacrine

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

MECHANISM OF ACTION: Fluvoxamine may inhibit the metabolism of tacrine by CYP P-450-1A2.(1-4)

CLINICAL EFFECTS: Concurrent use of fluvoxamine may result in elevated levels of and toxicity from tacrine.(1-4) Nausea, vomiting, sweating, and diarrhea have been reported.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent fluvoxamine should be monitored for adverse tacrine effects, including hepatotoxicity. The dosage of tacrine may need to be adjusted or fluvoxamine may need to be discontinued.

DISCUSSION: In a randomized, double-blind, placebo-controlled, cross-over study in 13 healthy subjects, pretreatment with fluvoxamine (100 mg daily for 6 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of tacrine (40 mg) by 5-fold and 8-fold, respectively. Five of 13 subjects reported nausea, vomiting, sweating, and diarrhea.(1,2) The AUC of 1-hydroxytacrine, 2-hydroxytacrine, and 4-hydroxytacrine increased 2.8-fold, 2-fold, and 5-fold, respectively. The Cmax of 4-hydroxytacrine increased 100%. Concomitant fluvoxamine decreased tacrine apparent oral clearance 8-fold.(2) In an open-label, randomized, cross-over study in 18 healthy subjects, concurrent administration of fluvoxamine (50 mg or 100 mg daily) decreased tacrine (20 mg single dose) oral clearance by 85%.(3) Fluvoxamine was shown to inhibit tacrine metabolism in vitro in human liver microsomes.(4)

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 And Weak Cyp3a4 Inhibitors/Tacrolimus

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

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

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

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

PATIENT MANAGEMENT: The US manufacturer of tacrolimus recommends monitoring tacrolimus whole blood trough concentrations and reducing tacrolimus dose if needed.(1) Consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

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

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/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/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/Lonafarnib

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 lonafarnib.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors with lonafarnib may increase the risk of adverse reactions including QT prolongation and potentially life-threatening cardiac arrhythmias like torsades de pointes, nausea and vomiting, increased liver enzymes, myelosuppression, and hypertension.(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 use of lonafarnib with moderate CYP3A4 inhibitors should be approached with caution. No dose adjustment of lonafarnib is recommended when moderate CYP3A4 inhibitors are added to steady-state lonafarnib. When initiating lonafarnib therapy in a patient already taking a moderate CYP3A4 inhibitor, monitor the patient closely for the first 7 days of therapy. If the patient does not tolerate lonafarnib, consider an alternative that is not a moderate CYP3A4 inhibitor.(1) Lonafarnib dose modification recommendation: if the QTc interval is greater than or equal to 500 msec, withhold lonafarnib until the QTc interval is less than 470 msec, then resume lonafarnib at the same dosage.(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.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: 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 area-under-curve (AUC) and maximum concentration (Cmax) were increased by 425% and 270%, respectively.(1) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, berotralstat, darunavir, diltiazem, duvelisib, fedratinib, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nirogacestat, 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/Mitapivat (<= 20 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 mitapivat.(1)

CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels of and effects from mitapivat including decreased estrone and estradiol levels in males, increased urate, back pain, and arthralgias.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of moderate CYP3A4 inhibitors with mitapivat should be monitored closely for increased risk of adverse reactions. Mitapivat dose should not exceed 20 mg twice daily with concurrent moderate CYP3A4 inhibitors.(1)

DISCUSSION: Mitapivat is a CYP3A4 substrate. In a pharmacokinetic study with mitapivat 5, 20, or 50 mg twice daily dosing, fluconazole increased mitapivat area-under-curve (AUC) and concentration maximum (Cmax) by 2.6-fold and 1.6-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2)(2)

Moderate 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/Pacritinib

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 pacritinib.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase levels of and effects from pacritinib.(1) Elevated levels of pacritinib may result in QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP). Other toxicities include bleeding, diarrhea, thrombocytopenia, major adverse cardiovascular events, thrombosis, and infection.(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 manufacturer of pacritinib recommends monitoring patients concomitantly receiving moderate CYP3A4 inhibitors (e.g., fluconazole) for increased adverse reactions and considering pacritinib dose modifications based on safety.(1) When concurrent therapy is warranted monitor for prolongation of the QTc interval.(1) 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.(1)

DISCUSSION: Fluconazole (200 mg once daily for 7 days, a moderate CYP3A4 inhibitor) increased maximum concentration (Cmax) and area-under-curve (AUC) of pacritinib (200 mg twice daily at steady state) by 41% and 45%, respectively.(1) Concomitant use of pacritinib with doses of fluconazole greater than 200 mg once daily have not been studied.(1) Clarithromycin (500 mg twice daily for 5 days, a strong CYP3A4 inhibitor) increased maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of pacritinib (400 mg) by 80% and 30%, respectively.(1) 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).(1) 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).(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, berotralstat, conivaptan, darunavir, diltiazem, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, letermovir, netupitant, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(3,4)

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/Tofacitinib

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 tofacitinib.(1)

CLINICAL EFFECTS: Concurrent use of 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: 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) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, erythromycin, fluvoxamine, fosamprenavir, fosnetupitant, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nirogacestat, schisandra, stiripentol, tofisopam, verapamil, and voxelotor.(3-4)

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)

P-Gp Inhibitors That Cause Bleeding/Edoxaban (<=30 Mg)

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

MECHANISM OF ACTION: This combination may interact via both a pharmacodynamic and a pharmacokinetic mechanism. Pharmacodynamically, serotonin release by platelets plays a role in hemostasis.(1) Fluvoxamine may cause a decrease in serotonin reuptake by platelets, resulting in an additive risk of bleeding with oral anticoagulants.(1) Mifepristone is an antagonist at the progesterone receptor which can result in endometrium thickening, cystic dilatation of endometrial glands, or excessive vaginal bleeding. Concurrent use with anticoagulants may further increase risk.(2) Pharmacokinetically, fluvoxamine and mifepristone are inhibitors of the P-glycoprotein (P-gp) transporter and may increase the absorption of edoxaban.(3)

CLINICAL EFFECTS: Concurrent use of P-gp inhibitors and edoxaban may result in bleeding.(2) The concurrent use of mifepristone with anticoagulants may result in endometrium thickening, cystic dilatation of endometrial glands, or excessive vaginal bleeding.(2)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Bleeding risk may be increased in patients with creatinine clearance below 50 mL per minute and in patients greater than 75 years of age.(4,5) Use of multiple agents which increase edoxaban exposure or affect hemostasis would be expected to increase the risk for bleeding.

PATIENT MANAGEMENT: The combination of P-gp inhibitors and edoxaban should be used with caution. Fluvoxamine and mifepristone are P-gp inhibitors. FDA approved prescribing recommendations for edoxaban are indication specific: - For prevention of stroke or embolic events due to nonvalvular atrial fibrillation, no edoxaban dose adjustments are recommended during concomitant therapy with P-gp inhibitors. - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE), the edoxaban dose is recommended to be reduced to 30 mg daily when used concurrently with specific P-gp inhibitors (azithromycin, clarithromycin, oral itraconazole, quinidine and verapamil).(5) The manufacturer of mifepristone states that mifepristone should be used with caution in patients receiving concurrent anticoagulant therapy. Women experiencing vaginal bleeding during concurrent use should be referred to a gynecologist for further evaluation.(2) Monitor patients receiving anticoagulant therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. anti Factor Xa inhibition) 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. Discontinue edoxaban in patients with active bleeding.

DISCUSSION: Edoxaban in vivo interactions studies have not been conducted with fluvoxamine and there is no recommendation on the appropriate dose of edoxaban with concomitant fluvoxamine. In an edoxaban DVT/PE trial, patients who had a 50% dose reduction (from 60 mg to 30 mg) during concomitant therapy with P-gp inhibitors (mostly verapamil and quinidine) had lower trough edoxaban concentrations (Ctrough) and lower total edoxaban exposure (AUC or area-under-curve) than patients who did not require any edoxaban dose adjustment. In this DVT/PE comparator trial, subgroup analysis revealed that warfarin had numerically better efficacy than edoxaban in patients receiving P-gp inhibitors. Based upon the overall lower exposure to edoxaban in P-gp dose adjusted subjects, both EMA and FDA Office of Clinical Pharmacology (OCP) concluded that the edoxaban 50% dose reduction overcorrected for the difference in exposure.(4,6) Consequently, EMA recommended no edoxaban dose adjustments for patients receiving concomitant therapy with quinidine or verapamil.(6,7) In a retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ration was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a selective serotonin reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(8) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with selective serotonin reuptake inhibitors and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6, respectively.(9) In a case-control study conducted in users of acenocoumarol or phenprocoumon, 1848 patients who had been hospitalized with abnormal bleeding were each matched to 4 control patients. When patients took both a SSRI and a coumarin, an increased risk of hospitalization due to major non-gastrointestinal bleeding was observed (adjusted OR 1.7), but not due to gastrointestinal bleeding (adjusted OR 0.8).(10) A retrospective review examined patients discharged from a hospital with antiplatelet therapy following a myocardial infarction. When compared to aspirin therapy alone, both aspirin therapy with a SSRI and aspirin, clopidogrel, and SSRI therapy were associated with an increased risk of bleeding (hazard ratios 1.42 and 2.35, respectively.) Compared with dual antiplatelet therapy (aspirin and clopidogrel), use of aspirin and clopidogrel and a SSRI was also associated with increased risk of bleeding (hazard ratio 1.57).(11) In The Rotterdam Study, fluvoxamine increased the risk of over anticoagulation (hazard ratio 2.63). Paroxetine was not associated with an increased risk. There were insufficient numbers of patients taking other SSRIs to assess increased risk.(12) A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of dabigatran and citalopram resulted in a ratio of rate ratios (95% CI) of 1.69 (1.11-2.57).(13)

P-Gp Inhibitors That Cause Bleeding/Edoxaban (>30 Mg)

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

MECHANISM OF ACTION: This combination may interact via both a pharmacodynamic and a pharmacokinetic mechanism. Pharmacodynamically, serotonin release by platelets plays a role in hemostasis.(1) Fluvoxamine may cause a decrease in serotonin reuptake by platelets, resulting in an additive risk of bleeding with oral anticoagulants.(1) Mifepristone is an antagonist at the progesterone receptor which can result in endometrium thickening, cystic dilatation of endometrial glands, or excessive vaginal bleeding. Concurrent use with anticoagulants may further increase risk.(2) Pharmacokinetically, fluvoxamine, and mifepristone are inhibitors of the P-glycoprotein (P-gp) transporter and may increase the absorption of edoxaban.(3)

CLINICAL EFFECTS: Concurrent use of P-gp inhibitors and edoxaban may result in bleeding.(4,5) The concurrent use of mifepristone with anticoagulants may result in endometrium thickening, cystic dilatation of endometrial glands, or excessive vaginal bleeding.(2)

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Bleeding risk may be increased in patients with creatinine clearance below 50 mL per minute and in patients greater than 75 years of age.(4,5) Use of multiple agents which increase edoxaban exposure or affect hemostasis would be expected to increase the risk for bleeding.

PATIENT MANAGEMENT: The combination of P-gp inhibitors and edoxaban should be used with caution. Fluvoxamine and mifepristone are P-gp inhibitors. FDA approved prescribing recommendations for edoxaban are indication specific: - For prevention of stroke or embolic events due to nonvalvular atrial fibrillation, no edoxaban dose adjustments are recommended during concomitant therapy with P-gp inhibitors. - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE), the edoxaban dose is recommended to be reduced to 30 mg daily when used concurrently with specific P-gp inhibitors (azithromycin, clarithromycin, oral itraconazole, quinidine and verapamil).(5) The manufacturer of mifepristone states that mifepristone should be used with caution in patients receiving concurrent anticoagulant therapy. Women experiencing vaginal bleeding during concurrent use should be referred to a gynecologist for further evaluation.(2) Monitor patients receiving anticoagulant therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. anti Factor Xa inhibition) 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. Discontinue edoxaban in patients with active bleeding.

DISCUSSION: Edoxaban in vivo interactions studies have not been conducted with fluvoxamine and there is no recommendation on the appropriate dose of edoxaban with concomitant fluvoxamine. In an edoxaban DVT/PE trial, patients who had a 50% dose reduction (from 60 mg to 30 mg) during concomitant therapy with P-gp inhibitors (mostly verapamil and quinidine) had lower trough edoxaban concentrations (Ctrough) and lower total edoxaban exposure (AUC or area-under-curve) than patients who did not require any edoxaban dose adjustment. In this DVT/PE comparator trial, subgroup analysis revealed that warfarin had numerically better efficacy than edoxaban in patients receiving P-gp inhibitors. Based upon the overall lower exposure to edoxaban in P-gp dose adjusted subjects, both EMA and FDA Office of Clinical Pharmacology (OCP) concluded that the edoxaban 50% dose reduction overcorrected for the difference in exposure.(4,6) Consequently, EMA recommended no edoxaban dose adjustments for patients receiving concomitant therapy with quinidine or verapamil.(6,7) In a retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ration was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a selective serotonin reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(8) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with selective serotonin reuptake inhibitors and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6, respectively.(9) In a case-control study conducted in users of acenocoumarol or phenprocoumon, 1848 patients who had been hospitalized with abnormal bleeding were each matched to 4 control patients. When patients took both a SSRI and a coumarin, an increased risk of hospitalization due to major non-gastrointestinal bleeding was observed (adjusted OR 1.7), but not due to gastrointestinal bleeding (adjusted OR 0.8).(10) A retrospective review examined patients discharged from a hospital with antiplatelet therapy following a myocardial infarction. When compared to aspirin therapy alone, both aspirin therapy with a SSRI and aspirin, clopidogrel, and SSRI therapy were associated with an increased risk of bleeding (hazard ratios 1.42 and 2.35, respectively.) Compared with dual antiplatelet therapy (aspirin and clopidogrel), use of aspirin and clopidogrel and a SSRI was also associated with increased risk of bleeding (hazard ratio 1.57).(11) In The Rotterdam Study, fluvoxamine increased the risk of over anticoagulation (hazard ratio 2.63). Paroxetine was not associated with an increased risk. There were insufficient numbers of patients taking other SSRIs to assess increased risk.(12) A self-controlled case study of 1,622 oral anticoagulant-precipitant drug pairs were reviewed and found 14% of drug pairs were associated with a statistically significant elevated risk of thromboembolism. Concurrent use of dabigatran and citalopram resulted in a ratio of rate ratios (95% CI) of 1.69 (1.11-2.57).(13)

Selected Cyp2c19 Inhibitors/Citalopram (<= 20 Mg)

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

MECHANISM OF ACTION: Citalopram is primarily metabolized by the CYP2C19 isoenzyme.(1)

CLINICAL EFFECTS: Concurrent use of an agent that inhibits CYP2C19 may result in elevated levels of and toxicity from citalopram, including including risks for serotonin syndrome or prolongation of the QTc interval.(1-5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(5)

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, advanced age, poor metabolizer status at CYP2C19, or higher blood concentrations of citalopram.(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) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,5) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

PATIENT MANAGEMENT: The dose of citalopram should be limited to 20 mg in patients receiving concurrent therapy with an inhibitor of CYP2C19.(1,4) Evaluate the patient for other drugs, diseases and conditions which increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, hypocalcemia, hypomagnesemia, discontinue other QT prolonging drugs) when possible.(1,2) Weigh the specific benefits versus risks for each patient. The US manufacturer recommends ECG monitoring for citalopram patients with congestive heart failure, bradyarrhythmias, taking concomitant QT prolonging medications or receiving concurrent therapy.(4) Citalopram should be discontinued in patients with persistent QTc measurements greater than 500 ms.(2) 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. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: Concurrent use of citalopram (40 mg daily) and cimetidine (400 mg twice daily) for 8 days increased the maximum concentration (Cmax) and area-under-curve (AUC) of citalopram by 39% and 43%, respectively.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), armodafinil, asciminib, berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, elagolix, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, tecovirimat, treosulfan, and vonoprazan.(7,8)

Selected Cyp2c19 Inhibitors/Escitalopram (<= 15 Mg)

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

MECHANISM OF ACTION: At lower systemic concentrations, escitalopram is primarily metabolized by CYP2C19; at higher concentrations is also metabolized by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of an agent which significantly inhibits CYP2C19, or which inhibits both CYP2C19 and CYP3A4 may result in elevated concentrations and toxicity from escitalopram, including risks for serotonin syndrome or prolongation of the QTc interval.(1,5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3)

PREDISPOSING FACTORS: The risk of QT prolongation may be increased in patients with congenital long QT syndrome, cardiovascular disease (e.g. heart failure, myocardial infarction), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female sex, advanced age, poor metabolizer status at CYP2C19, concurrent use of more than one agent known to cause QT prolongation, or with higher blood concentrations of escitalopram.(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) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,3) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

PATIENT MANAGEMENT: Evaluate patient for other drugs, diseases and conditions which may further increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, discontinue other QT prolonging drugs) when possible.(2,3) It would be prudent to limit the escitalopram dose to 10 mg daily in patients with QT prolonging risk factors who also receive concurrent therapy with selected CYP2C19 inhibitors.(5) Weigh the specific benefits versus risks for each patient. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: A thorough QT study evaluating escitalopram 10 mg or 30 mg once daily was conducted; a change of 10 msec for upper bound of the 95% confidence level is the threshold for regulatory concern. In this study, changes to the upper bound of the 95% confidence interval were 6.4 msec and 12.6 msec for the 10 mg and supratherapeutic 30 mg dose respectively. The Cmax for 30 mg was 1.7-fold higher than the Cmax for the maximum recommended escitalopram dose of 20 mg. Systemic exposure at the 30 mg dose was similar to expected steady state concentrations in 2C19 poor metabolizers following a 20 mg escitalopram dose.(1) In an interaction study, 30 mg of omeprazole, an irreversible inhibitor of CYP2C19 was administered daily for 6 days. On day 5 a single dose of escitalopram 20 mg was also administered; the area-under-curve (AUC) of escitalopram was increased by 50%. Manufacturer prescribing information recommends a maximum citalopram dose of 20mg daily in patients receiving CYP2C19 inhibitors.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), armodafinil, asciminib, berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, elagolix, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, tecovirimat, treosulfan, and vonoprazan.(4)

Selected Cyp2c19 Inhibitors/Escitalopram (> 15 Mg)

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

MECHANISM OF ACTION: At lower systemic concentrations, escitalopram is primarily metabolized by CYP2C19; at higher concentrations is also metabolized by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of an agent which significantly inhibits CYP2C19, or which inhibits both CYP2C19 and CYP3A4 may result in elevated concentrations and toxicity from escitalopram, including risks for serotonin syndrome or prolongation of the QTc interval.(1,5) Prolongation of the QT interval may result in life-threatening arrhythmias, including torsades de pointes.(2) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(3)

PREDISPOSING FACTORS: The risk of QT prolongation may be increased in patients with congenital long QT syndrome, cardiovascular disease (e.g. heart failure, myocardial infarction), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female sex, advanced age, poor metabolizer status at CYP2C19, concurrent use of more than one agent known to cause QT prolongation, or with higher blood concentrations of escitalopram.(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) Predisposing factors for serotonin-related adverse effects include use in the elderly, in patients with hepatic impairment, and in patients receiving multiple agents which increase central serotonin levels.(1,3) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

PATIENT MANAGEMENT: Evaluate patient for other drugs, diseases and conditions which may further increase risk for QT prolongation and correct risk factors (e.g. correct hypokalemia, discontinue other QT prolonging drugs) when possible.(2,3) It would be prudent to limit the escitalopram dose to 10 mg daily in patients with QT prolonging risk factors who also receive concurrent therapy with selected CYP2C19 inhibitors.(5) Weigh the specific benefits versus risks for each patient. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: A thorough QT study evaluating escitalopram 10 mg or 30 mg once daily was conducted; a change of 10 msec for upper bound of the 95% confidence level is the threshold for regulatory concern. In this study, changes to the upper bound of the 95% confidence interval were 6.4 msec and 12.6 msec for the 10 mg and supratherapeutic 30 mg dose respectively. The Cmax for 30 mg was 1.7-fold higher than the Cmax for the maximum recommended escitalopram dose of 20 mg. Systemic exposure at the 30 mg dose was similar to expected steady state concentrations in 2C19 poor metabolizers following a 20 mg escitalopram dose.(1) In an interaction study, 30 mg of omeprazole, an irreversible inhibitor of CYP2C19 was administered daily for 6 days. On day 5 a single dose of escitalopram 20 mg was also administered; the area-under-curve (AUC) of escitalopram was increased by 50%. Manufacturer prescribing information recommends a maximum citalopram dose of 20mg daily in patients receiving CYP2C19 inhibitors.(1) Inhibitors of CYP2C19 include: abrocitinib, allicin (garlic derivative), armodafinil, asciminib, berotralstat, cannabidiol (CBD), cenobamate, cimetidine strengths > or = 200 mg, elagolix, enasidenib, eslicarbazepine, esomeprazole, etravirine, fedratinib, felbamate, fluoxetine, fluvoxamine, givosiran, isoniazid, moclobemide, modafinil, obeticholic acid, omeprazole, piperine, rolapitant, stiripentol, tecovirimat, treosulfan, and vonoprazan.(4)

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/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/Ivosidenib

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 ivosidenib.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase systemic exposure and the risk for ivosidenib toxicities such as 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).(2)

PATIENT MANAGEMENT: The US manufacturer of ivosidenib recommends considering an alternative concomitant medication with less potential for CYP3A4 inhibition.(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 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) Moderate CYP3A4 inhibitors linked to this monograph include amprenavir, berotralstat, conivaptan, fluvoxamine, fosamprenavir, letermovir, schisandra, tofisopam, and treosulfan.(3)

Selected Serotonergic Agents/Dextromethorphan

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

MECHANISM OF ACTION: Dextromethorphan inhibits neuronal reuptake of serotonin. Concurrent administration with one or more serotonergic agents may increase serotonin effects, leading to serotonin toxicity.(1-11)

CLINICAL EFFECTS: The concurrent use of dextromethorphan with serotonergic agents may increase the risk for serotonin syndrome. Serotonin syndrome constitutes a range of toxicities from mild to life threatening.(3) Mild serotonin symptoms may include: shivering, diaphoresis, mydriasis, intermittent tremor, and/or myoclonus.(3) Moderate serotonin symptoms may include: tachycardia, hypertension, hyperthermia, mydriasis, diaphoresis, hyperactive bowel sounds, hyperreflexia, and/OR clonus.(3) Severe serotonin symptoms may include: severe hypertension and tachycardia, shock, agitated delirium, muscular rigidity, and/or hypertonicity.(3)

PREDISPOSING FACTORS: Concurrent use of additional drugs which increase CNS serotonin levels would be expected to further increase risk for serotonin syndrome.(1-11)

PATIENT MANAGEMENT: Monitor patients on multiple serotonergic agents for symptoms of serotonin toxicity. Patients in whom serotonin syndrome is suspected should receive immediate medical attention. If the interacting agents are prescribed by different providers, it would be prudent to assure that both are aware of concomitant therapy and monitoring the patient for serotonin toxicities. Advise patients not to exceed recommended dosages of dextromethorphan. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: Dextromethorphan inhibits neuronal reuptake of serotonin and may potentially precipitate dose-dependant serotonin toxicity in conjunction with other serotonergic agents.(4,5) Serotonin syndrome has been reported in patients following the addition of dextromethorphan containing cough syrups to duloxetine,(6) escitalopram,(7) fluoxetine,(8,9) paroxetine,(10) and sertraline.(11) Selected serotonergic agents linked to this monograph include: centanafadine, citalopram, clomipramine, duloxetine, escitalopram, fluvoxamine, imipramine, levomilnacipran, milnacipran, sertraline, venlafaxine, vilazodone and vortioxetine.

Selected Ssris That Inhibit Cyp1a2 Or Cyp2d6/Fenfluramine

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

MECHANISM OF ACTION: Strong CYP1A2 or CYP2D6 inhibitors may decrease the metabolism of fenfluramine.(1) Over 75% of fenfluramine is metabolized to norfenfluramine prior to elimination, primarily by CYP1A2, CYP2B6, and CYP2D6.(1) Concurrent administration may also result in additive effects on serotonin, resulting in serotonin syndrome.

CLINICAL EFFECTS: Concurrent use of agents that are strong CYP1A2 or CYP2D6 inhibitors may result in elevated levels of and toxicity from fenfluramine, including CNS depression, hypertension, and serotonin syndrome.(1) Serotonin syndrome is a potentially life-threatening syndrome which may include one or more of the following symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of fenfluramine states that the maximum daily dosage of fenfluramine with a strong CYP1A2 or CYP2D6 inhibitor in patients not on stiripentol is 20 mg. In patients on concomitant stiripentol and clobazam, the maximum fenfluramine dosage with strong CYP1A2 or CYP2D6 inhibitors is 17 mg.(1) If the strong CYP1A2 or CYP2D6 inhibitor is discontinued, consider gradually increasing the fenfluramine dosage to the usual recommended dose without the inhibitor.(1) The manufacturer of fenfluramine states that fenfluramine should be used with caution with other serotonergic agents such as selective serotonin reuptake inhibitors. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: In a study of healthy volunteers, fluvoxamine 50 mg daily (a strong CYP1A2 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose fenfluramine 0.4 mg/kg by 102% and 22%, respectively, and decreased the AUC and Cmax of norfenfluramine by 22% and 44%, respectively.(1) In a study of healthy volunteers, paroxetine 30 mg daily (a strong CYP2D6 inhibitor) increased the AUC and Cmax of single-dose fenfluramine 0.4 mg/kg by 81% and 13%, respectively, and decreased the AUC and Cmax of norfenfluramine by 13% and 29%, respectively.(1) Strong CYP1A2 inhibitors linked to this monograph include: fluvoxamine.(3,4) Strong CYP2D6 inhibitors linked to this monograph include: fluoxetine and paroxetine.(3,4)

Selected Ssris/Carbamazepine

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

MECHANISM OF ACTION: The exact mechanism is unknown. The SSRIs may inhibit the metabolism of carbamazepine, although evidence is conflicting.

CLINICAL EFFECTS: Possible increased levels of carbamazepine and clinical toxicity.

PREDISPOSING FACTORS: One set of authors speculated that the interaction may be less prevalent in long-term recipients of carbamazepine in whom carbamazepine has resulted in enzyme induction. Carbamazepine-induced enzyme induction could possibly decrease the amount of SSRI available to interact with carbamazepine.(1)

PATIENT MANAGEMENT: Consider monitoring carbamazepine levels when SSRI therapy is initiated or withdrawn. Patients receiving concurrent therapy should be monitored for clinical signs of toxicity.

DISCUSSION: Information on this interaction is conflicting. In a study in subjects maintained on carbamazepine (CBZ), the addition of fluoxetine or fluvoxamine to their regimens resulted in no changes in either CBZ or carbamazepine-10,11-epoxide (CBZ-E).(1) Another study compared subjects receiving concurrent therapy with CBZ and fluoxetine to subjects receiving CBZ therapy alone. There were no differences in the ratios of CBZ to CBZ-E levels between the groups, although there was a trend towards lower CBZ clearance in the group receiving concurrent therapy. The in-vitro section of this study found that fluoxetine did not inhibit the metabolism of CBZ until fluoxetine reached levels 20 times greater than those found clinically. In contrast, another study in healthy subjects found a 30% increase in area-under-curve (AUC) of CBZ and CBZ-E during concurrent therapy with fluoxetine.(3) There have been four case reports of parkinsonism developing after the addition of fluoxetine to CBZ therapy. (4-6) There have been two case reports of increased CBZ levels(7) and one report of serotonin syndrome(8) following the addition of fluoxetine therapy. Information on fluvoxamine is also conflicting. Although the addition of fluvoxamine to carbamazepine regimens resulted in no changes in either CBZ or CBZ-E levels in one study,(1) there have been five case reports of increases in CBZ levels, with clinical toxicity in two reports, during concurrent therapy.(9-10) Information on sertraline is also conflicting. Although the addition of sertraline to carbamazepine regimens resulted in no changes in either CBZ or CBZ-E levels in one study,(11) there has been one case report of increased CBZ levels with clinical toxicity during concurrent therapy.(12) One study has demonstrated that paroxetine had no effect on CBZ levels or effectiveness.(13)

Selected Ssris; Snris/Cyclobenzaprine

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

MECHANISM OF ACTION: Selected serotonin or serotonin-norepinephrine reuptake inhibitors (SSRIs or SNRIs) may impair the oxidative hepatic metabolism of cyclobenzaprine. Cyclobenzaprine is metabolized by CYP1A2, CYP3A4, and to a lesser extent CYP2D6.(4) Fluvoxamine is a strong inhibitor of CYP1A2 and a weak inhibitor of CYP3A4 and CYP2D6. Sertraline and venlafaxine are weak inhibitors of CYP2D6.

CLINICAL EFFECTS: Concurrent administration of selected SSRIs or SNRIs with cyclobenzaprine may result in an increase in serum levels, toxicities, and/or clinical effects of cyclobenzaprine, including serotonin syndrome.(4) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.

PREDISPOSING FACTORS: 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.(5)

PATIENT MANAGEMENT: Patients should be observed for increased adverse effects and clinical effects of cyclobenzaprine at the initiation of concurrent therapy with selected SSRIs or SNRIs. Plasma concentrations of cyclobenzaprine should be monitored and the dosage adjusted accordingly. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome, and seizure activity. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea. If the SSRI or SNRI is discontinued in a patient receiving cyclobenzaprine, the dosage of the cyclobenzaprine may need to be adjusted.

DISCUSSION: There have been case reports of serotonin syndrome with trazodone and amitriptyline with lithium, and cyclobenzaprine with duloxetine.(6) The affinity of the different SSRIs, SNRIs, and tricyclics for CYP P-450 may vary.

Selected Ssris; Snris/Tramadol

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

MECHANISM OF ACTION: The concurrent administration of tramadol with a selective serotonin reuptake inhibitor (SSRI) or a serotonin/norepinephrine reuptake inhibitor (SNRI) may result in additive blockade of serotonin reuptake, leading to central serotonergic hyperstimulation.(1) The combination of tramadol and SSRIs or SNRIs may also lower the seizure threshold.(1)

CLINICAL EFFECTS: Concurrent administration may increase the risk for serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(2) Concurrent administration may increase the risk for seizures, especially in susceptible individuals.(1)

PREDISPOSING FACTORS: Treatment with multiple medications which increase serotonin levels or with medications which inhibit the metabolism of serotonin increasing drugs are risk factors for serotonin syndrome.(2) Predisposing factors for a lower seizure threshold include a history of seizures, epilepsy, or a recognized risk for seizures (e.g. head trauma, metabolic disorders, alcohol, drug withdrawal, infections of the central nervous system). A genetic defect in CYP2D6 leading to the slow metabolizer phenotype may increase the risk for serotonin syndrome due to tramadol.

PATIENT MANAGEMENT: If concurrent therapy of tramadol with a SSRI or SNRI is warranted, patients should be closely monitored for signs and symptoms of serotonin syndrome and increased seizure activity.(1)

DISCUSSION: There are a number of serotonin syndrome case reports following the addition of tramadol to a stable selective serotonin reuptake inhibitor regimen. The syndrome developed between 12 hours to 3 weeks after the initiation of tramadol therapy. Patients recovered after tramadol and/or the SSRI/SNRI was discontinued.(3-14) One patient also developed mania.(3) Another patient developed nightmares and hallucinations after taking concurrent tramadol and paroxetine for 56 days.(15) One author suggests that although the combination of tramadol and SSRIs or SNRIs is associated with a risk for serotonin syndrome, given the high rate of co-prescribing for the combination it is an uncommon outcome.(16) A review of the 124 reports of seizures following tramadol therapy received by the FDA through July 31, 1996 revealed that 20 patients were receiving concurrent therapy with an selective serotonin reuptake inhibitor.(17) The manufacturer of tramadol states that the risk of seizure is increased in patients receiving concurrent therapy with selective serotonin reuptake inhibitors.(1) Selected SSRIs and SNRIs linked to this monograph include: citalopram, desvenlafaxine, escitalopram, fluvoxamine, levomilnacipran, milnacipran, sertraline, sibutramine, venlafaxine, vilazodone, and vortioxetine.

Selected Ssris; Snris/Trazodone

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

MECHANISM OF ACTION: Selected serotonin or serotonin-norepinephrine reuptake inhibitors (SSRIs or SNRIs) may impair the oxidative hepatic metabolism of trazodone. Trazodone is metabolized by CYP3A4 and its active metabolite meta-chlorophenylpiperazine (m-CPP) is metabolized by CYP2D6. Duloxetine is a moderate inhibitor of CYP2D6. Desvenlafaxine, fluvoxamine, sertraline, and venlafaxine are weak inhibitors of CYP2D6. Fluvoxamine is also a weak inhibitor of CYP3A4.

CLINICAL EFFECTS: Concurrent administration of selected SSRIs or SNRIs with trazodone may result in an increase in serum levels, toxicities (e.g. torsades de pointes), and/or clinical effects of trazodone. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.

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 inhibitors its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)

PATIENT MANAGEMENT: Patients should be observed for increased adverse effects and clinical effects of trazodone at the initiation of concurrent therapy with selected SSRIs or SNRIs. Plasma concentrations of trazodone should be monitored and the dosage adjusted accordingly. If the SSRI or SNRI is discontinued in a patient receiving trazodone, the dosage of trazodone may need to be adjusted. 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. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: There have been case reports of serotonin syndrome with trazodone and amitriptyline with lithium, and cyclobenzaprine (structurally related to the TCAs) with duloxetine.(3) The affinity of the different selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and tricyclics for CYP P-450 may vary.

Selected Strong Cyp1a2 Inhibitors/Olanzapine

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

MECHANISM OF ACTION: Strong CYP1A2 inhibitors may inhibit the metabolism of olanzapine by CYP1A2.(1-5)

CLINICAL EFFECTS: Concurrent use of strong CYP1A2 inhibitors may result in elevated levels of and toxicity from olanzapine.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for olanzapine side effects. The dose of olanzapine may need to be adjusted if a strong CYP1A2 inhibitor is initiated or discontinued.

DISCUSSION: In a study in 10 male smokers with schizophrenia, pretreatment with fluvoxamine (100 mg daily for 10 days) increased olanzapine area-under-curve (AUC), maximum concentration (Cmax), and half-life by 30-50%, 12-64%, and by 25-32%, respectively. Olanzapine volume of distribution and clearance were decreased by 4-26% and 26-38%, respectively.(1) In a study in 8 schizophrenic patients, the addition of fluvoxamine (100 mg daily) to olanzapine (10-20 mg daily) increased olanzapine levels from 12-112%. N-desmethylolanzapine levels were not significantly affected.(2) In a retrospective review, 10 patients receiving concurrent fluvoxamine and olanzapine were compared to 134 patients receiving olanzapine alone. The ratio of olanzapine concentration/daily dose was 2.3-fold higher in patients receiving concurrent fluvoxamine.(3) Fluvoxamine has been shown to increase olanzapine Cmax and AUC by 54% and by 52%, respectively, in female nonsmokers. Fluvoxamine has been shown to increase olanzapine Cmax and AUC by 77% and by 108%, respectively, in male smokers.(4,5) Strong CYP1A2 inhibitors linked include: enasidenib, enoxacin, fluvoxamine, and rofecoxib.(6)

Selected Strong Cyp2c19 Inhibitors/Abrocitinib

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

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

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

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of abrocitinib states that the dose of abrocitinib in patients who are taking strong CYP2C19 inhibitors should be reduced to 50 mg once daily. If an adequate response is not achieved after 12 weeks, consider increasing the dose to 100 mg once daily. If the response remains inadequate, discontinue therapy with abrocitinib.(1)

DISCUSSION: In a study, fluvoxamine (50 mg daily for 9 days), a strong CYP2C19 inhibitor, increased the maximum concentration (Cmax) and area-under-curve (AUC) of abrocitinib (100 mg) by 1.33-fold and 1.91-fold, respectively.(1) Strong CYP2C19 inhibitors linked to this monograph include: fluoxetine and fluvoxamine.(2,3)

Selected Weak Cyp2d6 Inhibitors/Tamoxifen

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

MECHANISM OF ACTION: Inhibitors of CYP2D6 may inhibit the conversion of tamoxifen to endoxifen (an active metabolite of tamoxifen).(1-2) The role of endoxifen in tamoxifen's efficacy has been debated and may involve a minimum concentration level.(3-5)

CLINICAL EFFECTS: Concurrent use of inhibitors of CYP2D6 may decrease the effectiveness of tamoxifen in preventing breast cancer recurrence.

PREDISPOSING FACTORS: Concurrent use of weak CYP2D6 inhibitors in patients who are CYP2D6 intermediate metabolizers should be avoided. Patients who are CYP2D6 poor metabolizers lack CYP2D6 function and are not affected by CYP2D6 inhibition.

PATIENT MANAGEMENT: Although data on this interaction are conflicting, it may be prudent to use alternatives to CYP2D6 inhibitors when possible in patients taking tamoxifen. The US manufacturer of tamoxifen states that the impact on the efficacy of tamoxifen by strong CYP2D6 inhibitors is uncertain and makes no recommendation regarding coadministration with inhibitors of CYP2D6.(12) The manufacturer of paroxetine (a strong CYP2D6 inhibitor) states that alternative agents with little or no CYP2D6 inhibition should be considered.(13) The National Comprehensive Cancer Network's breast cancer guidelines advises caution when coadministering strong CYP2D6 inhibitors with tamoxifen.(14) NCCN states when prescribing a selective serotonin reuptake inhibitor (SSRI), it is reasonable to avoid SSRIs that are strong and moderate CYP2D6 inhibitors, particularly fluoxetine and paroxetine, if an appropriate alternative exists.(14) Cancer Care Ontario breast cancer guidelines state concurrent use of weak CYP2D6 inhibitors should be closely monitored.(15) The European Society of Medical Oncology (ESMO) clinical practice guidelines for early breast cancer states patients on tamoxifen should be advised to avoid concurrent use of strong and moderate CYP2D6 inhibitors. Consider alternatives to tamoxifen if CYP2D6 inhibitors cannot be replaced with alternative agents.(16) If concurrent therapy is warranted, the risks versus benefits should be discussed with the patient.

DISCUSSION: Some studies have suggested that administration of fluoxetine, paroxetine, and quinidine with tamoxifen or a CYP2D6 poor metabolizer phenotype may result in a decrease in the formation of endoxifen (an active metabolite of tamoxifen) and a shorter time to breast cancer recurrence.(1-2,9) A retrospective study of 630 breast cancer patients found an increasing risk of breast cancer mortality with increasing durations of coadministration of tamoxifen and paroxetine. In the adjusted analysis, absolute increases of 25%, 50%, and 75% in the proportion of time of overlapping use of tamoxifen with paroxetine was associated with 24%, 54%, and 91% increase in the risk of death from breast cancer, respectively.(18) The CYP2D6 genotype of the patient may have a role in the effects of this interaction. Patients with wild-type CYP2D6 genotype may be affected to a greater extent by this interaction. Patients with a variant CYP2D6 genotype may have lower baseline levels of endoxifen and may be affected to a lesser extent by this interaction.(6-10) In a retrospective review, 1,325 patients treated with tamoxifen for breast cancer were classified as being poor 2D6 metabolizers (lacking functional CYP2D6 enzymes), intermediate metabolizers (heterozygous alleles), or extensive metabolizers (possessing 2 functional alleles). After a mean follow-up period of 6.3 years, the recurrence rates were 14.9%, 20.9%, and 29.0%, in extensive metabolizers, intermediate metabolizers, and poor metabolizers, respectively.(11) In October of 2006, the Advisory Committee Pharmaceutical Science, Clinical Pharmacology Subcommittee of the US Food and Drug Administration recommended that the US tamoxifen labeling be updated to include information about the increased risk of breast cancer recurrence in poor CYP2D6 metabolizers (either by genotype or drug interaction).(19-20) The labeling changes were never made due to ongoing uncertainty about the effects of CYP2D6 genotypes on tamoxifen efficacy. In contrast to the above information, two studies have shown no relationship between CYP2D6 genotype and breast cancer outcome.(21-23) As well, a number of studies found no association between use of CYP2D6 inhibitors and/or antidepressants in patients on tamoxifen and breast cancer recurrence,(24-28) though the studies were limited by problematic selection of CYP2D6 inhibitors and short follow-up. Weak inhibitors of CYP2D6 include: alogliptin, artesunate, celecoxib, chloroquine, cimetidine, clobazam, clomipramine, cobicistat, delavirdine, diltiazem, dimenhydrinate, diphenhydramine, dronabinol, dupilumab, echinacea, enasidenib, fedratinib, felodipine, fluvoxamine, gefitinib, hydralazine, imatinib, labetalol, lorcaserin, nicardipine, osilodrostat, ranitidine, ritonavir, sarpogrelate, sertraline, verapamil and viloxazine.(29)

Serotonergic Agents/Centanafadine

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

MECHANISM OF ACTION: Centanafadine is a norepinephrine, dopamine, and serotonin reuptake inhibitor.(1) Concurrent administration with one or more serotonergic agents may increase serotonin effects, resulting in serotonin toxicity.(1,2)

CLINICAL EFFECTS: Concurrent use of centanafadine with other serotonergic agents may increase the risk of serotonin syndrome, a potentially life-threatening syndrome which may include one or more of the following symptoms: tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(1,2)

PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity.(2) Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(2)

PATIENT MANAGEMENT: If concurrent use of centanafadine with other serotonergic agents is clinically warranted, counsel the patient on the increased risk of serotonin syndrome and monitor for symptoms. If symptoms of serotonin syndrome develop, discontinue centanafadine and/or the other serotonergic agents immediately and initiate supportive measures.(1)

DISCUSSION: Centanafadine inhibits reuptake of norepinephrine, dopamine, and serotonin.(1)

Serotonergic Agents/Ziprasidone

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

MECHANISM OF ACTION: Ziprasidone is a 5-HT1A agonist and serotonin and norepinephrine reuptake inhibitor. Concurrent administration with one or more serotonergic agents may increase serotonin effects, resulting in serotonin toxicity.(1,2)

CLINICAL EFFECTS: Concurrent use of ziprasidone and other serotonergic agents may result in serotonin syndrome, a potentially life-threatening condition with symptoms including altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor.(1)

PREDISPOSING FACTORS: Serotonin syndrome risk is dose-related. Higher systemic concentrations of either drug would be predicted to increase risk for serotonin toxicity.(2) Concomitant therapy with multiple agents which increase brain serotonin concentrations may also increase risk for serotonin syndrome.(2)

PATIENT MANAGEMENT: Caution patients about the risk of serotonin syndrome with the concomitant use of ziprasidone with other serotonergic drugs. Instruct patients to contact their healthcare provider, or report to the emergency room, should they experience signs or symptoms of serotonin syndrome.(1)

DISCUSSION: Several cases of serotonin syndrome have been reported in patients receiving ziprasidone.(4-6)

Slt Moderate And Weak Cyp3a4 Inhibit/Sirolimus Protein-Bound

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Snris; Ssris/Bupropion

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

MECHANISM OF ACTION: Both bupropion and the SSRIs and SNRIs are known to lower the seizure threshold.(1,2) In addition, bupropion, a strong inhibitor of CYP2D6, may inhibit the metabolism of SSRIs and SNRIs metabolized by CYP2D6. The potential for bupropion to inhibit the metabolism of the antidepressant differs. Antidepressants that are very sensitive to CYP2D6 inhibition have a greater potential for increased effects. Antidepressants which are very sensitive to CYP2D6 inhibition and have the greatest potential for increased effects are: fluoxetine,(3) paroxetine,(4) and venlafaxine.(5) Antidepressants which are moderately sensitive to CYP2D6 inhibition are: fluvoxamine.(6) Antidepressants which are metabolized by CYP2D6 but less susceptible to CYP2D6 inhibition and therefore have a lower potential for increased effects are: citalopram(7) and duloxetine.(8)

CLINICAL EFFECTS: Concurrent use of bupropion and a SSRI or SNRI may result in additive effects on the seizure threshold, increasing the risk of seizures.(1,2) Concurrent use may also increase levels of and side effects from antidepressants metabolized by CYP2D6, such as citalopram, duloxetine, fluoxetine, fluvoxamine, paroxetine, and venlafaxine.(3-10)

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids).(1,2) With paroxetine, 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.(11)

PATIENT MANAGEMENT: The concurrent use of bupropion and SSRIs or SNRIs should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) Single doses should not exceed 150 mg.(1,2) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1)

DISCUSSION: Because of the risk of seizure from concurrent bupropion and other agents that lower seizure threshold, the manufacturer of bupropion states that the concurrent use of bupropion and antidepressants should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) In a study in 15 male subjects who were extensive metabolizers of CYP2D6, bupropion (150 mg twice daily) increased the maximum concentration (Cmax), area-under-curve (AUC), and half-life (T1/2) of a single dose of desipramine (50 mg) by 2-fold, 5-fold, and 2-fold, respectively.(1,2) In a clinical study, citalopram steady state levels were not significantly different in poor metabolizers and extensive metabolizers of CYP2D6. Coadministration of a drug that inhibits CYP2D6 with citalopram is unlikely to have clinically significant effects on citalopram metabolism, based on the study results in CYP2D6 poor metabolizers.(7) Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily) increased the AUC of duloxetine by about 60%.(8) An in vivo study of single-dose fluvoxamine evaluated pharmacokinetic changes in 13 poor metabolizers (PM) compared to 16 extensive metabolizers (EM). The mean Cmax, AUC, and half-life were increased by 52%, 200%, and 62%, respectively, in the PM compared to the EM group.(6) Fluoxetine, paroxetine, and venlafaxine are classified as sensitive CYP2D6 substrates with an increase in AUC >= 5-fold.(9) The FDA defines sensitive substrates as drugs that have an increase in AUC >= 5-fold and moderate sensitive substrates have an increase in AUC >= 2-fold to <5-fold when administered with strong inhibitors.(10)

Ssris; Snris/Amphetamines; Phentermine

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

MECHANISM OF ACTION: Amphetamines may affect serotonin release and/or reuptake, depending on their molecular structure. Ring substitution tends to increase amphetamine-induced release of endogenous serotonin. However, the effect on serotonin release may also be dose related and is more likely if the amphetamine is taken in doses greater than those approved and generally employed in treating Attention-deficit-hyperactivity-disorder, or if abused, especially over long periods of time.(1) Amphetamines, phentermine and serotonin-norepinephrine reuptake inhibitors(SNRIs) may have additive effects on blood pressure.

CLINICAL EFFECTS: Concurrent use of amphetamines with agents that affect serotonin may increase the risk of serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(8) Concurrent use of amphetamines or phentermine and a SNRI may increase the risk for high blood pressure or make hypertension more difficult to control. SSRIs and SNRIs linked to this monograph are: citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone and vortioxetine.

PREDISPOSING FACTORS: High doses or long-term abuse of amphetamines may increase the risk of this interaction.

PATIENT MANAGEMENT: The concurrent use of amphetamines with SSRIs or SNRIs should be approached with appropriate monitoring. Instruct patients receiving concurrent therapy to report any signs or symptoms of serotonin syndrome immediately. Monitor blood pressure during concurrent therapy and adjust dosage or change medication for persistent increases in blood pressure. If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: In a case report, a 13 year-old female experienced tachycardia when amphetamine was added to her sertraline regimen.(2) Increased side effects have also been reported in patients maintained on fluoxetine who ingested illicit amphetamines.(3) In a case report, a 22 year-old female had previously been taking phentermine and oral contraceptive agents. The patient stopped taking phentermine and, after an undetermined length of time, started taking fluoxetine (20 mg daily). The patient discontinued her fluoxetine after three months. Eight days later, she took one dose of phentermine (30 mg). Within several hours, she developed jitteriness, stomach cramps, dry eyes, palpitations, and tremors. The patient received once dose of lorazepam (1.5 mg) and her symptoms resolved over night.(4) In a case report, a 32 year-old male developed agitation, anxiety, shivering, tremors, and diaphoresis two weeks after adding venlafaxine to his dexamphetamine.(5) There have also been reports of safe and effective use of amphetamines with fluoxetine,(6) dextroamphetamine and sertraline,(6) and dextroamphetamine with fluoxetine.(7)

Ssris; Snris/Selected Nsaids; Aspirin

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

MECHANISM OF ACTION: Serotonin release by platelets plays a role in hemostasis.(1,2) The increased risk of bleeding may be a result of a decrease in serotonin reuptake by platelets.

CLINICAL EFFECTS: Concurrent use of a selective serotonin reuptake inhibitor(1-7,13) or a serotonin-norepinephrine reuptake inhibitor(8-10) and a NSAID may result in bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with multiple disease-associated factors (e.g. thrombocytopenia, advanced liver disease). 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., anticoagulants, antiplatelets, or corticosteroids. Risk of GI bleed may be increased in patients who are of older age, in poor health status, or who use alcohol or smoke. Risk may also be increased with longer duration of NSAID use and prior history of peptic ulcer disease and/or GI bleeding. Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(15)

PATIENT MANAGEMENT: Selective serotonin reuptake inhibitors(1-7,13) or serotonin-norepinephrine reuptake inhibitors(8-10) and NSAIDs should be used concurrently with caution. Patients should be warned about the increased risk of bleeding and be educated about signs and symptoms of bleeding.(1-11,13) 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. Discontinue anti-platelet agents 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 retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ratio was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a selective serotonin reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(11) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with selective serotonin reuptake inhibitors and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6, respectively.(12)

Ssris; Snris/Tapentadol

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

MECHANISM OF ACTION: The concurrent administration of tapentadol(1) with a selective serotonin reuptake inhibitor (SSRI) or a serotonin/norepinephrine reuptake inhibitor (SNRI) may result in additive blockade of serotonin reuptake, leading to central serotonergic hyperstimulation.(1) The combination of tapentadol and SSRIs or SNRIs may impact seizure control.(1)

CLINICAL EFFECTS: Concurrent administration may increase the risk for serotonin syndrome. Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(2) Concurrent administration may increase the risk for seizures, especially in susceptible individuals.(1)

PREDISPOSING FACTORS: Treatment with multiple medications which increase serotonin levels or with medications which inhibit the metabolism of serotonin increasing drugs are risk factors for serotonin syndrome.(2)

PATIENT MANAGEMENT: If concurrent therapy of tapentadol with a SSRI or SNRI is warranted, patients should be closely monitored for signs and symptoms of serotonin syndrome or increased seizure frequency. Tapentadol may need to be discontinued.

DISCUSSION: Concurrent use of tapentadol with SSRIs or SNRIs may result in additive blockage of serotonin reuptake, leading to central serotonergic hyperstimulation. Cases of serotonin syndrome have been reported with tapentadol in combination with other serotonergic drugs.(1) Use of tapentadol has been associated with increased seizure frequency in patients with seizure disorders.(1) SSRIs and SNRIs linked to this monograph are: citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, sibutramine, venlafaxine, vilazodone, and vortioxetine.

Ssris; Vilazodone/Flurbiprofen

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

MECHANISM OF ACTION: Serotonin release by platelets plays a role in hemostasis.(1,2) The increased risk of bleeding may be a result of a decrease in serotonin reuptake by platelets.

CLINICAL EFFECTS: Concurrent use of a SSRI(1-8) or vilazodone(9) and flurbiprofen may result in bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(13) 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: Selective serotonin reuptake inhibitors(1-8) or vilazodone(9) and flurbiprofen should be used concurrently with caution. Patients should be warned about the increased risk of bleeding and be educated about signs and symptoms of bleeding.(1-10) 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. Discontinue anti-platelet agents 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 retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ratio was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a SSRI with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(10) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with selective serotonin reuptake inhibitors and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6, respectively.(11)

Ssris; Vilazodone/Selected Nsaids

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

MECHANISM OF ACTION: Serotonin release by platelets plays a role in hemostasis.(1,2) The increased risk of bleeding may be a result of a decrease in serotonin reuptake by platelets.

CLINICAL EFFECTS: Concurrent use of a SSRI(1-8) or vilazodone(9) and a NSAID may result in bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with multiple disease-associated factors (e.g. thrombocytopenia, advanced liver disease). 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., anticoagulants, antiplatelets, or corticosteroids. Risk of GI bleed may be increased in patients who are of older age, in poor health status, or who use alcohol or smoke. Risk may also be increased with longer duration of NSAID use and prior history of peptic ulcer disease and/or GI bleeding. Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(13)

PATIENT MANAGEMENT: Selective serotonin reuptake inhibitors(1-8) or vilazodone(9) and NSAIDs should be used concurrently with caution. Patients should be warned about the increased risk of bleeding and be educated about signs and symptoms of bleeding.(1-10) 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. Discontinue anti-platelet agents 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 retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ratio was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a SSRI with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(10) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with selective serotonin reuptake inhibitors and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6, respectively.(11)

Strong And Moderate Cyp1a2 Inhibitors/Ropinirole

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

MECHANISM OF ACTION: Ropinirole is a CYP1A2 substrate. Strong and moderate CYP1A2 inhibitors may decrease the metabolism of ropinirole.(1-3)

CLINICAL EFFECTS: The concurrent administration of strong or moderate CYP1A2 inhibitors and ropinirole may result in elevated levels of ropinirole, increased clinical effects, and signs of toxicity.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: In patients receiving strong or moderate CYP1A2 inhibitors who are started on ropinirole, ropinirole may be titrated to effect according to the manufacturer's dosage instructions. If the strong or moderate CYP1A2 inhibitor is started or discontinued in a patient receiving ropinirole, the dosage of ropinirole may need to be adjusted.(1-2)

DISCUSSION: In a study in 12 subjects, the concurrent administration of ropinirole with ciprofloxacin resulted in increases in the maximum concentration (Cmax) and area-under-curve (AUC) of ropinirole by 84% and 60%, respectively. The major pathway for ropinirole metabolism has been shown to be CYP1A2.(1-3) Strong CYP1A2 inhibitors linked to this monograph include: Angelica dahurica, enasidenib, enoxacin, and fluvoxamine. Moderate CYP1A2 inhibitors linked to this monograph include: capmatinib, centanafadine, ciprofloxacin, dipyrone, fexinidazole, genistein, estrogen-containing contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine.(4)

Strong And Moderate Cyp3a4 Inhibitors/Etrasimod

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 impair the CYP3A4-mediated metabolism of etrasimod.(1) Etrasimod is metabolized by CYP2C8, CYP2C9, and CYP3A4.(1)

CLINICAL EFFECTS: In patients who are poor metabolizers of CYP2C9 or are also taking a strong or moderate CYP2C9 inhibitor, 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.

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. Patients who are also taking a strong or moderate CYP2C9 inhibitor may also have decreased etrasimod clearance.(1)

PATIENT MANAGEMENT: Concomitant use of etrasimod with strong or moderate CYP3A4 inhibitors in patients who are CYP2C9 poor metabolizers is not recommended.(1) Concomitant use with strong or moderate CYP3A4 inhibitors in patients who are also taking a strong or moderate CYP2C9 inhibitor is not recommended. (1)

DISCUSSION: 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 moderate to strong 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) Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, ensitrelvir, grapefruit, indinavir, itraconazole, josamycin, ketoconazole, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, relacorilant, telaprevir, tipranavir, troleandomycin, and tucatinib.(2,3) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, conivaptan, darunavir, fluvoxamine, fosamprenavir, fosnetupitant, isavuconazonium, letermovir, lenacapavir, netupitant, schisandra, stiripentol, tofisopam, and voxelotor.(2,3)

Strong Cyp1a2 Inhibitors/Bromazepam

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

MECHANISM OF ACTION: Strong CYP1A2 inhibitors may decrease the metabolism of bromazepam.(1)

CLINICAL EFFECTS: The concurrent administration of bromazepam with strong CYP1A2 inhibitors may result in elevated levels of bromazepam, which may result in increased adverse effects including profound sedation, respiratory depression, coma, and/or death.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with bromazepam and strong CYP1A2 inhibitors should be monitored for increased benzodiazepine effects. If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. The dosage of the bromazepam may need to be decreased. Bromazepam may need to be discontinued.(2) Counsel patient to report excess drowsiness, confusion, memory problems including sleep-driving behaviors, loss of coordination, unusual dizziness of lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. Benzodiazepines that do not undergo extensive Phase I metabolism (lorazepam, oxazepam) may be an alternative in patients receiving a strong CYP1A2 inhibitor.

DISCUSSION: Fluvoxamine, a strong CYP1A2 inhibitor, increased bromazepam area-under-curve (AUC) by 2.4-fold and half life by 1.9-fold.(1-3) Strong CYP1A2 inhibitors linked to this monograph include: angelica root, enasidenib, enoxacin, fluvoxamine, and rofecoxib. (4)

Strong Cyp1a2 Inhibitors/Diazoxide

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

MECHANISM OF ACTION: Inhibitors of CYP1A2 may inhibit the metabolism of diazoxide.(1)

CLINICAL EFFECTS: Concurrent use of inhibitors of CYP1A2 may result in elevated levels of and toxicity from diazoxide including hyperglycemia and fluid retention.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer recommends a dose reduction of diazoxide when use concomitantly with strong CYP1A2 inhibitors.(1) -For patients weighing 20 kg to < 30 kg: Give 25 mg for four weeks, then increase by 25 mg every two weeks for a target maintenance dose of 75 mg -For patients weighing 30 kg to <40 kg: Give 50 mg for two weeks, then increase to a target maintenance dose of 100 mg -For patients weighing 40 kg to <65 kg: Give 50 mg for two weeks, then increase by 50 mg every two weeks for a target maintenance dose of 150 mg -For patients weighing 65 kg to <100 kg: Give 100 mg for two weeks, then increase by 50 mg every two weeks for a target maintenance dose of 250 mg -For patients weighing 100 kg to <135 kg: Give 100 mg for weeks 1 and 2, increase to 200 mg for weeks 3 and 4, increase to 300 mg for weeks 5 and 6, then increase to a target maintenance dose of 325 mg

DISCUSSION: In a clinical study with fluvoxamine (a strong CYP1A2 inhibitor), fluvoxamine increased single dose diazoxide maximum concentration (Cmax) by 17.5% and area-under-curve (AUC) by 60% compared to the same parameter measured on single dose in the absence of fluvoxamine co-administration.(1) Strong CYP1A2 inhibitors linked to this monograph include: angelica root, enasidenib, enoxacin, fluvoxamine, and rofecoxib.(2,3)

Strong Cyp1a2 Inhibitors/Lidocaine

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

MECHANISM OF ACTION: Strong CYP1A2 inhibitors may inhibit the metabolism of lidocaine by CYP1A2.(1-4)

CLINICAL EFFECTS: Concurrent or recent use of strong CYP1A2 inhibitors may result in increased effects of lidocaine.(1-4)

PREDISPOSING FACTORS: This interaction may be more severe in patients taking strong CYP3A4 inhibitors.(2,3) The interaction may be less clinically significant in patients with severe liver impairment.(4)

PATIENT MANAGEMENT: Patients receiving this combination should be closely monitored for signs of lidocaine toxicity. The dosage of lidocaine should be adjusted based on serum lidocaine levels and patient response.

DISCUSSION: In a study in 8 subjects, pretreatment with fluvoxamine (100 mg daily) for 6 days increased the peak concentration (Cmax) and area-under-curve (AUC) of oral lidocaine (1 mg/kg) by 220% and 305%, respectively. Pretreatment with fluvoxamine (100 mg daily) and erythromycin (1500 mg daily) for 6 days increased lidocaine Cmax and AUC by 250% and 360%, respectively.(2) In a study in 9 subjects, pretreatment with fluvoxamine (100 mg daily) for 6 days decreased the clearance of intravenous lidocaine by 41%. Pretreatment with fluvoxamine (100 mg daily) and erythromycin (1500 mg daily) for 6 days decreased the clearance of intravenous lidocaine by 53%.(3) In a study in 10 healths subjects, 10 patients with mild (Child grade A) liver impairment, and 10 patients with severe (Child grade C) liver impairment, fluvoxamine decreased lidocaine clearance by 60% in healthy subjects and by 44% in patients with mild liver impairment. However, there was no significant effect in patients with severe liver impairment.(4) Strong CYP1A2 inhibitors linked include: angelica root, enasidenib, enoxacin, fluvoxamine, and rofecoxib.(5,6)

Strong Cyp1a2 Inhibitors/Ropivacaine

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

MECHANISM OF ACTION: Strong CYP1A2 inhibitors may inhibit the metabolism of ropivacaine.

CLINICAL EFFECTS: Concurrent use of a strong CYP1A2 inhibitor may result in increased levels of and toxicity from ropivacaine.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: In patients receiving concurrent strong CYP1A2 inhibitors and ropivacaine, monitor patients closely for signs of toxicity.

DISCUSSION: In a double-blind, randomized, cross-over study in 9 healthy subjects, ciprofloxacin (500 mg twice daily) decreased the clearance of a single dose of ropivacaine (0.6 mg/kg) by 31%.(1) In a double-blind, randomized, cross-over study in 8 healthy subjects, fluvoxamine (100 mg daily) increased the area-under-curve (AUC) of a single dose of ropivacaine (0.6 mg/kg) by 3.7-fold.(2) In a randomized, cross-over study in 12 healthy subjects, fluvoxamine (25 mg daily) increased the clearance of a single dose of ropivacaine (40 mg) by 68%. Ropivacaine half-life almost doubled.(3) Strong inhibitors of CYP1A2 include angelica root (angelica dahurica radix), enasidenib, enoxacin, fluvoxamine, and rofecoxib.(4,5)

Strong Cyp2c19 Inhb Cause Bleeding/Cilostazol (<= 50 Mg Bid)

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

MECHANISM OF ACTION: Fluoxetine and fluvoxamine are strong CYP2C19 inhibitors. Strong CYP2C19 inhibitors may inhibit the metabolism of cilostazol.(1-3) In addition, serotonin release by platelets plays a role in hemostasis.(2,3) This may result in an increased risk of bleeding due to a decrease in serotonin reuptake by platelets.

CLINICAL EFFECTS: Concurrent use of cilostazol and strong CYP2C19 inhibitors may result in elevated levels and increased effects of cilostazol.(1) Concurrent use of a selective serotonin reuptake inhibitor(2,3) and cilostazol may result in bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Renal impairment has been associated with an elevated risk of GI bleed in patients on SSRIs.(5) 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: The dose of cilostazol should be limited to 50 mg twice daily in patients receiving concurrent therapy with strong CYP2C19 inhibitors.(1) Selective serotonin reuptake inhibitors and agents that affect coagulation should be used concurrently with caution. 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: A study in 20 subjects examined the effects of omeprazole (40 mg daily) on a single dose of cilostazol (100 mg). Concurrent omeprazole increased the cilostazol maximum concentration (Cmax) and area-under-curve (AUC) by 18% and 26%, respectively. The Cmax and AUC of the 3,4-dehydro-cilostazol metabolite of cilostazol increased 29% and 69%, respectively. The Cmax and AUC of the OPC-13213 metabolite of cilostazol decreased by 22% and 31%, respectively.(4) In a retrospective review of 5 years of data from the Pharmaco-Epidemiologic Prescription Database, hospitalizations for upper gastro-intestinal bleeding in antidepressant users were compared to those in non-antidepressant users. The risk of a bleed in a patient using an NSAID only based on an observed-expected ration was 4.5 and in a patient using low-dose aspirin only was 2.5. Concurrent use of a selective serotonin reuptake inhibitor with NSAIDs or low-dose aspirin increased the risk of bleeding to 12.2 and 5.2, respectively.(5) In another study, there were 16 cases of upper gastrointestinal bleeding in patients receiving concurrent therapy with selective serotonin reuptake inhibitors and NSAIDs. Adjusted relative risk of bleeding with NSAIDs, selective serotonin reuptake inhibitors, or both were 3.7, 2.6, or 15.6, respectively.(6) In a case-control study conducted in users of acenocoumarol or phenprocoumon, 1848 patients who had been hospitalized with abnormal bleeding were each matched to 4 control patients. When patients took both a SSRI and a coumarin, an increased risk of hospitalization due to major non-gastrointestinal bleeding was observed (adjusted OR 1.7), but not due to gastrointestinal bleeding (adjusted OR 0.8).(7) A retrospective review examined patients discharged from a hospital with antiplatelet therapy following a myocardial infarction. When compared to aspirin therapy alone, both aspirin therapy with a SSRI and aspirin, clopidogrel, and SSRI therapy were associated with an increased risk of bleeding (hazard ratios 1.42 and 2.35, respectively.) Compared with dual antiplatelet therapy (aspirin and clopidogrel), use of aspirin and clopidogrel and a SSRI was also associated with increased risk of bleeding (hazard ration 1.57).(8) In The Rotterdam Study, fluvoxamine increased the risk of over anticoagulation (hazard ratio 2.63). Paroxetine was not associated with an increased risk. There were insufficient numbers of patients taking other SSRIs to assess increased risk.(9)

Strong Cyp2c19 Inhibitors/Belzutifan

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

MECHANISM OF ACTION: Belzutifan is primarily metabolized by CYP2C19 and UGT2B17, and to a lesser extent by CYP3A4. Agents that are inhibitors of CYP2C19 may inhibit the metabolism of belzutifan.(1)

CLINICAL EFFECTS: Concurrent use of an inhibitor of CYP2C19 increases plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions of belzutifan. This may increase the incidence or severity of anemia or hypoxia that can require a blood transfusion.(1)

PREDISPOSING FACTORS: UGT2B17 and CYP2C19 ultrarapid metabolizers may increase the incidence or severity of adverse effects, including anemia.(1)

PATIENT MANAGEMENT: The manufacturer of belzutifan states concurrent administration of CYP2C19 inhibitors with belzutifan increases plasma exposure which may increase the incidence and severity of anemia or hypoxemia. Monitor patients closely for anemia or hypoxemia and reduce the dose of belzutifan as recommended.(1) Monitor for anemia before initiation of, and periodically throughout, treatment with belzutifan. Closely monitor patients who are dual UGT2B17 and CYP2C19 poor metabolizers due to potential increases in exposure that may increase the incidence or severity of anemia.(1) For patients with hemoglobin <9 g/dL, withhold belzutifan until the hemoglobin is greater than or equal to 9 g/dL, then resume at reduced dose or permanently discontinue belzutifan, depending on the severity of anemia.(1) See full prescribing information for dose modifications and recommendations.(1)

DISCUSSION: The effect of concurrent administration inhibitors of CYP2C19 may cause an increase in plasma levels that can increase side effects, including anemia.(1) In clinical studies, patients who are poor metabolizers of UGT2B17 and CYP2C19 had higher belzutifan area-under-curve (AUC). The belzutifan AUC increased by 2-fold, 1.6-fold, and 3.2-fold in patients who were UGT2B17, CYP2C19, or dual UGT2B17 and CYP2C19 poor metabolizers, respectively.(1) Strong CYP2C19 inhibitors linked to this monograph include: fluconazole, fluoxetine, fluvoxamine, and ticlopidine.(2,3)

Strong Or Mod 3A4 Inh; Dual 3A4 And 1A2 Inhibit/Roflumilast

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

MECHANISM OF ACTION: Agents that are either strong or moderate CYP3A4 inhibitors or dual inhibitors of CYP1A2 and CYP3A4 may inhibit the metabolism of roflumilast.(1)

CLINICAL EFFECTS: The coadministration of roflumilast with strong or moderate CYP3A4 inhibitors or dual inhibitors of CY3A4 and CYP1A2 may increase roflumilast systemic exposure and may result in increased adverse reactions.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of roflumilast states concurrent use with CYP3A4 inhibitors or dual inhibitors of CYP3A4 and CYP1A2 should be approached with caution and the risk should be weighed carefully against the benefit. Consider alternatives with no or minimal enzyme inhibition.(1)

DISCUSSION: In healthy subjects, concurrent use of roflumilast (500 mcg single dose) with erythromycin, a moderate CYP3A4 inhibitor, (500 mg three times daily for 15 days) increased the area-under-curve (AUC) and concentration maximum (Cmax) of roflumilast by 70% and 40%, respectively, and decreased the AUC and Cmax of roflumilast N-oxide by 4% and 34%, respectively.(1,2) In healthy subjects, concurrent use of roflumilast (500 mcg single dose) with ketoconazole, a strong CYP3A4 inhibitor, (200 mg twice daily for 13 days) increased the AUC and Cmax of roflumilast by 99% and 23%, respectively, and decreased the AUC and Cmax of roflumilast N-oxide by 3% and 38%, respectively.(1) In healthy subjects, concurrent use of roflumilast (500 mcg single dose) with fluvoxamine, a dual CYP3A4 and CYP1A2 inhibitor, (50 mg daily for 14 days) increased the AUC and Cmax of roflumilast by 156% and 12%, respectively, and decreased the AUC and Cmax of roflumilast N-oxide by 52% and 210%, respectively.(1) In healthy subjects, concurrent use of roflumilast (500 mcg single dose) with cimetidine, a dual CYP3A4 and CYP1A2 inhibitor, (400 mg twice daily for 14 days) increased the AUC and Cmax of roflumilast by 85% and 46%, respectively, and increased the AUC and decreased Cmax of roflumilast N-oxide by 27% and 4%, respectively.(1) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, saquinavir, telaprevir, tipranavir, tucatinib, and voriconazole.(3,4) 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, lefamulin (oral), lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, schisandra, stiripentol, tofisopam, treosulfan, and voxelotor.(3,4) Dual CYP3A4 and CYP1A2 inhibitors linked to this monograph include: belumosudil, cannabidiol, cimetidine, ciprofloxacin, fluvoxamine, glecaprevir/pibrentasvir, grapefruit, osilodrostat, piperine, ribociclib, rucaparib, simeprevir, telithromycin, troleandomycin, verapamil, and viloxazine.(3,4)

*Concurrent administration, or within 14 days of stopping, monoamine oxidase inhibitors (MAOIs; including linezolid and IV methylene blue) due to an increased risk of serotonin syndrome.

*Coadministration with tizanidine, thioridazine, alosetron, and pimozide. Coadministration with ramelteon is also contraindicated with fluvoxamine maleate extended-release capsules.

• Serotonin syndrome

• Angle-closure glaucoma
• Bipolar disorder
• Risk of angle-closure glaucoma due to narrow angle of anterior chamber of eye
• Suicidal ideation
• Upper GI bleed

• CYp2d6 poor metabolizer
• Disease of liver
• Hypomania
• Hyponatremia
• Increased risk of bleeding
• Manic disorder
• Seizure disorder
• SIADH syndrome
• Tobacco smoker

Immediate-release tablets:The most common adverse reactions (>=5% and at least twice placebo) in controlled trials with adult obsessive-compulsive disorder and depression patients include nausea, somnolence, insomnia, asthenia, nervousness, dyspepsia, abnormal ejaculation, sweating, anorexia, tremor, vomiting, anorgasmia, decreased libido, dry mouth, rhinitis, taste perversion, and urinary frequency.

The most common adverse reactions (>=5% and at least twice placebo) in pediatric patients with obsessive-compulsive disorder include agitation, depression, dysmenorrhea, flatulence, hyperkinesia, and rash.

Extended-release capsules:The most common adverse reactions (>=5% and at least twice placebo) in controlled trials in patients with obsessive-compulsive disorder include abnormal ejaculation, anorexia, anorgasmia, asthenia, diarrhea, nausea, somnolence, sweating, tremor, anxiety, decreased libido, myalgia, pharyngitis, vomiting, dyspepsia, dizziness, insomnia, and yawning.

Less Frequent

• Manic disorder
• Myoclonus
• Syncope

Rare or Very Rare

• Acquired dystonia
• Agranulocytosis
• Akathisia
• Anaphylaxis
• Anemia
• Angioedema
• Aplastic anemia
• Blurred vision
• Bullous dermatitis
• Cardiac conduction delay
• Extrapyramidal disease
• Gastrointestinal hemorrhage
• Hemorrhage
• Hepatitis
• Homicidal ideation
• Hostility
• Hyponatremia
• Hypotension
• Ileus
• Interstitial lung disease
• Neuroleptic malignant syndrome
• Pancreatitis
• Parkinsonism
• Porphyria
• Rhabdomyolysis
• Secondary angle-closure glaucoma
• Seizure disorder
• Serotonin syndrome
• Stevens-johnson syndrome
• Suicidal
• Suicidal ideation
• Toxic epidermal necrolysis
• Vasculitis
• Ventricular tachycardia

More Frequent

• Abnormal sexual function
• Anorexia
• Constipation
• Diarrhea
• Disorder of ejaculation
• Dizziness
• Drowsy
• Dysgeusia
• Dyspepsia
• General weakness
• Headache disorder
• Hyperhidrosis
• Insomnia
• Muscle fasciculation
• Nausea
• Nervousness
• Rhinitis
• Tremor
• Upper respiratory infection
• Xerostomia

Less Frequent

• Agitation
• Chills
• Cramps in legs
• Dysphagia
• Dyspnea
• Erectile dysfunction
• Flatulence
• Flushing
• Hyperkinesis
• Hypertonia
• Hypomania
• Increased urinary frequency
• Libido changes
• Malaise
• Mood changes
• Myalgia
• Palpitations
• Polyuria
• Symptoms of anxiety
• Tooth disorder
• Vomiting
• Weight gain
• Weight loss
• Yawning

Rare or Very Rare

• Abnormal vaginal bleeding
• Accidental fall
• Aggressive behavior
• Altered mental status
• Amenorrhea
• Anticholinergic toxicity
• Dream disorder
• Dysarthria
• Dyskinesia
• Ecchymosis
• Epistaxis
• Euphoria
• Fever
• Gastroesophageal reflux disease
• Hallucinations
• Hematospermia
• Hematuria
• Laryngismus
• Loss of sense of smell
• Menorrhagia
• Menstrual disorder
• Mydriasis
• Orgasm disorder
• Petechiae
• Purpura
• Skin photosensitivity
• Urinary retention
• Urticaria

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The efficacy of fluvoxamine maleate tablets for the treatment of obsessive-compulsive disorder was demonstrated in a 10-week, multicenter, placebo-controlled study with 120 outpatients (8 to 17 years of age). In addition, 99 of these outpatients continued open-label fluvoxamine maleate tablets treatment for up to another 1 to 3 years, equivalent to 94 patient-years. The adverse event profile observed was generally similar to that observed in adult studies with fluvoxamine. As with other SSRIs, decreased appetite and weight loss have occurred in association with fluvoxamine therapy. There are no studies that directly evaluate the effects of long-term fluvoxamine use on the growth, cognitive behavioral development, and maturation of children and adolescents.

The risks, if any, that may be associated with fluvoxamine's extended use in children and adolescents with obsessive-compulsive disorder have not been systematically assessed. Safety and effectiveness in the pediatric population other than pediatric patients with obsessive-compulsive disorder have not been established. When considering the use of fluvoxamine maleate in a child or adolescent, balance the potential risk with the clinical need.

Fluvoxamine maleate extended-release capsules have not been evaluated in pediatric patients.

Monitor all patients being treated with antidepressants for clinical worsening, suicidal thoughts, and unusual changes in behavior, especially during the initial few months of treatment, or at times of dose increases or decreases. Monitor weight and growth in pediatric patients.

Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage.

Prolonged experience with fluvoxamine in pregnant women over decades, based on published observational studies, has not identified a clear drug-associated risk of major birth defects or miscarriage. There are risks associated with untreated depression in pregnancy and risks of persistent pulmonary hypertension of the newborn (PPHN) and poor neonatal adaptation with exposure to SSRIs, including fluvoxamine, during pregnancy. Neonates exposed to fluvoxamine and other SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome.

When pregnant rats were treated orally with fluvoxamine throughout the period of organogenesis, increased embryofetal death and increased incidences of fetal eye abnormalities (folded retinas) were observed at doses >=3 times the maximum recommended human dose (MRHD) of 300 mg/day given to adolescents on a mg/m2 basis. In addition, decreased fetal body weight was seen at a dose 6 times the MRHD given to adolescents on a mg/m2 basis. There were no adverse developmental effects in rabbits treated with fluvoxamine during the period of organogenesis up to a dose 2 times the MRHD given to adolescents on a mg/m2 basis. When fluvoxamine was administered orally to rats during pregnancy and lactation, increased pup mortality at birth was seen at a dose 2 times the MRHD given to adolescents on a mg/m2 basis. In addition, decreases in pup body weight and survival were observed at doses that are >=0.13 times the MRHD given to adolescents.

Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy (National Pregnancy Registry for Antidepressants: 1-844-405-6185 or online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregi stry/antidepressants/).

Data from published literature report the presence of fluvoxamine in human milk. No adverse effects on the breast-fed infant have been reported in most cases of maternal use of fluvoxamine during breast-feeding. However, there are reports of diarrhea, vomiting, decreased sleep, and agitation. There are no data on the effects of fluvoxamine on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for fluvoxamine and any potential adverse effects on the breast-fed child from fluvoxamine or from the underlying maternal condition.

Monitor infants exposed to fluvoxamine through breast milk for diarrhea, vomiting, decreased sleep, and agitation.

A lower initial dose and slower dose titration should be considered due to reduced clearance in geriatric patients.

Approximately 230 and 5 patients participating in controlled premarketing studies with immediate-release fluvoxamine maleate tablets and fluvoxamine maleate extended-release capsules, respectively, were 65 years of age or older. No overall differences in safety were observed between these patients and younger patients. Other reported clinical experience has not identified differences in response between the elderly and younger patients. SSRIs and SNRIs, including fluvoxamine, have been associated with several cases of clinically significant hyponatremia in elderly patients. The clearance of fluvoxamine is decreased by about 50% in the elderly compared to younger patients, and greater sensitivity of some older individuals cannot be ruled out.

In a study of fluvoxamine maleate tablets at 50 and 100 mg comparing elderly (ages 66 to 73 years) and young subjects (ages 19 to 35 years), mean maximum plasma concentrations in the elderly were 40% higher. The multiple dose elimination half-life of fluvoxamine was 17.4 and 25.9 hours in the elderly compared to 13.6 and 15.6 hours in young subjects at steady state for 50 and 100 mg doses, respectively. In elderly patients, the clearance of fluvoxamine was reduced by about 50%.

Consider a lower starting dose and slower titration of fluvoxamine in elderly patients.