Hyrnuo (sevabertinib)

If adverse events occur during therapy, temporary interruption, dosage reduction, and/or discontinuance of sevabertinib may be necessary.

For the first dosage reduction, reduce the sevabertinib dosage to 10 mg twice daily.

For the second dosage reduction, reduce the dosage to 10 mg once daily.

Permanently discontinue sevabertinib in patients who are unable to tolerate a dosage of 10 mg once daily.

The recommended dosage modifications of sevabertinib for adverse reactions are present in Table 1.

Table 1. Recommended Dosage Modifications for Adverse Reactions

Adverse Reaction Severity Dosage Modification Diarrhea Intolerable Grade 2 or Interrupt until recovery Grade 3 to Grade <=1. Resume at the same dose or the next lower dosage. For recurrence, resume at the next lower dosage. Grade 4 Permanently discontinue. Hepatotoxicity Grade 2, 3, or 4 ALT Interrupt until recovery and/or AST without to Grade <=1 or increased total baseline. Resume at the bilirubin OR Grade 3 next lower dosage. total bilirubin ALT or AST >= 3 times Permanently discontinue. the upper limit of normal (ULN) with total bilirubin >=2 times ULN OR Grade 4 total bilirubin ILD/ Pneumonitis Any Grade Permanently discontinue. Ocular Toxicity Grade 2 Interrupt until recovery to Grade <=1. Resume at next lower dosage. For recurrence, permanently discontinue. Grade 3 or Grade 4 Permanently discontinue. Pancreatic Enzyme Grade 3 Interrupt until recovery Elevation to Grade <=2 or baseline. Resume at the next lower dosage. Grade 4 Permanently discontinue. Other Adverse Reactions Intolerable or recurrent Interrupt until recovery Grade 2 or Grade 3 to Grade <=1. Resume at the same dosage or the next lower dosage. For recurrence, resume at the next lower dosage. Grade 4 Permanently discontinue.

Avoid current use of sevabertinib with strong cytochrome P-450 (CYP) 3A inhibitors.

If concurrent use cannot be avoided, reduce the sevabertinib dosage from 20 mg twice daily to 10 mg twice daily or from 10 mg twice daily to 10 mg once daily; withhold sevabertinib therapy in patients receiving a dosage of 10 mg once daily until the strong CYP3A inhibitor is discontinued.

After the CYP3A inhibitor has been discontinued for 3-5 elimination half-lives, resume the sevabertinib dosage used before initiating the inhibitor.

No dosing information is available for this tab.

No dosing information is available for this tab.

Sevabertinib is a substrate of cytochrome P450 (CYP) isoenzyme 3A4, a weak to moderate CYP3A inhibitor, a substrate and inhibitor of P-glycoprotein, and a substrate of breast cancer resistance protein (BCRP).

Sevabertinib inhibits CYP1A1 and 2C8 but does not inhibit 2A6, 2C9, 1A2, 2B6, 2D6, 2C19, or 2E1. Sevabertinib does not induce 1A2, 2B6, or 2C19.

Sevabertinib inhibits multidrug and toxin extrusion protein (MATE) 1 and MATE2-K but does not inhibit organic anion transporting polypeptide (OATP) 1B1, OATP1B3, multidrug resistance-associated protein 2 (MRP2), organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, or OCT2.

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

Sevabertinib/Moderate Cyp3a4 Inducers

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

MECHANISM OF ACTION: Sevabertinib is a CYP3A4 substrate. Moderate CYP3A4 inducers may induce the metabolism of sevabertinib.(1)

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

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

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

DISCUSSION: In a study, carbamazepine (strong CYP3A4 inducer) decreased sevabertinib's area-under-curve (AUC) 79% and maximum concentration (Cmax) 57%.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3)

Sevabertinib/Strong Cyp3a4 Inducers

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

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

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

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

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

DISCUSSION: In a study, carbamazepine (strong CYP3A4 inducer) decreased sevabertinib's area-under-curve (AUC) 79% and maximum concentration (Cmax) 57%.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's Wort.(2,3)

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

Antineoplastic Syst Enzyme Inh That Inhibit 3A4/Carbamazepin

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

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

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

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

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

DISCUSSION: In a study in 19 healthy subjects, rifampin (600 mg daily for 14 days) decreased the Cmax and AUC of a single dose of ceritinib by 44% and 70%, respectively.(1) In a study in healthy subjects, rifampin (600 mg daily for 8 days) decreased the Cmax and AUC of idelalisib (150 mg single dose) by 58% and 75%, respectively.(5) Pretreatment of 14 healthy subjects with rifampin (600 mg daily for 10 days) increased the clearance of a single dose of imatinib (400 mg) by 3.8-fold. The area-under-curve (AUC) and maximum concentration (Cmax) decreased by 74% and 54%, respectively.(6,12) The Cmax of the CGP74588 metabolite increased by 88.6%, but the AUC of CGP74588 decreased by 11%.(12) In a study in healthy subjects, concurrent rifampin (600 mg daily for 12 days) decreased nilotinib AUC by 80%.(7) Carbamazepine is almost completely metabolized to carbamazepine-10,11-epoxide, with only 5% of the drug excreted unchanged. Pharmacokinetic studies have indicated the major pathway for carbamazepine metabolism is catalyzed by CYP3A4, with minor contributions from CYP2C8 and CYP3A5.(10,11) In a study, carbamazepine decreased sevabertinib's AUC 79% and Cmax 57%.(15)

Selected Cyp3a4 Inhibitors/Colchicine

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

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

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

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

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

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

Selected Cyp3a4 Inhibitors/Cyclosporine

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Selected Cyp3a4 Inhibitors/Everolimus

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Selected Cyp3a4 Inhibitors/Quinidine; Quinine

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

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

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

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

PATIENT MANAGEMENT: Patients receiving concurrent CYP3A4 inhibitors should be monitored for increased effects of quinidine or quinine.(1-2) The manufacturer of sevabertinib states that concurrent use of drugs that are extensively metabolized by CYP3A4 and have a narrow therapeutic window like quinidine or quinine should be avoided.(3) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have been reported in patients taking quinidine in combination with CYP3A4 inhibitors.(1) In a study of healthy volunteers, ketoconazole (100 mg twice daily for 3 days) increased the area-under-curve (AUC) of single-dose quinine (500 mg) by 45% compared to quinine alone.(2) In a clinical study, coadministration of midazolam (a sensitive CYP3A4 substrate) with sevabertinib (20 mg twice daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 2-fold and 1.8-fold.(3) Selected CYP3A4 inhibitors linked to this monograph include: camizestrant, relacorilant, and sevabertinib.(5,6)

Selected Cyp3a4 Inhibitors/Sirolimus

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Sevabertinib/Strong Cyp3a4 Inhibitors

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

MECHANISM OF ACTION: Sevabertinib is metabolized via CYP3A4. Strong inhibitors of CYP3A4 may inhibit the metabolism of sevabertinib.(1)

CLINICAL EFFECTS: Concurrent use of sevabertinib with strong CYP3A4 inhibitors may result in a significant increase in exposure of sevabertinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sevabertinib states coadministration with strong CYP3A4 inhibitors should be avoided.(1) If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce sevabertinib dosage as follows: - If current dosage is 20 mg twice daily; reduce to 10 mg twice daily - If current dosage is 10 mg twice daily; reduce to 10 mg once daily - If current dosage is 10 mg once daily; withhold sevabertinib until the strong CYP3A4 inhibitor is discontinued.(1) After the strong CYP3A4 inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the sevabertinib dosage that was used prior to initiating the strong inhibitor.(1)

DISCUSSION: Coadministration of sevabertinib with itraconazole 200 mg daily, a strong CYP3A4 inhibitor, resulted in a 2.3-fold increase in area-under-curve (AUC) and a 1.6-fold increase in maximum concentration (Cmax).(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.(2,3)

Weak Cyp3a4 Inhibitors/Lomitapide

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

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

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

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

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

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

Weak Cyp3a4 Inhibitors/Pimozide

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

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

CLINICAL EFFECTS: Concurrent use with weak CYP3A4 inhibitors may increase the levels and effects of pimozide including QTc prolongation and potentially life-threatening cardiac arrhythmias like torsades de pointes.(1-2) Concurrent use may also result in extrapyramidal symptoms such as akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, and oculogyric crisis.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increased systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: The US manufacturer of pimozide states that concomitant treatment with strong CYP3A4 inhibitors is contraindicated and treatment with less potent inhibitors of CYP3A4 should also be avoided.(1) The UK manufacturer of pimozide contraindicates concomitant use of pimozide with CYP3A4 inhibitors and CYP2D6 inhibitors, stating that inhibition of either or both CYP3A4 and CYP2D6 may result in the elevation of pimozide blood concentration and increase the possibility of QT-prolongation.(2) For patients on avapritinib: this interaction applies only to gastrointestinal stromal tumor (GIST) patients on avapritinib 200 mg or 300 mg.(5) If concurrent use cannot be avoided, then correct or minimize QT prolonging risk factors, use the lowest effective dose of pimozide, and discontinue other concurrent QT prolonging agents or CYP3A4 or CYP2D6 inhibitors if possible. If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Pimozide is metabolized at CYP3A.(1,5) Elevated levels of pimozide may prolong the QTc interval resulting in life-threatening ventricular arrhythmias.(1) Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have been reported in patients taking pimozide in combination with itraconazole and/or other CYP3A4 inhibitors.(1,2) Weak CYP3A4 inhibitors include: amlodipine, asciminib, avapritinib, belumosudil, berberine, bicalutamide, blueberry, brodalumab, camizestrant, cannabidiol, capivasertib, chlorzoxazone, cimetidine, clotrimazole, cranberry, cyclosporine, daclatasvir, daridorexant, dihydroberberine, diosmin, elinzanetant, everolimus, flibanserin, fostamatinib, ginkgo, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, larotrectinib, lazertinib, leflunomide, levamlodipine, linagliptin, lomitapide, lurasidone, marijuana, olaparib, palbociclib, peppermint, piperine, pirtobrutinib, propiverine, ranitidine, resveratrol, scutellarin, sevabertinib, simeprevir, sitaxsentan, teriflunomide, ticagrelor, tolvaptan, trofinetide, viloxazine, and vonoprazan.(7,8)

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

Moderate And Weak Cyp3a4 Inhibitors/Tacrolimus

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

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

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

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

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

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

Selected Cyp3a4 Inhibitors/Alfentanil

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

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

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

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

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

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

Selected Cyp3a4 Inhibitors/Fentanyl

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

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

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

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

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

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

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)

*None.

• Lactation

• Chronic heart failure
• Pregnancy

There are no moderate contraindications for this drug.

Most common adverse reactions (>20%) include diarrhea, rash, paronychia, stomatitis, and nausea.

Most common Grade 3 or 4 laboratory abnormalities (>=2%) include decreased potassium, increased lipase, decreased lymphocyte count, decreased sodium, increased amylase, increased ALT, and increased AST.

More Frequent

• Diarrhea
• Elevated serum lipase
• Hypokalemia

Less Frequent

• Cardiac arrhythmia
• Pleural effusions
• Pneumonia
• Sinus tachycardia
• Supraventricular premature beats

Rare or Very Rare

• Epithelial keratopathy
• Interstitial lung disease
• Prolonged QT interval

More Frequent

• Abnormal hepatic function tests
• Acute abdominal pain
• Anemia
• Anorexia
• Dry skin
• Dyspnea
• Elevated serum amylase
• Fatigue
• Hyperbilirubinemia
• Hyperglycemia
• Hypertriglyceridemia
• Hypoalbuminemia
• Hypocalcemia
• Hypomagnesemia
• Hyponatremia
• Increased alanine transaminase
• Increased alkaline phosphatase
• Increased aspartate transaminase
• Leukopenia
• Lymphopenia
• Nausea
• Ocular disorders
• Paronychia
• Pruritus of skin
• Skin rash
• Stomatitis
• Vomiting
• Weight loss

Less Frequent

• Alopecia
• Edema

No enhanced messaging available.

Safety and effectiveness of sevabertinib have not been established in pediatric patients.

Based on animal studies and its mechanism of action, sevabertinib can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform a drug-associated risk. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

There are no data on the presence of sevabertinib or its metabolites in human milk, effects on a breastfed child, or effects on milk production. Because of the potential for serious adverse reactions, advise women not to breastfeed during treatment with sevabertinib and for 1 week after the last dose.

The manufacturer makes no recommendation for dosage adjustment in geriatric patients.

Among 268 patients who received sevabertinib, 43% were >=65 years of age and 13% were >=75 years of age. No overall differences in effectiveness were observed between older and younger patients; however, Grade 3 diarrhea occurred more often in patients >=75 years of age than in those <75 years of age.