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Drug overview for HYRNUO (sevabertinib):
Generic name: SEVABERTINIB
Drug class: Antineoplastic - Protein-Tyrosine Kinase Inhibitors
Therapeutic class: Antineoplastics
Sevabertinib, a kinase inhibitor of human epidermal growth factor receptor 2 (HER2), is an antineoplastic agent.
No enhanced Uses information available for this drug.
Generic name: SEVABERTINIB
Drug class: Antineoplastic - Protein-Tyrosine Kinase Inhibitors
Therapeutic class: Antineoplastics
Sevabertinib, a kinase inhibitor of human epidermal growth factor receptor 2 (HER2), is an antineoplastic agent.
No enhanced Uses information available for this drug.
DRUG IMAGES
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The following indications for HYRNUO (sevabertinib) have been approved by the FDA:
Indications:
HER2 positive non-squamous non-small cell lung cancer w/ tyrosine kinase domain activating mutations
Professional Synonyms:
None.
Indications:
HER2 positive non-squamous non-small cell lung cancer w/ tyrosine kinase domain activating mutations
Professional Synonyms:
None.
The following dosing information is available for HYRNUO (sevabertinib):
It isessential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:
*Select patients for treatment with sevabertinib based on the presence of HER2 (ERBB2) TKD activating mutations in tumor specimens.
* Recommended dosage is 20 mg orally twice daily with food until disease progression or unacceptable toxicity.
*Swallow tablets whole. Do not cut, crush, or chew tablets.
*See Full Prescribing Information for dosage modification recommendations for adverse reactions and for concomitant use with strong CYP3A inhibitors.
*Select patients for treatment with sevabertinib based on the presence of HER2 (ERBB2) TKD activating mutations in tumor specimens.
* Recommended dosage is 20 mg orally twice daily with food until disease progression or unacceptable toxicity.
*Swallow tablets whole. Do not cut, crush, or chew tablets.
*See Full Prescribing Information for dosage modification recommendations for adverse reactions and for concomitant use with strong CYP3A inhibitors.
No enhanced Administration information available for this drug.
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| HYRNUO 10 MG TABLET | Maintenance | Adults take 2 tablets (20 mg) by oral route 2 times per day |
No generic dosing information available.
The following drug interaction information is available for HYRNUO (sevabertinib):
There are 1 contraindications.
These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.
| Drug Interaction | Drug Names |
|---|---|
| Lomitapide/Strong or Moderate CYP3A4 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: 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, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, 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, sevabertinib, stiripentol, treosulfan, and verapamil.(1-3) |
JUXTAPID |
There are 13 severe interactions.
These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.
| Drug Interaction | Drug Names |
|---|---|
| Colchicine (for Gout & FMF)/Moderate CYP3A4 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of colchicine(1-3) CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in elevated levels of and toxicity from colchicine. Symptoms of colchicine toxicity include muscle weakness or pain; numbness or tingling in the fingers or toes; myelosuppression; abdominal pain; nausea; severe diarrhea or vomiting; feeling weak or tired; increased infections; and pale or gray color of the lips, tongue, or palms of hands.(1-3) PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with renal and/or hepatic impairment.(1-3) PATIENT MANAGEMENT: Avoid use of colchicine concurrently with or within 14 days of taking moderate CYP3A4 inhibitors (without ritonavir). If concurrent use is unavoidable, the dosage of colchicine should be reduced.(1-3) For gout flares, the recommended dosage is 1.2 mg (2 tablets) for one dose. This dose should be repeated no earlier than in 3 days.(1-4) For gout prophylaxis, if the original dosage was 0.6 mg twice daily, use 0.3 mg twice daily or 0.6 mg daily. If the original dosage was 0.6 mg daily, use 0.3 mg daily.(1-4) For Familial Mediterranean fever (FMF), the recommended maximum daily dose is 1.2 mg (may be given as 0.6 mg twice a day).(1-4) Patients should be instructed to immediately report any signs of colchicine toxicity, such as muscle weakness/pain, numbness/tingling in fingers/toes, unusual bleeding or bruising, infections, weakness/tiredness, pale/gray color of the lips/tongue/palms of hands, and/or severe diarrhea/vomiting. DISCUSSION: Fluconazole (400 mg loading dose followed by 200 mg daily for 4 days) increased the area-under-curve (AUC) of colchicine by 40%.(2) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, avacopan, clofazimine, conivaptan, crizotinib, duvelisib, fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, sevabertinib, stiripentol, and treosulfan.(1,5,6) |
COLCHICINE, COLCRYS, GLOPERBA, MITIGARE, PROBENECID-COLCHICINE |
| Bosutinib/Moderate CYP3A4 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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, sevabertinib, stiripentol, treosulfan, and verapamil.(3-4) |
BOSULIF |
| Pimozide/Selected Moderate CYP3A4 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Moderate inhibitors of CYP3A4 may inhibit the metabolism of pimozide.(1) CLINICAL EFFECTS: Concurrent administration of a moderate inhibitor of CYP3A4 may result in elevated levels of pimozide, which may result in prolongation of the QTc interval and potentially life-threatening ventricular arrhythmias.(1) PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3) PATIENT MANAGEMENT: Avoid concurrent use, especially when other risk factors for QT prolongation are present. The manufacturer of pimozide states that concomitant treatment with strong CYP3A4 inhibitors is contraindicated and treatment with less potent inhibitors of CYP3A4 should also be avoided.(1) If concurrent use cannot be avoided, then correct or minimize QT prolonging risk factors, e.g. correct electrolyte disturbances, use the lowest effective dose of pimozide, and discontinue other concurrent QT prolonging agents or CYP3A4 inhibitors if possible. Consider ECG to evaluate baseline and/or concurrent QT prolongation risk. Monitor patients on the combination and counsel patients accordingly. DISCUSSION: Pimozide is metabolized at CYP3A.(1,4) Elevated levels of pimozide may prolong the QTc interval resulting in life-threatening ventricular arrhythmias.(1) Moderate inhibitors of CYP3A4 include: avacopan, berotralstat, conivaptan, diltiazem, duvelisib, fedratinib, fosnetupitant, imatinib, isavuconazonium, lenacapavir, netupitant, rilzabrutinib, schisandra, sevabertinib, tofisopam, treosulfan and verapamil.(5,6) |
PIMOZIDE |
| Ergot Alkaloids/Moderate CYP3A4 Inhibitors 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, sevabertinib, tofisopam, treosulfan and verapamil. |
BREKIYA, DIHYDROERGOTAMINE MESYLATE, ERGOLOID MESYLATES, ERGOMAR, ERGOTAMINE TARTRATE, ERGOTAMINE-CAFFEINE, METHYLERGONOVINE MALEATE, METHYSERGIDE MALEATE, MIGERGOT, MIGRANAL, TRUDHESA |
| Venetoclax/Moderate CYP3A4 Inhibitors 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, sevabertinib, stiripentol, tofisopam, treosulfan, and verapamil.(3-4) |
VENCLEXTA, VENCLEXTA STARTING PACK |
| Antineoplastic Syst Enzyme Inh that Inhibit 3A4/Carbamazepine 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) |
CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, EQUETRO, TEGRETOL, TEGRETOL XR |
| Colchicine (for Cardioprotection)/Moderate CYP3A4 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of colchicine.(1,2) CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in elevated levels of and toxicity from colchicine. Symptoms of colchicine toxicity include muscle weakness or pain; numbness or tingling in the fingers or toes; myelosuppression; abdominal pain; nausea; severe diarrhea or vomiting; feeling weak or tired; increased infections; and pale or gray color of the lips, tongue, or palms of hands.(1,2) PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with renal and/or hepatic impairment.(1,2) PATIENT MANAGEMENT: Monitor patients receiving moderate CYP3A4 inhibitors for signs of colchicine toxicity. Avoid concurrent use in patients with existing renal or hepatic impairment.(1) Patients should be instructed to immediately report any signs of colchicine toxicity, such as muscle weakness/pain, numbness/tingling in fingers/toes, unusual bleeding or bruising, infections, weakness/tiredness, pale/gray color of the lips/tongue/palms of hands, and/or severe diarrhea/vomiting. DISCUSSION: There is one case report of colchicine toxicity with concurrent erythromycin.(4) In a study in 20 subjects, pretreatment with diltiazem (240 mg daily for 7 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by 44.2% (range -46.6% to 318.3%) and by 93.4% (range -30.2% to 338.6%), respectively.(1) In a study in 18 subjects, pretreatment with ritonavir (100 mg twice daily for 5 days) increased the Cmax and AUC of a single dose of colchicine (0.6 mg) by 184.4% (range 79.2% to 447.4%) and by 296% (range 53.8% to 924.4%), respectively.(1) In a study in 24 subjects, pretreatment with verapamil (240 mg twice daily for 7 days) increased the Cmax and AUC of a single dose of colchicine (0.6 mg) by 40.1% (range -47.1% to 149.5%) and by 103.3% (range -9.8% to 217.2%), respectively.(1) Colchicine toxicity has been reported with concurrent use of CYP3A4 inhibitors such as clarithromycin, cyclosporine, diltiazem, erythromycin, and verapamil.(1,2) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, avacopan, clofazimine, conivaptan, crizotinib, duvelisib, fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, sevabertinib, stiripentol, and treosulfan.(1,5,6) |
LODOCO |
| Everolimus/Selected CYP3A4 Inhibitors 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 manufacturer of gepotidacin states that concurrent use of drugs that are extensively metabolized by CYP3A4 and have a narrow therapeutic window like everolimus should be avoided.(3) 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: gepotidacin and sevabertinib. |
AFINITOR, AFINITOR DISPERZ, EVEROLIMUS, TORPENZ, ZORTRESS |
| Cyclosporine/Selected CYP3A4 Inhibitors 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 manufacturer of gepotidacin states that concurrent use of drugs that are extensively metabolized by CYP3A4 and have a narrow therapeutic window like cyclosporine should be avoided.(2) 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.(3) 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.(4) 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: gepotidacin and sevabertinib. |
CYCLOSPORINE, CYCLOSPORINE MODIFIED, GENGRAF, NEORAL, SANDIMMUNE |
| Sevabertinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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) |
ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BRAFTOVI, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTALBITAL, BUTALBITAL-ACETAMINOPHEN, BUTALBITAL-ACETAMINOPHEN-CAFFE, BUTALBITAL-ASPIRIN-CAFFEINE, CEREBYX, DILANTIN, DILANTIN-125, DONNATAL, ERLEADA, FIORICET, FOSPHENYTOIN SODIUM, LYSODREN, MITOTANE, MYSOLINE, ORKAMBI, PENTOBARBITAL SODIUM, PHENOBARBITAL, PHENOBARBITAL SODIUM, PHENOBARBITAL-BELLADONNA, PHENOBARBITAL-HYOSC-ATROP-SCOP, PHENOHYTRO, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED, PRIFTIN, PRIMIDONE, RIFADIN, RIFAMPIN, SEZABY, TENCON, TIBSOVO, XTANDI |
| 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, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(2,3) |
APTIVUS, CLARITHROMYCIN, CLARITHROMYCIN ER, EVOTAZ, GENVOYA, ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KALETRA, KETOCONAZOLE, KISQALI, KORLYM, KRAZATI, LANSOPRAZOL-AMOXICIL-CLARITHRO, LOPINAVIR-RITONAVIR, MIFEPREX, MIFEPRISTONE, NEFAZODONE HCL, NOXAFIL, OMECLAMOX-PAK, PAXLOVID, POSACONAZOLE, PREZCOBIX, RECORLEV, SPORANOX, STRIBILD, SYMTUZA, TOLSURA, TUKYSA, VFEND, VFEND IV, VIRACEPT, VOQUEZNA TRIPLE PAK, VORICONAZOLE, VORICONAZOLE (HPBCD), ZOKINVY, ZYDELIG, ZYKADIA |
| Sevabertinib/Moderate CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. 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, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3) |
AQVESME, AUGTYRO, BOSENTAN, CAMZYOS, EFAVIRENZ, EFAVIRENZ-EMTRIC-TENOFOV DISOP, EFAVIRENZ-LAMIVU-TENOFOV DISOP, ETRAVIRINE, INTELENCE, LORBRENA, LUMAKRAS, MODAFINIL, NAFCILLIN, NAFCILLIN SODIUM, OJEMDA, ORIAHNN, ORILISSA, PROVIGIL, PYRUKYND, RIFABUTIN, SYMFI, TAFINLAR, TALICIA, THIORIDAZINE HCL, THIORIDAZINE HYDROCHLORIDE, TRACLEER, TURALIO, VONJO, WELIREG, XCOPRI, XERMELO |
| Quinidine; Quinine/Selected CYP3A4 Inhibitors 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: sevabertinib.(5,6) |
NUEDEXTA, QUALAQUIN, QUINIDINE GLUCONATE, QUINIDINE SULFATE, QUININE HCL, QUININE SULFATE |
There are 3 moderate interactions.
The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.
| Drug Interaction | Drug Names |
|---|---|
| Tacrolimus/Moderate and Weak CYP3A4 Inhibitors 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: aprepitant, berotralstat, conivaptan, fluvoxamine, lenacapavir, letermovir, netupitant, nirogacestat, sevabertinib, stiripentol, and tofisopam.(6) Weak CYP3A4 inhibitors linked to this monograph include: alprazolam, avacopan, baikal skullcap, berberine, bicalutamide, blueberry, brodalumab, chlorzoxazone, cimetidine, cranberry juice, daclatasvir, daridorexant, delavirdine, diosmin, elinzanetant, estrogens, flibanserin, fosaprepitant, 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, suvorexant, ticagrelor, tolvaptan, trofinetide, viloxazine, and vonoprazan-amoxicillin.(6) |
ASTAGRAF XL, ENVARSUS XR, PROGRAF, TACROLIMUS, TACROLIMUS XL |
| Sirolimus Protein-Bound/Slt Moderate and Weak CYP3A4 Inhibit 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: alprazolam, amlodipine, anamorelin, aprepitant, avacopan, azithromycin, berberine, berotralstat, bicalutamide, blueberry, brodalumab, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clofazimine, conivaptan, daclatasvir, daridorexant, delavirdine, diosmin, elinzanetant, entrectinib, erythromycin, estrogen, flibanserin, fluvoxamine, fosaprepitant, fosnetupitant, fostamatinib, ginkgo, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lazertinib, lenacapavir, levamlodipine, linagliptin, lomitapide, lumateperone, lurasidone, mavorixafor, netupitant, omeprazole, osilodrostat, peppermint oil, piperine, propiverine, propofol, ranitidine, ranolazine, resveratrol, rimegepant, roxithromycin, scutellarin, sevabertinib, simeprevir, sitaxsentan, stiripentol, suvorexant, ticagrelor, tofisopam, tolvaptan, trofinetide, and vonoprazan.(3,4) |
FYARRO |
| Fentanyl/Selected CYP3A4 Inhibitors 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: gepotidacin and sevabertinib.(2-3) |
FENTANYL, FENTANYL CITRATE, FENTANYL CITRATE-0.9% NACL, FENTANYL CITRATE-D5W, FENTANYL CITRATE-STERILE WATER, FENTANYL CITRATE-WATER, FENTANYL-BUPIVACAINE-0.9% NACL, FENTANYL-BUPIVACAINE-NACL, FENTANYL-ROPIVACAINE-0.9% NACL |
The following contraindication information is available for HYRNUO (sevabertinib):
Drug contraindication overview.
None.
None.
There are 1 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Lactation |
There are 1 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Pregnancy |
There are 0 moderate contraindications.
The following adverse reaction information is available for HYRNUO (sevabertinib):
Adverse reaction overview.
* Most common adverse reactions (>20%): diarrhea, rash, paronychia, stomatitis, and nausea. * Most common Grade 3 or 4 laboratory abnormalities (>=2%): decreased potassium, increased lipase, decreased lymphocyte count, decreased sodium, increased amylase, increased ALT, and increased AST.
* Most common adverse reactions (>20%): diarrhea, rash, paronychia, stomatitis, and nausea. * Most common Grade 3 or 4 laboratory abnormalities (>=2%): decreased potassium, increased lipase, decreased lymphocyte count, decreased sodium, increased amylase, increased ALT, and increased AST.
There are 11 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Diarrhea Elevated serum lipase Hypokalemia |
Cardiac arrhythmia Pleural effusions Pneumonia Sinus tachycardia Supraventricular premature beats |
| Rare/Very Rare |
|---|
|
Epithelial keratopathy Interstitial lung disease Prolonged QT interval |
There are 30 less severe adverse reactions.
| More Frequent | Less 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 |
Alopecia Edema |
| Rare/Very Rare |
|---|
| None. |
The following precautions are available for HYRNUO (sevabertinib):
The safety and effectiveness of sevabertinib have not been established in pediatric patients.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
Based on findings from animal studies and its mechanism of action, sevabertinib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of sevabertinib in pregnant women to inform a drug-associated risk. In embryo-fetal development studies, oral administration of sevabertinib to pregnant rats during the period of organogenesis resulted in alterations to growth at maternal exposures >=0.18
times the human exposure based on AUC at the clinical dose of 20 mg twice daily. Animal studies with disrupted or depleted HER2/EGFR and in vitro assays have demonstrated that inhibition of HER2 and/or EGFR results in structural abnormalities, alteration to growth, and embryo-fetal and infant mortality. Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
times the human exposure based on AUC at the clinical dose of 20 mg twice daily. Animal studies with disrupted or depleted HER2/EGFR and in vitro assays have demonstrated that inhibition of HER2 and/or EGFR results in structural abnormalities, alteration to growth, and embryo-fetal and infant mortality. Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
There are no data on the presence of sevabertinib or its metabolites in human milk or their effects on a breastfed child or on milk production. In rats, sevabertinib or its metabolites are excreted in milk. Because of the potential for serious adverse reactions in breastfed children from sevabertinib, advise women not to breastfeed during treatment with sevabertinib and for 1 week after the last dose.
Of the 268 patients with locally advanced or metastatic NSCLC harboring HER2 activating mutations who received sevabertinib at 20 mg twice daily in the SOHO-01 study, 43% were 65 years of age and older and 13% were 75 years of age and older. No overall differences in effectiveness were observed between these older and younger patients. Grade 3 diarrhea was observed in 23% of patients >=75 years of age and 14% of patients <75 years of age.
The following prioritized warning is available for HYRNUO (sevabertinib):
No warning message for this drug.
No warning message for this drug.
The following icd codes are available for HYRNUO (sevabertinib)'s list of indications:
| HEr2 (+) non-squamous NSCLC with ERBb2 | |
| C34 | Malignant neoplasm of bronchus and lung |
| C34.0 | Malignant neoplasm of main bronchus |
| C34.00 | Malignant neoplasm of unspecified main bronchus |
| C34.01 | Malignant neoplasm of right main bronchus |
| C34.02 | Malignant neoplasm of left main bronchus |
| C34.1 | Malignant neoplasm of upper lobe, bronchus or lung |
| C34.10 | Malignant neoplasm of upper lobe, unspecified bronchus or lung |
| C34.11 | Malignant neoplasm of upper lobe, right bronchus or lung |
| C34.12 | Malignant neoplasm of upper lobe, left bronchus or lung |
| C34.2 | Malignant neoplasm of middle lobe, bronchus or lung |
| C34.3 | Malignant neoplasm of lower lobe, bronchus or lung |
| C34.30 | Malignant neoplasm of lower lobe, unspecified bronchus or lung |
| C34.31 | Malignant neoplasm of lower lobe, right bronchus or lung |
| C34.32 | Malignant neoplasm of lower lobe, left bronchus or lung |
| C34.8 | Malignant neoplasm of overlapping sites of bronchus and lung |
| C34.80 | Malignant neoplasm of overlapping sites of unspecified bronchus and lung |
| C34.81 | Malignant neoplasm of overlapping sites of right bronchus and lung |
| C34.82 | Malignant neoplasm of overlapping sites of left bronchus and lung |
| C34.9 | Malignant neoplasm of unspecified part of bronchus or lung |
| C34.90 | Malignant neoplasm of unspecified part of unspecified bronchus or lung |
| C34.91 | Malignant neoplasm of unspecified part of right bronchus or lung |
| C34.92 | Malignant neoplasm of unspecified part of left bronchus or lung |
| C39.9 | Malignant neoplasm of lower respiratory tract, part unspecified |
Formulary Reference Tool