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Drug overview for COMETRIQ (cabozantinib s-malate):
Generic name: CABOZANTINIB S-MALATE (KA-boe-ZAN-ti-nib)
Drug class: Antineoplastic - Protein-Tyrosine Kinase Inhibitors
Therapeutic class: Antineoplastics
Cabozantinib S-malate, an inhibitor of multiple receptor tyrosine kinases, is an antineoplastic agent.
No enhanced Uses information available for this drug.
Generic name: CABOZANTINIB S-MALATE (KA-boe-ZAN-ti-nib)
Drug class: Antineoplastic - Protein-Tyrosine Kinase Inhibitors
Therapeutic class: Antineoplastics
Cabozantinib S-malate, an inhibitor of multiple receptor tyrosine kinases, is an antineoplastic agent.
No enhanced Uses information available for this drug.
DRUG IMAGES
COMETRIQ 140 MG DAILY-DOSE PK
COMETRIQ 60 MG DAILY-DOSE PACK
The following indications for COMETRIQ (cabozantinib s-malate) have been approved by the FDA:
Indications:
Medullary thyroid carcinoma
Professional Synonyms:
None.
Indications:
Medullary thyroid carcinoma
Professional Synonyms:
None.
The following dosing information is available for COMETRIQ (cabozantinib s-malate):
Dosage of cabozantinib, which is commercially available as cabozantinib S-malate, is expressed in terms of cabozantinib.
Cometriq(R) capsules and Cabometyx(R) tablets are not interchangeable.
Cometriq(R) capsules and Cabometyx(R) tablets are not interchangeable.
Cabozantinib S-malate is administered orally as capsules (Cometriq(R)) or tablets (Cabometyx(R)). Cometriq(R) capsules: Cabozantinib S-malate is administered orally once daily. The drug should not be administered with food; patients should not eat for at least 2 hours before and at least 1 hour after taking cabozantinib capsules.
Cabozantinib capsules should be swallowed whole with a full glass (at least 240 mL) of water; the capsules should not be opened or crushed. Cabometyx(R) tablets: Cabozantinib S-malate is administered orally once daily. The drug should not be administered with food; patients should take cabozantinib tablets at least 1 hour before or at least 2 hours after eating.
Cabozantinib tablets should be swallowed whole; the tablets should not be crushed. If a dose of cabozantinib is missed, the missed dose should not be taken within 12 hours of the next dose. Store cabozantinib capsules (Cometriq(R)) or tablets (Cabometyx(R)) at 20-25degreesC; excursions are permitted from 15-30degreesC.
Cabozantinib capsules should be swallowed whole with a full glass (at least 240 mL) of water; the capsules should not be opened or crushed. Cabometyx(R) tablets: Cabozantinib S-malate is administered orally once daily. The drug should not be administered with food; patients should take cabozantinib tablets at least 1 hour before or at least 2 hours after eating.
Cabozantinib tablets should be swallowed whole; the tablets should not be crushed. If a dose of cabozantinib is missed, the missed dose should not be taken within 12 hours of the next dose. Store cabozantinib capsules (Cometriq(R)) or tablets (Cabometyx(R)) at 20-25degreesC; excursions are permitted from 15-30degreesC.
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| COMETRIQ 60 MG DAILY-DOSE PACK | Maintenance | Adults take 3 capsules (60 mg) by oral route once daily on an empty stomach |
No generic dosing information available.
The following drug interaction information is available for COMETRIQ (cabozantinib s-malate):
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 |
|---|---|
| Live Vaccines; Live BCG/Selected Immunosuppressive Agents SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: A variety of disease modifying agents suppress the immune system. Immunocompromised patients may be at increased risk for uninhibited replication after administration of live, attenuated vaccines or intravesicular BCG. Immune response to vaccines may be decreased during periods of immunocompromise.(1) CLINICAL EFFECTS: The expected serum antibody response may not be obtained and/or the vaccine may result in illness.(1) After instillation of intravesicular BCG, immunosuppression may interfere with local immune response, or increase the severity of mycobacterial infection following inadvertent systemic exposure.(2) PREDISPOSING FACTORS: Immunosuppressive diseases (e.g. hematologic malignancies, HIV disease), treatments (e.g. radiation) and drugs may all increase the magnitude of immunodeficiency. PATIENT MANAGEMENT: The Centers for Disease Control(CDC) Advisory Committee on Immunization Practices (ACIP) states that live-virus and live, attenuated vaccines should not be administered to patients who are immunocompromised. The magnitude of immunocompromise and associated risks should be determined by a physician.(1) For patients scheduled to receive chemotherapy, vaccination should ideally precede the initiation of chemotherapy by 14 days. Patients vaccinated while on immunosuppressive therapy or in the 2 weeks prior to starting therapy should be considered unimmunized and should be revaccinated at least 3 months after discontinuation of therapy.(1) Patients who receive anti-B cell therapies should not receive live vaccines for at least 6 months after such therapies due to a prolonged duration of immunosuppression. An exception is the Zoster vaccine, which can be given at least 1 month after receipt of anti-B cell therapies.(1) The US manufacturer of abatacept states live vaccines should not be given during or for up to 3 months after discontinuation of abatacept.(2) The US manufacturer of live BCG for intravesicular treatment of bladder cancer states use is contraindicated in immunosuppressed patients.(3) The US manufacturer of daclizumab states live vaccines are not recommended during and for up to 4 months after discontinuation of treatment.(4) The US manufacturer of guselkumab states that live vaccines should be avoided during treatment with guselkumab.(5) The US manufacturer of inebilizumab-cdon states that live vaccines are not recommended during treatment and after discontinuation until B-cell repletion. Administer all live vaccinations at least 4 weeks prior to initiation of inebilizumab-cdon.(6) The US manufacturer of ocrelizumab states that live vaccines are not recommended during treatment and until B-cell repletion occurs after discontinuation of therapy. Administer all live vaccines at least 4 weeks prior to initiation of ocrelizumab.(7) The US manufacturer of ozanimod states that live vaccines should be avoided during and for up to 3 months after discontinuation of ozanimod.(8) The US manufacturer of siponimod states that live vaccines are not recommended during treatment and for up to 4 weeks after discontinuation of treatment.(9) The US manufacturer of ustekinumab states BCG vaccines should not be given in the year prior to, during, or the year after ustekinumab therapy.(10) The US manufacturer of satralizumab-mwge states that live vaccines are not recommended during treatment and should be administered at least four weeks prior to initiation of satralizumab-mwge.(11) The US manufacturer of ublituximab-xiiy states that live vaccines are not recommended during treatment and until B-cell recovery. Live vaccines should be administered at least 4 weeks prior to initiation of ublituximab-xiiy.(12) The US manufacturer of etrasimod states that live vaccines should be avoided during and for 5 weeks after treatment. Live vaccines should be administered at least 4 weeks prior to initiation of etrasimod.(13) The US manufacturer of emapalumab-lzsg states that live vaccines should not be administered to patients receiving emapalumab-lzsg and for at least 4 weeks after the last dose of emapalumab-lzsg. The safety of immunization with live vaccines during or following emapalumab-lzsg therapy has not been studied.(14) DISCUSSION: Killed or inactivated vaccines do not pose a danger to immunocompromised patients.(1) Patients with a history of leukemia who are in remission and have not received chemotherapy for at least 3 months are not considered to be immunocompromised.(1) |
ACAM2000 (NATIONAL STOCKPILE), ADENOVIRUS TYPE 4, ADENOVIRUS TYPE 4 AND TYPE 7, ADENOVIRUS TYPE 7, BCG (TICE STRAIN), BCG VACCINE (TICE STRAIN), DENGVAXIA, ERVEBO (NATIONAL STOCKPILE), FLUMIST TRIVALENT 2024-2025, IXCHIQ, M-M-R II VACCINE, PRIORIX, PROQUAD, ROTARIX, ROTATEQ, STAMARIL, VARIVAX VACCINE, VAXCHORA ACTIVE COMPONENT, VAXCHORA VACCINE, VIVOTIF, YF-VAX |
There are 7 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 |
|---|---|
| Selected Antineoplastic Systemic Enzyme Inhibitors/Rifabutin SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Rifabutin is a moderate inducer of the CYP3A4 isoenzyme and may increase the metabolism of some antineoplastic systemic enzyme inhibitors, including cabozantinib,(1,2) ceritinib,(3) erlotinib,(4) imatinib,(5) lapatinib,(6) and sorafenib.(7) CLINICAL EFFECTS: Concurrent use of rifabutin may decrease the levels and effectiveness of some antineoplastic systemic enzyme inhibitors, including cabozantinib,(1,2) ceritinib,(3) erlotinib,(4) imatinib,(5) lapatinib,(6) and sorafenib.(7) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid the concurrent use of rifabutin in patients receiving therapy with cabozantinib,(1,2) ceritinib,(3) erlotinib,(4) imatinib,(5) lapatinib,(6) and sorafenib.(7) Consider the use of alternative agents with less enzyme induction potential.(1-7) If concurrent use of rifabutin cannot be avoided: Increase the daily dose of cabozantinib TABlets by 20 mg (e.g. from 60 mg to 80 mg daily) as tolerated. The daily dose should not exceed 80 mg. Resume the dose that was used prior to initiating rifabutin 2 to 3 days after discontinuation of rifabutin.(1) Increase the daily dose of cabozantinib CAPsules by 40 mg (from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. The daily dose of cabozantinib should not exceed 180 mg. If rifabutin is discontinued, reduce the dosage of cabozantinib to the dose used prior to initiation of rifabutin 2 to 3 days after discontinuation of rifabutin.(2) Consider increasing the dosage of erlotinib by 50 mg increments as tolerated at two week intervals (to a maximum of 450 mg) while closely monitoring the patient. The highest dosage studied with concurrent rifampin is 450 mg. If the dosage of erlotinib is increased, it will need to be decreased when rifabutin is discontinued.(4) 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.(5) The dose of lapatinib should be gradually titrated from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer indication) or from 1,500 mg/day up to 5,500 mg/day (hormone receptor positive, HER2 positive breast cancer indication) based on patient tolerability. If rifabutin is discontinued, the dose of lapatinib should be adjusted to the normal dose.(6) DISCUSSION: The US manufacturers of cabozantinib,(2) erlotinib,(4) imatinib,(5) lapatinib,(6) and sorafenib,(7) and the UK manufacturer of ceritinib(3) include rifabutin in their list of strong CYP3A4 inducers to be avoided. Although the combinations of these agents with rifabutin have not been studied, they have been studied with other strong CYP3A4 inducers. In a study in healthy subjects, rifampin (600 mg daily for 31 days) decreased the area-under-curve (AUC) of a single dose of cabozantinib by 77%.(1) In a study in 19 healthy subjects, rifampin (600 mg daily for 14 days) decreased the maximum concentration (Cmax) and AUC of a single dose of ceritinib by 44% and 70%, respectively.(3) Pretreatment and concurrent therapy with rifampin increased erlotinib clearance by 3-fold and decreased the erlotinib AUC by 66% to 80%. This is equivalent to a dose of about 30 mg to 50 mg in NSCLC.(4) In a study, pretreatment with rifampin for 11 days decreased the AUC of a single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single 150 mg dose of erlotinib.(4) In a case report, coadministration of phenytoin (180mg daily) and erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from 1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold (from 3.53 L/h to 41.7 L/h).(8) 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 AUC and Cmax decreased by 74% and 54%, respectively.(5,9) The Cmax of the CGP74588 metabolite increased by 88.6%, but the AUC of CGP74588 decreased by 11%.(9) In healthy subjects, carbamazepine (100 mg twice daily for 3 days and 200 mg twice daily for 17 days), another CYP3A4 inducer, decreased the AUC of lapatinib by 72%. The dose adjustment recommendations are based on pharmacokinetic studies and are predicted to adjust lapatinib AUC to the range observed without concurrent CYP3A4 inducers; however, there are no clinical data with these doses in patients receiving strong CYP3A4 inducers.(6) Concurrent rifampin (600 mg daily for 5 days) decreased the AUC of a single dose of sorafenib (400 mg) by 37%.(7) |
RIFABUTIN, TALICIA |
| Cabozantinib/Strong CYP3A4 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of cabozantinib.(1,2) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from cabozantinib, including hemorrhage, thrombotic events, hypertension and hypertensive crisis, diarrhea, proteinuria, or osteonecrosis of the jaw.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with cabozantinib.(1,2) Consider alternatives with no or minimal enzyme inhibition. Dosage adjustments are specific to the formulation of cabozantinib prescribed.(1,2) If concurrent use of cabozantinib TABlets are warranted, reduce the daily dose of cabozantinib TABlets by 20 mg (e.g. from 60 mg to 40 mg daily, or from 40 mg to 20 mg daily).(1) If concurrent use of cabozantinib CAPsules are warranted, the dose of cabozantinib CAPsules should be reduced by 40 mg (e.g. from 140 mg to 100 mg daily or from 100 mg to 60 mg daily).(2) When the CYP3A4 inhibitor has been discontinued, resume the dose of cabozantinib that was used previously 2-3 days after discontinuation of the inhibitor.(1,2) DISCUSSION: In a study in healthy subjects, ketoconazole (400 mg daily for 27 days) increased the area-under-curve (AUC) of a single dose of cabozantinib by 38%.(3,4) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, or 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, TYBOST, VFEND, VFEND IV, VIRACEPT, VOQUEZNA TRIPLE PAK, VORICONAZOLE, ZOKINVY, ZYDELIG, ZYKADIA |
| Antineoplastic Systemic Enzyme Inhibitors/Carbamazepine SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Agents that induce the CYP3A4 isoenzyme, such as carbamazepine, may induce the metabolism of antineoplastic systemic enzyme inhibitors, including bosutinib,(1) cabozantinib,(2,3) dasatinib,(4) erlotinib,(5) gefitinib,(6) ibrutinib,(7) lapatinib,(8) pazopanib,(9) sorafenib,(10) sunitinib,(11) and vandetanib.(12) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may decrease the levels and effectiveness of antineoplastic systemic enzyme inhibitors, including bosutinib,(1) cabozantinib,(2,3) dasatinib,(4) erlotinib,(5) gefitinib,(6) ibrutinib,(7) lapatinib,(8) pazopanib,(9) sorafenib,(10) sunitinib,(11) and vandetanib.(12) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP3A4 inducers in patients receiving therapy with antineoplastic enzyme inhibitors. Consider the use of alternative agents with less enzyme induction potential.(1-12) Pazopanib should not be administered to patients who cannot avoid chronic use of strong CYP3A4 inducers.(8) If concurrent use of a CYP3A4 inducer cannot be avoided with other antineoplastic enzyme inhibitors: Increase the daily dose of cabozantinib TABlets by 20 mg (e.g. from 60 mg to 80 mg daily) as tolerated. The daily dose should not exceed 80 mg. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer.(2) Increase the daily dose of cabozantinib CAPsules by 40 mg (from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. The daily dose of cabozantinib should not exceed 180 mg. If the CYP3A4 inducer is discontinued, reduce the dosage of cabozantinib to the dose used prior to initiation of the inducer 2 to 3 days after discontinuation of the strong inducer.(3) Consider increasing the dose of dasatinib.(4) Consider increasing the dosage of erlotinib by 50 mg increments as tolerated at two week intervals (to a maximum of 450 mg) while closely monitoring the patient. The highest dosage studied with concurrent rifampin is 450 mg. If the dosage of erlotinib is increased, it will need to be decreased when the inducer is discontinued. If the inducer is dexamethasone, monitor the patient for sign of gastrointestinal perforation. Discontinue erlotinib in patients who develop gastrointestinal perforation.(5) Consider a dose increase to 500 mg daily of gefitinib in the absence of severe adverse drug reaction. Clinical response and adverse events should be closely monitored.(6) The dose of lapatinib should be gradually titrated from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer indication) or from 1,500 mg/day up to 5,500 mg/day (hormone receptor positive, HER2 positive breast cancer indication) based on patient tolerability. If the inducer is discontinued, the dose of lapatinib should be adjusted to the normal dose.(8) A dosage increase of sunitinib to a maximum of 87.5 mg daily in patients with gastrointestinal stromal tumors (GIST) or advanced renal cell carcinoma (RCC) or to a maximum of 62.5 mg in patients with pancreatic neuroendocrine tumors (pNET) should be considered.(11) DISCUSSION: In a study in 24 healthy subjects, rifampin (a strong CYP3A4 inducer) decreased bosutinib area-under-curve (AUC) and maximum concentration (Cmax) by 94% and 86%. Bosutinib clearance increased by 13-fold.(1,14) In a study in healthy subjects, rifampin (600 mg daily for 31 days) decreased the AUC of a single dose of cabozantinib by 77%.(2) In a study in healthy subjects, concurrent rifampin (600 mg daily) decreased the Cmax and AUC of a single dose of dasatinib by 81% and 82%, respectively.(4) Pretreatment and concurrent therapy with rifampin increased erlotinib clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by 66% to 80%. This is equivalent to a dose of about 30 mg to 50 mg in NSCLC.(5) In a study, pretreatment with rifampin for 11 days decreased the AUC of a single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single 150 mg dose of erlotinib.(5) In a case report, coadministration of phenytoin (180mg daily) and erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from 1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold (from 3.53 L/h to 41.7 L/h).(14) In a study in healthy male volunteers, rifampicin decreased AUC of gefitinib by 85%.(6) The coadministration of rifampin decreased the Cmax and AUC of ibrutinib by more than 13-fold and 10-fold.(7) In healthy subjects, carbamazepine (100 mg twice daily for 3 days and 200 mg twice daily for 17 days), another CYP3A4 inducer, decreased the AUC of lapatinib by 72%. The dose adjustment recommendations are based on pharmacokinetic studies and are predicted to adjust lapatinib AUC to the range observed without concurrent CYP3A4 inducers; however, there are no clinical data with these doses in patients receiving strong CYP3A4 inducers.(8) Pazopanib is primarily metabolized by CYP3A4.(9) Concurrent rifampin (600 mg daily for 5 days) decreased the AUC of a single dose of sorafenib (400 mg) by 37%.(10) In a study with healthy subjects, concurrent rifampin decreased the combined (sunitinib plus primary active metabolite) Cmax and AUC by 23% and 46%, respectively, of a single dose of sunitinib.(11) Strong CYP3A4 inducers are expected to alter vandetanib concentrations. The patient developed nystagmus, a sign of phenytoin toxicity.(12) |
CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, EPITOL, EQUETRO, TEGRETOL, TEGRETOL XR |
| Antineoplastic Systemic Enzyme Inhibitors/Apalutamide SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Apalutamide(1) may induce the metabolism of antineoplastic systemic enzyme inhibitors, including bosutinib,(2) cabozantinib,(3) erlotinib,(4) gefitinib,(5) ibrutinib,(6) idelalisib,(7) and imatinib.(8) CLINICAL EFFECTS: Concurrent use of apalutamide may decrease the levels and effectiveness of antineoplastic systemic enzyme inhibitors, including bosutinib,(2) cabozantinib,(3) erlotinib,(4) gefitinib,(5) ibrutinib,(6) idelalisib,(7) and imatinib.(8) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid the concurrent use of apalutamide in patients receiving therapy with antineoplastic enzyme inhibitors. Consider the use of alternative agents with less enzyme induction potential.(1-8) If concurrent use of apalutamide cannot be avoided with antineoplastic enzyme inhibitors: Increase the daily dose of cabozantinib TABlets by 20 mg (e.g. from 60 mg to 80 mg daily) as tolerated. The daily dose should not exceed 80 mg. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer.(9) Increase the daily dose of cabozantinib CAPsules by 40 mg (from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. The daily dose of cabozantinib should not exceed 180 mg. If the CYP3A4 inducer is discontinued, reduce the dosage of cabozantinib to the dose used prior to initiation of the inducer 2 to 3 days after discontinuation of the strong inducer.(3) Consider increasing the dosage of erlotinib by 50 mg increments as tolerated at two week intervals (to a maximum of 450 mg) while closely monitoring the patient. The highest dosage studied with concurrent rifampin is 450 mg. If the dosage of erlotinib is increased, it will need to be decreased when the inducer is discontinued.(4) Consider a dose increase to 500 mg daily of gefitinib in the absence of severe adverse drug reaction. Clinical response and adverse events should be closely monitored.(5) The dose of imatinib should be increased by at least 50% and clinical response should be carefully monitored. Dosages up to 1200 mg/day (600 mg twice daily) have been used in patients receiving concurrent therapy with strong CYP3A4 inducers.(8) DISCUSSION: In a study in 24 healthy subjects, rifampin (a strong CYP3A4 inducer) decreased bosutinib area-under-curve (AUC) and maximum concentration (Cmax) by 94% and 86%. Bosutinib clearance increased by 13-fold.(2,11) In a study in healthy subjects, rifampin (600 mg daily for 31 days) decreased the AUC of a single dose of cabozantinib by 77%.(3) Pretreatment and concurrent therapy with rifampin increased erlotinib clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by 66% to 80%. This is equivalent to a dose of about 30 mg to 50 mg in NSCLC.(4) In a study, pretreatment with rifampin for 11 days decreased the AUC of a single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single 150 mg dose of erlotinib.(4) In a case report, coadministration of phenytoin (180mg daily) and erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from 1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold (from 3.53 L/h to 41.7 L/h).(10) In a study in healthy male volunteers, rifampicin decreased AUC of gefitinib by 85%.(5) The coadministration of rifampin decreased the Cmax and AUC of ibrutinib by more than 13-fold and 10-fold.(6) 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.(7) 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.(8,12) The Cmax of the CGP74588 metabolite increased by 88.6%, but the AUC of CGP74588 decreased by 11%.(12) |
ERLEADA |
| Slt Antineoplastic Systemic Enzyme Inh/Lumacaftor-Ivacaftor SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Lumacaftor-ivacaftor(1) may induce the metabolism of antineoplastic systemic enzyme inhibitors, including bosutinib,(2) cabozantinib,(3) crizotinib,(4) dasatinib,(5) erlotinib,(6) gefitinib,(7) ibrutinib,(8) imatinib,(9) lapatinib,(10) nilotinib,(11) pazopanib,(12) sorafenib,(13) sunitinib,(14) and vandetanib.(15) CLINICAL EFFECTS: Concurrent use of lumacaftor-ivacaftor may decrease the levels and effectiveness of antineoplastic systemic enzyme inhibitors, including bosutinib,(2) cabozantinib,(3) crizotinib,(4) dasatinib,(5) erlotinib,(6) gefitinib,(7) ibrutinib,(8) imatinib,(9) lapatinib,(10) nilotinib,(11) pazopanib,(12) sorafenib,(13) sunitinib,(14) and vandetanib.(15) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid the concurrent use of lumacaftor-ivacaftor in patients receiving therapy with antineoplastic enzyme inhibitors. Consider the use of alternative agents with less enzyme induction potential.(2-15) Because of the nonlinear pharmacokinetic profile of nilotinib, increasing its dose is unlikely to compensate for enzyme induction.(11) Pazopanib should not be administered to patients who cannot avoid chronic use of strong CYP3A4 inducers.(12) If concurrent use of a CYP3A4 inducer cannot be avoided with other antineoplastic enzyme inhibitors: Increase the daily dose of cabozantinib TABlets by 20 mg (e.g. from 60 mg to 80 mg daily) as tolerated. The daily dose should not exceed 80 mg. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer.(16) Increase the daily dose of cabozantinib CAPsules by 40 mg (from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. The daily dose of cabozantinib should not exceed 180 mg. If the CYP3A4 inducer is discontinued, reduce the dosage of cabozantinib to the dose used prior to initiation of the inducer 2 to 3 days after discontinuation of the strong inducer.(2) Consider increasing the dose of dasatinib.(5) Consider increasing the dosage of erlotinib by 50 mg increments as tolerated at two week intervals (to a maximum of 450 mg) while closely monitoring the patient. The highest dosage studied with concurrent rifampin is 450 mg. If the dosage of erlotinib is increased, it will need to be decreased when the inducer is discontinued. If the inducer is dexamethasone, monitor the patient for sign of gastrointestinal perforation. Discontinue erlotinib in patients who develop gastrointestinal perforation.(6) Consider a dose increase to 500 mg daily of gefitinib in the absence of severe adverse drug reaction. Clinical response and adverse events should be closely monitored.(7) The dose of imatinib should be increased by at least 50% and clinical response should be carefully monitored. Dosages up to 1200 mg/day (600 mg twice daily) have been used in patients receiving concurrent therapy with strong CYP3A4 inducers.(9) The dose of lapatinib should be gradually titrated from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer indication) or from 1,500 mg/day up to 5,500 mg/day (hormone receptor positive, HER2 positive breast cancer indication) based on patient tolerability. If the inducer is discontinued, the dose of lapatinib should be adjusted to the normal dose.(10) A dosage increase of sunitinib to a maximum of 87.5 mg daily in patients with gastrointestinal stromal tumors (GIST) or advanced renal cell carcinoma (RCC) or to a maximum of 62.5 mg in patients with pancreatic neuroendocrine tumors (pNET) should be considered.(14) DISCUSSION: In a study, 24 healthy subjects received a single dose of bosutinib 500 mg (days 1 and 14) and rifampin 600 mg (days 8-17). Bosutinib Cmax and AUC decreased by 86% and 92%, respectively. Bosutinib clearance increased by 13-fold.(2,17) In a study in healthy subjects, rifampin (600 mg daily for 31 days) decreased the AUC of a single dose of cabozantinib by 77%.(3) Rifampin (600 mg daily) decreased the Cmax and AUC of a single dose of crizotinib (250 mg) by 69% and 82%, respectively.(4) In a study in healthy subjects, concurrent rifampin (600 mg daily) decreased the Cmax and AUC of a single dose of dasatinib by 81% and 82%, respectively.(5) Pretreatment and concurrent therapy with rifampin increased erlotinib clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by 66% to 80%. This is equivalent to a dose of about 30 mg to 50 mg in NSCLC.(6) In a study, pretreatment with rifampin for 11 days decreased the AUC of a single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single 150 mg dose of erlotinib.(6) In a case report, coadministration of phenytoin (180mg daily) and erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from 1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold (from 3.53 L/h to 41.7 L/h).(18) In a study in healthy male volunteers, rifampicin decreased AUC of gefitinib by 85%.(7) The coadministration of rifampin decreased the Cmax and AUC of ibrutinib by more than 13-fold and 10-fold.(8) 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.(9,19) The Cmax of the CGP74588 metabolite increased by 88.6%, but the AUC of CGP74588 decreased by 11%.(19) In healthy subjects, carbamazepine (100 mg twice daily for 3 days and 200 mg twice daily for 17 days), another CYP3A4 inducer, decreased the AUC of lapatinib by 72%. The dose adjustment recommendations are based on pharmacokinetic studies and are predicted to adjust lapatinib AUC to the range observed without concurrent CYP3A4 inducers; however, there are no clinical data with these doses in patients receiving strong CYP3A4 inducers.(10) In a study in healthy subjects, concurrent rifampin (600 mg daily for 12 days) decreased nilotinib AUC by 80%.(11) Pazopanib is primarily metabolized by CYP3A4.(12) Concurrent rifampin (600 mg daily for 5 days) decreased the AUC of a single dose of sorafenib (400 mg) by 37%.(13) In a study with healthy subjects, concurrent rifampin decreased the combined (sunitinib plus primary active metabolite) Cmax and AUC by 23% and 46%, respectively, of a single dose of sunitinib.(14) Strong CYP3A4 inducers are expected to alter vandetanib concentrations. The patient developed nystagmus, a sign of phenytoin toxicity.(15) |
ORKAMBI |
| Sodium Iodide I 131/Myelosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1) CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1) DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1) |
HICON, SODIUM IODIDE I-131 |
| Cabozantinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of cabozantinib.(1,2) CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of cabozantinib.(1,2) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP3A4 inducers in patients receiving therapy with cabozantinib. Consider the use of alternative agents with less enzyme induction potential.(1,2) If concurrent use of a CYP3A4 inducer cannot be avoided, increase the daily dose of cabozantinib TABlets by 20 mg (e.g. from 60 mg to 80 mg daily) as tolerated. The daily dose should not exceed 80 mg. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer.(1) Increase the daily dose of cabozantinib CAPsules by 40 mg (from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. The daily dose of cabozantinib should not exceed 180 mg. If the CYP3A4 inducer is discontinued, reduce the dosage of cabozantinib to the dose used prior to initiation of the inducer 2 to 3 days after discontinuation of the strong inducer.(2) DISCUSSION: In a study in healthy subjects, rifampin (600 mg daily for 31 days) decreased the AUC of a single dose of cabozantinib by 77%.(1,2) Strong inducers of CYP3A4 include: barbiturates, encorafenib, enzalutamide, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(3,4) |
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, FIORICET, FIORICET WITH CODEINE, FOSPHENYTOIN SODIUM, LYSODREN, MITOTANE, MYSOLINE, 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 |
There are 0 moderate interactions.
The following contraindication information is available for COMETRIQ (cabozantinib s-malate):
Drug contraindication overview.
None.
None.
There are 9 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Acute arterial thromboembolism |
| Arterial aneurysm |
| Arterial dissection |
| Child-pugh class C hepatic impairment |
| Gastrointestinal hemorrhage |
| Hemoptysis |
| Lactation |
| Severe uncontrolled hypertension |
| Thrombocytopenic disorder |
There are 17 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Child-pugh class A hepatic impairment |
| Child-pugh class B hepatic impairment |
| Disease of liver |
| Gastrointestinal fistula |
| Gastrointestinal perforation |
| Hemorrhage |
| Hypertension |
| Hypocalcemia |
| Impaired wound healing |
| Invasive dental procedure |
| Neutropenic disorder |
| Pregnancy |
| Stomatitis |
| Surgical wound dehiscence |
| Thromboembolic disorder |
| Tracheoesophageal fistula |
| Venous thrombosis |
There are 2 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Hypothyroidism |
| Proteinuria |
The following adverse reaction information is available for COMETRIQ (cabozantinib s-malate):
Adverse reaction overview.
Adverse effects reported in >=25% of patients receiving cabozantinib capsules (Cometriq(R)) include diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), weight loss, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. Laboratory abnormalities reported in >=25% of patients receiving cabozantinib capsules (Cometriq(R)) include increased AST concentrations, increased ALT concentrations, lymphopenia, increased alkaline phosphatase concentrations, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Adverse effects reported in >=20% of patients receiving cabozantinib tablets (Cabometyx(R)) as a single-agent: Diarrhea, fatigue, palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), decreased appetite, hypertension, nausea, vomiting, weight decreased, and constipation. Adverse effects reported in >=20% of patients receiving cabozantinib tablets (Cabometyx(R)) in combination with nivolumab: Diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.
Adverse effects reported in >=25% of patients receiving cabozantinib capsules (Cometriq(R)) include diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), weight loss, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. Laboratory abnormalities reported in >=25% of patients receiving cabozantinib capsules (Cometriq(R)) include increased AST concentrations, increased ALT concentrations, lymphopenia, increased alkaline phosphatase concentrations, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Adverse effects reported in >=20% of patients receiving cabozantinib tablets (Cabometyx(R)) as a single-agent: Diarrhea, fatigue, palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), decreased appetite, hypertension, nausea, vomiting, weight decreased, and constipation. Adverse effects reported in >=20% of patients receiving cabozantinib tablets (Cabometyx(R)) in combination with nivolumab: Diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome), stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.
There are 35 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Abnormal hepatic function tests Hyperbilirubinemia Hypocalcemia Hypophosphatemia Increased alanine transaminase Increased aspartate transaminase Lymphopenia Neutropenic disorder Palmar-plantar erythrodysesthesia Thrombocytopenic disorder |
Abscess Anemia Arterial thrombosis Aseptic necrosis of jaw bone Gastrointestinal fistula Gastrointestinal hemorrhage Gastrointestinal perforation Hemoptysis Hemorrhage Hypokalemia Hyponatremia Hypothyroidism Impaired wound healing Pneumonia Tracheoesophageal fistula Venous thrombosis |
| Rare/Very Rare |
|---|
|
Aortic aneurysm Arterial aneurysm Arterial dissection Cerebrovascular accident Cholestatic hepatitis Hypertensive crisis Nephrotic syndrome Pancreatitis Posterior reversible encephalopathy syndrome |
There are 45 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Acute abdominal pain Anorexia Constipation Diarrhea Dizziness Dysgeusia Fatigue General weakness Hair discoloration Headache disorder Hypertension Nausea Stomatitis Upper respiratory infection Voice change Vomiting Weight loss |
Alopecia Arthralgia Back pain Bone pain Cough Depression Dry skin Dyspepsia Dysphagia Dyspnea Elevated serum amylase Elevated serum lipase Erythema Folliculitis Fungal infection Hemorrhoids Hypoalbuminemia Hypomagnesemia Hypotension Muscle spasm Non-cardiac chest pain Paresthesia Peripheral neuropathy Proteinuria Skin rash Symptoms of anxiety Syncope |
| Rare/Very Rare |
|---|
|
Hyperkeratosis |
The following precautions are available for COMETRIQ (cabozantinib s-malate):
Safety and effectiveness of cabozantinib tablets (Cabometyx(R)) for the treatment of differentiated thyroid cancer (DTC) have been established in pediatric patients >=12 years of age; safety and effectiveness in patients <12 years of age have not been established. Safety and efficacy of cabozantinib tablets (Cabometyx(R)) for the treatment of previously treated, locally advanced or metastatic DTC in pediatric patients >=12 years of age is supported by extrapolation of data from clinical studies evaluating cabozantinib tablets in adults and population pharmacokinetic data indicating that exposure to the drug in pediatric patients >=12 years of age is similar to that in adults. Physeal widening has been observed in children with open growth plates when treated with cabozantinib tablets (Cabometyx(R)).
Physeal and longitudinal growth monitoringis recommended in children with open growth plates. Safety, efficacy, and pharmacokinetics of cabozantinib capsules (Cometriq(R)) have not been established in pediatric patients. Systemic exposure of cabozantinib (Cabometyx(R)) in pediatric patients >=12 years of age at the recommended dosages is expected to be comparable to the exposure in adults at a dosage of 60 mg once daily.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Physeal and longitudinal growth monitoringis recommended in children with open growth plates. Safety, efficacy, and pharmacokinetics of cabozantinib capsules (Cometriq(R)) have not been established in pediatric patients. Systemic exposure of cabozantinib (Cabometyx(R)) in pediatric patients >=12 years of age at the recommended dosages is expected to be comparable to the exposure in adults at a dosage of 60 mg once daily.
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
May cause fetal harm. A pregnancy test should be performed prior to initiation of the drug in females of reproductive potential and such females should be advised to use effective contraceptive methods while receiving the drug and for 4 months after the last dose. Patients should be apprised of the potential hazard to the fetus if the drug is used during pregnancy.
It is not known whether cabozantinib or its metabolites are distributed into human milk. The effects of the drug on breast-fed infants or on the production of milk are unknown. Because of the potential for serious adverse reactions to cabozantinib in breast-fed infants, advise women not to breast-feed during treatment with cabozantinib and for 4 months after the last dose.
The manufacturer makes no specific dosage recommendations for geriatric patients. Clinical studies of cabozantinib capsules (Cometriq(R)) did not include sufficient numbers of patients >=65 years of age to determine whether geriatric patients respond differently than younger adults. The pharmacokinetics of cabozantinib capsules (Cometriq(R)) do not appear to be affected by age in adults (20-86 years of age).
Clinical studies of cabozantinib (Cabometyx(R)) included patients >=65 years of age at frequencies of 41-50% for patients >=65 years of age and of 8-15% for patients >=75 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients.
Clinical studies of cabozantinib (Cabometyx(R)) included patients >=65 years of age at frequencies of 41-50% for patients >=65 years of age and of 8-15% for patients >=75 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients.
The following prioritized warning is available for COMETRIQ (cabozantinib s-malate):
No warning message for this drug.
No warning message for this drug.
The following icd codes are available for COMETRIQ (cabozantinib s-malate)'s list of indications:
| Medullary thyroid carcinoma | |
| C73 | Malignant neoplasm of thyroid gland |
| E31.22 | Multiple endocrine neoplasia [MEn] type IIA |
| E31.23 | Multiple endocrine neoplasia [MEn] type IIB |
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