constant [1%).:<20% reduction). 1 Inhibition of CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C19, 2D6, and 2E1 had no effect on metabolite formation. 1 Noncompetitive inhibitor of CYP2C8, a mixed-type inhibitor of CYP2C9 and CYP2C19, and a weak competitive inhibitor of CYP3A4 in human liver microsomal preparations. 1 Unlikely to inhibit CYP isoenzymes 1A2, 2D6, or 3A4 to a clinically important degree. 14 Inducer of CYP1A1 messenger RNA (mRNA) in human hepatocyte incubations, but not of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4 mRNA or isoenzyme-associated enzyme activities. 1 Inhibitor, but not a substrate, of P-glycoprotein (P-gp) transport activities in a bi-directional assay system. 1 Drugs and Foods Affecting Hepatic Microsomal Enzymes Potent CYP3A4 inhibitors: Possible pharmacokinetic interaction (increased systemic exposure of cabozantinib). 1 Avoid concomitant use. 1 If concomitant therapy cannot be avoided, reduce daily dosage of cabozantinib by 40 mg (e.g., from 140 mg daily to 100 mg daily or from 100 mg daily to 60 mg daily). 1 If the potent CYP3A4 inhibitor is discontinued, resume cabozantinib therapy (2 3 days following discontinuance of the CYP3A4 inhibitor) at the dosage used prior to initiation of the potent CYP3A4 inhibitor. 1 (See Specific Drugs and Foods under Interactions.) Potent CYP3A4 inducers: Possible pharmacokinetic interaction (reduced systemic exposure of cabozantinib) with chronic concomitant use. 1 Avoid chronic concomitant use if alternative therapy is available. 1 If concomitant therapy cannot be avoided, increase daily dosage of cabozantinib by 40 mg (e.g., from 140 mg daily to 180 mg daily or from 100 mg daily to 140 mg daily) as tolerated. 1 If the potent CYP3A4 inducer is discontinued, resume cabozantinib therapy (2 3 days following discontinuance of the CYP3A4 inducer) at the dosage used prior to initiation of the potent CYP3A4 inducer. 1 Do not exceed a cabozantinib daily dosage of 180 mg. 1 (See Specific Drugs and Foods under Interactions.) Do not ingest foods or nutritional supplements known to inhibit or induce CYP isoenzymes, including CYP3A4. 1 (See Specific Drugs and Foods under Interactions.) Drugs Affected by the P-glycoprotein Transport System Substrates of P-gp: Possible pharmacokinetic interaction (increased plasma concentrations of P-gp substrate). 1 Specific Drugs and Foods Drug Interaction Comments Antifungals, azoles (e.g., itraconazole, ketoconazole, voriconazole) Potent CYP3A4 inhibitors: Possible increased cabozantinib exposure 1 Ketoconazole (400 mg daily for 27 days) increased single-dose cabozantinib exposure by 38% in healthy individuals 1 Avoid concomitant use 1 If concomitant use cannot be avoided, reduce daily dosage of cabozantinib by 40 mg (e.g., from 140 mg daily to 100 mg daily or from 100 mg daily to 60 mg daily) 1 If the potent CYP3A4 inhibitor is discontinued, resume cabozantinib (2 3 days following discontinuance of the CYP3A4 inhibitor) at the dosage used prior to initiation of the potent CYP3A4 inhibitor 1 Antimycobacterials, rifamycins (e.g., rifabutin, rifampin, rifapentine) Possible reduced cabozantinib exposure 1 Rifampin (600 mg daily for 31 days) decreased cabozantinib (single dose) plasma exposure by 77% in healthy individuals 1 Avoid chronic concomitant use of potent CYP3A4 inducers if alternative therapy is available 1 If concomitant use cannot be avoided, increase daily dosage of cabozantinib by 40 mg (e.g., from 140 mg daily to 180 mg daily or from 100 mg daily to 140 mg daily) as tolerated; do not exceed a daily dosage of 180 mg 1 If the potent CYP3A4 inducer is discontinued, resume cabozantinib (2 3 days following discontinuance of the CYP3A4 inducer) at the dosage used prior to initiation of the potent CYP3A4 inducer 1 Antiretrovirals, HIV protease inhibitors (e.g., atazanavir, indinavir, nelfinavir, ritonavir, saquinavir) Possible increased cabozantinib exposure 1 Avoid concomitant use 1 If concomitant use cannot be avoided, reduce daily dosage of cabozantinib by 40 mg (e.g., from 140 mg daily to 100 mg daily or from 100 mg daily to 60 mg daily) 1 If the potent CYP3A4 inhibitor is discontinued, resume cabozantinib (2 3 days following discontinuance of the CYP3A4 inhibitor) at the dosage used prior to initiation of the potent CYP3A4 inhibitor 1 Carbamazepine Possible reduced cabozantinib exposure 1 Avoid chronic concomitant use of potent CYP3A4 inducers if alternative therapy is available 1 If concomitant use cannot be avoided, increase daily dosage of cabozantinib by 40 mg (e.g., from 140 mg daily to 180 mg daily or from 100 mg daily to 140 mg daily) as tolerated; do not exceed a cabozantinib daily dosage of 180 mg 1 If the potent CYP3A4 inducer is discontinued, resume cabozantinib dosage (2 3 days following discontinuance of the CYP3A4 inducer) at the dosage used prior to initiation of the potent CYP3A4 inducer 1 Dexamethasone Possible reduced cabozantinib exposure 1 14 Avoid chronic concomitant use of potent CYP3A4 inducers if alternative therapy is available 1 14 If concomitant use cannot be avoided, increase daily dosage of cabozantinib by 40 mg (e.g., from 140 mg daily to 180 mg daily or from 100 mg daily to 140 mg daily) as tolerated; do not exceed a daily dosage of 180 mg 1 14 If the potent CYP3A4 inducer is discontinued, resume cabozantinib (2 3 days following discontinuance of the CYP3A4 inducer) at the dosage used prior to initiation of the potent CYP3A4 inducer 1 14 Grapefruit or grapefruit juice Grapefruit products inhibit CYP, including CYP3A4; possible increased cabozantinib concentrations 1 13 Avoid concomitant use 1 Macrolides (clarithromycin, telithromycin) Possible increased cabozantinib exposure 1 Avoid concomitant use 1 If concomitant use cannot be avoided, reduce daily dosage of cabozantinib by 40 mg (e.g., from 140 mg daily to 100 mg daily or from 100 mg daily to 60 mg daily) 1 If the potent CYP3A4 inhibitor is discontinued, resume cabozantinib (2 3 days following discontinuance of the CYP3A4 inhibitor) at the dosage used prior to initiation of the potent CYP3A4 inhibitor 1 Nefazodone Possible increased cabozantinib exposure 1 Avoid concomitant use 1 If concomitant use cannot be avoided, reduce daily dosage of cabozantinib by 40 mg (e.g., from 140 mg daily to 100 mg daily or from 100 mg daily to 60 mg daily) 1 If the potent CYP3A4 inhibitor is discontinued, resume cabozantinib (2 3 days following discontinuance of the CYP3A4 inhibitor) at the dosage used prior to initiation of the potent CYP3A4 inhibitor 1 Phenobarbital Possible reduced cabozantinib exposure 1 Avoid chronic concomitant use of potent CYP3A4 inducers if alternative therapy is available 1 If concomitant use cannot be avoided, increase daily dosage of cabozantinib by 40 mg (e.g., from 140 mg daily to 180 mg daily or from 100 mg daily to 140 mg daily) as tolerated; do not exceed a daily dosage of 180 mg 1 If the potent CYP3A4 inducer is discontinued, resume cabozantinib (2 3 days following discontinuance of the CYP3A4 inducer) at the dosage used prior to initiation of the potent CYP3A4 inducer 1 Phenytoin Possible reduced cabozantinib exposure 1 Avoid chronic concomitant use of potent CYP3A4 inducers if alternative therapy is available 1 If concomitant use cannot be avoided, increase daily dosage of cabozantinib by 40 mg (e.g., from 140 mg daily to 180 mg daily or from 100 mg daily to 140 mg daily) as tolerated; do not exceed a daily dosage of 180 mg 1 If the potent CYP3A4 inducer is discontinued, resume cabozantinib (2 3 days following discontinuance of the CYP3A4 inducer) at the dosage used prior to initiation of the potent CYP3A4 inducer 1 Rosiglitazone No effect on rosiglitazone (a CYP2C8 substrate) peak plasma concentration and AUC; clinically important pharmacokinetic interaction unlikely 1 12 14 St. John s wort ( Hypericum perforatum ) Possible reduced cabozantinib exposure 1 14 Avoid concomitant use of potent CYP3A4 inducers if alternative therapy is available 1 14 If concomitant use cannot be avoided, increase daily dosage of cabozantinib by 40 mg (e.g., from 140 mg daily to 180 mg daily or from 100 mg daily to 140 mg daily) as tolerated; do not exceed a daily dosage of 180 mg 1 14 If the potent CYP3A4 inducer is discontinued, resume cabozantinib (2 3 days following discontinuance of the CYP3A4 inducer) at the dosage used prior to initiation of the potent CYP3A4 inducer 1 14 Cabozantinib S-malate Pharmacokinetics Absorption Bioavailability Absolute oral bioavailability not established. 4 Median time to peak plasma cabozantinib concentrations ranged from 2 5 hours after oral administration. 1 Steady-state concentrations achieved in 15 days. 1 Food Administration of 140-mg dose with a high-fat meal increased cabozantinib peak concentrations and AUC by 41 and 57%, respectively, relative to fasted conditions. 1 (See Administration under Dosage and Administration.) Special Populations Pharmacokinetics not studied in patients with hepatic impairment; limited data available in patients with serum bilirubin concentrations >1.5 times ULN. 1 Pharmacokinetics not studied in pediatric patients. 1 Pharmacokinetics in adults not affected by age (20 86 years of age). 1 Distribution Extent Not known whether cabozantinib or its metabolites are distributed into human milk. 1 Plasma Protein Binding ≥99.7%. 1 Elimination Metabolism Metabolized in the liver by CYP3A4; substrate of CYP3A4 in vitro. 1 4 Elimination Route Eliminated in feces (54%) and urine (27%). 1 Half-life Approximately 55 hours. 1 4 Special Populations Formal pharmacokinetic studies not conducted in patients with renal impairment. 1 Mild to moderate renal impairment (Cl cr ≥30 mL/minute) did not have a clinically important effect on clearance of cabozantinib in a population pharmacokinetic analysis. 1 No experience with cabozantinib in patients with severe renal impairment. 1 (See Renal Impairment under Dosage and Administration.) Gender and race do not substantially affect clearance of cabozantinib. 1 Stability Storage Oral Capsules 20 25°C (may be exposed to 15 30°C). 1 Actions Inhibits multiple receptor tyrosine kinases (RTKs), 1 4 8 9 10 which are involved in the initiation of various cascades of intracellular signaling events that lead to cell proliferation and/or influence processes critical to cell survival and tumor progression (e.g., angiogenesis, metastasis, inhibition of apoptosis), based on the respective kinase. 1 6 7 9 10 Various tyrosine kinases and pathways are abnormally activated in medullary thyroid carcinoma cells (e.g., rearranged during transfection [RET] proto-oncogene mutations are associated with development of hereditary medullary thyroid cancer). 6 7 9 In vitro, inhibits activity of multiple RTKs, including RET; met proto-oncogene encoding hepatocyte growth factor (c-MET); vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3; stem cell factor receptor (c-Kit); tropomyosin receptor kinase B (trkB); fms-like tyrosine kinase 3 (Flt-3); AXL; and TIE-2. 1 9 10 These RTKs are involved in both normal cellular function and pathologic processes (e.g., oncogenesis, metastasis, tumor angiogenesis, maintenance of the tumor microenvironment). 1 Advice to Patients Importance of informing patients that cabozantinib should not be taken with food; importance of instructing patients not to eat for ≥2 hours before and ≥1 hour after taking the drug. 1 Importance of swallowing cabozantinib capsules whole with a full glass (at least 240 mL) of water and not to open or crush the capsules. 1 Importance of avoiding grapefruit or grapefruit juice while taking the drug. 1 If a dose of is cabozantinib missed and it is ≥12 hours before the next scheduled dose, importance of taking the dose as soon as it is remembered, and taking the next dose at the regularly scheduled time. 1 If a dose is missed and there are> <12 hours before the next scheduled dose, importance of taking the next dose at the regularly scheduled time; the missed dose should not be replaced. 1 Importance of informing patients that diarrhea often occurs and may be severe in some cases. 1 Importance of contacting clinician if severe diarrhea occurs during therapy. 1 Risk of palmar-plantar erythrodysesthesia syndrome. 1 Importance of contacting clinician if progressive or intolerable rash occurs. 1 Importance of advising patients to protect their skin to avoid subclinical vascular damage and subsequent adverse cutaneous effects that may interrupt ongoing therapy. 11 Risk of mouth sores, oral pain, taste changes, nausea, or vomiting. 1 Importance of contacting clinician if any of these symptoms are severe or prevent eating or drinking. 1 Risk of weight loss, which may be substantial in some cases. 1 Importance of informing clinician if substantial weight loss occurs. 1 Risk of osteonecrosis of the jaw; symptoms may include jaw pain, toothache, or sores on the gums. 1 Importance of advising patients that their clinician should examine their mouth before and during cabozantinib therapy. 1 Importance of informing dentist about therapy with the drug. 1 Importance of maintaining good oral hygiene during treatment. 1 Importance of contacting clinician before any planned surgeries, including dental procedures. 1 Risk of fetal harm. 1 Necessity of advising women of childbearing potential and men who are partners of such women that they must use an effective method of contraception while receiving cabozantinib and for ≥4 months after discontinuance of therapy. 1 Importance of patients informing their clinicians if they or their partners become pregnant. 1 If pregnancy occurs, apprise patient of potential hazard to the fetus. 1 Importance of discontinuing nursing while receiving cabozantinib therapy. 1 Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements (e.g., St. John s wort), as well as any concomitant illnesses (e.g., hypertension, bleeding or wound disorders, hepatic impairment). 1 Importance of informing patients of other important precautionary information. 1 (See Cautions.) Preparations Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details. Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations. Distribution of cabozantinib S -malate is restricted. 5 (See Restricted Distribution under Dosage and Administration.) Cabozantinib S-malate Routes Dosage Forms Strengths Brand Names Manufacturer Oral Capsules 20 mg (of cabozantinib) Cometriq Exelixis Kit 84 Capsules, Cabozantinib S -malate 20 mg (of cabozantinib) (Cometriq ) Cometriq 60 mg Daily Dose Blister Cards (available in a package containing 4 blister cards) Exelixis 28 Capsules, Cabozantinib S -malate 20 mg (of cabozantinib) (Cometriq ) 28 Capsules, Cabozantinib S -malate 80 mg (of cabozantinib) (Cometriq ) Cometriq 100 mg Daily Dose Blister Cards (available in a package containing 4 blister cards) Exelixis 84 Capsules, Cabozantinib S -malate 20 mg (of cabozantinib) (Cometriq ) 28 Capsules, Cabozantinib S -malate 80 mg (of cabozantinib) (Cometriq ) Cometriq 140 mg Daily Dose Blister Cards (available in a package containing 4 blister cards) Exelixis AHFS DI Essentials. Copyright 2017, Selected Revisions October 31, 2013. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814. References 1. Exelixis, Inc. Cometriq (cabozantinib) capsules prescribing information. South San Francisco, CA; 2012 Nov. 2. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Rockville, MD. From FDA website. 3. Schoffski P, Elisei R, and the EXAM Study Group. An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline. J Clin Oncol . 2012; 30 (May 20 Suppl): Abstract No. 5508. 4. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 203756Orig1s000: Summary review. From FDA website. 5. Exelixis, Inc. Cometriq (cabozantinib) information for healthcare professionals. Accessed 2013 Apr 23. From Cometriq for healthcare professionals website. 6. Gómez K, Varghese J, Jiménez C. Medullary thyroid carcinoma: molecular signaling pathways and emerging therapies. J Thyroid Res . 2011; 2011:815826. [PubMed 21687607] 7. Giunti S, Antonelli A, Amorosi A et al. Cellular signaling pathway alterations and potential targeted therapies for medullary thyroid carcinoma. Int J Endocrinol . 2013; 2013:803171. [PubMed 23509459] 8. Kurzrock R, Sherman SI, Ball DW et al. Activity of XL184 (cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol . 2011; 29:2660-6. [PubMed 21606412] 9. Hart CD, De Boer RH. Profile of cabozantinib and its potential in the treatment of advanced medullary thyroid cancer. Onco Targets Ther . 2013; 6:1-7. [PubMed 23319867] 10. Nagilla M, Brown RL, Cohen EE. Cabozantinib for the treatment of advanced medullary thyroid cancer. Adv Ther . 2012; 29:925-34. [PubMed 23104465] 11. Cho YT, Chan CC. Cabozantinib-induced hand-foot skin reaction with subungual splinter hemorrhages and hypertension: a possible association with inhibition of the vascular endothelial growth factor signaling pathway. Eur J Dermatol . 2013; :. [PubMed 23518371] 12. Bowles DW, Kessler DW, Jimeno A. Multi-targeted tyrosine kinase inhibitors in clinical development: focus on XL-184 (cabozantinib). Drugs of Today . 2011; 47:857-68. [PubMed 22146228] 13. Hanley MJ, Cancalon P, Widmer WW et al. The effect of grapefruit juice on drug disposition. Expert Opin Drug Metab Toxicol . 2011; 7:267-86. [PubMed 21254874] 14. Exelixis, Inc., South San Francisco, CA: Personal communication. 15. GlaxoSmithKline. Votrient (pazopanib) tablets prescribing information. Research Triangle Park, NC: 2013 Feb. Next Interactions Print this page Add to My Med List More about cabozantinib Side Effects During Pregnancy Dosage Information Drug Interactions Support Group En Español 1 Review Add your own review/rating Drug class: multikinase inhibitors Consumer resources Cabozantinib ... +3 more Professional resources Cabozantinib (Wolters Kluwer) Other brands: Cabometyx , Cometriq Related treatment guides Renal Cell Carcinoma Thyroid Cancer> ]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx Availability Prescription only D Pregnancy Category Positive evidence of risk N/A CSA Schedule Not a controlled drug Approval History Drug history at FDA Drug Class Multikinase inhibitors VEGF / VEGFR inhibitors Related Drugs Renal Cell Carcinoma Avastin , Opdivo , nivolumab , Nexavar , Afinitor , Sutent , bevacizumab , Votrient , sorafenib , everolimus , pazopanib , Lenvima , More... 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