Cabozantinib

12.1 Mechanism of Action In vitro biochemical and/or cellular assays have shown that cabozantinib inhibits the tyrosine kinase activity of RET, MET, VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, ROS1, TYRO3, MER, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, drug resistance, and maintenance of the tumor microenvironment.

1 INDICATIONS AND USAGE COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). COMETRIQ is a kinase inhibitor indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). ( 1 )

2 DOSAGE AND ADMINISTRATION Recommended Dose: 140 mg orally, once daily. ( 2.1 ) Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. ( 2.1 ) Do NOT substitute COMETRIQ capsules with cabozantinib tablets. ( 2.1 ) Hepatic Impairment: The recommended starting dose of COMETRIQ is 80 mg in patients with mild or moderate hepatic impairment. ( 2.1 ) 2.1 Recommended Dosage Do NOT substitute COMETRIQ capsules with cabozantinib tablets. The recommended daily dose of COMETRIQ is 140 mg once daily without food until disease progression or unacceptable toxicity. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Swallow COMETRIQ capsules whole. Do not open COMETRIQ capsules. Do not take a missed dose within 12 hours of the next dose. Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 while taking COMETRIQ. 2.2 Dosage Modifications for Adverse Reactions Withhold COMETRIQ for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions, intolerable Grade 2 adverse reactions, or osteonecrosis of the jaw. Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows: If previously receiving 140 mg daily dose, resume treatment at 100 mg daily If previously receiving 100 mg daily dose, resume treatment at 60 mg daily If previously receiving 60 mg daily dose, resume at 60 mg if tolerated, otherwise, discontinue COMETRIQ Permanently discontinue COMETRIQ for any of the following: development of gastrointestinal (GI) perforation or Grade 4 fistula severe hemorrhage acute myocardial infarction or arterial or venous thromboembolic events that require medical intervention nephrotic syndrome severe hypertension that cannot be controlled with anti-hypertensive therapy or Grade 4 hypertension reversible posterior leukoencephalopathy syndrome cardiac failure, depending on severity 2.3 Dosage Modifications for Coadministration with Strong CYP3A4 Inhibitors Reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ]. 2.4 Dosage Modifications for Coadministration with Strong CYP3A4 Inducers Increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of COMETRIQ should not exceed 180 mg [see Drug Interactions (7.2) , Clinical Pharmacology (12.3) ]. 2.5 Dosage Modifications for Patients with Hepatic Impairment The recommended starting dose of COMETRIQ for patients with mild to moderate hepatic impairment is 80 mg [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed elsewhere in the labeling: Perforations and Fistula [see Warnings and Precautions (5.1) ] Hemorrhage [see Warnings and Precautions (5.2) ] Thromboembolic Events [see Warnings and Precautions (5.3) ] Impaired Wound Healing [see Warnings and Precautions (5.4) ] Hypertension and Hypertensive Crisis [see Warnings and Precautions (5.5) ] Cardiac Failure [see Warnings and Precautions (5.6) ] Osteonecrosis of the Jaw [see Warnings and Precautions (5.7) ] Diarrhea [see Warnings and Precautions (5.8) ] Palmar-Plantar Erythrodysesthesia [see Warnings and Precautions (5.9) ] Proteinuria [see Warnings and Precautions (5.10) ] Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.11) ] Hypocalcemia [see Warnings and Precautions (5.13) ] The most common adverse reactions (≥ 25%) are diarrhea, stomatitis, palmar-plantar erythrodysesthesia (PPE), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (≥ 25%) are increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Exelixis, Inc. at 1-855-500-3935 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of COMETRIQ was evaluated in 330 patients with progressive metastatic medullary thyroid cancer randomized to receive 140 mg COMETRIQ (n = 214) or placebo (n = 109) administered daily until disease progression or intolerable toxicity in a randomized, doubleblind, controlled trial (Study 1) [see Clinical Studies ( 14 )] . The data described below reflect a median exposure to COMETRIQ for 204 days. The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years. Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving placebo and resulted from septicemia, pneumonia, and general deterioration. The COMETRIQ dose was reduced in 79% of patients receiving COMETRIQ and in 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ and in no patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ. The most frequent adverse reactions leading to permanent discontinuation of COMETRIQ were: hypocalcemia, increased lipase, PPE, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation and vomiting. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose. Adverse reactions which occurred in ≥ 25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥ 5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia (PPE), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (≥25%) were increased AST, increased ALT, lymphopenia, increased ALP, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥ 5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥ 2% included, in order of decreasing frequency; diarrhea, PPES, lymphopenia, hypocalcemia, fatigue, hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite ( Table 1 and Table 2 summarize the adverse reactions and laboratory abnormalities reported in Study 1). Table 1. Selected Adverse Reactions Occurring at a Higher Incidence in COMETRIQ-Treated Patients (Study 1) [Between Arm Difference of ≥ 5% (All Grades) National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 or ≥ 2% (Grades 3-4)] System Organ Class/Preferred Terms COMETRIQ (n=214) Placebo (n=109) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) GASTROINTESTINAL DISORDERS Diarr

7 DRUG INTERACTIONS Strong CYP3A4 Inhibitors: Reduce the COMETRIQ dosage. ( 2.2 , 7.1 ) Strong CYP3A4 Inducers: Increase the COMETRIQ dosage. ( 2.2 , 7.2 ) 7.1 Effect of CYP3A4 Inhibitors Administration of a strong CYP3A4 inhibitor, ketoconazole to healthy subjects increased single-dose plasma cabozantinib exposure by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) while taking COMETRIQ or reduce the dosage of COMETRIQ if concomitant use with strong CYP3A4 inhibitors cannot be avoided [see Dosage and Administration ( 2.2 ), Clinical Pharmacology ( 12.3 )] . Avoid ingestion of foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 while taking COMETRIQ. 7.2 Effect of CYP3A4 Inducers Administration of a strong CYP3A4 inducer, rifampin to healthy subjects decreased single-dose plasma cabozantinib exposure by 77%. Avoid chronic co-administration of strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s Wort) with COMETRIQ or increase the dosage of COMETRIQ if concomitant use with strong CYP3A4 inducers cannot be avoided [see Dosage and Administration ( 2.2 ), Clinical Pharmacology ( 12.3 )]. 7.3 Effect of MRP2 Inhibitors Concomitant administration of MRP2 inhibitors may increase the exposure to cabozantinib. Monitor patients for increased toxicity when MRP2 inhibitors (e.g., abacavir, adefovir, cidofovir, furosemide, lamivudine, nevirapine, ritonavir, probenecid, saquinavir, and tenofovir) are co-administered with COMETRIQ [see Clinical Pharmacology ( 12.3 )] .