Cabozantinib

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 Diarrhea 63 16 33 2 Stomatitis Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation 51 5 6 0 Nausea 43 1 21 0 Oral pain Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia 36 2 6 0 Constipation 27 0 6 0 Abdominal pain Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain 27 3 13 1 Vomiting 24 2 2 1 Dysphagia 13 4 6 1 Dyspepsia 11 0 0 0 Hemorrhoids 9 0 3 0 SKIN AND SUBCUTANEOUS TISSUE DISORDERS PPE Palmar-plantar erythrodysesthesia 50 13 2 0 Hair color changes/ depigmentation, graying 34 0 1 0 Rash 19 1 10 0 Dry skin 19 0 3 0 Alopecia 16 0 2 0 Erythema 11 1 2 0 Hyperkeratosis 7 0 0 0 INVESTIGATIONS Decreased weight 48 5 10 0 METABOLISM AND NUTRITION DISORDERS Decreased appetite 46 5 16 1 Dehydration 7 2 2 1 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue 41 9 28 3 Asthenia 21 6 15 1 NERVOUS SYSTEM DISORDERS Dysgeusia 34 0 6 0 Headache 18 0 8 0 Dizziness 14 0 7 0 Paresthesia 7 0 2 0 Peripheral sensory neuropathy 7 0 0 0 Peripheral neuropathy 5 0 0 0 VASCULAR DISORDERS Hypertension 33 8 4 0 Hypotension 7 1 0 0 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Dysphonia 20 0 9 0 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia 14 1 7 0 Muscle spasms 12 0 5 0 Musculoskeletal chest pain 9 1 4 0 PSYCHIATRIC DISORDERS Anxiety 9 0 2 0 Table 2 Laboratory Abnormalities Occurring at a Higher Incidence in COMETRIQ-Treated Patients (Study 1) [Between Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3-4)] Test COMETRIQ (n=214) Placebo (N=109) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Chemistries Increased AST 86 3 35 2 Increased ALT 86 6 41 2 Increased ALP 52 3 35 3 Hypocalcemia 52 12 27 3 Hypoalbuminemia 43 2 16 0 Hypophosphatemia 28 3 10 1 Hyperbilirubinemia 25 2 14 5 Hypomagnesemia 19 1 4 0 Hypokalemia 18 4 9 3 Hyponatremia 10 2 5 0 Hematologic Lymphopenia 53 16 51 11 Neutropenia 35 3 15 2 Thrombocytopenia 35 0 4 3 ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase Nearly all COMETRIQ-treated patients (96% vs. 84% placebo) experienced elevated blood pressure and there was a doubling in the incidence of overt hypertension in COMETRIQ-treated patients over placebo-treated patients (61% vs. 30%) according to modified Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) staging criteria. No patients developed malignant hypertension. Table 3 Per-Patient Incidence of Hypertension (Study 1) Hypertension, JNC Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003: 289:2560. Criteria applied were modified, as multiple readings were not available per timepoint, and therefore not averaged. Stage Patients classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose. COMETRIQ N=211 Patients with at least two blood pressure measurements after the first dose (%) Placebo N=107 (%) Normal: Grade 0: Systolic < 120 mmHg and Diastolic < 80 mmHg 4 15 Pre-hypertension: Systolic ≥ 120 mmHg or Diastolic ≥ 80 mmHg 34 54 Stage 1: Systolic ≥ 140 mmHg or Diastolic ≥ 90 mmHg 46 25 Stage 2: Systolic ≥ 160 mmHg or Diastolic ≥ 100 mmHg 15 5 Malignant: Diastolic ≥ 120 mmHg 0 0 Other clinically important adverse reactions (all grades) that were reported in clinical trials include: hepatitis cholestatic (<1%). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of COMETRIQ. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hematology: A case of supratherapeutic international normalized ratio (INR) and epistaxis during concomitant use of warfarin Musculoskeletal and Connective Tissue Disorders: Extremity pain Vascular Disorders: Arterial (including aortic) aneurysms, dissections, and rupture

12.3 Pharmacokinetics A population pharmacokinetic analysis of cabozantinib was performed using data collected from 289 patients with solid tumors including MTC following oral administration of 140 mg daily doses. Repeat daily dosing of COMETRIQ at 140 mg for 19 days resulted in 4- to 5-fold mean cabozantinib accumulation (based on AUC) compared to a single dose administration; steady state was achieved by Day 15. Absorption Following oral administration of COMETRIQ, median time to peak cabozantinib plasma concentrations (T max ) ranged from 2 to 5 hours post-dose. A 19% increase in the C max of the tablet formulation (CABOMETYX ™ ) compared to the capsule formulation (COMETRIQ) was observed following a single 140 mg dose. A less than 10% difference in the AUC was observed between cabozantinib tablet (CABOMETYX) and capsule (COMETRIQ) formulations [see Dosage and Administration ( 2.1 )] . Cabozantinib C max and AUC values increased by 41% and 57%, respectively, following a high-fat meal relative to fasted conditions in healthy subjects administered a single 140 mg oral COMETRIQ dose. Distribution The oral volume of distribution (V/F) of cabozantinib is approximately 349 L. Cabozantinib is highly protein bound in human plasma (≥ 99.7%). Elimination The predicted effective half-life is approximately 55 hours and the clearance (CL/F) at steady-state is estimated to be 4.4 L/hr. Metabolism Cabozantinib is a substrate of CYP3A4 in vitro . Excretion Approximately 81% of the total administered radioactivity was recovered within a 48-day collection period following a single 140 mg dose of an investigational 14 C-cabozantinib formulation in healthy subjects. Approximately 54% was recovered in feces and 27% in urine. Unchanged cabozantinib accounted for 43% of the total radioactivity in feces and was not detectable in urine following a 72 hour collection. Specific Populations The following patient characteristics did not result in a clinically relevant difference in the pharmacokinetics of cabozantinib: age (20-86 years), sex, race (Whites and non-Whites), or mild to moderate renal impairment (eGFR greater than or equal to 30 mL/min/1.73 m 2 as estimated by MDRD (modification of diet in renal disease equation)). The pharmacokinetics of cabozantinib is unknown in patients with worse than moderate renal impairment (eGFR less than 29 mL/min/1.73m 2 ) as estimated by MDRD equation or renal impairment requiring dialysis. Patients with Hepatic Impairment Following a single oral 60 mg COMETRIQ, mean AUC 0-inf for cabozantinib increased by 81% in subjects with mild (Child-Pugh A) hepatic impairment and 63% in subjects with moderate (Child-Pugh B) hepatic impairment compared to subjects with normal hepatic function [see Dosage and Administration (2.5) , Use in Specific Populations (8.6) ] . The pharmacokinetics of cabozantinib has not been studied in patients with severe (Child-Pugh C) hepatic impairment [see Use in Specific Populations (8.6) ] . Drug Interaction Studies CYP3A4 Inhibition on Cabozantinib Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased single-dose plasma cabozantinib exposure (AUC 0-inf ) by 38%. CYP3A4 Induction on Cabozantinib Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased single-dose plasma cabozantinib exposure (AUC 0-inf ) by 77%. Cabozantinib on CYP2C8 substrates No clinically-significant effect on single-dose rosiglitazone (a CYP2C8 substrate) plasma exposure (C max and AUC) was observed when co-administered with cabozantinib at steady-state plasma concentrations (≥ 100 mg/day daily for a minimum of 21 days) in patients with solid tumors. Gastric pH modifying agents on Cabozantinib No clinically-significant effect on plasma cabozantinib exposure (AUC) was observed following co-administration of the proton pump inhibitor (PPI) esomeprazole (40 mg daily for 6 days) with a single dose of 100 mg cabozantinib to healthy volunteers. In vitro Studies Metabolic Pathways: Inhibition of CYP3A4 reduced the formation of the XL184 N -oxide metabolite by >80%. Inhibition of CYP2C9 had a minimal effect on cabozantinib metabolite formation (i.e., a <20% reduction). Inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite formation. Although cabozantinib is an inhibitor of CYP2C8 in vitro , a clinical study of this potential interaction concluded that concurrent use did not result in a clinically relevant effect on CYP2C8 substrate exposure. Given this finding, other less sensitive substrates of pathways affected by cabozantinib in vitro (i.e., CYP2C9, CYP2C19, and CYP3A4) were not evaluated in a clinical study because, although a clinically relevant exposure effect cannot be ruled out, it is unlikely. Cabozantinib does not inhibit CYP1A2 and CYP2D6 isozymes in vitro . Cabozantinib is an inducer of CYP1A1 mRNA; however, the clinical relevance of this finding is unknown. Cabozantinib does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4. Drug Transporter Systems: Cabozantinib is an inhibitor, but not a substrate, of P-gp transport activities and has the potential to increase plasma concentrations of co-administered substrates of P-gp. The clinical relevance of this finding is unknown. Cabozantinib is a substrate of MRP2 in vitro and MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib. The clinical relevance of this finding is unknown.