COMETRIQ

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) ] .

4 CONTRAINDICATIONS None None. ( 4 )

5 WARNINGS AND PRECAUTIONS Perforations and Fistulas: Monitor for symptoms. Discontinue COMETRIQ for Grade 4 fistula or perforation. ( 5.1 ) Hemorrhage: Do not administer COMETRIQ if recent history of hemorrhage. ( 5.2 ) Thrombotic Events: Discontinue COMETRIQ for myocardial infarction or serious arterial or venous thromboembolic events. ( 5.3 ) Impaired Wound Healing: Withhold COMETRIQ for at least 3 weeks before elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of COMETRIQ after resolution of wound healing complications has not been established. ( 5.4 ) Hypertension and hypertensive crisis: Monitor blood pressure regularly. Interrupt for hypertension that is not adequately controlled with anti- hypertensive therapy. Discontinue COMETRIQ for hypertensive crisis or severe hypertension that cannot be controlled with anti-hypertensive therapy. ( 5.5 ) Cardiac Failure: Monitor patients for signs and symptoms of cardiac failure throughout treatment. ( 5.6 ) Osteonecrosis of the Jaw (ONJ): Withhold COMETRIQ for at least 3 weeks prior to invasive dental procedure and for development of ONJ. ( 5.7 ) Diarrhea: May be severe. Interrupt COMETRIQ immediately until diarrhea resolves or decreases to Grade 1. Recommend standard antidiarrheal treatments. ( 5.8 ) Palmar-Plantar Erythrodysesthesia (PPE): Interrupt COMETRIQ until PPE resolves or decreases to Grade 1. ( 5.9 ) Proteinuria: Monitor urine protein. Discontinue for nephrotic syndrome. ( 5.10 ) Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Discontinue COMETRIQ. ( 5.11 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.12 , 8.1 , 8.3 ) Hypocalcemia: Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold COMETRIQ and resume at reduced dose upon recovery or permanently discontinue COMETRIQ depending on severity. ( 5.13 ) 5.1 Perforations and Fistulas Gastrointestinal (GI) perforations and fistulas, including fatal cases, were reported in 3% and 1% of COMETRIQ-treated patients (N=214), respectively. Non-GI fistulas including tracheal/esophageal, including fatal cases, were reported in 4% of COMETRIQ-treated patients. Monitor patients for symptoms of perforations and fistulas, including abscess and sepsis. Discontinue COMETRIQ in patients who experience a Grade 4 fistula or a GI perforation [see Dosage and Administration (2.2) ] . 5.2 Hemorrhage Severe and fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥ 3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%). Discontinue COMETRIQ for Grade 3 or 4 hemorrhage [see Dosage and Administration (2.2) ] . Do not administer COMETRIQ to patients with a recent history of hemorrhage, including hemoptysis, hematemesis, or melena. 5.3 Thromboembolic Events COMETRIQ increased the incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or arterial or venous thromboembolic events that require medical intervention [see Dosage and Administration (2.2) ] . 5.4 Impaired Wound Healing Wound complications have been reported with COMETRIQ. Withhold COMETRIQ for at least 3 weeks prior to elective surgery. Do not administer COMETRIQ for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of COMETRIQ after resolution of wound healing complications has not been established. 5.5 Hypertension and Hypertensive Crisis COMETRIQ can cause hypertension, including hypertensive crisis. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension was identified in 61% in COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial [see Adverse Reactions (6.1) ] . Do not initiate COMETRIQ in patients with uncontrolled hypertension. Monitor blood pressure regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy and for hypertensive crisis [see Dosage and Administration (2.2) ] . 5.6 Cardiac Failure COMETRIQ can cause severe and fatal cardiac failure [see Adverse Reactions (6.1) ] . Cardiac failure occurred in 0.9% of patients treated with COMETRIQ as a single agent. Median time to onset of cardiac failure was 76 days (range: 60 days to 92 days). Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Withhold and resume at a reduced dose upon recovery or permanently discontinue COMETRIQ depending on the severity [see Dosage and Administration (2.2) ] . 5.7 Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. Withhold COMETRIQ treatment for at least 3 weeks prior to scheduled dental surgery, or invasive dental procedures, if possible. Withhold COMETRIQ for development of ONJ until complete resolution [see Dosage and Administration (2.2) ] . 5.8 Diarrhea Diarrhea occurred in 63% of patients treated with COMETRIQ. Grade 3-4 diarrhea occurred in 16% of patients treated with COMETRIQ [see Adverse Reactions (6.1) ] . Withhold COMETRIQ until improvement to Grade 1 and resume COMETRIQ at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea. 5.9 Palmar-Plantar Erythrodysesthesia Palmar-plantar erythrodysesthesia (PPE) occurred in 50% of patients treated with COMETRIQ, including 13% Grade 3 [see Adverse Reactions (6.1) ] . Withhold COMETRIQ until improvement to Grade 1 and resume COMETRIQ at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE. 5.10 Proteinuria Proteinuria was observed in 2% of patients receiving COMETRIQ, including one with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. 5.11 Reversible Posterior Leukoencephalopathy Syndrome Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS [see Dosage and Administration (2.2) ] . 5.12 Embryo-Fetal Toxicity Based on data from animal studies and its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib administration to pregnant animals during organogenesis resulted in embryolethality at exposures below those occurring clinically at the recommended dose, and in increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with COMETRIQ and for 4 months after the last dose [see Use in Specific Populations ( 8.1 ), ( 8.3 ), and Clinical Pharmacology ( 12.1 )] . 5.13 Hypocalcemia COMETRIQ can cause hypocalcemia. Based on the safety population [see Clinical Trial Experience ( 6.1 )] , hypocalcemia occurred in 52% of patients treated with COMETRIQ, including Grade 3 or 4 in 12% of patients. Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at a reduced dose upon recovery or discontinue COMETRIQ depending on severity [see Dosage and Administration ( 2.2 )] .

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 )] .

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

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . There are no available data in pregnant women to inform the drug-associated risk. In animal developmental and reproductive toxicology studies administration of cabozantinib to pregnant rats and rabbits during organogenesis resulted in embryofetal lethality and structural anomalies at exposures that were below those occurring clinically at the recommended dose (see Data ) . Advise pregnant women or women of childbearing potential of the potential hazard to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In an embryo-fetal development study in pregnant rats, daily oral administration of cabozantinib throughout organogenesis caused increased embryo-fetal lethality compared to controls at a dose of 0.03 mg/kg (less than 1% of the human exposure by AUC at the 140 mg dose). Findings included delayed ossifications and skeletal variations at a dose of 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the 140 mg dose). In pregnant rabbits, daily oral administration of cabozantinib throughout organogenesis resulted in findings of visceral malformations and variations including reduced spleen size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the 140 mg dose). In a pre- and postnatal study in rats, cabozantinib was administered orally from gestation day 10 through postnatal day 20. Cabozantinib did not produce adverse maternal toxicity or affect pregnancy, parturition or lactation of female rats, and did not affect the survival, growth or postnatal development of the offspring at doses up to 0.3 mg/kg/day (approximately 0.02 times the recommended clinical dose of 140 mg based on body surface area).