1 INDICATIONS AND USAGE

COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

Do NOT substitute COMETRIQ capsules with cabozantinib tablets.

The recommended daily dose of COMETRIQ is 140 mg (one 80-mg and three 20-mg capsules). Do not administer COMETRIQ with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Continue treatment until disease progression or unacceptable toxicity occurs.

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.

In 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)].

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 or intolerable Grade 2 adverse reactions.

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 (one 80-mg and one 20-mg capsule)
• If previously receiving 100 mg daily dose, resume treatment at 60 mg daily (three 20-mg capsules)
• 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 visceral perforation or fistula formation
• severe hemorrhage
• serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction)
• nephrotic syndrome
• malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management
• osteonecrosis of the jaw
• reversible posterior leukoencephalopathy syndrome

In Patients Concurrently Taking a Strong CYP3A4 Inhibitor

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)].

In Patients Concurrently Taking a Strong CYP3A4 Inducer

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)].

3 DOSAGE FORMS AND STRENGTHS

COMETRIQ 20-mg gelatin capsules are grey with "XL184 20mg" printed in black on the body of the capsule.

COMETRIQ 80-mg gelatin capsules are Swedish orange with "XL184 80mg" printed in black on the body of the capsule.

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 Perforations and Fistulas

Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and one GI fistula was fatal (< 1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal.

Monitor patients for symptoms of perforations and fistulas, including abscess. Discontinue COMETRIQ in patients who experience a perforation or a fistula.

5.2 Hemorrhage

Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%).

Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis.

5.3 Thrombotic Events

COMETRIQ treatment results in an increased 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, cerebral infarction, or any other clinically significant arterial thromboembolic complication.

5.4 Wound Complications

Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention.

5.5 Hypertension

COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% in COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and 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.

5.6 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. Discontinue COMETRIQ for ONJ. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible.

5.7 Palmar-Plantar Erythrodysesthesia Syndrome

Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with COMETRIQ and was severe (Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.

5.8 Proteinuria

Proteinuria was observed in 4 (2%) of patients receiving COMETRIQ, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.

5.9 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.

5.10 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)].

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in the label:

• Perforations and Fistula [see Boxed Warning, Warnings and Precautions (5.1)]
• Hemorrhage [see Boxed Warning, Warnings and Precautions (5.2)]
• Thromboembolic Events [see Warnings and Precautions (5.3)]
• Wound Complications [see Warnings and Precautions (5.4)]
• Hypertension [see Warnings and Precautions (5.5)]
• Osteonecrosis of the Jaw [see Warnings and Precautions (5.6)]
• Palmar-plantar erythrodysesthesia syndrome [see Warnings and Precautions (5.7)]
• Proteinuria [see Warnings and Precautions (5.8)]
• Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.9)]

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.

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 syndrome (PPES), 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 (see Table 1, Table 2).

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 dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, 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.

6.1 Clinical Trial Experience (Cont'd)

6.1 Clinical Trial Experience (Cont'd)

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.

Other clinically important adverse reactions (all grades) that were reported in clinical trials include: hepatitis cholestatic (<1%).

7 DRUG INTERACTIONS

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)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

Risk Summary

There is no information regarding the presence of cabozantinib or its metabolites in human milk, or their effects on the breastfed infant, or milk production. Because of the potential for serious adverse reactions in a breastfed infant from COMETRIQ, advise a lactating woman not to breastfeed during treatment with COMETRIQ and for 4 months after the final dose.

8.3 Females and Males of Reproductive Potential

Contraception

Females

COMETRIQ can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with COMETRIQ and for 4 months after the final dose.

Infertility

Females and Males

Based on findings in animals, COMETRIQ may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of COMETRIQ in pediatric patients have not been studied.

Juvenile Animal Data

Juvenile rats were administered cabozantinib daily at doses of 1 or 2 mg/kg/day from Postnatal Day 12 (comparable to less than 2 years in humans) through Postnatal Day 35 or 70. Mortalities occurred at doses equal and greater than 1 mg/kg/day (approximately 0.07 times the clinical dose of 140 mg/day based on body surface area). Hypoactivity was observed at both doses tested on Postnatal Day 22. Targets were generally similar to those seen in adult animals, occurred at both doses, and included the kidney (nephropathy, glomerulonephritis), reproductive organs, gastrointestinal tract (cystic dilatation and hyperplasia in Brunner’s gland and inflammation of duodenum; and epithelial hyperplasia of colon and cecum), bone marrow (hypocellularity and lymphoid depletion), and liver. Tooth abnormalities and whitening as well as effects on bones including reduced bone mineral content and density, physeal hypertrophy, and decreased cortical bone also occurred at all dose levels. Recovery was not assessed at the 2 mg/kg dose level (approximately 0.14 times the clinical dose of 140 mg based on body surface area) due to high levels of mortality. At the low dose level, effects on bone parameters were partially resolved but effects on the kidney and epididymis/testis persisted after treatment ceased.

8.5 Geriatric Use

Clinical studies of COMETRIQ did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.

8.6 Hepatic Impairment

Increased exposure to cabozantinib has been observed in patients with mild to moderate hepatic impairment. Reduce the starting dose of COMETRIQ in patients with mild (Child-Pugh score (C-P) A) or moderate (C-P B) hepatic impairment. COMETRIQ is not recommended for use in patients with severe hepatic impairment [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)].

8.7 Renal Impairment

Dosage adjustment is not required in patients with mild or moderate renal impairment. There is no experience with COMETRIQ in patients with severe renal impairment [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented.

11 DESCRIPTION

COMETRIQ is the (S)-malate salt of cabozantinib. Cabozantinib (S)-malate is described chemically as N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluorophenyl)cyclopropane- 1,1-dicarboxamide, (2S)-hydroxybutanedioate. The molecular formula is C28H24FN3O5•C4H6O5 and the molecular weight is 635.6 Daltons as malate salt. The chemical structure of cabozantinib (S)-malate salt is:

Cabozantinib (S)-malate salt is a white to off-white solid that is practically insoluble in aqueous media.

COMETRIQ (cabozantinib) capsules are supplied as printed hard gelatin capsules containing cabozantinib (S)-malate equivalent to 20 mg or 80 mg cabozantinib and the following inactive ingredients: silicified microcrystalline cellulose, croscarmellose sodium, sodium starch glycolate, fumed silica, and stearic acid.

The grey gelatin capsule shells contain black iron oxide and titanium dioxide and the Swedish orange gelatin capsule shells contain red iron oxide, and titanium dioxide. The printing ink contains shellac glaze, black iron oxide, N-butyl alcohol, isopropyl alcohol, propylene glycol, and ammonium hydroxide.

12 CLINICAL PHARMACOLOGY

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.

12.2 Pharmacodynamics

Cardiac Electrophysiology

The effect of orally administered COMETRIQ 140 mg on QTc interval was evaluated in a randomized, double-blinded, placebo-controlled study in patients with MTC. A mean increase in QTcF of 10 - 15 ms was observed at 4 weeks after initiating COMETRIQ. A concentration-QTc relationship could not be definitively established. Changes in cardiac wave form morphology or new rhythms were not observed. No COMETRIQ-treated patients had a QTcF > 500 ms [see Clinical Studies (14)].

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 (Tmax) ranged from 2 to 5 hours post-dose.

A 19% increase in the Cmax 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 Cmax 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 14C-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 m2 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/1.73m2) as estimated by MDRD equation or renal impairment requiring dialysis.

Hepatic Impairment

Following a single oral 60 mg COMETRIQ, mean AUC0-inf for cabozantinib increased by 81% in subjects with mild (C-P A) hepatic impairment and 63% in subjects with moderate (C-P B) hepatic impairment compared to subjects with normal hepatic function [see Dosage and Administration (2.1), Use in Specific Populations (8.6)].

The pharmacokinetics of cabozantinib has not been studied in patients with severe (C-P C) hepatic impairment [see Use in Specific Populations (8.6)].

Pediatric Population

The pharmacokinetics of cabozantinib has not been studied in the pediatric population [see Use in Specific Populations (8.4)].

Drug Interactions

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 (AUC0-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 (AUC0-inf) by 77%.

Cabozantinib on CYP2C8 substrates

No clinically-significant effect on single-dose rosiglitazone (a CYP2C8 substrate) plasma exposure (Cmax 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of cabozantinib has been evaluated in two species: rasH2 transgenic mice and Sprague-Dawley rats. In the 2-year rat carcinogenicity study, once daily oral administration of cabozantinib resulted in a statistically significant increase in the incidence of malignant/complex malignant pheochromocytoma in combination with benign pheochromocytoma or in benign pheochromocytoma alone in male rats at a dose of 1 mg/kg (approximately 0.6 times the human exposure by AUC at the recommended 140 mg dose). Cabozantinib was not carcinogenic in a 26-week carcinogenicity study in rasH2 transgenic mice at a slightly higher exposure than the intended human therapeutic exposure.

Cabozantinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Based on nonclinical findings, male and female fertility may be impaired by treatment with COMETRIQ. In a fertility study in which cabozantinib was administered to male and female rats at doses of 1, 2.5, and 5 mg/kg/day, male fertility was significantly compromised at doses equal to or greater than 2.5 mg/kg/day (approximately equal to the human exposure by AUC at the recommended dose), with a decrease in sperm counts and reproductive organ weights. In females, fertility was significantly reduced at doses equal to or greater than 1 mg/kg/day (approximately 50% of the human exposure by AUC at the 140 mg recommended dose) with a significant decrease in the number of live embryos and a significant increase in pre- and post-implantation losses.

Observations of effects on reproductive tract tissues in general toxicology studies were supportive of effects noted in the dedicated fertility study and included hypospermia and absence of corpora lutea in male and female dogs in a 6-month repeat dose study at exposures equal to 6% and 3%, respectively, the human exposure by AUC at the recommended dose. In addition, female rats administered 5 mg/kg/day for 14 days (approximately equal to the human exposure by AUC at the 140 mg recommended dose) exhibited ovarian necrosis.

14 CLINICAL STUDIES

The safety and efficacy of COMETRIQ was assessed in an international, multi-center, randomized, double-blind, controlled trial (Study 1) of 330 patients with metastatic medullary thyroid carcinoma (MTC). Patients were required to have evidence of actively progressive disease within 14 months prior to study entry confirmed by an Independent Radiology Review Committee (IRRC) masked to treatment assignment (89%) or the treating physician (11%). Patients were randomized (2:1) to receive COMETRIQ 140 mg (n = 219) or placebo (n = 111) orally once daily, without food, until disease progression determined by the treating physician or until intolerable toxicity. Randomization was stratified by age (≤ 65 years vs. > 65 years) and prior use of a tyrosine kinase inhibitor (TKI) (yes vs. no). No cross-over was allowed at the time of progression. The main efficacy outcome measures of progression-free survival (PFS), objective response (OR), and response duration were based on IRRC-confirmed events using modified RECIST criteria.

Of 330 patients randomized, 67% were male, the median age was 55 years, 23% were 65 years or older, 89% were white, 54% had a baseline ECOG performance status of 0, and 92% had undergone a thyroidectomy. The RET mutation status determined by a research-use assay was positive in 51%, negative in 14%, and was unknown in 35%. Twenty-five percent (25%) had two or more prior systemic therapies and 21% had been previously treated with a TKI.

A statistically significant prolongation in PFS was demonstrated among COMETRIQ-treated patients compared to those receiving placebo [HR 0.28 (95% CI: 0.19, 0.40); p<0.0001], with median PFS times of 11.2 months and 4.0 months in the COMETRIQ and placebo arms, respectively.

Partial responses were observed on;ly among patients in the COMETRIQ arm (27% vs. 0; p<0.0001). The median duration of objective responses was 14.7 months (95% CI: 11.1, 19.3) for patients treated with COMETRIQ. There was no statistically significant difference in overall survival (median OS: 26.6 months in the COMETRIQ arm vs. 21.1 months in the placebo arm [HR = 0.85 (95% CI: 0.64, 1.12), p = 0.2409]).

16 HOW SUPPLIED/STORAGE AND HANDLING

COMETRIQ 20 mg capsules are supplied as hard gelatin capsules with grey cap and grey body, printed with "XL184 20mg" in black ink and containing cabozantinib (S)-malate salt equivalent to 20 mg cabozantinib.

COMETRIQ 80 mg capsules are supplied as hard gelatin capsules with Swedish orange cap and Swedish orange body, printed with "XL184 80mg" in black ink and containing cabozantinib (S)- malate salt equivalent to 80 mg cabozantinib.

COMETRIQ capsules are supplied as follows:
Cartons

• 140 mg daily-dose carton NDC#42388-011-14

Containing four 140 mg daily-dose blister cards
(each blister card contains seven 80-mg and twenty-one 20-mg capsules)

• 100 mg daily-dose carton NDC#42388-012-14

Containing four 100 mg daily-dose blister cards
(each blister card contains seven 80-mg and seven 20-mg capsules)

• 60 mg daily-dose carton NDC#42388-013-14

Containing four 60 mg daily-dose blister cards
(each blister card contains twenty-one 20-mg capsules)

Store COMETRIQ at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Advise patients to read the FDA-approved patient labeling (Patient Information).

Inform patients of the following:

• Diarrhea: Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment with COMETRIQ.
• Palmar-plantar erythrodysesthesia syndrome: Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.7)].
• Mucositis and oral pain: Advise patients to contact their healthcare provider if they experience sores in the mouth, oral pain, changes in taste, nausea or vomiting that are severe or prevents them from eating and drinking.

Weight loss: COMETRIQ often causes weight loss which may be significant in some cases. Advise patients to report significant weight loss.

• Wound complications: Advise patients to contact their healthcare provider before any planned surgeries, including dental procedures [see Warnings and Precautions (5.4)].
• Embryo-fetal toxicity: Advise females of reproductive potential of the potential risk to a fetus. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with COMETRIQ [see Warnings and Precautions (5.10), Use in Specific Populations (8.1)].

Females of reproductive potential: Advise patients of reproductive potential to use effective contraception during treatment with COMETRIQ and for at least four months after the final dose of COMETRIQ [see Use in Specific Populations (8.3)].

• Lactation: Advise women not to breastfeed during treatment with COMETRIQ and for 4 months following the last dose [see Use in Specific Populations (8.2)].

Important Administration Information

• Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Instruct patients that COMETRIQ capsules should not be opened or crushed and to take COMETRIQ capsules with a full glass (at least 8 ounces) of water.
• Advise patients not to consume grapefruits or grapefruit juice while taking COMETRIQ. [see Dosage and Administration (2.1)].

Manufactured for Exelixis, Inc. South San Francisco, CA 94080

PATIENT INFORMATION

PATIENT INFORMATION
COMETRIQ® (Ko-me-trik)
cabozantinib
capsules

What is the most important information I should know about COMETRIQ?

COMETRIQ can cause serious side effects which can lead to death, including:

A tear in your stomach or intestinal wall (perforation), or an abnormal connection between 2 parts of your body (fistula). Tell your healthcare provider right away if you get:
ο severe pain in your stomach-area (abdomen)
ο coughing, gagging, and choking especially when eating or drinking
Severe bleeding (hemorrhage). Tell your healthcare provider right away if you get any signs of bleeding while taking or after you stop taking COMETRIQ, including:
ο coughing up blood or blood clots
ο vomiting blood or if your vomit looks like coffee-grounds
ο red or black (looks like tar) stools
ο menstrual bleeding that is heavier than normal
ο any unusual or heavy bleeding

What is COMETRIQ?

COMETRIQ is a prescription medicine used to treat people with medullary thyroid cancer that has spread to other parts of the body.

• It is not known if COMETRIQ is safe and effective in children.
• Before you take COMETRIQ, tell your healthcare provider about all of your medical conditions including if you:
• have a recent history of coughing up blood or bleeding or any unusual bleeding
• have an open wound
• have high blood pressure
• plan to have any surgery or a dental procedure
• have liver problems
• are pregnant or plan to become pregnant. COMETRIQ can harm your unborn baby. If you are able to become pregnant, you should use effective birth control during treatment and for 4 months after the final dose of COMETRIQ. Talk to your healthcare provider about birth control methods that may be right for you. If you become pregnant or think you are pregnant, tell your healthcare provider right away.
• are breastfeeding or plan to breastfeed. It is not known if COMETRIQ passes into your breast milk. Do not breastfeed during treatment and for 4 months after the final dose of COMETRIQ.

Tell your healthcare provider about all the medicines you take, including prescription or over-the-counter medicines, vitamins, and herbal supplements. COMETRIQ and certain other medicines may affect each other causing side effects.

How should I take COMETRIQ?

Take COMETRIQ exactly as your healthcare provider tells you to take it.
Do not take COMETRIQ with food. Do not eat for at least 2 hours before and at least 1 hour after taking COMETRIQ.
Swallow COMETRIQ capsules whole with a full glass (at least 8 ounces) of water.
Do not crush or open COMETRIQ capsules.
If you miss a dose and your next dose is in:
ο less than 12 hours, take your next dose at the normal time. Do not make up the missed dose.
ο 12 hours or more, take the missed dose as soon as you remember. Take your next dose at the normal time.

What should I avoid while taking COMETRIQ?

Do not drink grapefruit juice, eat grapefruit or supplements that contain grapefruit during treatment with COMETRIQ.

What are the possible side effects of COMETRIQ?

COMETRIQ may cause serious side effects, including:

See "What is the most important information I should know about COMETRIQ?"
blood clots, stroke, heart attack, and chest pain. Get emergency help right away if you get:
ο swelling or pain in your arms or legs
ο shortness of breath
ο feel lightheaded or faint
ο sweating more than usual
ο numbness or weakness of your face, arm or leg, especially on one side of your body
ο sudden confusion, trouble speaking or understanding
ο sudden trouble seeing in one or both eyes
ο sudden trouble walking
ο dizziness, loss of balance or coordination
ο a sudden severe headache

• wound healing problems. If you need to have surgery, tell your healthcare provider that you are taking COMETRIQ. Your healthcare provider should stop your treatment with COMETRIQ at least 28 days before any planned surgery, including dental procedures. Your healthcare provider should tell you when you may start taking COMETRIQ again after surgery.
• high blood pressure (hypertension). Hypertension is common with COMETRIQ and can be severe. Your healthcare provider will check your blood pressure before starting COMETRIQ and during treatment with COMETRIQ. If needed, your healthcare provider may prescribe medicine to treat your high blood pressure.
• severe jaw bone problems (osteonecrosis). Symptoms may include jaw pain, toothache, or sores on your gums. Your healthcare provider should examine your mouth before you start and during treatment with COMETRIQ. Tell your dentist that you are taking COMETRIQ. It is important for you to practice good mouth care during treatment with COMETRIQ.
• a skin problem called hand-foot skin reaction. Hand-foot skin reactions are common with COMETRIQ and can be severe. Tell your healthcare provider right away if you have rashes, redness, pain, swelling, or blisters on the palms of your hands or soles of your feet.
• protein in your urine and possible kidney problems. Symptoms may include swelling in your hands, arms, legs, or feet.
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS). A condition called reversible posterior leukoencephalopathy syndrome can happen during treatment with COMETRIQ. Tell your healthcare provider right away if you have headaches, seizures, confusion, changes in vision, or problems thinking.

Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with COMETRIQ if you have certain side effects.

The most common side effects of COMETRIQ are:

diarrhea
redness, swelling or pain in your mouth or throat, or mouth sores. Tell your healthcare provider if these symptoms prevent you from eating or drinking.
weight loss
decreased appetite
nausea
tiredness
hair color turning lighter
change in taste
pain in your abdomen
constipation
increased liver function blood tests
decreased calcium and phosphate blood levels
decreased white blood cell counts
decreased platelet counts
increased bilirubin blood levels

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of COMETRIQ. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store COMETRIQ?

Store COMETRIQ at room temperature 68°F to 77°F (20°C to 25°C).

Keep COMETRIQ and all medicines out of the reach of children.

General information about COMETRIQ.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use COMETRIQ for a condition for which it was not prescribed. Do not give COMETRIQ to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about COMETRIQ that is written for health professionals.

What are the ingredients in COMETRIQ?

Active ingredient: cabozantinib

Inactive ingredients: silicified microcrystalline cellulose, croscarmellose sodium, sodium starch glycolate, fumed silica, and stearic acid

Capsule shells: Grey gelatin capsule shells contain black iron oxide and titanium dioxide. Swedish orange gelatin capsule shells contain red iron oxide, and titanium dioxide.

The printing ink contains shellac glaze, black iron oxide, N-butyl alcohol, isopropyl alcohol, propylene glycol, and ammonium hydroxide.

Manufactured for Exelixis, Inc. South San Francisco, CA 94080

For more information, go to www.cometriq.com or call 1-855-292-3935.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Carton Label - 140mg Daily Dose of COMETRIQ

Package Label - CARTON - 140 mg Daily Dose of COMETRIQ

PRINCIPAL DISPLAY PANEL

Cometriq™
(cabozantinib) capsules

140 mg Daily Dose
Blister Cards

Each 140 mg daily dose contains a combination of
one Swedish orange 80 mg and three grey 20 mg
capsules. Each capsule contains cabozantinib
(S)-malate equivalent to 80 mg or 20 mg of
cabozantinib.

EXELIXIS®

NDC 42388-011-14

Carton containing 4 blister cards:
The blister cards in this carton are for
patients prescribed a 140 mg daily dose.

Rx Only

Blister Card Label - 140mg Daily Dose of COMETRIQ

Blister Card Label - 140mg Daily Dose of COMETRIQ

Each Blister Cards contains:

Seven 80mg Capsules

Tweenty-one 20mg Capsules

Shipper Label - 140mg Daily Dose of COMETRIQ

Shipper Label - 140mg Daily Dose of COMETRIQ

Carton Label - 100 mg Daily Dose of COMETRIQ

Package Label - CARTON - 100 mg Daily Dose of COMETRIQ

PRINCIPAL DISPLAY PANEL

Cometriq™
(cabozantinib) capsules

100 mg Daily Dose
Blister Cards

Each 100 mg daily dose contains a combination
of one Swedish orange 80 mg and one grey
20 mg capsule. Each capsule contains
cabozantinib (S)-malate equivalent to 80 mg
or 20 mg of cabozantinib.

EXELIXIS®

NDC 42388-012-14

Carton containing 4 blister cards:
The blister cards in this carton are for
patients prescribed a 100 mg daily dose.

Rx Only

Blister Label - 100mg Daily Dose of COMETRIQ

Blister Label - 100mg Daily Dose of COMETRIQ

Each Blister Card contains:

Seven 80mg Capsules

Seven 20mg Capsules

Shipper Label - 100mg Daily Dose of COMETRIQ

Shipper Label - 100mg Daily Dose of COMETRIQ

Carton Label - 60mg Daily Dose of COMETRIQ

Package Label - CARTON - 60 mg Daily Dose of COMETRIQ

PRINCIPAL DISPLAY PANEL

Cometriq™
(cabozantinib) capsules

60 mg Daily Dose
Blister Cards

Each 60 mg daily dose contains three grey 20 mg
capsules. Each capsule contains cabozantinib
(S)-malate equivalent to 20 mg of cabozantinib.

EXELIXIS®

NDC 42388-013-14

Carton containing 4 blister cards:
The blister cards in this carton are for
patients prescribed a 60 mg daily dose.

Rx Only

Blister Card - 60mg Daily Dose of COMETRIQ

Blister Card - 60mg Daily Dose of COMETRIQ

Each Blister Card contains:

Twenty-one 20mg of capsules

Shipper Label - 60mg Daily Dose of COMETRIQ

Shipper Label - 60mg Daily Dose of COMETRIQ