CABOMETYX

is the ( S )-malate salt of cabozantinib, a kinase inhibitor.

Cabozantinib ( S )-malate is described chemically as N -(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl).

• N' -(4-fluorophenyl)cyclopropane.

• 1,1-dicarboxamide, (2 S )-hydroxybutanedioate.

The molecular formula is

C 28 H 24 FN 3 O 5 •C 4 H 6 O 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 for oral use 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.

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).

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. 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 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.

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.

The oral volume of distribution (V/F) of cabozantinib is approximately 349 L. Cabozantinib is highly protein bound in human plasma (≥ 99.7%).

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.

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.

The following 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 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.

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.

The pharmacokinetics of cabozantinib has not been studied in patients with severe (Child-Pugh C) hepatic impairment.

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).

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

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 following clinically significant adverse reactions are discussed elsewhere in the labeling: Perforations and Fistula Hemorrhage Thromboembolic Events Impaired Wound Healing Hypertension and Hypertensive Crisis Cardiac Failure Osteonecrosis of the Jaw Diarrhea Palmar-Plantar Erythrodysesthesia Proteinuria Reversible Posterior Leukoencephalopathy Syndrome Hypocalcemia 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.

To report SUSPECTED ADVERSE

REACTIONS, contact Exelixis, Inc.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) .

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.

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 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.

Patients classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose.

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.

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.

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.

140 mg orally, once daily.

Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ.

Do NOT substitute

COMETRIQ capsules with cabozantinib tablets.

The recommended starting dose of COMETRIQ is 80 mg in patients with mild or moderate hepatic impairment. 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.

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 to 3 days after discontinuation of the strong inhibitor. 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 to 3 days after discontinuation of the strong inducer.

The daily dose of

COMETRIQ should not exceed 180 mg. 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.

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) .

Based on findings from animal studies and its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman.

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.

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.

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).

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.

The safety and effectiveness of

COMETRIQ in pediatric patients have not been studied.

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.

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.