COMETRIQ

Exelixis, Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use COMETRIQ safely and effectively. See full prescribing information for COMETRIQ.COMETRIQ (cabozantinib) capsules, for oral useInitial U.S. Approval: 2012BOXED WARNING WARNING: PERFORATIONS AND FISTULAS, andHEMORRHAGE See full prescribing information for complete boxed warning. Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. (5.1) Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. (5.2) INDICATIONS AND USAGECOMETRIQ is a kinase inhibitor indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). (1)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) DOSAGE FORMS AND STRENGTHS20 mg and 80 mg capsules. (3)CONTRAINDICATIONSNone. (4)WARNINGS AND PRECAUTIONS Thrombotic Events: Discontinue COMETRIQ for myocardial infarction, cerebral infarction, or other serious arterial thromboembolic events. (5.3) Wound Complications: Withhold COMETRIQ for dehiscence or complications requiring medical intervention. (5.4) Hypertension: Monitor blood pressure regularly. Discontinue COMETRIQ for hypertensive crisis. (5.5) Osteonecrosis of the jaw: Discontinue COMETRIQ. (5.6). Palmar-plantar Erythrodysesthesia syndrome (PPES): Interrupt COMETRIQ, decrease dose. (5.7) Proteinuria: Monitor urine protein. Discontinue for nephrotic syndrome. (5.8) Reversible posterior leukoencephalopathy syndrome (RPLS): Discontinue COMETRIQ. (5.9) Embryofetal toxicity: Can cause fetal harm. Advise women of potential risk to a fetus. (5.11, 8.1) Side EffectsThe most commonly reported adverse drug reactions (≥25%) are 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%) 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. DRUG INTERACTIONSCabozantinib is a CYP3A4 substrate (5.10, 7.1, 7.2). Coadministration of strong CYP3A4 inhibitors can increase cabozantinib exposure (2.1, 5.10, 7.1). Chronic co-administration of strong CYP3A4 inducers can reduce cabozantinib exposure. (2.1, 5.10, 7.2).

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE
• 1 COMETRIQ INDICATIONS AND USAGE
• 2 COMETRIQ DOSAGE AND ADMINISTRATION
  • 2.1 Recommended Dose
  • 2.2 Dosage Adjustments
• 3 DOSAGE FORMS AND STRENGTHS
• 4 COMETRIQ CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Perforations and Fistulas
  • 5.2 Hemorrhage
  • 5.3 Thrombotic Events
  • 5.4 Wound Complications
  • 5.5 Hypertension
  • 5.6 Osteonecrosis of the Jaw
  • 5.7 Palmar-Plantar Erythrodysesthesia Syndrome
  • 5.8 Proteinuria
  • 5.9 Reversible Posterior Leukoencephalopathy Syndrome
  • 5.10 Drug Interactions
  • 5.11 Hepatic Impairment
  • 5.12 Embryo-fetal Toxicity
• 6 COMETRIQ ADVERSE REACTIONS
  • 6.1 Clinical Trial Experience
• 7 DRUG INTERACTIONS
  • 7.1 Effect of CYP3A4 Inhibitors
  • 7.2 Effect of CYP3A4 Inducers
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.2 Nursing Mothers
  • 8.3 Pediatric Use
  • 8.4 Geriatric Use
  • 8.5 Females and Males of Reproductive Potential
  • 8.6 Hepatic Impairment
  • 8.7 Renal Impairment
• 10 OVERDOSAGE
• 11 COMETRIQ DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.3 Pharmacokinetics
  • 12.6 Cardiac Electrophysiology
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

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

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 during COMETRIQ treatment.

2.2 Dosage Adjustments

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 with Hepatic Impairment

COMETRIQ is not recommended for use in patients with moderate and severe hepatic impairment [see Warnings and Precautions (5.11) and Use in Specific Populations (8.6)].

In Patients Taking CYP3A4 Inhibitors

Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving COMETRIQ [see Warnings and Precautions (5.10) and Drug Interactions 7.1)].

For patients who require treatment with 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.

In Patients Taking Strong CYP3A4 Inducers

Avoid the chronic use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available [see Warnings and Precautions (5.10) and Drug Interactions (7.2)].

Do not ingest foods or nutritional supplements (e.g., St. John’s Wort (Hypericum perforatum)) that are known to induce cytochrome P450 activity.

For patients who require treatment with 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.

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. 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 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. 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 3-4 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 Drug Interactions

Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors [see Dosage and Administration (2.1) and Drug Interactions (7.1, 7.2)].

5.11 Hepatic Impairment

COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment [see Use in Specific Populations (8.6)].

5.12 Embryo-fetal Toxicity

COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [See Use in Specific Populations (8.1)].

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. [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.

Table 1 Per-Patient Incidence of Selected Adverse Reactions in Protocol XL184-301 Occurring at a Higher Incidence in COMETRIQ-Treated Patients [Between Arm Difference of ≥ 5% (All Grades)National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 or ≥ 2% (Grades 3-4)]

MedDRA 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
StomatitisIncludes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation	51	5	6	0
Nausea	43	1	21	0
Oral painIncludes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia	36	2	6	0
Constipation	27	0	6	0
Abdominal painIncludes 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
GENERAL DISORDERS AND    ADMINISTRATION SITE CONDITIONS
Fatigue	41	9	28	3
Asthenia	21	6	15	1
INVESTIGATIONS
Decreased weight	48	5	10	0
METABOLISM AND NUTRITION DISORDERS
Decreased appetite	46	5	16	1
Dehydration	7	2	2	1
MUSCULOSKELETAL AND CONNECTIVE    TISSUE DISORDERS
Arthralgia	14	1	7	0
Muscle spasms	12	0	5	0
Musculoskeletal chest pain	9	1	4	0
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
PSYCHIATRIC DISORDERS
Anxiety	9	0	2	0
RESPIRATORY, THORACIC AND    MEDIASTINAL DISORDERS
Dysphonia	20	0	9	0
SKIN AND SUBCUTANEOUS TISSUE    DISORDERS
PPESPalmar-plantar erythrodysesthesia syndrome	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
VASCULAR DISORDERS
Hypertension	33	8	4	0
Hypotension	7	1	0	0

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 in Protocol XL184-301

Hypertension, JNCJoint 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	COMETRIQ N=211Subjects classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose.(%)	Placebo N=107Subjects with at least two blood pressure measurements after the first dose(%)
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

7 DRUG INTERACTIONS

7.1 Effect of CYP3A4 Inhibitors

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%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) when taking COMETRIQ [see Dosage and Administration (2.1) and Warnings and Precautions (5.10)].

7.2 Effect of CYP3A4 Inducers

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%. Avoid chronic co-administration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s Wort) with COMETRIQ [see Dosage and Administration (2.1) and Warnings and Precautions (5.10)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D

Risk Summary

Based on its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Animal Data

In an embryo-fetal development study in which pregnant rats were administered daily doses of cabozantinib during organogenesis, increased loss of pregnancy compared to controls was observed at doses as low as 0.03 mg/kg (less than 1% of the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations at doses equal to or greater than 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the recommended dose).

In pregnant rabbits administered cabozantinib daily during organogenesis there were 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 recommended dose).

8.2 Nursing Mothers

It is unknown whether cabozantinib or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from COMETRIQ, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.3 Pediatric Use

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

8.4 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

8.5 Females and Males of Reproductive Potential

Contraception

Use effective contraception during treatment with COMETRIQ and up to 4 months after completion of therapy.

Infertility

There are no data on the effect of COMETRIQ on human fertility. Cabozantinib impaired male and female fertility in animal studies [see Nonclinical Toxicology (13.1)].

8.6 Hepatic Impairment

Cabozantinib pharmacokinetics has not been studied in patients with hepatic impairment. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment, as safety and efficacy have not been established [see Dosage and Administration (2.1) and Warnings and Precautions (5.11)].

8.7 Renal Impairment

No dose adjustment is recommended for patients with mild or moderate renal impairment. There is no experience with COMETRIQ in patients with severe renal impairment.

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: