Data from FDA - Curated by EPG Health - Last updated 25 January 2018

Indication(s)

1 INDICATIONS AND USAGE COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). COMETRIQ is a kinase inhibitor indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). (1)

Learning Zones

An epgonline.org Learning Zone (LZ) is an area of the site dedicated to providing detailed self-directed medical education about a disease, condition or procedure.

Chronic Lymphocytic Leukaemia (CLL)

Chronic Lymphocytic Leukaemia (CLL)

Refine your knowledge of chronic lymphocytic leukaemia (CLL) with information on pathophysiology, diagnosis, treatment options and more

+ 1 more

Biosimilars Knowledge Centre

Biosimilars Knowledge Centre

What are biologics and how do they differ from small molecule medicines? Discover more about their development, as well as the manufacturing and regulatory processes in the Biosimilars in Oncology Knowledge Centre.

CDK 4/6 inhibitors in metastatic breast cancer

CDK 4/6 inhibitors in metastatic breast cancer

The CDK 4/6 Inhibitors in Metastatic Breast Cancer Learning Zone provides insights and information for metastatic breast cancer (mBC) and CDK 4/6 signalling. This includes the burden and pathophysiology of the disease, the role of CDK 4/6 in cell proliferation and an overview of the CDK 4/6 inhibitors that have been approved for the management of mBC.

Load more

Related Content

Advisory information

contraindications
4 CONTRAINDICATIONS None None. (4)
Adverse reactions
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)] The 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. 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. Table 1. Per-Patient Incidence of 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)] 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 Table 2 Percent-Patient Incidence of 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 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, 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. StagePatients classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose. COMETRIQ N=211Patients 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 Post-Marketing Experience The following adverse reactions have been identified during postapproval use of COMETRIQ. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hematology: A case of supratherapeutic international normalized ratio (INR) and epistaxis during concomitant use of warfarin

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Recommended Dose: 140 mg orally, once daily. (2.1) Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. (2.1) Do NOT substitute COMETRIQ capsules with cabozantinib tablets. (2.1) Hepatic Impairment: The recommended starting dose of COMETRIQ is 80 mg in patients with mild or moderate hepatic impairment. (2.1) 2.1 Recommended 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)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed while taking COMETRIQ. (8.2) 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform the drug-associated risk. In animal developmental and reproductive toxicology studies administration of cabozantinib to pregnant rats and rabbits during organogenesis resulted in embryofetal lethality and structural anomalies at exposures that were below those occurring clinically at the recommended dose [see Data ]. Advise pregnant women or women of childbearing potential of the potential hazard to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In an embryo-fetal development study in pregnant rats, daily oral administration of cabozantinib throughout organogenesis caused increased embryo-fetal lethality compared to controls at a dose of 0.03 mg/kg (less than 1% of the human exposure by AUC at the 140 mg dose). Findings included delayed ossifications and skeletal variations at a dose of 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the 140 mg dose). In pregnant rabbits, daily oral administration of cabozantinib throughout organogenesis resulted in findings of visceral malformations and variations including reduced spleen size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the 140 mg dose). In a pre- and postnatal study in rats, cabozantinib was administered orally from gestation day 10 through postnatal day 20. Cabozantinib did not produce adverse maternal toxicity or affect pregnancy, parturition or lactation of female rats, and did not affect the survival, growth or postnatal development of the offspring at doses up to 0.3 mg/kg/day (approximately 0.02 times the recommended clinical dose of 140 mg based on body surface area). 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)].
Pregnancy and lactation
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.

Interactions

7 DRUG INTERACTIONS Strong CYP3A4 inhibitors: Reduce the COMETRIQ dosage. (2.2, 7.1) Strong CYP3A4 inducers: Increase the COMETRIQ dosage. (2.2, 7.2) 7.1 Effect of CYP3A4 Inhibitors Administration of a strong CYP3A4 inhibitor, ketoconazole to healthy subjects increased single-dose plasma cabozantinib exposure by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) while taking COMETRIQ or reduce the dosage of COMETRIQ if concomitant use with strong CYP3A4 inhibitors cannot be avoided [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)]. Avoid ingestion of foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 while taking COMETRIQ. 7.2 Effect of CYP3A4 Inducers Administration of a strong CYP3A4 inducer, rifampin to healthy subjects decreased single-dose plasma cabozantinib exposure by 77%. Avoid chronic co-administration of strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s Wort) with COMETRIQ or increase the dosage of COMETRIQ if concomitant use with strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)]. 7.3 Effect of MRP2 Inhibitors Concomitant administration of MRP2 inhibitors may increase the exposure to cabozantinib. Monitor patients for increased toxicity when MRP2 inhibitors (e.g., abacavir, adefovir, cidofovir, furosemide, lamivudine, nevirapine, ritonavir, probenecid, saquinavir, and tenofovir) are co-administered with COMETRIQ [see Clinical Pharmacology (12.3)].

More information

Category Value
Authorisation number NDA203756
Agency product number DR7ST46X58
Orphan designation No
Product NDC 42388-011,42388-012,42388-013
Date Last Revised 15-01-2018
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Exelixis, Inc.
Warnings WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE Perforations and fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ®-treated patients. Discontinue COMETRIQ for perforation or for fistula formation [See Warnings and Precautions (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 [See Warnings and Precautions (5.2)]. WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE 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)