Included as part of the "PRECAUTIONS" Section
Perforations And Fistulas
Gastrointestinal (GI) perforations and fistulas, including fatal cases, were reported in 3% and 1% of COMETRIQ-treated patients (N=214), respectively. Non-GI fistulas including tracheal/esophageal, including fatal cases, were reported in 4% of COMETRIQ-treated patients.
Monitor patients for symptoms of perforations and fistulas, including abscess and sepsis. Discontinue COMETRIQ in patients who experience a Grade 4 fistula or a GI perforation [see DOSAGE AND ADMINISTRATION].
Severe and fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥ 3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%).
Discontinue COMETRIQ for Grade 3 or 4 hemorrhage [see DOSAGE AND ADMINISTRATION]. Do not administer COMETRIQ to patients with a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.
COMETRIQ increased the incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively).
Discontinue COMETRIQ in patients who develop an acute myocardial infarction or arterial or venous thromboembolic events that require medical intervention [see DOSAGE AND ADMINISTRATION].
Impaired Wound Healing
Wound complications have been reported with COMETRIQ. Withhold COMETRIQ for at least 3 weeks prior to elective surgery. Do not administer COMETRIQ for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of COMETRIQ after resolution of wound healing complications has not been established..
Hypertension And Hypertensive Crisis
COMETRIQ can increase the 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 [see ADVERSE REACTIONS].
Do not initiate COMETRIQ in patients with uncontrolled hypertension. Monitor blood pressure regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy and for hypertensive crisis [see DOSAGE AND ADMINISTRATION].
Osteonecrosis Of The Jaw
Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. Withhold COMETRIQ treatment for at least 3 weeks prior to scheduled dental surgery, or invasive dental procedures, if possible. Withhold COMETRIQ for development of ONJ until complete resolution [see DOSAGE AND ADMINISTRATION].
Diarrhea occurred in 63% of patients treated with COMETRIQ. Grade 3-4 diarrhea occurred in 16% of patients treated with COMETRIQ [see ADVERSE REACTIONS].
Withhold COMETRIQ until improvement to Grade 1 and resume COMETRIQ at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.
Palmar-plantar erythrodysesthesia (PPE) occurred in 50% of patients treated with COMETRIQ, including 13% Grade 3 [see ADVERSE REACTIONS].
Withhold COMETRIQ until improvement to Grade 1 and resume COMETRIQ at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.
Proteinuria was observed in 2% of patients receiving COMETRIQ, including one with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.
Reversible Posterior Leukoencephalopathy Syndrome
Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS [see DOSAGE AND ADMINISTRATION].
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, and CLINICAL PHARMACOLOGY].
Patient Counseling Information
Advise patients to read the FDA-approved patient labeling (PATIENT INFORMATION).
Perforations And Fistulas
Advise patients that gastrointestinal disorders such as diarrhea, nausea, vomiting, and constipation may develop during COMETRIQ treatment and to seek immediate medical attention if they experience persistent or severe abdominal pain because cases of gastrointestinal perforation and fistula have been reported in patients taking COMETRIQ [see WARNINGS AND PRECAUTIONS].
Instruct patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual severe bleeding or hemorrhage [see WARNINGS AND PRECAUTIONS].
Venous and arterial thrombotic events have been reported. Advise patients to report signs or symptoms of an arterial thrombosis. Venous thromboembolic events including pulmonary embolus have been reported. Advise patients to contact their health care provider if new onset of dyspnea, chest pain, or localized limb edema occurs [see WARNINGS AND PRECAUTIONS].
Impaired Wound Healing
Advise patients that COMETRIQ may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure [see WARNINGS AND PRECAUTIONS].
Hypertension And Hypertensive Crisis
Inform patients of the signs and symptoms of hypertension. Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if they experience signs or symptoms of hypertension [see WARNINGS AND PRECAUTIONS].
Osteonecrosis Of The Jaw
Advise patients regarding good oral hygiene practices. Advise patients to immediately contact their healthcare provider for signs or symptoms associated with osteonecrosis of the jaw [see WARNINGS AND PRECAUTIONS].
Advise patients to notify their healthcare provider at the first signs of poorly formed or loose stool or an increased frequency of bowel movements [see WARNINGS AND PRECAUTIONS].
Advise patients to contact their healthcare provider for progressive or intolerable rash [see WARNINGS AND PRECAUTIONS].
Reversible Posterior Leukoencephalopathy Syndrome
Advise patients to immediately contact their health care provider for new onset or worsening neurological function [see WARNINGS AND PRECAUTIONS].
- Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].
- Advise patients of reproductive potential to use effective contraception during treatment with COMETRIQ and for at least 4 months after the final dose [see Use In Specific Populations].
Advise women not to breastfeed during treatment with COMETRIQ and for 4 months following the last dose [see Use In Specific Populations].
Advise patients to inform their healthcare provider of all prescription or nonprescription medications, vitamins or herbal products. Inform patients to avoid grapefruit, grapefruit juice, and St. John’s wort [see DRUG INTERACTIONS].
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.
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 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 recommended dose) exhibited ovarian necrosis.
Use In Specific Populations
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]. 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.
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.
Females And Males Of Reproductive Potential
Verify the pregnancy status of females of reproductive potential prior to initiating COMETRIQ [see Pregnancy].
COMETRIQ can cause fetal harm when administered to a pregnant woman [see Pregnancy].
Advise females of reproductive potential to use effective contraception during treatment with COMETRIQ and for 4 months after the final dose.
Females and Males
Based on findings in animals, COMETRIQ may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology].
The safety and effectiveness of COMETRIQ in pediatric patients have not been studied.
Juvenile Animal Toxicity 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.
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.
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, CLINICAL PHARMACOLOGY].
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].