Perforations and Fistulas
Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQtreated 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.
Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis.
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.
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.
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.
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.
Palmar-Plantar Erythrodysesthesia Syndrome
Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with cabozantinib 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.
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.
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.
COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment [see Use In Specific Populations].
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].
Patient Counseling Information
See FDA-approved patient labeling (Patient Information and Instructions for Use).
Inform patients of the following:
- COMETRIQ often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment with COMETRIQ.
- COMETRIQ often causes palmar plantar erythrodysesthesia syndrome. Advise patients to contact their healthcare provider for progressive or intolerable rash.
- COMETRIQ often causes sores in the mouth, oral pain, changes in taste, nausea or vomiting. Advise patients to contact their healthcare provider if any of these symptoms are severe or prevent patients from eating and drinking.
- COMETRIQ often causes weight loss which may be significant in some cases. Advise patients to report significant weight loss.
- To contact their healthcare provider before any planned surgeries, including dental procedures.
- COMETRIQ may interact with other drugs; advise patients to inform their healthcare provider of all prescription or nonprescription medication or herbal products that they are taking.
- Patients of childbearing potential must use effective contraception during therapy and for at least four months following their last dose of COMETRIQ.
- Breast-feeding mothers must discontinue nursing while receiving COMETRIQ therapy.
- COMETRIQ should not be taken with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. COMETRIQ capsules should not be opened or crushed but should be taken with a full glass (at least 8 ounces) of water.
- Patients should not consume grapefruits or grapefruit juice while taking COMETRIQ treatment.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies examining the carcinogenic potential of cabozantinib have not been conducted.
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 postimplantation 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
Pregnancy Category D
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.
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).
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.
The safety and effectiveness of COMETRIQ in pediatric patients have not been studied.
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
Females and Males of Reproductive Potential
Use effective contraception during treatment with COMETRIQ and up to 4 months after completion of therapy.
There are no data on the effect of COMETRIQ on human fertility. Cabozantinib impaired male and female fertility in animal studies [see Nonclinical Toxicology].
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 and WARNINGS AND PRECAUTIONS].
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.
Last reviewed on RxList: 12/6/2012
This monograph has been modified to include the generic and brand name in many instances.
Additional Cometriq Information
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