July 29, 2016
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Cometriq

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Cometriq




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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.

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.

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, cerebral infarction, or any other clinically significant arterial thromboembolic complication.

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.

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.

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. Discontinue COMETRIQ for ONJ. 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 COMETRIQ and was severe (Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.

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.

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.

Embryo-Fetal Toxicity

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). Inform patients of the following:

  • Diarrhea: Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment with COMETRIQ.
  • Palmar-plantar erythrodysesthesia syndrome: Advise patients to contact their healthcare provider for progressive or intolerable rash [see WARNINGS AND PRECAUTIONS].
  • Mucositis and oral pain: Advise patients to contact their healthcare provider if they experience sores in the mouth, oral pain, changes in taste, nausea or vomiting that are severe or prevents them from eating and drinking.
  • Weight loss: COMETRIQ often causes weight loss which may be significant in some cases. Advise patients to report significant weight loss.
  • Wound complications: Advise patients to contact their healthcare provider before any planned surgeries, including dental procedures [see WARNINGS AND PRECAUTIONS].
  • Embryo-fetal toxicity: Advise females of reproductive potential of the potential risk to a fetus. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with COMETRIQ [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].
  • Females of reproductive potential: Advise patients of reproductive potential to use effective contraception during treatment with COMETRIQ and for at least four months after the final dose of COMETRIQ [see Use in Specific Populations].
  • Lactation: Advise women not to breastfeed during treatment with COMETRIQ and for 4 months following the last dose [see Use in Specific Populations].
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.
  • Advise patients not to consume grapefruits or grapefruit juice while taking COMETRIQ. [see DOSAGE AND ADMINISTRATION]

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Cabozantinib was not carcinogenic in a 26-week carcinogenicity study in rasH2 transgenic mice.

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

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]. 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).

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.

Females And Males Of Reproductive Potential

Contraception

Females

COMETRIQ can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations]. 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].

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.

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.

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, CLINICAL PHARMACOLOGY].

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].

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 6/6/2016

Warnings
Precautions

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You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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