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: Cabozantinib (S)-malate salt is a white to off-white solid that is practically insoluble in aqueous media. COMETRIQ (cabozantinib) capsules are supplied as printed hard gelatin capsules containing cabozantinib (S)-malate equivalent to 20 mg or 80 mg cabozantinib and the following inactive ingredients: silicified microcrystalline cellulose, croscarmellose sodium, sodium starch glycolate, fumed silica, and stearic acid. The grey gelatin capsule shells contain black iron oxide and titanium dioxide and the Swedish orange gelatin capsule shells contain red iron oxide, and titanium dioxide. The printing ink contains shellac glaze, black iron oxide, N-butyl alcohol, isopropyl alcohol, propylene glycol, and ammonium hydroxide.

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The following serious adverse reactions are discussed elsewhere in the label:

• Perforations and Fistula [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
• Hemorrhage [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
• Thromboembolic Events [see WARNINGS AND PRECAUTIONS]
• Wound Complications [see WARNINGS AND PRECAUTIONS]
• Hypertension [see WARNINGS AND PRECAUTIONS]
• Osteonecrosis of the Jaw [see WARNINGS AND PRECAUTIONS]
• Palmar-plantar erythrodysesthesia syndrome [see WARNINGS AND PRECAUTIONS]
• Proteinuria [see WARNINGS AND PRECAUTIONS]
• Reversible Posterior Leukoencephalopathy Syndrome [see WARNINGS AND PRECAUTIONS]

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] 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)1or ≥ 2% (Grades 3-4)]
MedDRA System Organ Class/ Preferred Terms Cabozantinib
(n=214) Placebo
(n=109) All Grades Grades 3-4 All Grades Grades 3-4 GASTROINTESTINAL DISORDERS   Diarrhea 63 16 33 2   Stomatitis2 51 5 6 0   Nausea 43 1 21 0   Oral pain3 36 2 6 0   Constipation 27 0 6 0   Abdominal pain4 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   PPES5 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 1 National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0
2 Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation
3 Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia
4 Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain
5 Palmar-plantar erythrodysesthesia syndrome Table 2: Percent-Patient Incidence of Laboratory Abnormalities Occurring at a Higher Incidence in COMETRIQ-Treated Patients in Protocol XL184-301 [Between Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3-4)]
Adverse Event 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 Hypertensio n in Protocol XL184-301
Hypertension, JNC1 Stage COMETRIQ
N = 2113(%) Placebo
N = 1073 (%) 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 1Joint 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.
2Subjects classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose.
3Subjects with at least two blood pressure measurements after the first dose Read the Cometriq (cabozantinib capsules) Side Effects Center for a complete guide to possible side effectsLearn More »

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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. 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 and Use In Specific Populations]. 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 and DRUG INTERACTIONS]. 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 and DRUG INTERACTIONS]. 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.

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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 (AUC0-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 and WARNINGS AND PRECAUTIONS]. 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 (AUC0-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 and WARNINGS AND PRECAUTIONS]. Last reviewed on RxList: 12/6/2012
This monograph has been modified to include the generic and brand name in many instances.

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COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).

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None Last reviewed on RxList: 12/6/2012
This monograph has been modified to include the generic and brand name in many instances.

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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.

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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. Storage And Handling COMETRIQ 20 mg capsules are supplied as hard gelatin capsules with grey cap and grey body, printed with “XL184 20mg” in black ink and containing cabozantinib (S)-malate salt equivalent to 20 mg cabozantinib. COMETRIQ 80 mg capsules are supplied as hard gelatin capsules with Swedish orange cap and Swedish orange body, printed with “XL184 80mg” in black ink and containing cabozantinib (S)- malate salt equivalent to 80 mg cabozantinib. COMETRIQ capsules are supplied as follows: Cartons 140 mg daily-dose carton NDC#42388-011-14 Containing four 140 mg daily-dose blister cards (each blister card contains seven 80-mg and twenty-one 20-mg capsules) 100 mg daily-dose carton NDC#42388-012-14 Containing four 100 mg daily-dose blister cards (each blister card contains seven 80-mg and seven 20-mg capsules) 60 mg daily-dose carton NDC#42388-013-14 Containing four 60 mg daily-dose blister cards (each blister card contains twenty-one 20-mg capsules) Bottle containing sixty 20-mg COMETRIQ capsules NDC#42388-014-25 Store COMETRIQ at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Distributed by Exelixis, Inc. Revised: 11/2012 Last reviewed on RxList: 12/6/2012
This monograph has been modified to include the generic and brand name in many instances.

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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. 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 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. 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 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. Drug Interactions Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS]. Hepatic Impairment COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment [see Use In Specific Populations]. 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]. 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.

Nonclinical Toxicology 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 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). 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. Pediatric Use The safety and effectiveness of COMETRIQ in pediatric patients have not been studied. 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 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]. 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 and WARNINGS AND PRECAUTIONS]. 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. Last reviewed on RxList: 12/6/2012
This monograph has been modified to include the generic and brand name in many instances.

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