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INDICATIONS AND IMPORTANT SAFETY INFORMATION
INDICATIONS
CABOMETYX® (cabozantinib) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).
CABOMETYX, in combination with nivolumab, is indicated for the treatment of patients with advanced RCC.
CABOMETYX is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3-5 hemorrhagic events was 5% in CABOMETYX patients in RCC and HCC studies. In RCC patients treated with CABOMETYX in combination with nivolumab, Grade 3-5 hemorrhage occurred in 1%. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.
Perforations and Fistulas: Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. In patients treated with CABOMETYX in combination with nivolumab, fistulas occurred in 1%, and GI perforations, including fatal cases, occurred in 1%. Monitor patients for signs and symptoms of GI perforations and fistulas, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.
Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. In patients treated with CABOMETYX in combination with nivolumab, venous thromboembolism occurred in 11% (including 6% pulmonary embolism) and arterial thromboembolism occurred in 2%. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic event requiring medical intervention.
Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension occurred in 36% (17% Grade 3 and <1% Grade 4) of CABOMETYX patients. In patients treated with CABOMETYX in combination with nivolumab, hypertension was reported in 35% (13% Grade 3 and <1% Grade 4). Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.
Diarrhea: Diarrhea occurred in 63% (11% Grade 3) of CABOMETYX patients. In patients treated with CABOMETYX in combination with nivolumab, diarrhea occurred in 64% (7% Grade 3-4). Withhold CABOMETYX until improvement to Grade 1 and resume 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): PPE occurred in 44% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. In patients treated with CABOMETYX in combination with nivolumab, PPE occurred in 40% (8% Grade 3). Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.
Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to CABOMETYX alone. Monitor for liver enzymes before initiation of and periodically throughout treatment. For elevated liver enzymes, consider interruption of CABOMETYX and nivolumab and/or administering corticosteroids as needed. With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT (10%) and increased AST (8%) were seen. In patients with Grade ≥2 increased ALT or AST (n=83): median time to onset was 2.3 months (range: 2.0 to 88.3 weeks), 28% received corticosteroids for median duration of 1.7 weeks (range: 0.9 to 52.3 weeks), and resolution to Grades 0-1 occurred in 89.2% with median time to resolution of 2.1 weeks (range: 0.4 to 83.6+ weeks). Among the XYZ patients who were rechallenged with either CABOMETYX (XYZ%) or nivolumab (XYZ%) monotherapy or with both (XYZ%), XYZ% had no recurrence of Grade ≥2.
Proteinuria: Proteinuria occurred in 7% of CABOMETYX patients. In patients treated with CABOMETYX in combination with nivolumab, proteinuria was observed in 10%. Monitor urine protein regularly during CABOMETYX treatment. Discontinue CABOMETYX in patients who develop nephrotic syndrome.
Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. In patients treated with CABOMETYX in combination with nivolumab, ONJ occurred in <1%. 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 CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution.
Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing is observed. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.
Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.
ADVERSE REACTIONS
For CABOMETYX single-agent use, the most commonly reported (≥20%) adverse reactions were: diarrhea, fatigue, decreased appetite, PPE, nausea, hypertension, vomiting, weight decreased, constipation, and dysphonia.
For CABOMETYX in combination with nivolumab, the most commonly reported (≥20%) adverse reactions were: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.
DRUG INTERACTIONS
Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.
Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.
USE IN SPECIFIC POPULATIONS
Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.
Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. CABOMETYX is not recommended for use in patients with severe hepatic impairment.
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