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Severe and fatal hemorrhages occurred with Cabozantinib. The incidence of Grade 3 to 5 hemorrhagic events was 5% in Cabozantinib-treated patients in RCC, HCC, and DTC studies.
Discontinue Cabozantinib for Grade 3 or 4 hemorrhage and prior to surgery as recommended. Do not administer Cabozantinib to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.
Fistulas, including fatal cases, occurred in 1% of Cabozantinib-treated patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of Cabozantinib-treated patients.
Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue Cabozantinib in patients who experience a Grade 4 fistula or a GI perforation.
Cabozantinib increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism occurred in 2% of Cabozantinib-treated patients. Fatal thrombotic events occurred in Cabozantinib-treated patients.
Discontinue Cabozantinib in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.
Cabozantinib can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of Cabozantinib-treated patients.
Do not initiate Cabozantinib in patients with uncontrolled hypertension. Monitor blood pressure regularly during Cabozantinib treatment. Withhold Cabozantinib for hypertension that is not adequately controlled with medical management; when controlled, resume Cabozantinib at a reduced dose. Permanently discontinue Cabozantinib for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.
Diarrhea occurred in 62% of patients treated with Cabozantinib. Grade 3 diarrhea occurred in 10% of patients treated with Cabozantinib.
Monitor and manage patients using antidiarrheals as indicated. Withhold Cabozantinib until improvement to ≤ Grade 1, resume Cabozantinib at a reduced dose.
Palmar-plantar erythrodysesthesia (PPE) occurred in 45% of patients treated with Cabozantinib. Grade 3 PPE occurred in 13% of patients treated with Cabozantinib.
Withhold Cabozantinib until improvement to Grade 1 and resume Cabozantinib at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.
Cabozantinib in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to Cabozantinib alone.
Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt Cabozantinib and nivolumab and consider administering corticosteroids.
With the combination of Cabozantinib and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST > 3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%).Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either Cabozantinib (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving Cabozantinib 2 patients receiving nivolumab, and 7 patients receiving both Cabozantinib and nivolumab. Withhold and resume at a reduced dose based on severity.
Cabozantinib in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold Cabozantinib and/or nivolumab and resume Cabozantinib at a reduced dose depending on severity.
Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received Cabozantinib with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of Cabozantinib and nivolumab in 0.9% and withholding of Cabozantinib and nivolumab in 2.8% of patients with RCC.
Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom Cabozantinib with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.
Proteinuria was observed in 8% of patients receiving Cabozantinib.
Monitor urine protein regularly during Cabozantinib treatment. For Grade 2 or 3 proteinuria, withhold Cabozantinib until improvement to ≤ Grade 1 proteinuria, resume Cabozantinib at a reduced dose. Discontinue Cabozantinib in patients who develop nephrotic syndrome.
Osteonecrosis of the jaw (ONJ) occurred in <1% of patients treated with Cabozantinib.
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 Cabozantinib and periodically during Cabozantinib. Advise patients regarding good oral hygiene practices. Withhold Cabozantinib for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold Cabozantinib for development of ONJ until complete resolution, resume at a reduced dose.
Wound complications occurred with Cabozantinib. Withhold Cabozantinib for at least 3 weeks prior to elective surgery. Do not administer Cabozantinib for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of Cabozantinib after resolution of wound healing complications has not been established.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, can occur with Cabozantinib.Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue Cabozantinib in patients who develop RPLS.
Thyroid dysfunction, primarily hypothyroidism, has been observed with Cabozantinib. Based on the safety population, thyroid dysfunction occurred in 19% of patients treated with Cabozantinib, including Grade 3 in 0.4% of patients.
Patients should be assessed for signs of thyroid dysfunction prior to the initiation of Cabozantinib and monitored for signs and symptoms of thyroid dysfunction during Cabozantinib treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated.
Cabozantinib can cause hypocalcemia. Based on the safety population, hypocalcemia occurred in 13% of patients treated with Cabozantinib, including Grade 3 in 2% and Grade 4 in 1% of patients. Laboratory abnormality data were not collected in CABOSUN.
In COSMIC-311, hypocalcemia occurred in 36% of patients treated with Cabozantinib, including Grade 3 in 6% and Grade 4 in 3% of patients.
Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue Cabozantinib depending on severity.
Based on data from animal studies and its mechanism of action, Cabozantinib can cause fetal harm when administered to a pregnant woman. Cabozantinib administration to pregnant animalsduring 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 Cabozantinib and for 4 months after the last dose.
from FDA，2023.09
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