20mg 40mg 60mg Cabozantinib XL184 Cancer Treatment Tablets

【Drug Name】
English name: Cabozantinib

Other names: cabozantinib/XL184

【Indications】
Treatment of progressive, unresectable locally advanced or metastatic medullary thyroid cancer.

Advanced kidney cancer that has failed Sutent.

【Dosage form and specification】
Tablets: 20mg, 40mg, 60mg.

【Dosage】

Dosage and Administration

Recommended dosage

• Do not substitute cabozantinib capsules for cabozantinib tablets.
• The recommended daily dose of cabozantinib is 60 mg. Do not take cabozantinib with food.
• Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking cabozantinib.
• Treatment is continued until the patient no longer experiences clinical benefit or experiences unacceptable toxicity.
• Swallow the cabozantinib tablet whole; do not crush the cabozantinib tablet.
• Do not take the missed dose within 12 hours of your next dose.

Do not consume foods (e.g., grapefruit, grapefruit juice) or nutritional supplements known to inhibit cytochrome P450 during cabozantinib treatment.

Dosage adjustment

Discontinue treatment with cabozantinib at least 28 days before scheduled surgery in patients undergoing surgery, including dental surgery. National Cancer Institute Common Terms for Adverse Events [NCI CTCAE] Grade 4 adverse reactions, and for grade 3 or intolerable grade 2 adverse reactions, withhold cabozantinib when a dose reduction or supportive medical management is not possible.

Upon resolution/improvement of an adverse reaction (i.e., return to baseline or resolution to grade 1), reduce the dose as follows:

• As previously receiving the 60 mg daily dose, resume treatment at 40 mg daily.
• As previously receiving the 40 mg daily dose, resume treatment at 20 mg daily.
• If previously receiving a 20 mg daily dose, if tolerance is restored at 20 mg, otherwise, discontinue cabozantinib.

Permanently discontinue cabozantinib for any of the following conditions:

• Severe bleeding from fistula or GI perforation that cannot be treated
• Arterial thromboembolic events (eg, myocardial infarction, cerebral infarction)

【Warnings and Precautions】
Bleeding Serious bleeding occurred with cabozantinib

• Grade ≥ 3 bleeding events occurred in 2.1% of cabozantinib-treated patients
• and 1.6% in everolimus-treated patients.
• Fatal bleeding also occurred during the cabozantinib clinical program. Do not give cabozantinib to patients with or at risk for severe bleeding

GI perforation and fistula in a randomized renal cell carcinoma study

• Fistulas were reported in 1.2% of cabozantinib-treated patients (including 0.6% anal fistulas) and in 0% of everolimus-treated patients.

Gastrointestinal (GI) perforation was reported in 0.9% of cabozantinib-treated patients and 0.6% of everolimus-treated patients. Fatal perforation occurred during the cabozantinib clinical program. Monitor patients for symptoms of fistulas and perforations. Discontinue cabozantinib in patients who experience a fistula that cannot be managed appropriately or a GI perforation

thrombotic events

• Cabozantinib treatment is associated with an increased incidence of thrombotic events.
• Venous thromboembolism was reported in 7.3% of cabozantinib-treated patients and 2.5% of everolimus-treated patients.
• Pulmonary embolism occurred in 3.9% of cabozantinib-treated patients and 0.3% of everolimus-treated patients.
• Arterial thromboembolic events were reported in 0.9% of cabozantinib-treated patients and 0.3% of everolimus-treated patients.

A fatal thrombotic event occurred during the cabozantinib clinical program. Discontinue cabozantinib in patients who experience an acute myocardial infarction or any other arterial thromboembolic comorbidity

Hypertension and hypertensive crisis

• Cabozantinib treatment resulted in an increased incidence of treatment-emergent hypertension.
• Hypertension was reported in 37% (15% ≥ grade 3) of cabozantinib-treated patients and 7.1% (3.1% ≥ grade 3) of everolimus-treated patients.
• Monitor blood pressure before starting cabozantinib and regularly during treatment, and withhold cabozantinib for hypertension that cannot be adequately controlled with medical treatment;
• When controlled, resume cabozantinib at reduced dose.
• Discontinue cabozantinib in severe hypertension not controlled with anti-hypertensive therapy.

Discontinue cabozantinib if medically managed hypertensive crisis or evidence of severe hypertension

• Diarrhea occurred in 74% of patients treated with cabozantinib and in 28% of patients treated with everolimus
• Grade 3 diarrhea occurred in 11% of cabozantinib-treated patients and 2% of everolimus-treated patients.
• Withhold cabozantinib in patients who develop intolerable Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be treated with standard antidiarrheal treatment until improvement to Grade 1;
• Resume cabozantinib at reduced dose. Dose modification due to diarrhea in 26% of patients

Palmoplantar dysesthesia syndrome

• Palmoplantar erythrodysesthesia syndrome (PPES) occurred in 42% of patients treated with cabozantinib and in 6% of patients treated with everolimus.
• Grade 3 PPES occurred in 8.2% of cabozantinib-treated patients and <1% of everolimus-treated patients.
• Patients who cannot tolerate grade 2 PPES or grade 3 PPES will not be given cabozantinib until they improve to grade 1;
• Resume cabozantinib at reduced dose. PPES dose modification occurred in 16% of patients.

reversible posterior leukoencephalopathy syndrome

• Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome diagnosed by characteristic findings on MRI of subcortical angioedema, occurred during the cabozantinib clinical program. Any patient with epilepsy, headache, visual impairment, confusion, or changes in mental function should be evaluated for RPLS. Discontinue cabozantinib in patients who develop RPLS.

Embryo-fetal toxicity

• Based on data from animal studies and its mechanism of action, cabozantinib may cause fetal harm when administered to pregnant women. Cabozantinib caused embryofetal lethality when administered to pregnant animals during organogenesis at exposures below clinically recommended doses, and increased incidence of skeletal mutations in rats and visceral mutations and malformations in rabbits. Advise pregnant women of the potential risks to the fetus. Advise females of reproductive potential to use effective contraception during treatment with cabozantinib and for 4 months after the last dose.

​【Adverse reactions】

• The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, nausea, anorexia, palmoplantar erythrodysesthesia syndrome (PPES), hypertension, vomiting, weight loss, and constipation.

[Use among special groups]
pregnancy risks

• Summary Based on findings from animal studies and its mechanism of action, cabozantinib can cause fetal harm when administered to a pregnant woman. There are no data available to inform drug-associated risks in pregnant women. In animal developmental and reproductive toxicology studies, administration of cabozantinib to pregnant rats and rabbits during organogenesis resulted in embryofetal lethality and structural abnormalities at exposures lower than clinically occurring at recommended doses. Advise pregnant women or women of childbearing potential of the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage in the indication population is not known. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. Data Animal Data In a study of embryofetal development in pregnant rats, oral administration of cabozantinib daily throughout the period of organogenesis resulted in increased embryofetal lethality compared with control at a dose of 0.03 mg/kg (at the recommended dose human AUC of approximately 0.12- times). Findings included delayed ossification and skeletal variability at a dose of 0.1 mg/kg/day (approximately 0.04-times the human AUC at the recommended dose). In pregnant rabbits, daily administration of cabozantinib throughout the period of organogenesis resulted in findings and variations in visceral malformations including reduced spleen size and missing lung lobes at 3 mg/kg (approximately 1.1-fold the human AUC at the recommended dose). In a perinatal study in rats, cabozantinib was administered orally from day 10 of pregnancy to day 20 postpartum. Cabozantinib did not produce adverse maternal toxicity or affect pregnancy, parturition, or lactation in female rats at doses up to 0.3 mg/kg/day (0.05-times the maximum recommended clinical dose), and did not affect offspring survival, growth, or postnatal development .

Breastfeeding risks

• Summary There are no data regarding the presence of cabozantinib or its metabolites in human milk, or their effects on the breastfed infant, or on milk production. Because of the potential for serious adverse reactions in a breastfed infant from cabozantinib, advise a nursing woman not to breastfeed during treatment with cabozantinib and for 4 months after the final dose.

reproductive potential

• Female and Male Contraception Female Cabozantinib may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with cabozantinib and for 4 months after the final dose. Infertility in Women and Men Based on findings in animals, reproductive potential Cabozantinib may impair fertility in women and men.

For children

• The safety and effectiveness of cabozantinib have not been studied in pediatric patients. Juvenile Animal Data Juvenile rats were administered cabozantinib at doses of 1 or 2 mg/kg/day from postpartum day 12 (comparable to humans younger than 2 years of age) through postpartum day 35 or 70. At doses equal to or greater than 1 mg/kg/day (approximately 0.16 times the clinical dose of 60 mg/day based on body surface area). Low activity was observed at both test doses on postpartum day 22. Targets are generally similar to those seen in adult animals, occur at both doses, and include the kidneys (nephropathy, glomerulonephritis), reproductive organs, gastrointestinal tract (cystic dilation and hyperplasia of Brenner's glands, and duodenum). intestinal inflammation; and epithelial hyperplasia of the colon and cecum), bone marrow (hypocellularity and lymphodepletion), and liver. Teeth abnormalities and whitening at all dose levels as well as effects on bone include reduced mineral content and density, epiphyseal hypertrophy, and cortical bone loss. Recovery was not assessed at the 2 mg/kg dose level due to high levels of mortality (approximately 0.32 times the clinical dose of 60 mg based on body surface area). At low dose levels, effects on bone parameters were partially resolved but effects on kidneys and epididymis/testes persisted after cessation of treatment.

Used by the elderly

• In the Phase 3 study, 41% of patients treated with cabozantinib were age 65 and older, and 8% were age 75 and older. No differences in safety or efficacy were observed between older and younger patients.

liver damage

• Increased exposure to cabozantinib has been observed in patients with mild to moderate hepatic impairment. Reduce cabozantinib dose in patients with mild (Child-Pugh score (C-P) A) or moderate (C-P B) hepatic impairment. It is recommended not to use cabozantinib in patients with severe hepatic impairment.
• Renal Impairment No dose adjustment is required in patients with mild or moderate renal impairment. There is no experience with CABOMETYX in patients with severe renal impairment.

【store】

• Store cabozantinib at 20°C to 25°C (68°F to 77°F); excursions allowed from 15°C to 30°C (59°F to 86°F).