Cabozantinib

Indications

Cabozantinib is used for: Medullary thyroid carcinoma, Advanced renal cell carcinoma, Hepatocellular carcinoma

Adult Dose

Oral Metastatic medullary thyroid carcinoma, Unresectable locally advanced medullary thyroid carcinoma Adult: As Capsule: Initially, 140 mg once daily. Adjust dose in decrements of 40 mg daily, if necessary. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety or tolerability. This indication and dosage is specific for cap formulation. Do not use interchangeably with the tab formulation due to different bioequivalence. Advanced renal cell carcinoma, Hepatocellular carcinoma Adult: As Tablet: Initially, 60 mg once daily. Adjust dose in decrements of 20 mg daily, if necessary. Dose reduction, dosing interruption, or discontinuation may be required according to individual safety or tolerability. This indication and dosage is specific for tab formulation. Do not use interchangeably with the cap formulation due to different bioequivalence. Hepatic impairment Capsule Mild-to-moderate (Child-Pugh A or B): Reduce starting dose to 80 mg/day Moderate (Child-Pugh C): Not recommended Tablet Mild (Child-Pugh A): No dosage adjustment necessary Moderate (Child-Pugh B): Reduce starting dose to 40 mg/day Severe (Child-Pugh C): Avoid use

Child Dose

Renal Dose

Renal impairment Mild-to-moderate (CrCl >30 mL/min): No dosage adjustment necessary Severe (CrCl <30 mL/min): No experience

Administration

Should be taken on an empty stomach. Take at least 1 hr before or at least 2 hr after meals. Swallow whole, do not crush.

Contra Indications

History of haemorrhage or haemoptysis. Lactation.

Precautions

Increases risk of treatment-emergent hypertension; discontinue for severe hypertension that cannot be controlled with antihypertensive therapy. May impair wound healing; stop treatment at least 28 days prior to schedules surgery; withhold with dehiscence or wound healing complications requiring medical intervention. GI perforations and fistulas reported; monitor patients for symptoms of perforations and fistulas, including abscess and discontinue therapy in patients who experience a Grade 4 fistula or a GI perforation. Serious and fatal hemorrhage reported; do not administer to patients with risk for severe hemorrhage. Renal and hepatic impairment. Pregnancy.

Pregnancy-Lactation

Pregnancy Based on its mechanism of action, can cause fetal harm when administered to pregnant women Verify pregnancy status of females of reproductive potential before initiation Advise females of reproductive potential to use effective contraception during treatment and for 4 months after the final dose May impair male and female fertility Lactation Unknown whether distributed in breast milk Because of potential for serious adverse reactions in a breastfed infant from cabozantinib, advise females of reproductive potential to not breastfeed during treatment and for 4 months after the final dose

Interactions

Increased plasma concentration with strong CYP3A4 enzyme inhibitors (e.g. ketoconazole, itraconazole). Decreased plasma concentration with strong CYP3A4 enzyme inducers (e.g. rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine).

Side Effects

Side effects of Cabozantinib : >10% AST, ALT increased (86%) Diarrhea (63%) Hypertension, treatment-emergent (61%) Increased TSH (57%) Lymphopenia (53%) ALP increased (52%) Hypocalcemia (52%) Stomatitis (51%) Palmar-plantar erythrodysesthesia syndrome (50%) Weight decreased (48%) Appetite decreased (46%) Nausea (43%) Fatigue (41%) Oral pain (36%) Neutropenia (35%) Thrombocytopenia (35%) Dysgeusia (34%) Hair color changes, depigmentation, graying (34%) Hypertension (33%) Hypophosphatemia (28%) Constipation (27%) Abdominal pain (27%) Hypobilirubinemia (25%) Vomiting (24%) Asthenia (21%) Dysphonia (20%) Rash (19%) Dry skin (19%) Hypomagnesemia (19%) Hypokalemia (18%) Headache (18%) Alopecia (16%) Dizziness (14%) Arthralgia (14%) Palmar-plantar erythrodysesthesia syndrome, Grade 3 or 4 (13%) Dysphagia (13%) Muscle spasms (12%) Dyspepsia (11%) Erythema (11%) 1-10% Hyponatremia (10%) Hemorrhoids (9%) Musculoskeletal chest pain (9%) Anxiety (9%) Paresthesia (7%) Peripheral sensory neuropathy (7%) Dehydration (7%) Hyperkeratosis (7%) Hypotension (7%) Venous thromboembolism (6%) Peripheral neuropathy (5%) Non-GI fistula (4%) GI perforation (3%) Arterial thromboembolism (2%) Proteinuria (2%) GI fistula (1%) Osteonecrosis of the jaw (1%)

Mode of Action

Tyrosine kinase inhibitor that targets RET, MET, VEGFR-1, -2, and -3, KIT, TrkB, FLT-3, AXL, and TIE-2 pathways; these tyrosine kinases are involved in both normal cellular function and pathologic processes (eg, oncogenesis, metastasis, tumor angiogenesis, and maintenance of tumor microenvironment).