CABOMETYX

Cabozantinib was first approved in and is a non-specific tyrosine kinase inhibitor.

It was initially approved in the US under the brand name Cometriq, which is indicated for the treatment of metastatic medullary thyroid cancer.

In 2016, a capsule formulation (Cabometyx) was approved for the treatment of advanced renal cell carcinoma, and this same formulation gained additional approval in both the US and Canada in for the treatment of hepatocellular carcinoma in previously treated patients. 7, 8 Cabometyx has since been granted several additional approvals for endocrine cancers, including differentiated thyroid cancer and neuroendocrine tumors.

Cabozantinib, marketed under the brand name Cometriq, is indicated for the treatment of progressive, metastatic medullary thyroid cancer (MTC).

Cabozantinib, marketed under the brand name Cabometyx, is indicated for the treatment of renal cell carcinoma, alone or as a first-line therapy in combination with nivolumab.

It is also indicated for the treatment of hepatocellular carcinoma in patients previously treated with sorafenib.

Cabozantanib,marketed under the brand name Cabometyx, is also indicated in adult and pediatric patients ≥12 years of age for the treatment of: Locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy in patients who are radioactive iodine-refractory or ineligible 9 Previously treated, unresectable, locally advanced or metastatic, well-differentiated pancreatic neuroendocrine tumors (pNET) 9 Previously treated, unresectable, locally advanced or metastatic, well-differentiated extra-pancreatic neuroendocrine tumors (epNET)

Cabozantinib suppresses metastasis, angiogenesis, and oncognesis by inhibiting receptor tyrosine kinases.

Hepatocyte growth factor receptor Inhibitor

Proto-oncogene tyrosine-protein kinase receptor Ret Inhibitor Vascular endothelial growth factor receptor 2 Inhibitor + 10 more targets.

After oral administration, peak plasma concentration was achieved in 2-5 hours.

The volume of distribution is 349 L.

Cabozantinib is metabolized mostly by

CYP3A4 and, to a minor extent, by CYP2C9.

Both enzyme produce an

N-oxide metabolite.

Cabozantinib is eliminated mostly by the feces (54%) and also by the urine (27%).

Cabozantinib has a long half-life of 55 hours.

At steady state, the clearance is 4.4 L/hr.

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Cabozantinib carries a warning of serious gastrointestinal fistulas and perforations, and potentially fatal hemoptysis and gastrointestinal hemorrhage.

140 mg orally, once daily.

Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ.

Do NOT substitute

COMETRIQ capsules with cabozantinib tablets.

The recommended starting dose of COMETRIQ is 80 mg in patients with mild or moderate hepatic impairment. 2.1 Recommended Dosage Do NOT substitute COMETRIQ capsules with cabozantinib tablets.

The recommended daily dose of

COMETRIQ is 140 mg once daily without food until disease progression or unacceptable toxicity.

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 while taking COMETRIQ. 2.2 Dosage Modifications for Adverse Reactions Withhold COMETRIQ for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions, intolerable Grade 2 adverse reactions, or osteonecrosis of the jaw.

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 If previously receiving 100 mg daily dose, resume treatment at 60 mg daily 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 gastrointestinal (GI) perforation or Grade 4 fistula severe hemorrhage acute myocardial infarction or arterial or venous thromboembolic events that require medical intervention nephrotic syndrome severe hypertension that cannot be controlled with anti-hypertensive therapy or Grade 4 hypertension reversible posterior leukoencephalopathy syndrome cardiac failure, depending on severity 2.3 Dosage Modifications for Coadministration with Strong CYP3A4 Inhibitors 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 to 3 days after discontinuation of the strong inhibitor. 2.4 Dosage Modifications for Coadministration with Strong CYP3A4 Inducers 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 to 3 days after discontinuation of the strong inducer.

The daily dose of

COMETRIQ should not exceed 180 mg. 2.5 Dosage Modifications for Patients with Hepatic Impairment The recommended starting dose of COMETRIQ for patients with mild to moderate hepatic impairment is 80 mg.

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) 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) .

Based on findings from animal studies and its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman.

There are no available data in pregnant women to inform the drug-associated risk.

In animal developmental and reproductive toxicology studies administration of cabozantinib to pregnant rats and rabbits during organogenesis resulted in embryofetal lethality and structural anomalies at exposures that were below those occurring clinically at the recommended dose.

Advise pregnant women or women of childbearing potential of the potential hazard to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

In an embryo-fetal development study in pregnant rats, daily oral administration of cabozantinib throughout organogenesis caused increased embryo-fetal lethality compared to controls at a dose of 0.03 mg/kg (less than 1% of the human exposure by AUC at the 140 mg dose).

Findings included delayed ossifications and skeletal variations at a dose of 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the 140 mg dose).

In pregnant rabbits, daily oral administration of cabozantinib throughout organogenesis resulted in 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 140 mg dose).

In a pre.

• and postnatal study in rats, cabozantinib was administered orally from gestation day 10 through postnatal day 20.

Cabozantinib did not produce adverse maternal toxicity or affect pregnancy, parturition or lactation of female rats, and did not affect the survival, growth or postnatal development of the offspring at doses up to 0.3 mg/kg/day (approximately 0.02 times the recommended clinical dose of 140 mg based on body surface area).

There is no information regarding the presence of cabozantinib or its metabolites in human milk, or their effects on the breastfed infant, or milk production.

Because of the potential for serious adverse reactions in a breastfed infant from COMETRIQ, advise a lactating woman not to breastfeed during treatment with COMETRIQ and for 4 months after the final dose.

The safety and effectiveness of

COMETRIQ in pediatric patients have not been studied.

Juvenile rats were administered cabozantinib daily at doses of 1 or 2 mg/kg/day from Postnatal Day 12 (comparable to less than 2 years in humans) through Postnatal Day 35 or 70.

Mortalities occurred at doses equal and greater than 1 mg/kg/day (approximately 0.07 times the clinical dose of 140 mg/day based on body surface area).

Hypoactivity was observed at both doses tested on Postnatal Day 22.

Targets were generally similar to those seen in adult animals, occurred at both doses, and included the kidney (nephropathy, glomerulonephritis), reproductive organs, gastrointestinal tract (cystic dilatation and hyperplasia in Brunner’s gland and inflammation of duodenum; and epithelial hyperplasia of colon and cecum), bone marrow (hypocellularity and lymphoid depletion), and liver.

Tooth abnormalities and whitening as well as effects on bones including reduced bone mineral content and density, physeal hypertrophy, and decreased cortical bone also occurred at all dose levels.

Recovery was not assessed at the 2 mg/kg dose level (approximately 0.14 times the clinical dose of 140 mg based on body surface area) due to high levels of mortality.

At the low dose level, effects on bone parameters were partially resolved but effects on the kidney and epididymis/testis persisted after treatment ceased.

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.