Cabozantinib

Uses

Cabozantinib is a kinase inhibitor used for the treatment of-

• Patients with advanced renal cell carcinoma (RCC)
• Patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib

• Pediatric Use: The safety and effectiveness of Cabozantinib in pediatric patients have not been established.
• Geriatric Use: No overall differences in safety or effectiveness were observed between these patients and younger patients.
• Renal Impairment: No dosage adjustment is recommended in patients with mild or moderate renal impairment.

Cabozantinib is also used to associated treatment for these conditions: Advanced Renal Cell Carcinoma, Hepatocellular Carcinoma, Metastatic Clear Cell Renal Cell Carcinoma, Progressive, metastatic Medullary thyroid cancer

How Cabozantinib works

Cabozantinib inhibits specific receptor tyrosine kinases such as VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, RET, MET, and TIE-2.

Dosage

Cabozantinib dosage

Recommended Dosage for Renal Cell Carcinoma: The recommended dosage of Cabozantinib is 60 mg once daily without food until the patient no longer experiences clinical benefit or experiences unacceptable toxicity.

Recommended Dosage for Hepatocellular Carcinoma: The recommended dosage of Cabozantinib is 60 mg once daily without food until disease progression or unacceptable toxicity.

• Stop treatment with Cabozantinib at least 28 days prior to scheduled surgery, including dental surgery
• Do not substitute Cabozantinib tablets with cabozantinib capsules.
• Do not administer Cabozantinib with food. Administer at least 1 hour before or at least 2 hours after eating
• Swallow Cabozantinib tablets whole. Do not crush Cabozantinib tablets.
• Do not take a missed dose within 12 hours of the next dose.
• Modify the dose for certain patients with hepatic impairment and for patients taking drugs known to strongly induce or inhibit CYP450

Side Effects

Cabozantinib may cause serious side effects, including:

• bleeding (hemorrhage)
• a tear in your stomach or intestinal wall (perforation) or an abnormal connection between 2
• parts of your body (fistula)
• blood clots, stroke, heart attack, and chest pain
• high blood pressure (hypertension)
• diarrhea
• a skin problem called hand-foot skin reaction
• protein in your urine and possible kidney problems

Toxicity

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

Precaution

• Hemorrhage: Do not administer Cabozantinib if recent history of hemorrhage.
• Perforations and Fistulas: Monitor for symptoms. Discontinue Cabozantinib for unmanageable fistula or GI perforation.
• Thrombotic Events: Discontinue Cabozantinib for myocardial infarction, cerebral infarction, or other serious thromboembolic events.
• Hypertension and Hypertensive Crisis: Monitor blood pressure regularly. Interrupt for hypertension that is not adequately controlled with anti-hypertensive therapy. Discontinue Cabozantinib for hypertensive crisis or severe hypertension that cannot be controlled with
• anti-hypertensive therapy.
• Diarrhea: May be severe. Interrupt Cabozantinib immediately until diarrhea resolves or decreases to Grade 1. Recommend standard antidiarrheal treatments.
• Palmar-plantar erythrodysesthesia (PPE): Interrupt Cabozantinib treatment until PPE resolves or decreases to Grade 1.
• Proteinuria: Monitor urine protein. Discontinue for nephrotic syndrome.
• Osteonecrosis of the jaw: Withhold Cabozantinib for at least 28 days prior to invasive dental procedures and for development of ONJ.
• Wound complications: Withhold Cabozantinib for dehiscence or complications requiring medical intervention. 
• Reversible posterior leukoencephalopathy syndrome (RPLS): Discontinue Cabozantinib.
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 4 months after the last dose.

Interaction

• Strong CYP3A4 inhibitors: Reduce the Cabozantinib dosage if coadministration cannot be avoided.
• Strong CYP3A4 inducers: Increase the Cabozantinib dosage if coadministration cannot be avoided.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase levels of cabozantinib.
• Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce serum levels of cabozantinib.
• Take on an empty stomach. Separate the administration of cabozantinib from food by at least 1 hour before or 2 hours after eating.
• Take with a full glass of water.

[Moderate] ADJUST DOSING INTERVAL: Food may alter the oral bioavailability of cabozantinib.

When healthy subjects were given a single 140 mg oral dose with a high-fat meal, cabozantinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 41% and 57%, respectively, relative to administration under fasting conditions.

In clinical studies, patients were administered cabozantinib without food.

GENERALLY AVOID: Coadministration with grapefruit juice is likely to increase the plasma concentrations of cabozantinib, which is primarily metabolized by CYP450 3A4.

However, the interaction has not been studied.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

MANAGEMENT: Cabozantinib should be administered at least one hour before or two hours after a meal.

The consumption of grapefruit, grapefruit juice, and supplements that contain grapefruit extract should be avoided.

Cabozantinib Hypertension interaction

[Moderate] The use of cabozantinib causes hypertension.

Blood pressure should be well-controlled prior to initiating cabozantinib and monitored and treated as needed with standard anti-hypertensive therapy.

It is recommended to reduce the dose in case of persistent hypertension despite use of anti-hypertensive medications and to discontinue therapy if hypertension is severe and persistent despite these measures.

Discontinue cabozantinib therapy for severe hypertension that cannot be controlled with anti-hypertensive therapy and if there is evidence of hypertensive crisis or severe hypertension despite optimal medical management.

Close monitoring is recommended.

Cabozantinib Drug Interaction

Major: doxorubicin, aspirin, apixabanModerate: paclitaxel protein-bound, umeclidinium / vilanterol, glycerinMinor: sulfamethoxazole / trimethoprimUnknown: charcoal, nifedipine, amphetamine / dextroamphetamine, zolpidem, zolpidem, amoxicillin / clavulanate, ubiquinone, copper gluconate, metoprolol, bioflavonoids, diazepam, cyanocobalamin, cholecalciferol

Cabozantinib Disease Interaction

Major: hemorrhagic eventsModerate: GI perforation, hepatic impairment, hypertension, renal impairment, RPL syndrome, thromboembolism, lung toxicity

Volume of Distribution

The volume of distribution is 349L.

Elimination Route

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

Half Life

Cabozantinib has a long half-life of 55 hours.

Clearance

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

Elimination Route

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

Pregnancy & Breastfeeding use

Based on findings from animal studies and its mechanism of action, Cabozantinib can cause fetal harm when administered to a pregnant woman. There is no information regarding the presence of Cabozantinib or its metabolites in human milk, or their effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with Cabozantinib and for 4 months after the final dose.

Acute Overdose

One case of overdosage was reported following administration of another formulation of cabozantinib; a patient inadvertently took twice the intended dose for 9 days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented.

Storage Condition

Store Cabozantinib at room temperature 20°C to 25°C

Innovators Monograph

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