Cometriq (cabozantinib)

Cometriq (cabozantinib) is a prescription medicine used to treat people with medullary thyroid cancer that has spread to other parts of the body.

It is not known if Cometriq is safe and effective in children.

WARNING

PERFORATIONS AND FISTULAS, and HEMORRHAGE

Perforations and fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of Cometriq-treated patients. Discontinue Cometriq for perforation or for fistula formation.

Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of Cometriq-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer Cometriq to patients with severe hemorrhage.

Cometriq may cause serious side effects, including:

• a tear in your stomach or intestinal wall (perforation) or an abnormal connection between 2 partsof your body (fistula) that may lead to death. Tell your healthcare provider right away if you get tenderness or pain in your stomach-area (abdomen).
• bleeding (hemorrhage). Cometriq can cause severe bleeding that may lead to death. Tell your healthcare provider right away if you get any signs of bleeding during treatment with Cometriq, including:
  • coughing up blood or blood clots
  • vomiting blood or if your vomit looks like coffee-grounds
  • red or black (looks like tar) stools
  • menstrual bleeding that is heavier than normal
  • any unusual or heavy bleeding
• blood clots, stroke, heart attack, and chest pain. Get emergency help right away if you get:
  • swelling or pain in your arms or legs
  • shortness of breath
  • feel lightheaded or faint
  • sweating more than usual
  • numbness or weakness of your face, arm or leg, especially on one side of your body
  • sudden confusion, trouble speaking or understanding
  • sudden trouble seeing in one or both eyes
  • sudden trouble walking
  • dizziness, loss of balance or coordination
  • a sudden severe headache
• wound healing problems. Wound healing problems have happened in some people who take Cometriq. Tell your healthcare provider if you plan to have any surgery before or during treatment with Cometriq.
  • You should stop taking Cometriq at least 3 weeks before planned surgery.
  • Your healthcare provider should tell you when you may start taking Cometriq again after surgery.
• high blood pressure (hypertension). Hypertension is common with Cometriq and can be severe. Your healthcare provider will check your blood pressure before starting Cometriq and during treatment with Cometriq. If needed, your healthcare provider may prescribe medicine to treat your high blood pressure.
• severe jaw bone problems (osteonecrosis). Symptoms may include jaw pain, toothache, or sores on your gums. Your healthcare provider should examine your mouth before you start and during treatment with Cometriq. Tell your dentist that you are taking Cometriq. It is important for you to practice good mouth care during treatment with Cometriq.
• diarrhea. Diarrhea is common with Cometriq and can be severe. If needed, your healthcare provider may prescribe medicine to treat your diarrhea. Tell your healthcare provider right away, if you have frequent loose, watery bowel movements.
• a skin problem called hand-foot skin reaction. Hand-foot skin reactions are common with Cometriq and can be severe. Tell your healthcare provider right away if you have rashes, redness, pain, swelling, or blisters on the palms of your hands or soles of your feet.
• protein in your urine and possible kidney problems. Symptoms may include swelling in your hands, arms, legs, or feet.
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS). A condition called reversible posterior leukoencephalopathy syndrome can happen during treatment with Cometriq. Tell your healthcare provider right away if you have headaches, seizures, confusion, changes in vision, or problems thinking.

Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with Cometriq if you have certain side effects.

The most common side effects of Cometriq are:

• diarrhea
• redness, swelling or pain in your mouth or throat, or mouth sores. Tell your healthcare provider if these symptoms prevent you from eating or drinking.
• weight loss
• decreased appetite
• nausea
• tiredness
• hair color turning lighter
• change in taste
• pain in your abdomen
• constipation
• increased liver function blood tests
• decreased calcium and phosphate blood levels
• decreased white blood cell counts
• decreased platelet counts
• increased bilirubin blood levels

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Cometriq. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA1088.

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

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 hypertensive crisis
• reversible posterior leukoencephalopathy syndrome

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 2 to 3 days after discontinuation of the strong inhibitor.

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 2 to 3 days after discontinuation of the strong inducer.
• The daily dose of Cometriq should not exceed 180 mg.

Dosage Modifications For Patients With Hepatic Impairment

• The recommended starting dose of Cometriq for patients with mild to moderate hepatic impairment is 80 mg.

Effect Of CYP3A4 Inhibitors

• Administration of a strong CYP3A4 inhibitor, ketoconazole to healthy subjects increased single-dose plasma cabozantinib exposure by 38%.
• Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) while taking Cometriq or reduce the dosage of Cometriq if concomitant use with strong CYP3A4 inhibitors cannot be avoided.
• Avoid ingestion of foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 while taking Cometriq.

Effect Of CYP3A4 Inducers

• Administration of a strong CYP3A4 inducer, rifampin to healthy subjects decreased single-dose plasma cabozantinib exposure by 77%.
• Avoid chronic co-administration of strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s Wort) with Cometriq or increase the dosage of Cometriq if concomitant use with strong CYP3A4 inducers cannot be avoided.

Effect Of MRP2 Inhibitors

• Concomitant administration of MRP2 inhibitors may increase the exposure to cabozantinib.
• Monitor patients for increased toxicity when MRP2 inhibitors (e.g., abacavir, adefovir, cidofovir, furosemide, lamivudine, nevirapine, ritonavir, probenecid, saquinavir, and tenofovir) are co-administered with Cometriq.

• 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.
• 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, a lactating woman should not breastfeed during treatment with Cometriq and for 4 months after the final dose.