COMETRIQ
Clinical safety rating: caution
Comprehensive clinical and safety monograph for COMETRIQ (COMETRIQ).
COMETRIQ (cabozantinib) is a multikinase inhibitor that targets MET, VEGFR2, RET, AXL, TIE2, and FLT3. It inhibits tumor growth and angiogenesis by blocking these receptor tyrosine kinases.
| Metabolism | Primarily metabolized by CYP3A4. Also undergoes amide hydrolysis and oxidation. |
| Excretion | Primarily fecal (approximately 43% of total radioactivity) and renal (approximately 60% of total radioactivity, with <10% as unchanged drug). |
| Half-life | Terminal elimination half-life is approximately 55 hours (range 30-100 hours), supporting once-daily dosing. |
| Protein binding | 99.7% bound to human plasma proteins, primarily albumin. |
| Volume of Distribution | Apparent volume of distribution (Vd/F) is approximately 406 L (5.8 L/kg for a 70 kg adult), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is approximately 55% under fed conditions; absorption increased by high-fat meal. |
| Onset of Action | Not well-defined; clinical effects observed within 2-4 weeks of continuous dosing orally. |
| Duration of Action | Sustained inhibition of receptor tyrosine kinases; continuous daily dosing required for therapeutic effect. |
| Molecular Weight | 501.5 |
60 mg orally once daily for 3 weeks, followed by a 1-week rest period (28-day cycle), until disease progression or unacceptable toxicity.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Insufficient data for severe renal impairment (CrCl <30 mL/min) or dialysis; use with caution. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce starting dose to 40 mg once daily. Child-Pugh C: not recommended. |
| Pediatric use | Safety and efficacy not established in pediatric patients; no recommended dose. |
| Geriatric use | No specific dose adjustment; monitor for adverse effects due to potential age-related renal/hepatic decline and comorbidities. |
| 1st trimester | Based on animal studies and mechanism of action, cabozantinib can cause fetal harm. There are no adequate and well-controlled studies in pregnant women. Avoid use during first trimester. |
| 2nd trimester | Cabozantinib is embryotoxic and teratogenic in animal studies. Use only if maternal benefit outweighs potential fetal risk. |
| 3rd trimester | Use during third trimester may cause fetal harm. Consider discontinuing prior to delivery if possible. |
Clinical note
Comprehensive clinical and safety monograph for COMETRIQ (COMETRIQ).
| Placental transfer | Based on molecular weight (501.5 Da) and animal studies, cabozantinib is likely to cross the placenta. |
| Breastfeeding | Unknown if cabozantinib is excreted in human milk. Due to potential for serious adverse reactions, advise women not to breastfeed during treatment and for at least 4 months after last dose. |
■ FDA Black Box Warning
None.
| Serious Effects |
PregnancyHypersensitivity to cabozantinib or any excipients in COMETRIQ
| Precautions | Hemorrhage: Severe and fatal hemorrhages can occur; do not administer to patients with recent hemorrhage., Gastrointestinal perforations and fistulas: Monitor for signs; discontinue if occur., Thrombotic events: Venous thromboembolism and arterial thromboembolism reported; discontinue if acute MI or other arterial thrombosis., Hypertension: Monitor blood pressure regularly; manage with antihypertensives; withhold if uncontrolled., Osteonecrosis of the jaw: Perform dental exam prior to therapy; avoid invasive dental procedures., Palmar-plantar erythrodysesthesia syndrome: Manage with supportive measures., Proteinuria: Monitor urine protein; discontinue if nephrotic syndrome., Reversible posterior leukoencephalopathy syndrome (RPLS): Discontinue if diagnosed., Impaired wound healing: Withhold for at least 28 days before elective surgery; do not administer until wound fully healed., Thyroid dysfunction: Monitor thyroid function., Hepatotoxicity: Monitor liver function; discontinue if severe. |
| Food/Dietary |
Loading safety data…
| Lactation Rating | L5 - Contraindicated |
| Teratogenic Risk | COMETRIQ (cabozantinib) is embryotoxic and teratogenic in animal studies. Based on its mechanism of action (VEGFR2, MET, RET, AXL inhibition) and animal data, there is a potential risk of fetal harm in all trimesters. Pregnancy should be excluded prior to initiation. Effective contraception is required during treatment and for at least 4 months after the last dose. In the first trimester, cabozantinib may cause major congenital malformations including cardiovascular and skeletal abnormalities. In the second and third trimesters, there is a risk of fetal growth restriction, oligohydramnios, and placental dysfunction due to anti-angiogenic effects. Use is contraindicated during pregnancy. |
| Fetal Monitoring | Pregnancy testing before treatment initiation and periodically during therapy. Contraception use verification. If pregnant, consider discontinuing cabozantinib and discuss potential risks. Monitor for fetal growth restriction and oligohydramnios via ultrasound if exposure occurs. Monitor maternal blood pressure, proteinuria, thyroid function, liver function, and electrolytes due to cabozantinib's toxicity profile. |
| Fertility Effects | Cabozantinib may impair fertility in both males and females based on animal studies. In female rats, ovarian and uterine atrophy, disrupted estrous cycles, and reduced fertility were observed at clinically relevant exposures. In male rats, decreased sperm counts, abnormal sperm morphology, and testicular degeneration were noted. Female reproductive potential may be compromised during treatment. Effects may be reversible after cessation, but data are lacking. |
| Avoid grapefruit and grapefruit juice as they may increase cabozantinib levels. Take on an empty stomach: at least 1 hour before or 2 hours after a meal. |
| Clinical Pearls | COMETRIQ (cabozantinib) is a multikinase inhibitor indicated for progressive, metastatic medullary thyroid cancer (MTC). Monitor for perforations and fistulas; discontinue if they occur. Severe hemorrhage and arterial thromboembolic events can occur. Manage hypertension and proteinuria; monitor blood pressure and urine protein periodically. Dose reductions may be necessary for adverse reactions. Avoid use in patients with recent history of hemorrhage. |
| Patient Advice | Take COMETRIQ on an empty stomach, at least 1 hour before or 2 hours after eating. · Do not crush or chew capsules; swallow whole. · Avoid grapefruit and grapefruit juice during treatment. · Report any signs of bleeding (e.g., black stools, unusual bruising) or new abdominal pain. · Use effective contraception during treatment and for at least 4 months after last dose. · Avoid pregnancy and breastfeeding; may cause fetal harm. · Notify your doctor if you experience severe diarrhea, nausea, or vomiting. · Have blood pressure and urine protein checked regularly. |