CABOMETYX
Clinical safety rating: caution
Comprehensive clinical and safety monograph for CABOMETYX (CABOMETYX).
Cabozantinib is a small molecule inhibitor of multiple receptor tyrosine kinases, including MET, VEGFR2, RET, AXL, KIT, and FLT3. It inhibits tumor growth, angiogenesis, and metastasis by blocking these pathways.
| Metabolism | Primarily metabolized by CYP3A4. Minor contributions from CYP2C8 and CYP2C9. |
| Excretion | Primarily fecal (54%) with minimal renal excretion (27% unchanged drug; <10% as metabolites). Biliary excretion contributes to fecal elimination. |
| Half-life | Terminal half-life approximately 99 hours (range 80–120 h). Supports once-daily dosing with steady-state achieved within 15 days. |
| Protein binding | ≥99.5% bound to plasma proteins (primarily albumin and alpha-1-acid glycoprotein). |
| Volume of Distribution | Vd approximately 319 L (4.5 L/kg based on 70 kg), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability approximately 20% (range 12–30%). |
| Onset of Action | Oral: Clinical effect onset within 2–4 weeks; maximum plasma concentration reached 2–4 hours post-dose. |
| Duration of Action | Duration corresponds to dosing interval (24 hours) with sustained target inhibition. Continuous daily dosing required for therapeutic effect. |
60 mg orally once daily for the first 21 days of a 21-day cycle, with or without food, for renal cell carcinoma; for hepatocellular carcinoma, 60 mg orally once daily.
| Dosage form | TABLET |
| Renal impairment | For mild to moderate renal impairment (CrCl 30-89 mL/min): no adjustment recommended. For severe renal impairment (CrCl 15-29 mL/min): reduce dose to 40 mg orally once daily. For end-stage renal disease (CrCl <15 mL/min): not recommended. |
| Liver impairment | For mild hepatic impairment (Child-Pugh A): no adjustment recommended. For moderate hepatic impairment (Child-Pugh B): reduce dose to 40 mg orally once daily. For severe hepatic impairment (Child-Pugh C): not recommended. |
| Pediatric use | Safety and efficacy not established in pediatric patients. No recommended dosing. |
| Geriatric use | No specific dose adjustment required for elderly patients. Monitor for adverse events such as hypertension, fatigue, and diarrhea more frequently. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for CABOMETYX (CABOMETYX).
| Breastfeeding | No human data; cabozantinib is excreted in rat milk. M/P ratio not determined. Due to potential adverse effects in nursing infants (e.g., growth impairment, angiogenesis inhibition), breastfeeding is contraindicated during treatment and for at least 4 weeks after the last dose. |
| Teratogenic Risk | Cabozantinib is embryotoxic and teratogenic in animal studies. Based on its mechanism of action (VEGFR, MET, RET, TAM kinase inhibitor) and animal data, there is a risk of fetal harm if used during pregnancy. First trimester exposure carries the highest risk for major malformations; second and third trimester exposure may cause fetal growth retardation, oligohydramnios, and placental dysfunction. Avoid use in pregnancy unless no safer alternative. |
■ FDA Black Box Warning
Hemorrhage: Severe and fatal hemorrhages occur more frequently with cabozantinib than placebo. Do not administer to patients with recent history of hemorrhage or hemoptysis.
| Serious Effects |
["None absolute; avoid use in patients with recent hemorrhage or hemoptysis"]
| Precautions | ["Hemorrhage","Gastrointestinal perforations and fistulas","Thrombotic events (venous and arterial)","Hypertension including hypertensive crisis","Reversible posterior leukoencephalopathy syndrome (RPLS)","Diarrhea, hand-foot skin reaction, proteinuria, wound healing complications"] |
| Food/Dietary | Avoid grapefruit and grapefruit juice (increase cabozantinib exposure). Take cabozantinib on an empty stomach (at least 1 hour before or 2 hours after eating). Avoid high-fat meals as they may increase absorption and side effects. |
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| Fetal Monitoring | Monitor for hypertension (closely, especially in preeclampsia), proteinuria, hypothyroidism, hemorrhage, thromboembolic events, wound healing complications, and gastrointestinal perforation. Assess fetal growth and amniotic fluid volume via ultrasound every 4-6 weeks. Monitor maternal CBC, liver and renal function, thyroid panel, and urinalysis periodically. |
| Fertility Effects | Cabozantinib may impair fertility in both male and female patients. In females, it caused irregular estrous cycles and reduced fertility in rats; in males, testicular atrophy and reduced sperm count were observed. Reversibility unknown; advise discussing fertility preservation options before treatment. |
| Clinical Pearls | Monitor for hepatotoxicity; obtain LFTs at baseline and regularly. Cabozantinib inhibits multiple tyrosine kinases including VEGFR2, MET, RET, AXL. Dose reduction required for moderate hepatic impairment. Avoid strong CYP3A4 inducers and inhibitors. Manage hypertension with antihypertensives; monitor BP weekly for first 6 weeks. Increase risk of bleeding; avoid in patients with recent hemorrhage. Monitor for proteinuria. Thyroid dysfunction common; check TSH at baseline and periodically. Palmar-plantar erythrodysesthesia syndrome (hand-foot skin reaction) is frequent; manage with supportive measures and dose interruption/reduction. Osteonecrosis of the jaw risk; perform dental exam before therapy. Reversible posterior leukoencephalopathy syndrome (RPLS) reported; discontinue if symptoms occur. |
| Patient Advice | Do not crush, cut, or chew tablets; swallow whole. · Take at least 1 hour before or 2 hours after a meal. Do not eat grapefruit or drink grapefruit juice while on this medication. · Report any signs of bleeding (unusual bruising, black/bloody stools, coughing up blood) immediately. · Monitor blood pressure at home and report high readings to your doctor. · Use effective contraception during treatment and for 4 months after the last dose. · Avoid sun exposure; use sunscreen and protective clothing as this medication can increase skin sensitivity. · Report symptoms of liver problems (yellowing skin/eyes, dark urine, abdominal pain) or thyroid changes (fatigue, weight changes, heat/cold intolerance). · Seek immediate medical help if you experience severe headache, vision changes, confusion, or seizures (signs of RPLS). · Your doctor may need to adjust the dose based on side effects; do not change the dose on your own. · Keep all appointments for blood tests and check-ups. |