CABOZANTINIB
Clinical safety rating: caution
Comprehensive clinical and safety monograph for CABOZANTINIB (CABOZANTINIB).
Small molecule tyrosine kinase inhibitor that targets MET, VEGFR2, RET, AXL, KIT, TIE2, FLT3, and TRKB. Inhibits tumor growth, angiogenesis, and metastasis.
| Metabolism | Primarily metabolized by CYP3A4; minor contribution from CYP2C8 and CYP2C9. |
| Excretion | Primarily fecal (approximately 54% of administered dose as unchanged drug and metabolites), with renal excretion accounting for approximately 27% (largely as metabolites). Mean total recovery in feces and urine is about 81%. |
| Half-life | Terminal elimination half-life is approximately 99 hours (range 68–136 hours) in patients with advanced solid tumors, supporting once-daily dosing. |
| Protein binding | Highly protein bound (≥99.7%) primarily to human serum albumin. |
| Volume of Distribution | Volume of distribution is approximately 319 L (geometric mean) in patients, exceeding total body water, indicating extensive tissue distribution. Not typically normalized per kg, but estimated ~4–5 L/kg. |
| Bioavailability | Absolute bioavailability in humans has not been determined; however, oral absorption is good, and food has no meaningful effect on exposure. The relative bioavailability is considered high based on systemic exposure data. |
| Onset of Action | Time to peak plasma concentration (Tmax) is 2–5 hours after oral administration; onset of clinical effect (tumor response) is expected after 2–4 weeks of continuous dosing. |
| Duration of Action | Duration of action is approximately 24 hours due to once-daily dosing; steady-state is reached within 15 days. Clinical benefit (e.g., tumor shrinkage) is assessed after 8–12 weeks. |
60 mg orally once daily, taken without food (at least 1 hour before or 2 hours after eating).
| Dosage form | TABLET |
| Renal impairment | For mild to moderate renal impairment (CrCl 30-89 mL/min): no dose adjustment required. For severe renal impairment (CrCl 15-29 mL/min): reduce dose to 40 mg once daily. For end-stage renal disease (CrCl <15 mL/min): not recommended. |
| Liver impairment | Child-Pugh A: no dose adjustment. Child-Pugh B: reduce starting dose to 40 mg once daily. Child-Pugh C: not recommended. |
| Pediatric use | Not approved for pediatric patients. Safety and efficacy not established. |
| Geriatric use | Patients aged ≥65 years show increased risk of adverse reactions (e.g., fatigue, hypertension, palmar-plantar erythrodysesthesia). No specific dose adjustment; monitor closely. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for CABOZANTINIB (CABOZANTINIB).
| Breastfeeding | No human data on excretion in breast milk. M/P ratio unknown. Theoretical risk of severe adverse effects in nursing infant due to high protein binding and long half-life. Contraindicated during breastfeeding. |
| Teratogenic Risk | Cabozantinib is embryotoxic and teratogenic in animal studies. In humans, category D: first trimester exposure carries risk of major congenital malformations including cardiac, skeletal, and CNS defects. Second and third trimester exposure may cause fetal growth restriction, oligohydramnios, and placental insufficiency due to antiangiogenic effects. Use contraindicated in pregnancy. |
■ FDA Black Box Warning
None
| Serious Effects |
["None known"]
| Precautions | ["Hemorrhage","Gastrointestinal perforation/fistula","Thrombotic events","Hypertension","Proteinuria","Reversible posterior leukoencephalopathy syndrome","Osteonecrosis of the jaw","Wound healing complications","Thyroid dysfunction","Adrenal insufficiency","Pregnancy and reproductive toxicity"] |
| Food/Dietary | Avoid grapefruit, grapefruit juice, and Seville oranges. Take on an empty stomach at least 1 hour before or 2 hours after eating. High-fat meals increase absorption; maintain consistent timing relative to meals. |
| Clinical Pearls |
Loading safety data…
| Fetal Monitoring | Pre-pregnancy: negative serum pregnancy test. If unintentional exposure, serial fetal ultrasound for growth, amniotic fluid volume, and anatomy. Maternal monitoring of blood pressure, proteinuria, liver function, and thyroid function. After delivery, neonatal assessment for growth parameters and organ function. |
| Fertility Effects | Cabozantinib may impair fertility in males and females based on animal studies (decreased spermatogenesis, ovarian effects). In humans, reversible amenorrhea and oligospermia possible. Advise fertility preservation counseling prior to treatment. |
| Cabozantinib is a multikinase inhibitor targeting MET, VEGFR2, RET, AXL, and KIT. Monitor for hypertension, diarrhea, palmar-plantar erythrodysesthesia, and hypothyroidism. Dose reduce for moderate hepatotoxicity. Avoid in patients with recent GI perforation or fistula. Check UTI and proteinuria regularly. |
| Patient Advice | Take cabozantinib on an empty stomach, at least 1 hour before or 2 hours after a meal. · Swallow capsules whole; do not crush or open. · Avoid grapefruit, grapefruit juice, and Seville oranges due to CYP3A4 interaction. · Report severe diarrhea, blood in stool, or abdominal pain immediately. · Use effective contraception during treatment and for 4 months after. · Avoid sun exposure; use sunscreen and protective clothing. · Do not breastfeed during therapy. |