BRAFTOVI
Clinical safety rating: caution
Comprehensive clinical and safety monograph for BRAFTOVI (BRAFTOVI).
BRAFTOVI (encorafenib) is a kinase inhibitor that targets BRAF V600E, V600K, and V600D mutant kinases, including BRAF V600E. It inhibits the MAPK/ERK signaling pathway by blocking the phosphorylation of MEK by BRAF, thereby reducing cell proliferation in BRAF-mutant tumors.
| Metabolism | Primarily metabolized by CYP3A4, with minor contributions from CYP2C8 and CYP3A5. The active metabolite, LHY685, is formed via N-dealkylation by CYP3A4. |
| Excretion | Primarily hepatic metabolism, with negligible renal excretion. Approximately 47% of a dose recovered in feces (mainly as metabolites) and 5% in urine. |
| Half-life | Terminal elimination half-life: ~30 hours (range 22–44 h) in patients; supports twice-daily dosing. |
| Protein binding | 97% bound to human plasma proteins (primarily albumin and alpha-1-acid glycoprotein). |
| Volume of Distribution | Steady-state volume of distribution (Vd/F) ~510 L (≈7.3 L/kg for a 70 kg adult), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability ≈ 50% (range 42–62%) under fasting conditions; increased by high-fat meal (Cmax ↑ 1.5-fold, AUC ↑ 1.3-fold). |
| Onset of Action | Oral: Clinical benefit (tumor response) typically assessed after 4–8 weeks of continuous dosing; no acute onset. |
| Duration of Action | Sustained with continuous dosing; treatment continues until disease progression or unacceptable toxicity. |
450 mg (6 capsules of 75 mg) orally once daily in combination with binimetinib 45 mg orally twice daily, 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). Not studied in severe renal impairment (CrCl <30 mL/min) or ESRD. |
| Liver impairment | Mild hepatic impairment (Child-Pugh A): no adjustment. Moderate (Child-Pugh B): reduce dose to 300 mg (4 capsules) once daily. Severe (Child-Pugh C): not recommended. |
| Pediatric use | Safety and efficacy not established in pediatric patients. No weight-based guidelines available. |
| Geriatric use | No specific dose adjustments required for elderly patients based on age alone. Monitor renal function and for increased risk of adverse events such as rash, fatigue, and visual disturbances. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for BRAFTOVI (BRAFTOVI).
| Breastfeeding | No data on the presence of encorafenib in human milk, effects on the breastfed infant, or effects on milk production. Because of the potential for serious adverse reactions in nursing infants, breastfeeding is not recommended during treatment and for 2 weeks after the last dose. M/P ratio: unknown. |
| Teratogenic Risk | BRAFTOVI (encorafenib) is embryotoxic and teratogenic in animal studies. Based on its mechanism of action (inhibition of RAF kinases involved in cell proliferation), there is a potential risk of fetal harm when administered to pregnant women. First trimester exposure may increase risk of congenital anomalies; second and third trimester exposure may impair fetal growth and development. Adequate contraceptive measures should be used during therapy and for at least 2 weeks after the last dose. |
■ FDA Black Box Warning
None. BRAFTOVI does not have a black box warning. However, it is important to monitor for new primary malignancies, including cutaneous squamous cell carcinoma and other skin cancers, as well as non-cutaneous malignancies.
| Serious Effects |
Known hypersensitivity to encorafenib or any excipient. Concomitant use with strong or moderate CYP3A4 inducers or sensitive CYP3A4 substrates with narrow therapeutic index due to potential loss of efficacy or toxicity.
| Precautions | New primary malignancies (cutaneous and non-cutaneous), hemorrhagic events, uveitis, interstitial lung disease/pneumonitis, hepatotoxicity, venous thromboembolism, cardiomyopathy, skin toxicity, and increased risk of severe adverse reactions when combined with BRAF inhibitors. Also, risk of tumor promotion in BRAF wild-type tumors. |
| Food/Dietary | Avoid grapefruit, grapefruit juice, Seville oranges, and star fruit due to CYP3A4 inhibition risk. No other specific food restrictions. BRAFTOVI can be taken with or without food. |
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| Fetal Monitoring | Monitor fetal growth and development via serial ultrasound if used during pregnancy. Monitor maternal liver function tests, blood glucose, and for signs of hemorrhage (gastrointestinal, intracranial) or cardiac dysfunction (QT prolongation, left ventricular ejection fraction). |
| Fertility Effects | BRAFTOVI may impair fertility in females and males based on animal studies. In females, it caused disruption of estrous cycles and reduced ovarian weight. In males, it caused degeneration of seminiferous tubules and reduced sperm motility and count. Reversibility unknown. |
| Clinical Pearls | BRAFTOVI (encorafenib) is a BRAF kinase inhibitor indicated in combination with binimetinib for BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma. Monitor for cutaneous squamous cell carcinoma (cuSCC), new primary melanomas, and palmar-plantar erythrodysesthesia syndrome (PPES). Dose reduction may be required for toxicity. Encorafenib is a moderate CYP3A4 inducer; avoid strong CYP3A4 inhibitors and inducers. QT prolongation possible; monitor ECG and electrolytes. |
| Patient Advice | Take BRAFTOVI exactly as prescribed, usually once daily with or without food. · Do not crush, break, or chew the capsules. Swallow whole. · Avoid grapefruit, grapefruit juice, Seville oranges, and star fruit during treatment as they may increase side effects. · Report any new skin lesions, warts, or changes in existing moles to your healthcare provider immediately. · Use effective non-hormonal contraception during treatment and for at least 2 weeks after stopping, as BRAFTOVI may make hormonal contraceptives less effective. · Avoid sun exposure, wear protective clothing, and use broad-spectrum sunscreen SPF ≥ 30. · Contact your doctor if you experience severe nausea, vomiting, diarrhea, or signs of bleeding. · Do not take St. John's wort, carbamazepine, rifampin, or other strong CYP3A4 inducers or inhibitors without consulting your doctor. |