NEXAVAR
Clinical safety rating: caution
Comprehensive clinical and safety monograph for NEXAVAR (NEXAVAR).
Multikinase inhibitor targeting Raf, VEGFR-2, VEGFR-3, PDGFR-β, c-KIT, Flt-3, and RET kinases, inhibiting tumor growth and angiogenesis.
| Metabolism | Hepatic via CYP3A4 and UGT1A9; active metabolite sorafenib N-oxide via CYP3A4. |
| Excretion | Fecal (77% as unchanged drug and metabolites), renal (19% as metabolites, <1% as unchanged drug). |
| Half-life | Terminal half-life 25-48 hours; supports twice-daily dosing with steady state achieved in 7-14 days. |
| Protein binding | 99.5% bound to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Vd 1.7-2.6 L/kg (total) reflecting extensive tissue distribution. |
| Bioavailability | Oral: 38-49% (relative to oral solution); increased by 50% with high-fat meal. |
| Onset of Action | Oral: Tumor response observed within 4-8 weeks; time to maximal plasma concentration 2-4 hours. |
| Duration of Action | Dosing interval 12 hours; continuous daily dosing required for sustained antiangiogenic and antitumor effects. |
| Action Class | Tyrosine kinase inhibitors |
| Brand Substitutes | Soranib Tablet, Sorafina Tablet, Shilfenib 200mg Tablet, Sorepto 200mg Tablet, Sorafenat 200mg Tablet |
400 mg (two 200 mg tablets) orally twice daily approximately 12 hours apart on an empty stomach (at least 1 hour before or 2 hours after a meal).
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl 30-89 mL/min). Not recommended in severe renal impairment (CrCl <30 mL/min) due to lack of data. |
| Liver impairment | Child-Pugh A or B: No dose adjustment. Child-Pugh C: Not recommended due to increased systemic exposure. |
| Pediatric use | Not approved for use in pediatric patients. No established dosing guidelines. |
| Geriatric use | No specific dose adjustment required based on age alone. Monitor renal function and adjust if needed per renal guidelines. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for NEXAVAR (NEXAVAR).
| Breastfeeding | It is not known whether sorafenib is excreted in human milk. However, sorafenib and its metabolites are excreted in the milk of lactating rats (concentrations approximately 10 times higher than in maternal plasma). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from sorafenib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. No M/P ratio is available in humans. |
| Teratogenic Risk | Pregnancy Category D. Based on animal studies and its mechanism of action (angiogenesis inhibition), sorafenib can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. Sorafenib was teratogenic in rats at doses ≥ 1 mg/kg/day (approximately 0.2 times the AUC at the recommended human dose) and in rabbits at doses ≥ 9 mg/kg/day (approximately 2.7 times the AUC at the recommended human dose). Fetal effects included increased post-implantation loss, resorptions, skeletal retardations, and shortened mandible. Use during pregnancy should be avoided unless the potential benefit outweighs the risk to the fetus. |
■ FDA Black Box Warning
None
| Serious Effects |
["Hypersensitivity to sorafenib or any excipients"]
| Precautions | ["Hepatic impairment: Monitor liver function; severe cases may require dose reduction or discontinuation","Cardiac ischemia: Risk of myocardial ischemia and/or infarction; consider temporary or permanent discontinuation","Hemorrhage: Risk of serious bleeding; monitor for bleeding events","Hand-foot skin reaction: Manage with supportive measures; dose interruption or reduction may be needed","Hypertension: Monitor blood pressure; manage with antihypertensives","Wound healing complications: Consider temporary interruption for major surgical procedures"] |
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| Fetal Monitoring | If sorafenib is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Monitor fetal growth and development via ultrasound and assess for oligohydramnios, as sorafenib may impair angiogenesis. Monitor maternal blood pressure and renal function due to potential hypertension and proteinuria. Liver function tests and thyroid function tests should be monitored periodically. |
| Fertility Effects | Sorafenib may impair fertility in both males and females. Animal studies showed that sorafenib caused testicular atrophy and degeneration in rats at doses ≥ 5 mg/kg/day (approximately 0.5 times the AUC at the recommended human dose). It also caused decreased corpora lutea and increased pre-implantation loss in female rats, suggesting potential effects on female fertility. In humans, oligospermia has been reported in male patients. The long-term effects on fertility are unknown. |