SORAFENIB — 200 mg film‑coated tablets

Sorafenib is an oral multikinase inhibitor that was first approved by the U.S. FDA in 2005 for advanced renal cell carcinoma (RCC), followed by approval in 2007 for unresectable hepatocellular carcinoma (HCC) — becoming the first systemic therapy to demonstrate a survival benefit in advanced HCC. In 2013, its indication was expanded to include locally recurrent or metastatic, progressive differentiated thyroid carcinoma (DTC) refractory to radioactive iodine. Sorafenib represents a targeted approach to cancer therapy by simultaneously inhibiting multiple kinases involved in tumor cell proliferation and angiogenesis.

Mechanism of action: Sorafenib is a bi-aryl urea that inhibits several intracellular and cell surface kinases. It targets Raf kinase (including Raf-1 and B-Raf), blocking the Raf/MEK/ERK signaling pathway that regulates tumor cell proliferation and survival. It also inhibits vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3) and platelet-derived growth factor receptor-β (PDGFR-β), which are critical for tumor angiogenesis. Additional targets include c-KIT, FLT-3, and RET receptor tyrosine kinases. This multi-targeted profile contributes to its antitumor activity through direct effects on tumor growth and indirect effects on tumor vasculature.

Clinical efficacy: In the landmark Phase 3 SHARP trial involving 602 patients with advanced HCC, sorafenib 400 mg twice daily demonstrated a significant improvement in overall survival (OS) compared to placebo, with median OS of 10.7 months vs. 7.9 months (HR 0.69, p=0.00058). Time to progression was 5.5 months vs. 2.8 months (HR 0.58, p=0.000007). For RCC, the TARGET study showed sorafenib doubled median progression-free survival compared to placebo (24 weeks vs. 12 weeks). In the DECISION trial for DTC, sorafenib significantly improved progression-free survival (10.8 months vs. 5.8 months, HR 0.49, p<0.001). While sorafenib has been largely supplanted by immunotherapy combinations as first-line therapy for HCC in patients eligible for checkpoint inhibitors (atezolizumab/bevacizumab, durvalumab/tremelimumab), it remains an important option for patients with contraindications to immunotherapy and for Child-Pugh B cirrhosis where immunotherapy data are limited.

Pharmacokinetics: Sorafenib is absorbed after oral administration, with peak plasma concentrations reached in approximately 3 hours. Bioavailability is reduced by high-fat meals (29% decrease), so it should be taken on an empty stomach. It is highly protein-bound (99.5%) and metabolized primarily in the liver by CYP3A4 and UGT1A9, with an elimination half-life of approximately 25-48 hours. Steady-state concentrations are achieved within 7 days. Excretion is via feces (77%) and urine (19%).

• Known hypersensitivity to sorafenib or any component of the formulation.

• Strong CYP3A4 inhibitors (ketoconazole, itraconazole, voriconazole, ritonavir, clarithromycin, grapefruit juice): May increase sorafenib concentrations. Monitor for increased toxicity.
• Strong CYP3A4 inducers (rifampin, rifabutin, phenytoin, carbamazepine, phenobarbital, dexamethasone, St. John’s wort): May decrease sorafenib concentrations, potentially reducing efficacy. Avoid concomitant use if possible.
• Neomycin: May decrease sorafenib absorption by disrupting enterohepatic circulation.
• Warfarin: Increased INR and bleeding risk. Monitor INR weekly during initial treatment and after dose changes.
• Drugs that increase gastric pH (PPIs, H2 blockers, antacids): May decrease sorafenib solubility and absorption. Monitor for reduced efficacy.

• Pregnancy: FDA Category D. Can cause fetal harm based on animal studies. Women of reproductive potential should use effective contraception during treatment and for at least 2 weeks after last dose.
• Lactation: It is not known whether sorafenib is excreted in human milk. Advise women not to breastfeed during treatment and for 2 weeks after last dose.
• Pediatric use: Safety and efficacy not established in pediatric patients. Not indicated.
• Geriatric use: No overall differences in safety or efficacy observed, but greater sensitivity cannot be ruled out.
• Hepatic impairment: Limited safety data for Child-Pugh Class B or C; use with extreme caution. Dosing is uncertain. Monitor LFTs closely.
• Renal impairment: No dose adjustment required for mild to moderate impairment. Not studied in severe impairment.

• HCC, RCC, DTC: 400 mg (two 200 mg tablets) orally twice daily on an empty stomach (at least 1 hour before or 2 hours after food).
• Dose modifications: For suspected adverse reactions, dose reduction may be to 400 mg once daily or 400 mg every other day. Further dose reduction may be considered to 200 mg twice daily if needed. Permanently discontinue for severe adverse reactions (e.g., severe hemorrhage, cardiac ischemia, GI perforation).
• Administration: Swallow tablets whole with water. Do not crush or chew. If a dose is missed, do not make up the missed dose; take the next dose as scheduled.

• Symptoms: Exaggerated adverse reactions including severe diarrhea, hand-foot skin reaction, hypertension, and hepatotoxicity.
• Management: No specific antidote. Discontinue sorafenib, provide supportive care, monitor vital signs, and manage symptoms. Hemodialysis unlikely to be effective due to high protein binding.