Hepatocellular Carcinoma: Sorafenib is used for the treatment of patients with unresectable hepatocellular carcinoma (HCC).

Renal Cell Carcinoma: Sorafenib is used for the treatment of patients with advanced renal cell carcinoma (RCC).

Sorafenib is a kinase inhibitor that reduces the proliferation of tumor cells. It has been shown to block multiple intracellular kinases (CRAF, BRAF, and mutant BRAF) as well as cell surface kinases (KIT, FLT-3, RET, VEGFR-1, VEGFR-2, VEGFR-3, and PDGFR-β). These kinases play important roles in tumor cell signaling, angiogenesis, and apoptosis. Sorafenib has demonstrated the ability to inhibit tumor growth and angiogenesis in human hepatocellular carcinoma, renal cell carcinoma, and various other human tumor xenograft models in immunocompromised mice.

The recommended daily dose of Sorafenib is 400 mg tablets taken twice daily without food (at least 1 hour before or 2 hours after a meal). Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.

Management of suspected adverse drug reactions may require temporary interruption and/or dose reduction of Sorafenib therapy. When dose reduction is necessary, the Sorafenib dose may be reduced to 400 mg once daily. If additional dose reduction is required, Sorafenib may be reduced to a single 400 mg dose every other day.

Recommended regimens and treatment duration for Sorafenib therapy.

Grade 1: Numbness, dysesthesia, paresthesia, tingling, painless swelling, erythema or discomfort of the hands or feet which does not disrupt the patient's:

• Any occurrence: Continue treatment with Sorafenib and consider topical therapy for symptomatic relief.

Grade 2: Painful erythema and swelling of the hands or feet and/ or discomfort affecting the patient’s normal activities

• 1st occurrence: Continue treatment with Sorafenib and consider topical therapy for symptomatic relief. If no improvement within 7 days, see below.
• No improvement within 7 days or 2nd or 3rd occurrence: Interrupt Sorafenib treatment until toxicity resolves to Grade 0-1 When resuming treatment, decrease Sorafenib dose by one dose level (400 mg daily or 400 mg every other day).
• 4th occurrence: Discontinue Sorafenib treatment.

Grade 3: Moist desquamation, ulceration, blistering or severe pain of the hands or feet, or severe discomfort that causes the patient to be unable to work or perform activities of daily living:

• 1st or 2nd occurrence: Interrupt Sorafenib treatment until toxicity resolves to Grade 0-1 When resuming treatment, decrease Sorafenib dose by one dose level (400 mg daily or 400 mg every other day).
• 3rd occurrence: Discontinue Sorafenib treatment.

No dose adjustment is required on the basis of patient age, gender, or body weight.

Missed doses: If a dose of Sorafenib is missed, skip the missed dose, and take next dose at regular time. Do not double your dose of Sorafenib.

Carboplatin and Paclitaxel: The use of Sorafenib together with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer, as higher mortality has been observed compared to treatment with carboplatin and paclitaxel alone. The exact reason for this increased risk has not been clearly determined.
UGT1A1 and UGT1A9 Substrates: Co-administration with Sorafenib may increase the systemic exposure of drugs that are substrates of UGT1A1 and UGT1A9.
Docetaxel: Concurrent use of Docetaxel (75 or 100 mg/m² every 21 days) with Sorafenib (200 or 400 mg twice daily), with a 3-day dosing break around Docetaxel administration, resulted in a 36–80% increase in Docetaxel AUC and a 16–32% increase in Cmax. Caution should be exercised when both are used together.
Doxorubicin: Co-administration with Sorafenib led to a 21% increase in the AUC of Doxorubicin. Careful monitoring is advised when these drugs are used together.
Fluorouracil: Both increases (21%–47%) and decreases (10%) in Fluorouracil AUC have been observed when used with Sorafenib. Caution is recommended during combined use with Fluorouracil/Leucovorin.
CYP2B6 and CYP2C8 Substrates: Exposure to substrates of CYP2B6 and CYP2C8 may increase when given alongside Sorafenib.
CYP3A4 Inducers: Continuous co-administration with Rifampicin reduced Sorafenib AUC by about 37%. Other CYP3A4 inducers (e.g., Hypericum perforatum [St. John’s wort], Phenytoin, Carbamazepine, Phenobarbital, and Dexamethasone) may also enhance Sorafenib metabolism and lower its plasma levels.
CYP3A4 Inhibitors and CYP Isoform Substrates: Sorafenib metabolism is unlikely to be significantly affected by CYP3A4 inhibitors and is also unlikely to influence the metabolism of drugs processed by these enzymes.

P-glycoprotein Substrates: Sorafenib inhibits P-glycoprotein in vitro and may increase concentrations of drugs that are P-glycoprotein substrates when used together.
CYP Enzyme Induction: Studies in cultured human hepatocytes showed no change in CYP1A2 and CYP3A4 activity, suggesting Sorafenib is unlikely to induce these enzymes.
Combination with other Antineoplastic Agents: Sorafenib does not significantly affect the pharmacokinetics of gemcitabine or oxaliplatin.
Neomycin: Co-administration with oral Neomycin should be carefully evaluated, as it reduced Sorafenib plasma exposure (AUC) by approximately 54%.

Sorafenib is contraindicated in patients with known severe hypersensitivity to Sorafenib or any of its components. It is also contraindicated when used with carboplatin and paclitaxel in patients with squamous cell lung cancer.

Severe adverse effects include cardiac ischemia, myocardial infarction, bleeding, hypertension, hand-foot skin reaction, rash, gastrointestinal perforation, and complications in wound healing.

Based on its mechanism and animal studies, Sorafenib may cause harm to the fetus if administered during pregnancy. Women of reproductive potential should avoid pregnancy while receiving this medication. It is not known whether Sorafenib passes into human breast milk.

Cardiac Ischemia, Infarction: Temporary or permanent discontinuation of Sorafenib should be considered in patients who develop cardiac ischemia and/or myocardial infarction.

Risk of Hemorrhage: Sorafenib may increase the risk of bleeding. One fatal hemorrhage was reported in each treatment group in the RCC study. If clinically significant bleeding occurs requiring medical intervention, permanent discontinuation of Sorafenib should be considered.

Risk of Hypertension: In the HCC study, hypertension occurred in about 9.4% of patients, while in the RCC study it was about 16.9%. In cases of severe or persistent hypertension despite antihypertensive therapy, temporary or permanent discontinuation of Sorafenib should be considered.

Risk of Dermatologic Toxicities: The most common adverse reactions include hand-foot skin reaction and skin rash.

Risk of Gastrointestinal Perforation: In case of gastrointestinal perforation, Sorafenib therapy should be discontinued.

Warfarin Co-Administration: Patients receiving concomitant warfarin should be regularly monitored for changes in prothrombin time, INR, or any clinical signs of bleeding.

Wound Healing Complications: Resumption of Sorafenib after major surgery should be based on clinical assessment of adequate wound healing.

Use with Carboplatin and Paclitaxel in Non-small Cell Lung Cancer: In patients with squamous cell carcinoma, higher mortality was observed when Sorafenib was added to carboplatin and paclitaxel compared to chemotherapy alone.

Interactions with UGT1A1 Substrates: Sorafenib may increase plasma concentrations of drugs that are metabolized by UGT1A1.

Interaction with Docetaxel & Doxorubicin: Sorafenib may increase plasma levels of Docetaxel and Doxorubicin.

Hepatic Impairment: Liver impairment may reduce plasma concentrations of Sorafenib.

Neomycin: Co-administration with oral Neomycin reduces Sorafenib exposure.

Pediatric Use: The safety and efficacy of Sorafenib in pediatric patients have not yet been established.

Geriatric Use: No significant differences in safety or efficacy have been observed between elderly and younger patients.

Renal Impairment: No dose adjustment of Sorafenib is required in patients with renal impairment.

Hepatic Impairment: In mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment, Sorafenib AUC may be reduced by approximately 23–65% compared to individuals with normal liver function. However, overall exposure and safety in these patients were considered comparable. Sorafenib has not been studied in patients with severe hepatic impairment (Child-Pugh C).

Sorafenib has no specific antidote for overdose. Clinically, the highest studied dose is 800 mg twice daily. In cases of overdose, the main observed adverse effects are diarrhea and dermatologic reactions.

Targeted Cancer Therapy

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