Indication and Usage, Hepatocellular Carcinoma (1.1)11/2007

Warnings and Precautions,

Interaction with Docetaxel (5.9)11/2007

Interaction with Doxorubicin (5.10)11/2007

Hepatic Impairment (5.12)11/2007

INDICATIONS AND USAGE

NEXAVAR is a kinase inhibitor indicated for the treatment of

• Unresectable hepatocellular carcinoma (1.1)
• Advanced renal cell carcinoma (1.2)

DOSAGE AND ADMINISTRATION

• 400 mg (2 tablets) orally twice daily without food. (2)
• Treatment interruption and/or dose reduction may be needed to manage suspected adverse drug reactions. Dose may be reduced to 400 mg once daily or to 400 mg every other day. (2)

DOSAGE FORMS AND STRENGTHS

200 mg Tablets (see 3)

CONTRAINDICATIONS

NEXAVAR is contraindicated in patients with known severe hypersensitivity to sorafenib or any other component of NEXAVAR. (4)

WARNINGS AND PRECAUTIONS

• Cardiac ischemia and/or infarction may occur. Consider temporary or permanent discontinuation of NEXAVAR. (5.1)
• Bleeding may occur. If bleeding necessitates medical intervention, consider discontinuation of NEXAVAR. (5.2)
• Hypertension usually occurred early in the course of treatment and was managed with antihypertensive therapy. Monitor blood pressure weekly during the first 6 weeks and periodically thereafter and treat, as required. (5.3)
• Hand-foot skin reaction and rash are common. Management may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose modification, or in severe or persistent cases, permanent discontinuation. (5.4)
• Gastrointestinal perforation is an uncommon adverse reaction. In the event of a gastrointestinal perforation, NEXAVAR therapy should be discontinued. (5.5)
• Temporary interruption of NEXAVAR therapy is recommended in patients undergoing major surgical procedures. (5.7)
• Caution is recommended when co-administering substances metabolized/eliminated predominantly by the UGT1A1 pathway (e.g. irinotecan). (5.8, 7.1)
• Caution is recommended when co-administering docetaxel. (5.9, 7.2)
• Caution is recommended when co-administering doxorubicin (5.10, 7.3)
• Nexavar may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while on NEXAVAR. (5.11)

ADVERSE REACTIONS

The most common adverse reactions (≥20%), which were considered to be related to NEXAVAR, are fatigue, weight loss, rash/desquamation, hand-foot skin reaction, alopecia, diarrhea, anorexia, nausea and abdominal pain (6).

DRUG INTERACTIONS

• UGT1A1 (e.g. irinotecan) and UGT1A9 substrates: Caution, drug AUC increases when co-administered with NEXAVAR. (7.1, 5.8)
• Docetaxel: Caution, docetaxel AUC increases when co-administered with NEXAVAR. (7.2, 5.9)
• Doxorubicin: Caution, doxorubicin AUC increases when co-administered with NEXAVAR. (7.3)
• Fluorouracil: Caution, fluorouracil AUC changes when co-administered with NEXAVAR. (7.4)
• CYP2B6 and CYP2C8 substrates: Caution, systemic exposure is expected to increase when co-administered with NEXAVAR. (7.5)
• CYP3A4 inducers: Expected to increase metabolism of sorafenib and decrease sorafenib concentrations. (7.6, 2)

USE IN SPECIFIC POPULATIONS

• Hepatic impairment: No dose adjustment is necessary in HCC patients with Child-Pugh A and B hepatic impairment. NEXAVAR has not been studied in patients with Child-Pugh C hepatic impairment. (8.6)
• Renal impairment: NEXAVAR has not been studied in patients undergoing dialysis. (8.7)