Sorafenib Tosylate

2 DOSAGE AND ADMINISTRATION • The recommended dosage is 400 mg orally twice daily without food. ( 2.1 ) 2.1 Recommended Dosage The recommended dosage of sorafenib tablets is 400 mg orally twice daily without food (at least 1 hour before or 2 hours after a meal) until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity. 2.2 Dosage Modifications for Adverse Reactions Recommended Dosage Modifications The recommended dosage modifications for adverse reactions are provided in Tables 1, 2, and 3. Table 1: Recommended Dose Reductions for Adverse Reactions Dose Reduction Hepatocellular Carcinoma and Renal Cell Carcinoma Differentiated Thyroid Carcinoma First Dose Reduction 400 mg orally once daily 400 mg orally in the morning and 200 mg orally in the evening about 12 hours apart OR 200 mg orally in the morning and 400 mg orally in the evening about 12 hours apart Second Dose Reduction 200 mg orally once daily OR 400 every other day 200 mg orally twice daily Third Dose Reduction None 200 mg orally once daily Table 2: Recommended Dosage Modifications of Sorafenib Tablets for Adverse Reactions Adverse Reaction Severity Adverse reactions graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0). Sorafenib Tablets Dosage Modification Cardiovascular Events [see Warnings and Precautions (5.1) ] Cardiac Ischemia and/or Infarction Grade 2 and above Permanently discontinue. Congestive Heart Failure Grade 3 Interrupt If no recovery after 30 day interruption, discontinue treatment unless the patient is deriving clinical benefit. until Grade 1 or less, resume at reduced dose by 1 dose level. If more than 2 dose reductions are required, permanently discontinue treatment. Grade 4 Permanently discontinue. Hemorrhage [see Warnings and Precautions (5.2) ] Grade 2 and above requiring medical intervention Permanently discontinue. Hypertension [see Warnings and Precautions (5.3) ] Grade 2 (symptomatic/persistent) OR Grade 2 symptomatic increase by greater than 20 mm Hg (diastolic) or greater than 140/90 mm Hg if previously within normal limits OR Grade 3 Interrupt until symptoms resolve and diastolic blood pressure less than 90 mm Hg, then resume at reduced dose by 1 dose level. If needed, reduce another dose level. Grade 4 Permanently discontinue. Gastrointestinal Perforation [see Warnings and Precautions (5.5) ] Any grade Permanently discontinue. QT Interval Prolongation [see Warnings and Precautions (5.9) ] Greater than 500 milliseconds OR Increase from baseline of 60 milliseconds or greater Interrupt and correct electrolyte abnormalities (magnesium, potassium, calcium). Use medical judgement before restarting. Drug-Induced Liver Injury [see Warnings and Precautions (5.10) ] Grade 3 ALT or higher in the absence of another cause In addition, any grade increased alkaline phosphatase in the absence of known bone pathology and Grade 2 or worse increased bilirubin; any 1 of the following: INR of 1.5 or greater, ascites and/or encephalopathy in the absence of underlying cirrhosis or other organ failure considered to be due to drug-induced liver injury. OR AST/ALT greater than 3 x upper limit normal (ULN) with bilirubin greater than 2 x ULN in the absence of another cause Permanently discontinue. Non-hematological toxicities [see Adverse Reactions (6.1) ] Grade 2 Continue treatment at reduced dose by 1 dose level. Grade 3 1 st occurrence Interrupt until Grade 2 or less, then resume at reduced dose by 1 dose level. No improvement within 7 days OR 2 nd or 3 rd occurrence Interrupt until Grade 2 or less, then resume at reduced dose by 2 dose levels. 4 th occurrence Interrupt until Grade 2 or less, then resume at reduced dose by 2 dose levels for HCC and RCC or 3 dose levels for DTC. Grade 4 Permanently discontinue. Table 3: Recommended Dosage Modifications for Dermatologic Toxicities Dermatologic Toxicity Grade Occurrence Sorafenib Tablets Dosage Modification Hepatocellular and Renal Cell Carcinoma Differentiated Thyroid Carcinoma Grade 2: Painful erythema and swelling of the hands or feet and/or discomfort affecting the patient’s normal activities 1 st occurrence Continue sorafenib tablets and consider topical therapy for symptomatic relief. If no improvement within 7 days, see below. Decrease sorafenib tablets to 600 mg daily. If no improvement within 7 days, see below. No improvement within 7 days at reduced dose OR 2 nd and 3 rd occurrence Interrupt sorafenib tablets until resolved or improved to Grade 0 to 1. Interrupt sorafenib tablets until completely resolved or improved to Grade 1. When resuming treatment, decrease dose by 1 dose level. When resuming treatment, decrease dose by 1 dose level for 2 nd occurrence and 2 dose levels for 3 rd occurrence. 4 th occurrence Discontinue sorafenib tablets treatment. Grade 3: Moist desquamation, ulceration, blistering, or severe pain of the hands or feet, resulting in inability to work or perform activities of daily living 1 st occurrence Interrupt sorafenib tablets until resolved or improved to Grade 0 to 1. Interrupt sorafenib tablets until completely resolved or improved to Grade 1. When resuming treatment, decrease dose by 1 dose level. When resuming treatment, decrease dose by 1 dose level. 2 nd occurrence Interrupt sorafenib tablets until resolved or improved to Grade 0 to 1. Interrupt sorafenib tablets until completely resolved or improved to Grade 1. When resuming treatment, decrease dose by 1 dose level. When resuming treatment, decrease dose by 2 dose levels. 3 rd occurrence Discontinue sorafenib tablets treatment. Following improvement of Grade 2 or 3 dermatologic toxicity to Grade 0 or 1 for at least 28 days on a reduced dose of sorafenib tablets, the dose of sorafenib tablets may be increased 1 dose level from the reduced dose. Approximately 50% of patients requiring a dose reduction for dermatologic toxicity are expected to meet these criteria for resumption of the higher dose and roughly 50% of patients resuming the previous dose are expected to tolerate the higher dose (that is, maintain the higher dose level without recurrent Grade 2 or higher dermatologic toxicity).

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1 INDICATIONS AND USAGE Sorafenib tablets are a kinase inhibitor indicated for the treatment of • Unresectable hepatocellular carcinoma ( 1.1 ) • Advanced renal cell carcinoma ( 1.2 ) • Locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment ( 1.3 ) 1.1 Hepatocellular Carcinoma Sorafenib tablets are indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC).