sorafenib

Sorafenib tablets are a kinase inhibitor indicated for the treatment of Unresectable hepatocellular carcinoma(1.1) 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). 1.3 Differentiated Thyroid Carcinoma Sorafenib tablets are indicated for the treatment of patients with locally recurrent or metastatic, progressive,differentiated thyroid carcinoma (DTC) that is refractory to radioactive iodine treatment.

•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 orallytwice daily without food (at least 1 hourbefore or 2 hours after a meal) until the patient is no longer clinically benfiting from therapy or untilunacceptable toxicity. 2.2 Dose 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 forAdverse Reactions Dose Reduction Hepatocellular 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 1 Sorafenib T ablets Dosage M odification Cardiovascular Events [see Warnings and Precautions (5.1)] Cardiac Ischemia and/or Infarction Grade 2 and above Permanently discontinue. Congestive Heart Failure Grade 3 Interrupt2 until Grade 1 or less, resume at reduced dose by 1 dose level.3 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.3 If needed, reduce another dose level.3 Grade 4 Permanently discontinue. G astrointestinal 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 cause4 OR AST/ALT greater than 3 × upper limit normal (ULN) with bilirubin greater than 2 × ULN in the absence of another cause4 Permanently discontinue. Non-hematological toxicities [see Adverse Reactions (6.1)] Grade 2 Continue treatment at reduced dose by 1 dose level. Grade 3 1st occurrence Interrupt until Grade 2 or less, then resume at reduced dose by 1 dose level. No improvement within 7 days OR 2nd or 3rd occurrence Interrupt until Grade 2 or less, then resume at reduced dose by 2 dose levels. 4th occurrence Interrupt until Grade 2 or less, then resume at reduced dose by 2 dose levels for HCC or 3 dose levels for DTC. Grade 4 Permanently discontinue. 1 Adverse reactions graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0). 2 If no recovery after 30 day interruption, discontinue treatment unless the patient is deriving clinical benefit. 3 If more than 2 dose reductions are required, permanently discontinue treatment. 4 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. Table 3: Recommended Dosage Modifications for Dermatologic Toxicities Dermatologic Toxicity Grade Occurrence Sorafenib T ablets Dosage Modification Hepatocellular Differentiated Thyroid Carcinoma Grade 2: Painfu…

Cardiovascular Events: Consider temporary or permanent discontinuation of sorafenib tablets.(2.2, 5.1) Hemorrhage: Discontinue sorafenib tablets if needed. (5.2) Hypertension: Monitor blood pressure weekly during the first 6 weeks and periodically thereafter. Consider temporary or permanent discontinuation for severe or persistent hypertension despite antihypertensive therapy.(5.3) Dermatologic Toxicities: Interrupt and/or decrease dose. Discontinue for severe or persistent reactions, or if Stevens-Johnson syndrome and toxic epidermal necrolysis is suspected.(5.4) Gastrointestinal Perforation: Discontinue sorafenib tablets. (5.5) Risk of Impaired Wound Healing: Withhold sorafenib tablets for at least 10 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of sorafenib tablets after resolution of wound healing complications has not been established. (5.7) QT Prolongation: Monitor electrocardiograms and electrolytes in patients at increased risk for ventricular arrhythmias. Correct electrolytes. Interrupt if QTc greater than 500 msec or increases greater than 60 msec from baseline.( 2.2, 5.9, 12.2) Drug-Induced Liver Injury: Monitor liver function tests regularly; discontinue for unexplained transaminase elevations. (5.10) Embryo-Fetal Toxicity: Sorafenib tablets may cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. (5.11, 8.1, 8.3) Impairment of Thyroid Stimulating Hormone Suppression (TSH) in DTC: Monitor TSH monthly and adjust thyroid replacement therapy in patients with thyroid cancer. (5.12) 5.1 Cardiovascular Events In the SHARP (HCC) study, the incidence of cardiac ischemia/infarction was 2.7% in sorafenib tablets-treated patients compared with 1.3% in those receiving placebo, and in the DECISION (DTC) study, the incidence of cardiac ischemia/infarction was 1.9% in the sorafenib tablets -treated group compared with 0% in patients receiving placebo. Patients with unstable coronary artery disease or recent myocardial infarction were excluded from this study. In multiple clinical trials, congestive heart failure has been reported in 1.9% of sorafenib tablets - treated patients (N=2276) [see Adverse Reactions (6.2)]. Consider temporary or permanent discontinuation of sorafenib tablets in patients who develop cardiovascular events [see Dosage and Administration (2.2)]. 5.2 Hemorrhage An increased risk of bleeding may occur following sorafenib tablets administration. In the SHARP (HCC) study, the rates of bleeding from esophageal varices (2.4% and 4%) and of bleeding with a fatal outcome from any site (2.4% and 4%) were similar in sorafenib tablets -treated patients and those receiving placebo, respectively. In the DECISION (DTC) study, bleeding was reported in 17.4% of sorafenib tablets -treated patients and 9.6% of those receiving placebo; however, the incidence of Grade 3 bleeding was similar (1% and 1.4%) in sorafenib tablets -treated patients and in those receiving placebo. If any bleeding necessitates medical intervention, consider permanent discontinuation of sorafenib tablets [see Dosage and Administration (2.2)]. Due to the potential risk of bleeding, treat tracheal, bronchial, and esophageal infiltration with local therapy prior to administering sorafenib tablets in patients with DTC. 5.3 Hypertension In the SHARP (HCC) study, hypertension was reported in 9.4% of sorafenib tablets -treated patients and 4.3% of patients receiving placebo. In the DECISION (DTC) study, hypertension was reported in 40.6% of sorafenib tablets -treated patients and 12.4% of patients receiving placebo. Hypertension was usually mild to moderate, occurred early in the course of treatment, and was managed with standard antihypertensive therapy. Permanent discontinuation due to hypertension occurred in 1 of 297 sorafenib tablets -treated patients in the SHARP (HCC) study, and 1 of 207 sorafenib…

Sorafenib tablets are contraindicated in patients with known severe hypersensitivity to sorafenib or any other component of sorafenib tablets. (4) Sorafenib tablets in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer. (4) 4 CONTRAINDICATIONS Sorafenib tablets are contraindicated in patients with known severe hypersensitivity to sorafenib or any other component of sorafenib tablets. Sorafenib tablets in combination with carboplatin and paclitaxel are contraindicated in patients with squamous cell lung cancer [see Warnings and Precautions (5.8)].

Strong CYP3A Inducers: Avoid strong CYP3A4 inducers.(7.1) 7.1 Effect of Other Drugs on Sorafenib Tablets Strong CYP3A4 Inducers The concomitant use of sorafenib tablets with rifampin, a strong CYP3A4 inducer decreased the mean AUC of sorafenib, which may decrease the antitumor activity [see Clinical Pharmacology (12.3)]. Avoid concomitant use of sorafenib tablets with strong CYP3A4 inducers, when possible, because these drugs can decrease the systemic exposure to sorafenib. Neomycin The concomitant use of sorafenib tablets with neomycin decreased the mean AUC of sorafenib, which may decrease the antitumor activity. Avoid concomitant use of sorafenib tablets with neomycin. The effects of other antibiotics on the pharmacokinetics of sorafenib have not been studied [see Clinical Pharmacology (12.3)]. 7.2 Concomitant Use of Warfarin The concomitant use of sorafenib tablets and warfarin may increase the risk of bleeding or increased the INR. Monitor INR and for clinical bleeding episodes in patients taking warfarin while receiving sorafenib tablets [see Warnings and Precautions (5.6)]. 7.3 Drugs That Prolong the QT Interval Sorafenib tablets are associated with QTc interval prolongation. Avoid coadministration of sorafenib tablets with medicinal products with a known potential to prolong QT/QTc interval [see Warnings and Precautions (5.9), Clinical Pharmacology (12.2)]. 8.7 Hepatic Impairment No dose adjustment is necessary for patients with mild or moderate hepatic impairment. The pharmacokinetics of sorafenib have not been studied in patients with severe (Child-Pugh C) hepatic impairment [see Clinical Pharmacology (12.3)].

The most common adverse reactions (≥20%) are diarrhea, fatigue, infection, alopecia, hand-foot skin reaction, rash, weight loss, decreased appetite, nausea, gastrointestinal and abdominal pains, hypertension, and hemorrhage. (6) To report SUSPECTED ADVERSE REACTIONS, contact Yabao Pharmaceutical Co., Ltd. Beijing at 914-656-3049 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed elsewhere in the labeling: Cardiovascular events [see Warnings and Precautions ( 5.1 )] Hemorrhage [see Warnings and Precautions ( 5.2 )] Hypertension [see Warnings and Precautions ( 5.3 )] Dermatologic toxicities [see Warnings and Precautions ( 5.4 )] Gastrointestinal perforation [see Warnings and Precautions ( 5.5 )] QT interval prolongation [see Warnings and Precautions ( 5.9 ) and Clinical Pharmacology( 12.2 )] Drug-induced liver injury [see Warnings and Precautions ( 5.10 )] Impairment of TSH suppression in DTC [see Warnings and Precautions ( 5.12 )] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described reflect exposure to sorafenib tablets in 504 patients who participated in placebo-controlled studies in hepatocellular carcinoma N=297), or differentiated thyroid carcinoma (N = 207). The most common adverse reactions (≥20%), which were considered to be related to sorafenib tablets, in patients with HCC or DTC are diarrhea, fatigue, infection, alopecia, hand-foot skin reaction, rash, weight loss, decreased appetite, nausea, gastrointestinal and abdominal pains, hypertension, and hemorrhage. Hepatocellular Carcinoma Table 4 shows the percentage of patients in the SHARP (HCC) study experiencing adverse reactions that were reported in at least 10% of patients and at a higher rate in the Sorafenib Tablets -treated group than in those eceiving placebo. Table 4: Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in Sorafenib Tablets Arm than the Placebo Arm–SHARP (HCC) Adverse Reaction 1 Sorafenib Tablets N = 297 Placebo N = 302 All Grades% Grade 3% Grade 4% All Grades % Grade 3% Grade 4% Any Adverse Reaction 98 39 6 96 24 8 Gastrointestinal Diarrhea 55 10 < 1 25 2 0 Anorexia 29 3 0 18 3 < 1 Nausea 24 1 0 20 3 0 Vomiting 15 2 0 11 2 0 Constipation 14 0 0 10 0 0 Constitutional symptoms Fatigue 46 9 1 45 12 2 Weight loss 30 2 0 10 1 0 Pain Pain, abdomen 31 9 0 26 5 1 Dermatology/skin Hand-foot skin reaction 21 8 0 3 < 1 0 Rash/desquamation 19 1 0 14 0 0 Alopecia 14 0 0 2 0 0 Pruritus 14 < 1 0 11 < 1 0 Dry skin 10 0 0 6 0 0 Hepatobiliary/pancreas Liver dysfunction 11 2 1 8 2 1 1Adverse reactions graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0). Hypertension was reported in 9% of patients treated with sorafenib tablets and 4% of those receiving placebo. Grade 3 hypertension was reported in 4% of sorafenib tablets -treated patients and 1% of those receiving placebo. Hemorrhage/bleeding was reported in 18% of those receiving sorafenib tablets and 20% of patients receiving placebo. The rates of Grade 3 and 4 bleeding were also higher in patients receiving placebo (Grade 3 – 3% sorafenib tablets and 5% placebo and Grade 4 – 2% sorafenib tablets and 4% placebo). Bleeding from esophageal varices was reported in 2.4% in sorafenib tablets -treated patients and 4% of patients receiving placebo. Renal failure was reported in <1% of patients treated with sorafenib tablets and 3% of patients receiving placebo. Clinical pancreatitis was reported in 1 of 297 sorafenib tablets -treated patients (Grade 2). The rate of adverse reactions (including those associated with progressive disease) resulting in permanent discontinuation was simila…