Sorafenib, a kinase inhibitor, is the tosylate salt of sorafenib. Sorafenib tosylate has the chemical name 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)N2-methylpyridine-2-carboxamide 4-methylbenzenesulfonate. The molecular formula of sorafenib tosylate is C 21 H 16 ClF 3 N 4 O 3 x C 7 H 8 O 3 S and the molecular weight of sorafenib tosylate is 637.0 g/mole. Its structural formula is: Sorafenib tosylate is a white to yellowish or brownish solid. Sorafenib tosylate is practically insoluble in aqueous media, slightly soluble in ethanol and soluble in PEG 400. NEXAVAR (sorafenib), for oral use is supplied as film-coated tablets containing 200 mg sorafenib equivalent to 274 mg sorafenib tosylate and the following inactive ingredients: croscarmellose sodium, ferric oxide red, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol sodium lauryl sulphate, and titanium dioxide. chemical structure

NEXAVAR is a kinase inhibitor indicated for the treatment of • Unresectable hepatocellular carcinoma • Advanced renal cell carcinoma • Locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment 1.1 Hepatocellular Carcinoma NEXAVAR ® is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC)

Renal Cell Carcinoma NEXAVAR is indicated for the treatment of patients with advanced renal cell carcinoma (RCC)

Differentiated Thyroid Carcinoma NEXAVAR is indicated for the treatment of patients with locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) that is refractory to radioactive iodine treatment.

Tablets: • 200 mg sorafenib, round, biconvex, red film-coated tablets, debossed with the “Bayer cross” on one side and “200” on the other side. • 200 mg sorafenib, round, faceted biconvex, red film-coated tablets, debossed with the “Bayer cross” on one side and “200” on the other side. Tablets: 200 mg

The recommended dosage is 400 mg orally twice daily without food

Recommended Dosage The recommended dosage of NEXAVAR 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

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 NEXAVAR for Adverse Reactions Adverse Reaction Severity 1 NEXAVAR Dosage Modification Cardiovascular Events Cardiac Ischemia and/or Infarction Grade 2 and above Permanently discontinue. Congestive Heart Failure Grade 3 Interrupt 2 until Grade 1 or less, resume at reduced dose by 1 dose level. 3 Grade 4 Permanently discontinue. Hemorrhage Grade 2 and above requiring medical intervention Permanently discontinue. Hypertension 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. Gastrointestinal Perforation Any grade Permanently discontinue. QT Interval Prolongation 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 Grade 3 ALT or higher in the absence of another cause 4 OR AST/ALT greater than 3 × upper limit normal (ULN) with bilirubin greater than 2 × ULN in the absence of another cause 4 Permanently discontinue. Non-hematological toxicities 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. 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 NEXAVAR 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 NEXAVAR and consider topical therapy for symptomatic relief. If no improvement within 7 days, see below. Decrease NEXAVAR 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 NEXAVAR until resolved or improved to Grade 0 to 1. Interrupt NEXAVAR until completely resolved or improved to Grade1. When resuming treatment, decrease dose by 1 dose level. When resuming treatment, decrease dose by 1 dose level for 2 nd occurrence and 2 doses levels for 3 rd occurrence. 4 th occurrence Discontinue NEXAVAR 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 NEXAVAR until resolved or improved to Grade 0 to 1 Interrupt NEXAVAR 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 NEXAVAR until resolved or improved to Grade 0 to 1 Interrupt NEXAVAR 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 NEXAVAR 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 NEXAVAR, the dose of NEXAVAR 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).

• Cardiovascular Events : Consider temporary or permanent discontinuation of NEXAVAR. • Hemorrhage: Discontinue NEXAVAR if needed. • 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. • Dermatologic Toxicities : Interrupt and/or decrease dose. Discontinue for severe or persistent reactions, or if Stevens-Johnson syndrome and toxic epidermal necrolysis is suspected. • Gastrointestinal Perforation : Discontinue NEXAVAR. • Risk of Impaired Wound Healing : Withhold NEXAVAR 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 NEXAVAR after resolution of wound healing complications has not been established. • 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. • Embryo-Fetal Toxicity : NEXAVAR 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. 5.1 Cardiovascular Events In the SHARP (HCC) study, the incidence of cardiac ischemia/infarction was 2.7% in NEXAVAR-treated patients compared with 1.3% in those receiving placebo; in the TARGET (RCC) study, the incidence of cardiac ischemia/infarction was higher in the NEXAVAR-treated group (2.9%) compared with patients receiving placebo (0.4%), and in the DECISION (DTC) study, the incidence of cardiac ischemia/infarction was 1.9% in the NEXAVAR-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 NEXAVAR-treated patients (N=2276) . Consider temporary or permanent discontinuation of NEXAVAR in patients who develop cardiovascular events

Hemorrhage An increased risk of bleeding may occur following NEXAVAR 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 NEXAVAR-treated patients and those receiving placebo, respectively . In the TARGET (RCC) study, bleeding was reported in 15.3% of patients in the NEXAVAR-treated group and 8.2% of patients receiving placebo. The incidence of Grade 3 and 4 bleeding was 2% and 0%, respectively, in NEXAVAR-treated patients, and 1.3% and 0.2%, respectively, in those receiving placebo. There was one fatal hemorrhage in each treatment group in the TARGET (RCC) study. In the DECISION (DTC) study, bleeding was reported in 17.4% of NEXAVAR-treated patients and 9.6% of those receiving placebo; however, the incidence of Grade 3 bleeding was similar (1% and 1.4%) in NEXAVAR-treated patients and in those receiving placebo. If any bleeding necessitates medical intervention, consider permanent discontinuation of NEXAVAR . Due to the potential risk of bleeding, treat tracheal, bronchial, and esophageal infiltration with local therapy prior to administering NEXAVAR in patients with DTC

Hypertension In the SHARP (HCC) study, hypertension was reported in 9.4% of NEXAVAR-treated patients and 4.3% of patients receiving placebo. In the TARGET (RCC) study, hypertension was reported in 16.9% of NEXAVAR-treated patients and 1.8% of patients receiving placebo. In the DECISION (DTC) study, hypertension was reported in 40.6% of NEXAVAR-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 NEXAVAR-treated patients in the SHARP (HCC) study, 1 of 451 NEXAVAR-treated patients in the TARGET (RCC) study, and 1 of 207 NEXAVAR-treated patients in the DECISION (DTC) study. Monitor blood pressure weekly during the first 6 weeks of NEXAVAR. Thereafter, monitor blood pressure and treat hypertension, if required, in accordance with standard medical practice. In cases of severe or persistent hypertension despite institution of antihypertensive therapy, consider temporary or permanent discontinuation of NEXAVAR

Dermatologic Toxicities Hand-foot skin reaction and rash represent the most common adverse reactions attributed to NEXAVAR. Rash and hand-foot skin reaction are usually Grade 1 and 2 and generally appear during the first six weeks of treatment with NEXAVAR. Permanent discontinuation of therapy due to hand-foot skin reaction occurred in 4 (1.3%) of 297 NEXAVAR-treated patients with HCC, 3 (0.7%) of 451 NEXAVAR-treated patients with RCC, and 11 (5.3%) of 207 NEXAVAR-treated patients with DTC. Management of dermatologic toxicities may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose reduction of NEXAVAR, or in severe or persistent cases, permanent discontinuation of NEXAVAR . There have been reports of severe dermatologic toxicities, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These cases may be life-threatening. Discontinue NEXAVAR if SJS or TEN are suspected

Gastrointestinal Perforation Gastrointestinal perforation has been reported in less than 1% of patients taking NEXAVAR. In some cases this was not associated with apparent intra-abdominal tumor. In the event of a gastrointestinal perforation, permanently discontinue NEXAVAR

Increased Risk of Bleeding with Concomitant Use of Warfarin Infrequent bleeding or elevations in the International Normalized Ratio (INR) have been reported in some patients taking warfarin while on NEXAVAR. Monitor patients taking concomitant warfarin regularly for changes in prothrombin time (PT), INR or clinical bleeding episodes

Risk of Impaired Wound Healing Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, NEXAVAR has the potential to adversely affect wound healing. Withhold NEXAVAR 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 NEXAVAR after resolution of wound healing complications has not been established

Increased Mortality Observed with NEXAVAR Administered in Combination with Carboplatin/Paclitaxel and Gemcitabine/Cisplatin in Squamous Cell Lung Cancer In a subset analysis of two randomized controlled trials in chemo-naive patients with Stage IIIB-IV non-small cell lung cancer, patients with squamous cell carcinoma experienced higher mortality with the addition of NEXAVAR compared to those treated with carboplatin/paclitaxel alone (HR 1.81; 95% CI 1.19, 2.74) and gemcitabine/cisplatin alone (HR 1.22; 95% CI 0.82, 1.80). The use of NEXAVAR in combination with carboplatin/paclitaxel is contraindicated in patients with squamous cell lung cancer. NEXAVAR in combination with gemcitabine/cisplatin is not recommended in patients with squamous cell lung cancer. The safety and effectiveness of NEXAVAR has not been established in patients with non-small cell lung cancer

QT Interval Prolongation NEXAVAR can prolong the QT/QTc interval. QT/QTc interval prolongation increases the risk for ventricular arrhythmias. Avoid NEXAVAR in patients with congenital long QT syndrome. Monitor electrolytes and electrocardiograms in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Correct electrolyte abnormalities (magnesium, potassium, calcium). Interrupt NEXAVAR if QTc interval is greater than 500 milliseconds or for an increase from baseline of 60 milliseconds or greater

Drug-Induced Liver Injury Sorafenib-induced hepatitis is characterized by a hepatocellular pattern of liver damage with significant increases of transaminases which may result in hepatic failure and death. Increases in bilirubin and INR may also occur. The incidence of severe drug-induced liver injury, defined as elevated transaminase levels above 20 times the upper limit of normal or transaminase elevations with significant clinical sequelae (for example, elevated INR, ascites, fatal, or transplantation), was two of 3,357 patients (0.06%) in a global monotherapy database. Monitor liver function tests regularly. In case of significantly increased transaminases without alternative explanation, such as viral hepatitis or progressing underlying malignancy, discontinue NEXAVAR

Embryo-Fetal Toxicity Based on its mechanism of action and findings in animals, NEXAVAR may cause fetal harm when administered to a pregnant woman. Sorafenib caused embryo-fetal toxicities in animals at maternal exposures that were significantly lower than the human exposures at the recommended dose of 400 mg twice daily. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of NEXAVAR. Advise male patients with female partners of reproductive potential and pregnant partners to use effective contraception during treatment and for 3 months following the last dose of NEXAVAR

Impairment of Thyroid Stimulating Hormone Suppression in Differentiated Thyroid Carcinoma NEXAVAR impairs exogenous thyroid suppression. In the DECISION (DTC) study, 99% of patients had a baseline thyroid stimulating hormone (TSH) level less than 0.5 mU/L. Elevation of TSH level above 0.5 mU/L was observed in 41% of NEXAVAR-treated patients as compared with 16% of those receiving placebo patients. For patients with impaired TSH suppression while receiving NEXAVAR, the median maximal TSH was 1.6 mU/L and 25% had TSH levels greater than 4.4 mU/L. Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC.

• Strong CYP3A Inducers: Avoid strong CYP3A4 inducers

Effect of Other Drugs on NEXAVAR Strong CYP3A4 Inducers The concomitant use of NEXAVAR with rifampin, a strong CYP3A4 inducer decreased the mean AUC of sorafenib, which may decrease the antitumor activity . Avoid concomitant use of NEXAVAR with strong CYP3A4 inducers, when possible, because these drugs can decrease the systemic exposure to sorafenib. Neomycin The concomitant use of NEXAVAR with neomycin decreased the mean AUC of sorafenib, which may decrease the antitumor activity. Avoid concomitant use of NEXAVAR with neomycin. The effects of other antibiotics on the pharmacokinetics of sorafenib have not been studied

Concomitant Use of Warfarin The concomitant use of NEXAVAR 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 NEXAVAR

Drugs That Prolong the QT Interval NEXAVAR is associated with QTc interval prolongation. Avoid coadministration of NEXAVAR with medicinal products with a known potential to prolong QT/QTc interval .