Nexavar

1 INDICATIONS AND USAGE NEXAVAR is 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 NEXAVAR ® is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC). 1.2 Renal Cell Carcinoma NEXAVAR is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). 1.3 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.

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 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. 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 NEXAVAR for Adverse Reactions Adverse Reaction Severity 1 NEXAVAR 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 2 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. 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 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 [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. 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 …

3 DOSAGE FORMS AND STRENGTHS 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 ( 3 )

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

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 )] 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 Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 NEXAVAR in 955 patients who participated in placebo-controlled studies in hepatocellular carcinoma (N=297), advanced renal cell carcinoma (N=451), or differentiated thyroid carcinoma (N = 207). The most common adverse reactions (≥20%), which were considered to be related to NEXAVAR, in patients with HCC, RCC 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 NEXAVAR-treated group than in those receiving placebo. Table 4: Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in NEXAVAR Arm than the Placebo Arm – SHARP (HCC) Adverse Reaction 1 NEXAVAR 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 1 Adverse 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 NEXAVAR and 4% of those receiving placebo. Grade 3 hypertension was reported in 4% of NEXAVAR-treated patients and 1% of those receiving placebo. Hemorrhage/bleeding was reported in 18% of those receiving NEXAVAR and 20% of patients receiving placebo. The rates of Grade 3 and 4 bleeding were also higher in patients receiving placebo (Grade 3 – 3% NEXAVAR and 5% placebo and Grade 4 – 2% NEXAVAR and 4% placebo). Bleeding from esophageal varices was reported in 2.4% in NEXAVAR-treated patients and 4% of patients receiving placebo. Renal failure was reported in <1% of patients treated with NEXAVAR and 3% of patients receiving placebo. Clinical pancreatitis was reported in 1 of 297 NEXAVAR-treated patients (Grade 2). The rate of adverse reactions (including those associated with progressive disease) resulting in permanent discontinuation was similar in both the NEXAVAR-treated patients and those receiving placebo ( …

7 DRUG INTERACTIONS • Strong CYP3A Inducers: Avoid strong CYP3A4 inducers. ( 7.1 ) 7.1 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 [see Clinical Pharmacology ( 12.3 )] . 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 [see Clinical Pharmacology ( 12.3 )]. 7.2 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 [see Warnings and Precautions ( 5.6 )]. 7.3 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 [see Warnings and Precautions ( 5.9 ), Clinical Pharmacology ( 12.2 )] .

8 USE IN SPECIFIC POPULATIONS • Lactation : Advise women not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology ( 12.1 )] , NEXAVAR may cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform a drug-associated risk. In animal reproduction studies, oral administration of sorafenib to pregnant rats and rabbits during the period of organogenesis resulted in embryo-fetal toxicities at maternal exposures that were significantly lower than human exposures at the recommended dose of 400 mg twice daily (see Data). Advise pregnant women and females of reproductive potential of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In animal reproduction studies, sorafenib was teratogenic and induced embryo-fetal toxicity (including increased post-implantation loss, resorptions, skeletal retardations, and retarded fetal weight) when administered orally to pregnant rats and rabbits during the period of organogenesis. The effects occurred at doses considerably below the recommended human dose of 400 mg twice daily (approximately 500 mg/m 2 /day on a body surface area basis). Adverse intrauterine development effects were seen at doses >0.2 .mg/kg/day (1.2 mg/m 2 /day) in rats and ≥0.3 mg/kg/day (≥3.6 mg/m 2 /day) in rabbits. These doses result in exposures (AUC) that are approximately 0.008 times the AUC in patients at the recommended dose. 8.2 Lactation Risk Summary There are no data on the presence of sorafenib or its metabolites in human milk, or its effects on the breast-fed child or on milk production. Sorafenib was present in milk of lactating rats (see Data) . Because of the potential for serious adverse reactions in a breastfed child from NEXAVAR, advise women not to breastfeed during treatment with NEXAVAR and for 2 weeks after the last dose. Data Animal Data Following administration of radiolabeled sorafenib to lactating Wistar rats, approximately 27% of the radioactivity was secreted into milk. The milk to plasma AUC ratio was approximately 5:1. 8.3 Females and Males of Reproductive Potential NEXAVAR may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to the initiation of NEXAVAR. Contraception Females Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of NEXAVAR. Males Based on genotoxicity and findings in animal reproduction studies, advise males with female partners of reproductive potential and pregnant partners to use effective contraception during treatment with NEXAVAR and for 3 months following the last dose of NEXAVAR [see Use in Specific Populations ( 8.1 ), Nonclinical Toxicology ( 13.1 )] . Infertility Males Based on findings in animal studies, NEXAVAR may impair fertility in males of reproductive potential [see Nonclinical Toxicology ( 13.1 )] . 8.4 Pediatric Use The safety and effectiveness of NEXAVAR have not been established in pediatric patients. Juvenile Animal Toxicity Data Repeat dosing of sorafenib to young and growing dogs resulted in irregular thickening of the femoral growth plate at daily sorafenib doses ≥600 mg/m 2 (approximately 0.3 times the AUC at the recommended human dose), hypocellularity of the bone marrow adjoining the growth plate at 200 mg/m 2 /day (approximately 0.1 times the AUC at the recommended human dose), and alterations of the dentin composition at 600 mg/m 2 /day. Similar effects were not observed in adult dogs when dosed for 4 weeks or less. 8.5 Geriatric Use …

12.1 Mechanism of Action Sorafenib is a kinase inhibitor that decreases tumor cell proliferation in vitro. Sorafenib was shown to inhibit multiple intracellular (c-CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT- 3, RET, RET/PTC, VEGFR-1, VEGFR- 2, VEGFR- 3, and PDGFR-ß). Several of these kinases are thought to be involved in tumor cell signaling, angiogenesis and apoptosis. Sorafenib inhibited tumor growth of HCC, RCC, and DTC human tumor xenografts in immunocompromised mice. Reductions in tumor angiogenesis were seen in models of HCC and RCC upon sorafenib treatment, and increases in tumor apoptosis were observed in models of HCC, RCC, and DTC.

11 DESCRIPTION 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

10 OVERDOSAGE The adverse reactions observed at a dose of 800 mg twice daily (2 times the recommended dose) were primarily diarrhea and dermatologic. No information is available on symptoms of acute overdose in animals because of the saturation of absorption in oral acute toxicity studies conducted in animals. In cases of suspected overdose, withhold NEXAVAR and institute supportive care.

16 HOW SUPPLIED/STORAGE AND HANDLING NEXAVAR is supplied in bottles of 120: • 200 mg, round, biconvex, red film-coated tablets, debossed with the “Bayer cross” on one side and “200” on the other side. NDC 50419-488-58 • 200 mg, round, faceted, biconvex, red film-coated tablets, debossed with the “Bayer cross” on one side and “200” on the other side. NDC 50419-489-01 Store at 20°C to 25° C (68°F to 77° F); excursions permitted to 15°C to 30° C (59°F to 86° F) [see USP controlled room temperature]. Store in a dry place.