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 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).

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 )

Not available.

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 (32% of NEXAVAR-treated patients and 35% of patients receiving placebo). Laboratory test abnormalities reported in SHARP are presented in Table 5. Table 5: Laboratory Test Abnormalities Reported in SHARP (HCC) Laboratory Parameter 1 NEXAVAR N=297 Placebo N=302 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hypoalbuminemia 59 0 47 0 Elevated Lipase 40 9 37 9 Lymphopenia 47 NR 42 NR Thrombocytopenia 46 4 41 <1 Elevated INR 42 4 34 2 Hypophosphatemia 35 11 11 2 Elevated Amylase 34 2 29 2 Hypocalcemia 27 2.4 15 1 Hypokalemia 10 <1 6 <1 1- Laboratory parameters graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0). NR = not reported Renal Cell Carcinoma Table 6 shows the percentage of patients in the TARGET (RCC) study experiencing adverse reactions that were reported in at least 10% of patients and at a higher rate in NEXAVAR-treated patients arm than in those receiving placebo. The rate of adverse reactions (including those associated with progressive disease) resulting in permanent discontinuation was similar in both the NEXAVAR-treated patients and patients receiving placebo (10% and 8%, respectively). Clinical pancreatitis was reported in 3 of 451 NEXAVAR-treated patients (one Grade 2 and two Grade 4). Table 6: Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in NEXAVAR Arm than the Placebo Arm – TARGET (RCC) Adverse Reaction 1 NEXAVAR N=451 Placebo N=451 All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Any Adverse Reactions 95 31 7 86 22 6 Gastrointestinal symptoms Diarrhea 43 2 0 13 <1 0 Nausea 23 <1 0 19 <1 0 Anorexia 16 <1 0 13 1 0 Vomiting 16 <1 0 12 1 0 Constipation 15 <1 0 11 <1 0 Dermatology/skin Rash/desquamation 40 <1 0 16 <1 0 Hand-foot skin reaction 30 6 0 7 0 0 Alopecia 27 <1 0 3 0 0 Pruritus 19 <1 0 6 0 0 Dry skin 11 0 0 4 0 0 Constitutional symptoms Fatigue 37 5 <1 28 3 <1 Weight loss 10 <1 0 6 0 0 Cardiovascular, General Hypertension 17 3 <1 2 <1 0 Hemorrhage/bleeding Hemorrhage – all sites 15 2 0 8 1 <1 Pulmonary Dyspnea 14 3 <1 12 2 <1 Neurology Neuropathy-sensory 13 <1 0 6 <1 0 Pain Pain, abdomen 11 2 0 9 2 0 Pain, headache 10 <1 0 6 <1 0 Pain, joint 10 2 0 6 <1 0 1 Adverse reactions graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0). Laboratory test abnormalities reported in TARGET are presented in Table 7. Table 7: Laboratory Test Abnormalities Reported in TARGET (RCC) Laboratory Parameter 1 NEXAVAR N=451 Placebo N=451 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hypophosphatemia 45 13 11 3 Anemia 44 2 49 4 Elevated Lipase 41 12 30 7 Elevated Amylase 30 1 23 3 Lymphopenia 23 13 13 7 Neutropenia 18 5 10 2 Thrombocytopenia 12 1 5 0 Hypocalcemia 12 2 8 <1 Hypokalemia 5 1 <1 <1 1 Laboratory parameters graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0). Differentiated Thyroid Carcinoma The safety of NEXAVAR was evaluated in DECISION in 416 patients with locally recurrent or metastatic, progressive differentiated thyroid carcinoma (DTC) refractory to radioactive iodine (RAI) treatment randomized to receive 400 mg twice daily NEXAVAR (n=207) or matching placebo (n=209) until disease progression or intolerable toxicity in a double-blind trial [see Clinical Studies ( 14.3 )]. The data described below reflect a median exposure to NEXAVAR for 46 weeks (range 0.3 to 135). The population exposed to NEXAVAR was 50% male, and had a median age of 63 years. Dose interruptions for adverse reactions were required in 66% of patients receiving NEXAVAR and dose reductions were required in 64% of patients. Adverse reactions that resulted in treatment discontinuation were reported in 14% of NEXAVAR-treated patients compared to 1.4% of patients receiving placebo. Table 8 shows the percentage of DTC patients experiencing adverse reactions at a higher rate in NEXAVAR-treated patients than in patients receiving placebo in the double-blind phase of the DECISION study. Grade 3 adverse reactions occurred in 53% of NEXAVAR-treated patients compared to 23% of patients receiving placebo. Grade 4 adverse reactions occurred in 12% of NEXAVAR-treated patients compared to 7% of patients receiving placebo. Table 8: Selected Adverse Reactions Occurring at a Higher Incidence in NEXAVAR-Treated Patients [Between Arm Difference of ≥ 5% (All Grades)1 or ≥ 2% (Grades 3 and 4)] Adverse Reaction NEXAVAR N = 207 Placebo N = 209 All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) Skin and subcutaneous tissue disorders PPES 5 69 19 8 0 Alopecia 67 0 8 0 Rash 35 5 7 0 Pruritus 20 0.5 11 0 Dry skin 13 0.5 5 0 Erythema 10 0 0.5 0 Hyperkeratosis 7 0 0 0 Gastrointestinal disorders Diarrhea 68 6 15 1 Stomatitis 3 24 2 3 0 Nausea 21 0 12 0 Abdominal pain 2 20 1 7 1 Constipation 16 0 8 0.5 Oral pain 4 14 0.5 6 0 Vomiting 11 0 3 0 Investigations Weight loss 49 6 14 1 General disorders and administration site conditions Fatigue 41 5 20 1 Asthenia 12 0 7 0 Pyrexia 11 1 5 0 Vascular disorders Hypertension 6 41 10 12 2 Metabolism and nutrition disorders Decreased appetite 30 2 5 0 Nervous system disorders Headache 17 0 6 0 Dysgeusia 6 0 0 0 Musculoskeletal and connective tissue disorders Pain in extremity 15 1 7 0 Muscle spasms 10 0 3 0 Respiratory, thoracic and mediastinal disorders Dysphonia 13 0.5 3 0 Epistaxis 7 0 1 0 Neoplasms benign, malignant and unspecified Squamous cell carcinoma of skin 3 3 0 0 1 National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 2 Includes the following terms: abdominal pain, abdominal discomfort, hepatic pain, esophageal pain, esophageal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, abdominal rigidity 3 Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation 4 Includes the following terms: oral pain, oropharyngeal discomfort, glossitis, burning mouth syndrome, glossodynia 5 Palmar-plantar erythrodysesthesia syndrome (Hand-foot skin reaction) 6 Includes the following terms: hypertension, blood pressure increased, blood pressure systolic increased The relative increase for the following laboratory abnormalities observed in NEXAVAR-treated patients as compared to patients receiving placebo in the DECISION study is similar to that observed in the RCC and HCC studies: lipase, amylase, hypokalemia, hypophosphatemia, neutropenia, lymphopenia, anemia, and thrombocytopenia. Hypocalcemia was more frequent and more severe in patients with DTC, especially those with a history of hypoparathyroidism, compared to patients with RCC or HCC. Other laboratory test abnormalities reported in DECISION are presented in Table 9 Table 9: Laboratory Test Abnormalities Reported in DECISION (DTC Laboratory Parameter 1 NEXAVAR N=207 Placebo N=209 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Elevated ALT 59 4 24 0 Elevated AST 54 2 15 0 Hypocalcemia 36 10 11 3 1 Laboratory parameters graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0). Additional Data from Multiple Clinical Trials The following additional drug-related adverse reactions and laboratory abnormalities were reported from clinical trials of NEXAVAR ( very common 10% or greater, common 1 to less than 10%, uncommon 0.1% to less than 1%, rare less than 0.1 %): Cardiovascular: Common : congestive heart failure* † , myocardial ischemia and/or infarction Uncommon: hypertensive crisis* Rare: QT prolongation* Dermatologic: Very common: erythema Common: exfoliative dermatitis, acne, flushing, folliculitis, hyperkeratosis Uncommon: eczema, erythema multiforme Digestive: Very common: increased lipase, increased amylase Common: mucositis, stomatitis (including dry mouth and glossodynia), dyspepsia, dysphagia, gastrointestinal reflux Uncommon: pancreatitis, gastritis, gastrointestinal perforations*, cholecystitis, cholangitis Note that elevations in lipase are very common (41%, see below); a diagnosis of pancreatitis should not be made solely on the basis of abnormal laboratory values General Disorders: Very common: infection, hemorrhage (including gastrointestinal* and respiratory tract* and uncommon cases of cerebral hemorrhage*), asthenia, pain (including mouth, bone, and tumor pain), pyrexia, decreased appetite Common: influenza-like illness Hematologic: Very common: leukopenia, lymphopenia Common: anemia, neutropenia, thrombocytopenia Uncommon: INR abnormal Hepatobiliary disorders: Rare: drug-induced liver injury (including hepatic failure and death) Hypersensitivity: Uncommon: hypersensitivity reactions (including skin reactions and urticaria), anaphylactic reaction Metabolic and Nutritional: Very common: hypophosphatemia Common: transient increases in transaminases, hypocalcemia, hypokalemia, hyponatremia, hypothyroidism Uncommon: dehydration, transient increases in alkaline phosphatase, increased bilirubin (including jaundice), hyperthyroidism Musculoskeletal: Very common: arthralgia Common: myalgia, muscle spasms Nervous System and Psychiatric: Common: depression, dysgeusia Uncommon: tinnitus, reversible posterior leukoencephalopathy* Renal and Genitourinary: Common : renal failure, proteinuria Rare: nephrotic syndrome Reproductive: Common: erectile dysfunction Uncommon: gynecomastia Respiratory: Common: rhinorrhea Uncommon: interstitial lung disease-like events (includes reports of pneumonitis, radiation pneumonitis, acute respiratory distress, interstitial pneumonia, pulmonitis and lung inflammation) In addition, the following medically significant adverse reactions were uncommon during clinical trials of NEXAVAR: transient ischemic attack, arrhythmia, and thromboembolism. For these adverse reactions, the causal relationship to NEXAVAR has not been established. *adverse reactions may have a life-threatening or fatal outcome. † reported in 1.9% of patients treated with NEXAVAR (N= 2276). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of NEXAVAR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic disorders: Thrombotic microangiopathy (TMA) Dermatologic: Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) Hypersensitivity: Angioedema Musculoskeletal: Rhabdomyolysis, osteonecrosis of the jaw Respiratory : Interstitial lung disease-like events (which may have a life-threatening or fatal outcome) Vascular: Arterial (including aortic) aneurysms, dissections, and rupture