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NEXAVAR (Sorafenib) Tablets, for Oral Use  QT Prolongation: Monitor Electrocardiograms and Electrolytes in Initial U.S

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NEXAVAR (Sorafenib) Tablets, for Oral Use  QT Prolongation: Monitor Electrocardiograms and Electrolytes in Initial U.S HIGHLIGHTS OF PRESCRIBING INFORMATION Dermatologic Toxicities: Interrupt and/or decrease dose. Discontinue for These highlights do not include all the information needed to use severe or persistent reactions, or if Stevens-Johnson syndrome and toxic NEXAVAR safely and effectively. epidermal necrolysis is suspected. (5.4) See full prescribing information for NEXAVAR. Gastrointestinal Perforation: Discontinue NEXAVAR. (5.5) NEXAVAR (sorafenib) tablets, for oral use QT Prolongation: Monitor electrocardiograms and electrolytes in Initial U.S. Approval: 2005 patients at increased risk for ventricular arrhythmias. (5.9, 12.2) Drug-Induced Liver Injury: Monitor liver function tests regularly; --------------------------- RECENT MAJOR CHANGES --------------------------- discontinue for unexplained transaminase elevations. (5.10) Warnings and Precautions, Cardiovascular Events (5.1) 12/2018 Embryo-Fetal Toxicity: NEXAVAR may cause fetal harm. Advise Dosage and Administration, patients of the potential risk to a fetus and to use effective contraception. Dose Modifications for Adverse Reactions (2.2) 12/2018 (5.11, 8.1, 8.3) --------------------------- INDICATIONS AND USAGE ---------------------------- Impairment of TSH suppression in DTC: Monitor TSH monthly and NEXAVAR is a kinase inhibitor indicated for the treatment of adjust thyroid replacement therapy in patients with thyroid cancer. (5.12) Unresectable hepatocellular carcinoma (1.1) ------------------------------ ADVERSE REACTIONS ------------------------------ Advanced renal cell carcinoma (1.2) The most common adverse reactions (≥20%) for NEXAVAR are diarrhea, Locally recurrent or metastatic, progressive, differentiated thyroid fatigue, infection, alopecia, hand-foot skin reaction, rash, weight loss, carcinoma refractory to radioactive iodine treatment (1.3) decreased appetite, nausea, gastrointestinal and abdominal pains, ----------------------- DOSAGE AND ADMINISTRATION ----------------------- hypertension, and hemorrhage. (6) 400 mg (2 tablets) orally twice daily without food. (2.1) To report SUSPECTED ADVERSE REACTIONS, contact Bayer Treatment interruption and/or dose reduction may be needed to manage HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at adverse reactions. (2.2) 1-800-FDA-1088 or www.fda.gov/medwatch. --------------------- DOSAGE FORMS AND STRENGTHS ---------------------- ------------------------------ DRUG INTERACTIONS------------------------------- 200 mg Tablets (3) Avoid strong CYP3A4 inducers. (7.1) ------------------------------ CONTRAINDICATIONS ------------------------------ ----------------------- USE IN SPECIFIC POPULATIONS ----------------------- NEXAVAR is contraindicated in patients with known severe Lactation: Advise women not to breastfeed. (8.2) hypersensitivity to sorafenib or any other component of NEXAVAR. (4) Females and Males of Reproductive Potential: Verify pregnancy status NEXAVAR in combination with carboplatin and paclitaxel is prior to initiation of NEXAVAR. (8.3) contraindicated in patients with squamous cell lung cancer. (4) See 17 for PATIENT COUNSELING INFORMATION and ----------------------- WARNINGS AND PRECAUTIONS ------------------------ FDA-Approved Patient Labeling. Cardiovascular Events: Consider temporary or permanent discontinuation of NEXAVAR. (2.2, 5.1) Bleeding: Discontinue NEXAVAR if needed. (5.2) Revised: 12/2018 Hypertension: Monitor blood pressure weekly during the first 6 weeks and periodically thereafter. (5.3) _______________________________________________________________________________________________________________________________________ FULL PRESCRIBING INFORMATION: CONTENTS* 8.2 Lactation 1 INDICATIONS AND USAGE 8.3 Females and Males of Reproductive Potential 1.1 Hepatocellular Carcinoma 8.4 Pediatric Use 1.2 Renal Cell Carcinoma 8.5 Geriatric Use 1.3 Differentiated Thyroid Carcinoma 8.6 Patients with Hepatic Impairment 2 DOSAGE AND ADMINISTRATION 8.7 Patients with Renal Impairment 2.1 Recommended Dose for Hepatocellular Carcinoma, Renal Cell 10 OVERDOSAGE Carcinoma, and Differentiated Thyroid Carcinoma 11 DESCRIPTION 2.2 Dose Modifications for Adverse Reactions 12 CLINICAL PHARMACOLOGY 3 DOSAGE FORMS AND STRENGTHS 12.1 Mechanism of Action 4 CONTRAINDICATIONS 12.2 Pharmacodynamics 5 WARNINGS AND PRECAUTIONS 12.3 Pharmacokinetics 5.1 Cardiovascular Events 13 NONCLINICAL TOXICOLOGY 5.2 Hemorrhage 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.3 Hypertension 14 CLINICAL STUDIES 5.4 Dermatologic Toxicities 14.1 Hepatocellular Carcinoma 5.5 Gastrointestinal Perforation 14.2 Renal Cell Carcinoma 5.6 Warfarin 14.3 Differentiated Thyroid Carcinoma 5.7 Wound Healing Complications 16 HOW SUPPLIED/STORAGE AND HANDLING 5.8 Increased Mortality Observed with NEXAVAR Administered in 17 PATIENT COUNSELING INFORMATION Combination with Carboplatin/Paclitaxel and *Sections or subsections omitted from the full prescribing information are not Gemcitabine/Cisplatin in Squamous Cell Lung Cancer listed. 5.9 QT Interval Prolongation 5.10 Drug-Induced Liver Injury 5.11 Embryo-Fetal Toxicity 5.12 Impairment of Thyroid Stimulating Hormone Suppression in Differentiated Thyroid Carcinoma 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Effect of Strong CYP3A4 Inducers on Sorafenib 7.2 Effect of Strong CYP3A4 Inhibitors on Sorafenib 7.3 Effect of Sorafenib on Other Drugs 7.4 Neomycin 7.5 Drugs that Increase Gastric pH 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Reference ID: 4357655 ____________________________________________________________________________________ FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 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 2.1 Recommended Dose for Hepatocellular Carcinoma, Renal Cell Carcinoma, and Differentiated Thyroid Carcinoma The recommended daily dose of NEXAVAR is 400 mg (2 x 200 mg tablets) taken twice daily without food (at least 1 hour before or 2 hours after a meal). Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs. 2.2 Dose Modifications for Adverse Reactions Temporary interruption of NEXAVAR is recommended in patients undergoing major surgical procedures [see Warnings and Precautions (5.7)]. Temporary interruption or permanent discontinuation of NEXAVAR may be required [see Table 1 and Warnings and Precautions (5)]. Reference ID: 4357655 Table 1: Adverse Reactions Requiring Dose Modification of Nexavar Dose Reduce and Adverse Reaction CTCAE Grade Action Resume Nexavar Cardiovascular Events Cardiac Ischemia Grade 2 and above Permanently discontinue Do not resume and/or Infarction Decrease one dose Grade 3 Interrupt a until Grade 1 Congestive Heart levelb c Failure Grade 4 Permanently discontinue Do not resume Hemorrhage requiring medical Grade 2 and above Permanently discontinue Do not resume intervention Continue NEXAVAR dosing Grade 2 asymptomatic Treat with anti-hypertensive as scheduled and and diastolic pressure 90- therapy closely monitor 99 mm Hg blood pressure. Grade 2 Treat with anti- (symptomatic/persistent) hypertensives. OR Reduce dose to one Hypertension Grade 2 symptomatic Interrupt until symptoms dose levelc when increase by >20 mm Hg resolve and diastolic blood resumed. (diastolic) or >140/90 mm pressure < 90 mm Hg If needed, reduce Hg if previously within another dose level. b normal limits c OR Grade 3 Grade 4 Permanently discontinue Do not resume Gastrointestinal Any grade Permanently discontinue Do not resume Perforation Monitor electrolytes and electrocardiograms If QTc Interrupt Use medical is >500 milliseconds or Correct electrolyte QT Prolongation judgement before for an increase from abnormalities (magnesium, restarting baseline of 60 potassium, calcium). milliseconds or greater > Grade 3 ALT in the absence of another caused Severe DILI AST/ALT > 3xULN with Permanently discontinue Do not resume bilirubin > 2xULN in the absence of another caused Non-hematological Grade 2 Treat on time Decrease one dose toxicities levelc Grade 3 1st occurrence Interrupt until ≤ Grade 2 Decrease one dose levelc No improvement within 7 Interrupt until ≤ Grade 2 Decrease two dose days or 2nd or 3rd levelsc occurrence 4th occurrence Interrupt until ≤ Grade 2 Decrease three dose levelsc Reference ID: 4357655 Grade 4 Permanently discontinue Do not resume ULN-upper limit of normal; DILI-drug induced liver injury a If no recovery after 30 day interruption, treatment will be discontinued unless the patient is deriving clinical benefit b If more than 2 dose reductions are required, treatment will be discontinued c Hepatocellular and renal cell carcinoma (400 mg daily, 200 mg daily or 400 every other day) and thyroid cancer (800 mg to 600 mg, 400 mg, and 200 mg). See details below for reduction per indication d In addition, any grade Alkaline phosphatase increase in the absence of known bone pathology and Grade 2 or worse Bilirubin increase; Any 1 of the following: INR ≥ 1.5, Ascites and/or encephalopathy in the absence of underlying cirrhosis or other
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