HIGHLIGHTS OF PRESCRIBING INFORMATION should be discontinued immediately if myopathy is diagnosed or These highlights do not include all the information needed to use suspected. (5.1) VYTORIN safely and effectively. See full prescribing information • Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks for VYTORIN. increase with higher doses and concomitant use of certain medicines. Predisposing factors include advanced age (≥65), VYTORIN® (ezetimibe/simvastatin) Tablets female gender, uncontrolled hypothyroidism, and renal impairment. Initial U.S. Approval: 2004 Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported. (4, 5.1, 8.5, 8.6) --------------------------- RECENT MAJOR CHANGES --------------------------­ • Liver enzyme abnormalities: Persistent elevations in hepatic Dosage and Administration transaminases can occur. Check liver enzyme tests before initiating Patients with Hepatic Impairment (2.5) removal 02/2014 therapy and as clinically indicated thereafter. (5.2) Contraindications (4) 02/2014 Warnings and Precautions ------------------------------ ADVERSE REACTIONS -----------------------------­ Myopathy/Rhabdomyolysis (5.1) 02/2014 • Common (incidence ≥2% and greater than placebo) adverse Hepatic Impairment (5.3) removal 02/2014 reactions in clinical trials: headache, increased ALT, myalgia, upper respiratory tract infection, and diarrhea. (6.1) ---------------------------- INDICATIONS AND USAGE ---------------------------­ VYTORIN, which contains a cholesterol absorption inhibitor and an To report SUSPECTED ADVERSE REACTIONS, contact Merck HMG-CoA reductase inhibitor (statin), is indicated as adjunctive Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877­ therapy to diet to: 888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. • reduce elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and to increase HDL-C in patients with primary (heterozygous familial and ------------------------------- DRUG INTERACTIONS ------------------------------­ non-familial) hyperlipidemia or mixed hyperlipidemia. (1.1) Drug Interactions Associated with Increased • reduce elevated total-C and LDL-C in patients with homozygous Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2, familial hypercholesterolemia (HoFH), as an adjunct to other lipid- 7.3, 7.8, 12.3) lowering treatments. (1.2) Interacting Agents Prescribing Limitations of Use (1.3) Recommendations • No incremental benefit of VYTORIN on cardiovascular morbidity Contraindicated with VYTORIN and mortality over and above that demonstrated for simvastatin has Strong CYP3A4 Inhibitors, been established. (e.g., itraconazole, • VYTORIN has not been studied in Fredrickson Type I, III, IV, and V ketoconazole, dyslipidemias. posaconazole, voriconazole, erythromycin, ----------------------- DOSAGE AND ADMINISTRATION-----------------------­ clarithromycin, telithromycin, • Dose range is 10/10 mg/day to 10/40 mg/day. (2.1) HIV protease inhibitors, • Recommended usual starting dose is 10/10 or 10/20 mg/day. (2.1) boceprevir, telaprevir, • Due to the increased risk of myopathy, including rhabdomyolysis, nefazodone, cobicistat­ use of the 10/80-mg dose of VYTORIN should be restricted to containing products), patients who have been taking VYTORIN 10/80 mg chronically gemfibrozil, cyclosporine, (e.g., for 12 months or more) without evidence of muscle toxicity. danazol (2.2) Verapamil, diltiazem, Do not exceed 10/10 mg • Patients who are currently tolerating the 10/80-mg dose of dronedarone VYTORIN daily VYTORIN who need to be initiated on an interacting drug that is Amiodarone, amlodipine, Do not exceed 10/20 mg contraindicated or is associated with a dose cap for simvastatin ranolazine VYTORIN daily should be switched to an alternative statin or statin-based regimen Lomitapide For patients with HoFH, do not with less potential for the drug-drug interaction. (2.2) exceed 10/20 mg VYTORIN • Due to the increased risk of myopathy, including rhabdomyolysis, daily* associated with the 10/80-mg dose of VYTORIN, patients unable to Grapefruit juice Avoid grapefruit juice achieve their LDL-C goal utilizing the 10/40-mg dose of VYTORIN * For patients with HoFH who have been taking 80 mg simvastatin should not be titrated to the 10/80-mg dose, but should be placed chronically (e.g., for 12 months or more) without evidence of on alternative LDL-C-lowering treatment(s) that provides greater muscle toxicity, do not exceed 10/40 mg VYTORIN when taking LDL-C lowering. (2.2) lomitapide. • Dosing of VYTORIN should occur either ≥2 hours before or • Coumarin anticoagulants: simvastatin prolongs INR. Achieve stable ≥4 hours after administration of a bile acid sequestrant. (2.3, 7.5) INR prior to starting VYTORIN. Monitor INR frequently until stable --------------------- DOSAGE FORMS AND STRENGTHS --------------------­ upon initiation or alteration of VYTORIN therapy. (7.8) • • Tablets (ezetimibe mg/simvastatin mg): 10/10, 10/20, 10/40, 10/80 Cholestyramine: Combination decreases exposure of ezetimibe. (3) (2.3, 7.5) • Other Lipid-lowering Medications: Use with fenofibrates or lipid- ------------------------------- CONTRAINDICATIONS ------------------------------­ modifying doses (≥1 g/day) of niacin increases the risk of adverse • Concomitant administration of strong CYP3A4 inhibitors. (4, 5.1) skeletal muscle effects. Caution should be used when prescribing • Concomitant administration of gemfibrozil, cyclosporine, or danazol. with VYTORIN. (5.1, 7.2, 7.4) (4, 5.1) • Fenofibrates: Combination increases exposure of ezetimibe. If • Hypersensitivity to any component of this medication (4, 6.2) cholelithiasis is suspected in a patient receiving ezetimibe and a • Active liver disease or unexplained persistent elevations of hepatic fenofibrate, gallbladder studies are indicated and alternative lipid- transaminase levels (4, 5.2) lowering therapy should be considered. (7.2, 7.7, 12.3) • Women who are pregnant or may become pregnant (4, 8.1) ----------------------- USE IN SPECIFIC POPULATIONS ----------------------­ • Nursing mothers (4, 8.3) • Moderate to severe renal impairment: Doses exceeding 10/20 ----------------------- WARNINGS AND PRECAUTIONS -----------------------­ mg/day should be used with caution and close monitoring (2.5, 8.6). • Patients should be advised of the increased risk of myopathy, including rhabdomyolysis, with the 10/80-mg dose. (5.1) See 17 for PATIENT COUNSELING INFORMATION and • Patients should be advised to report promptly any unexplained FDA-approved patient labeling. and/or persistent muscle pain, tenderness, or weakness. VYTORIN Revised: 02/2015 Reference ID: 3695651 FULL PRESCRIBING INFORMATION: CONTENTS* 7.6 Digoxin 7.7 Fenofibrates (e.g., fenofibrate and fenofibric acid) 1 INDICATIONS AND USAGE 7.8 Coumarin Anticoagulants 1.1 Primary Hyperlipidemia 7.9 Colchicine 1.2 Homozygous Familial Hypercholesterolemia (HoFH) 8 USE IN SPECIFIC POPULATIONS 1.3 Limitations of Use 8.1 Pregnancy 2 DOSAGE AND ADMINISTRATION 8.3 Nursing Mothers 2.1 Recommended Dosing 8.4 Pediatric Use 2.2 Restricted Dosing for 10/80 mg 8.5 Geriatric Use 2.3 Coadministration with Other Drugs 8.6 Renal Impairment 2.4 Patients with Homozygous Familial Hypercholesterolemia 8.7 Hepatic Impairment 2.5 Patients with Renal Impairment/Chronic Kidney Disease 10 OVERDOSAGE 2.6 Geriatric Patients 11 DESCRIPTION 2.7 Chinese Patients Taking Lipid-Modifying Doses (greater 12 CLINICAL PHARMACOLOGY than or equal to 1 g/day Niacin) of Niacin-Containing 12.1 Mechanism of Action Products 12.2 Pharmacodynamics 3 DOSAGE FORMS AND STRENGTHS 12.3 Pharmacokinetics 4 CONTRAINDICATIONS 13 NONCLINICAL TOXICOLOGY 5 WARNINGS AND PRECAUTIONS 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.1 Myopathy/Rhabdomyolysis 13.2 Animal Toxicology and/or Pharmacology 5.2 Liver Enzymes 14 CLINICAL STUDIES 5.3 Endocrine Function 14.1 Primary Hyperlipidemia 6 ADVERSE REACTIONS 14.2 Homozygous Familial Hypercholesterolemia (HoFH) 6.1 Clinical Trials Experience 14.3 Chronic Kidney Disease (CKD) 6.2 Postmarketing Experience 16 HOW SUPPLIED/STORAGE AND HANDLING 7 DRUG INTERACTIONS 17 PATIENT COUNSELING INFORMATION 7.1 Strong CYP3A4 Inhibitors, Cyclosporine, or Danazol 17.1 Muscle Pain 7.2 Lipid-Lowering Drugs That Can Cause Myopathy When 17.2 Liver Enzymes Given Alone 17.3 Pregnancy 7.3 Amiodarone, Dronedarone, Ranolazine, or Calcium Channel 17.4 Breastfeeding Blockers 7.4 Niacin *Sections or subsections omitted from the full prescribing information 7.5 Cholestyramine are not listed. FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. 1.1 Primary Hyperlipidemia VYTORIN® is indicated for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary (heterozygous familial and non-familial) hyperlipidemia or mixed hyperlipidemia. 1.2 Homozygous Familial Hypercholesterolemia (HoFH) VYTORIN is indicated for the reduction of elevated total-C and LDL-C in patients