HIGHLIGHTS OF PRESCRIBING INFORMATION • Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks These highlights do not include all the information needed to use increase with higher doses and concomitant use of certain medicines. VYTORIN safely and effectively. See full prescribing information for Predisposing factors include advanced age (≥65), female gender, VYTORIN. uncontrolled hypothyroidism, and renal impairment. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria VYTORIN® (ezetimibe and simvastatin) tablets, for oral use have been reported. (4, 5.1, 8.5, 8.6) Initial U.S. Approval: 2004 • Liver enzyme abnormalities: Persistent elevations in hepatic --------------------------- RECENT MAJOR CHANGES --------------------------­ transaminases can occur. Check liver enzyme tests before initiating Dosage and Administration therapy and as clinically indicated thereafter. (5.2) Chinese Patients Taking Lipid-Modifying Doses ------------------------------ ADVERSE REACTIONS -----------------------------­ (greater than or equal to 1 g/day Niacin) of Niacin-Containing Products • Common (incidence ≥2% and greater than placebo) adverse – removal (2.7) 04/2019 reactions in clinical trials: headache, increased ALT, myalgia, upper Warnings and Precautions respiratory tract infection, and diarrhea. (6.1) Myopathy/Rhabdomyolysis (5.1) 10/2019 ----------------------------INDICATIONS AND USAGE ---------------------------­ To report SUSPECTED ADVERSE REACTIONS, contact Merck VYTORIN, which contains a cholesterol absorption inhibitor and an Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877­ HMG-CoA reductase inhibitor (statin), is indicated as adjunctive therapy 888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. to diet to: ------------------------------- DRUG INTERACTIONS ------------------------------­ • reduce elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and to Drug Interactions Associated with Increased increase HDL-C in patients with primary (heterozygous familial and Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2, non-familial) hyperlipidemia or mixed hyperlipidemia. (1.1) 7.3, 7.8, 12.3) • reduce elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH), as an adjunct to other lipid- Interacting Agents Prescribing lowering treatments. (1.2) Recommendations Limitations of Use (1.3) Strong CYP3A4 Inhibitors, Contraindicated with VYTORIN • No incremental benefit of VYTORIN on cardiovascular morbidity and (e.g., itraconazole, mortality over and above that demonstrated for simvastatin has been ketoconazole, established. posaconazole, voriconazole, • VYTORIN has not been studied in Fredrickson Type I, III, IV, and V erythromycin, clarithromycin, dyslipidemias. telithromycin, HIV protease inhibitors, boceprevir, ----------------------- DOSAGE AND ADMINISTRATION ----------------------­ telaprevir, nefazodone, • Dose range is 10/10 mg/day to 10/40 mg/day. (2.1) cobicistat-containing • Recommended usual starting dose is 10/10 or 10/20 mg/day. (2.1) products), gemfibrozil, • Due to the increased risk of myopathy, including rhabdomyolysis, use cyclosporine, danazol of the 10/80-mg dose of VYTORIN should be restricted to patients Niacin (≥1 g/day) For Chinese patients, not who have been taking VYTORIN 10/80 mg chronically (e.g., for 12 recommended with VYTORIN months or more) without evidence of muscle toxicity. (2.2) Verapamil, diltiazem, Do not exceed 10/10 mg • Patients who are currently tolerating the 10/80-mg dose of VYTORIN dronedarone VYTORIN daily who need to be initiated on an interacting drug that is contraindicated Amiodarone, amlodipine, Do not exceed 10/20 mg or is associated with a dose cap for simvastatin should be switched ranolazine VYTORIN daily to an alternative statin or statin-based regimen with less potential for Lomitapide For patients with HoFH, do not 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 achieve their LDL-C goal utilizing the 10/40-mg dose of VYTORIN Daptomycin Temporarily suspend VYTORIN should not be titrated to the 10/80-mg dose, but should be placed on Grapefruit juice Avoid grapefruit juice alternative LDL-C-lowering treatment(s) that provides greater LDL-C * For patients with HoFH who have been taking 80 mg simvastatin lowering. (2.2) chronically (e.g., for 12 months or more) without evidence of muscle • Dosing of VYTORIN should occur either ≥2 hours before or ≥4 hours toxicity, do not exceed 10/40 mg VYTORIN when taking lomitapide. after administration of a bile acid sequestrant. (2.3, 7.5) • Coumarin anticoagulants: simvastatin prolongs INR. Achieve stable 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. (2.3, (3) 7.5) • Other Lipid-lowering Medications: Use with fenofibrates increases the ------------------------------- CONTRAINDICATIONS ------------------------------­ risk of adverse skeletal muscle effects. Caution should be used when • Concomitant administration of strong CYP3A4 inhibitors. (4, 5.1) prescribing with VYTORIN. (5.1, 7.2) • Concomitant administration of gemfibrozil, cyclosporine, or danazol. • Fenofibrates: Combination increases exposure of ezetimibe. If (4, 5.1) cholelithiasis is suspected in a patient receiving ezetimibe and a • Hypersensitivity to any component of this medication (4, 6.2) fenofibrate, gallbladder studies are indicated and alternative lipid- • Active liver disease or unexplained persistent elevations of hepatic lowering therapy should be considered. (7.2, 7.7, 12.3) transaminase levels (4, 5.2) • 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 mg/day should be used with caution and close monitoring (2.5, 8.6). ----------------------- WARNINGS AND PRECAUTIONS -----------------------­ • Chinese patients: May be at higher risk of myopathy; monitor • Patients should be advised of the increased risk of myopathy, appropriately (5.1, 8.8). including rhabdomyolysis, with the 10/80-mg dose. (5.1) • Patients should be advised to report promptly any unexplained and/or See 17 for PATIENT COUNSELING INFORMATION and persistent muscle pain, tenderness, or weakness. VYTORIN should FDA-approved patient labeling. be discontinued immediately if myopathy is diagnosed or suspected. (5.1) Revised: 10/2019 FULL PRESCRIBING INFORMATION: CONTENTS* Reference ID: 4502078 1 INDICATIONS AND USAGE 8 USE IN SPECIFIC POPULATIONS 1.1 Primary Hyperlipidemia 8.1 Pregnancy 1.2 Homozygous Familial Hypercholesterolemia (HoFH) 8.3 Nursing Mothers 1.3 Limitations of Use 8.4 Pediatric Use 2 DOSAGE AND ADMINISTRATION 8.5 Geriatric Use 2.1 Recommended Dosing 8.6 Renal Impairment 2.2 Restricted Dosing for 10/80 mg 8.7 Hepatic Impairment 2.3 Coadministration with Other Drugs 8.8 Chinese Patients 2.4 Patients with Homozygous Familial Hypercholesterolemia 10 OVERDOSAGE 2.5 Patients with Renal Impairment/Chronic Kidney Disease 11 DESCRIPTION 2.6 Geriatric Patients 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 Myopathy/Rhabdomyolysis 13 NONCLINICAL TOXICOLOGY 5.2 Liver Enzymes 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.3 Endocrine Function 13.2 Animal Toxicology and/or Pharmacology 6 ADVERSE REACTIONS 14 CLINICAL STUDIES 6.1 Clinical Trials Experience 14.1 Primary Hyperlipidemia 6.2 Postmarketing Experience 14.2 Homozygous Familial Hypercholesterolemia (HoFH) 7 DRUG INTERACTIONS 14.3 Chronic Kidney Disease (CKD) 7.1 Strong CYP3A4 Inhibitors, Cyclosporine, or Danazol 16 HOW SUPPLIED/STORAGE AND HANDLING 7.2 Lipid-Lowering Drugs That Can Cause Myopathy When 17 PATIENT COUNSELING INFORMATION Given Alone 17.1 Muscle Pain 7.3 Amiodarone, Dronedarone, Ranolazine, or Calcium Channel 17.2 Liver Enzymes Blockers 17.3 Pregnancy 7.4 Niacin 17.4 Breastfeeding 7.5 Cholestyramine 7.6 Digoxin *Sections or subsections omitted from the full prescribing information 7.7 Fenofibrates (e.g., fenofibrate and fenofibric acid) are not listed. 7.8 Coumarin Anticoagulants 7.9 Colchicine 7.10 Daptomycin 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