HIGHLIGHTS OF PRESCRIBING INFORMATION • Hypersensitivity to rosiglitazone, glimepiride, or any of the product’s These highlights do not include all the information needed to use AVANDARYL ingredients. (4) safely and effectively. See full prescribing information for AVANDARYL. • Hypersensitivity to sulfonamide derivatives. (4) AVANDARYL (rosiglitazone maleate and glimepiride) tablets Initial U.S. Approval: 2005 ----------------------- WARNINGS and PRECAUTIONS -----------------------­ • Fluid retention, which may exacerbate or lead to heart failure, may occur. Combination use with insulin and use in congestive heart failure NYHA Class CONGESTIVE HEART FAILURE WARNING: I and II may increase risk of other cardiovascular effects. (5.1) See full prescribing information for complete boxed warning. • Meta-analysis of 52 mostly short-term trials suggested a potential risk of • Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive ischemic cardiovascular (CV) events relative to placebo, not confirmed in a heart failure in some patients (5.1). After initiation of AVANDARYL, and long-term CV outcome trial versus metformin or sulfonylurea. (5.2) after dose increases, observe patients carefully for signs and symptoms of • Severe hypoglycemia may occur. Use particular care in elderly or debilitated heart failure (including excessive, rapid weight gain, dyspnea, and/or patients and those with adrenal, pituitary, renal, or hepatic insufficiency. (5.3) edema). If these signs and symptoms develop, the heart failure should be • managed according to current standards of care. Furthermore, Dose-related edema (5.4), weight gain (5.5), and anemia (5.10) may occur. • discontinuation or dose reduction of AVANDARYL must be considered. Macular edema has been reported. (5.7) • • AVANDARYL is not recommended in patients with symptomatic heart Increased incidence of bone fracture. (5.8) failure. Initiation of AVANDARYL in patients with established NYHA Class • Postmarketing reports for glimepiride include anaphylaxis, angioedema, and III or IV heart failure is contraindicated. (4, 5.1) Stevens-Johnson syndrome. Promptly discontinue AVANDARYL, assess for other causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. (5.9) --------------------------- RECENT MAJOR CHANGES --------------------------­ • Hemolytic anemia can occur if glucose 6-phosphate dehydrogenase (G6PD) Boxed Warning, AVANDIA-Rosiglitazone Medicines 05/2014 deficient. Consider a non-sulfonylurea alternative. (5.11) Access Program removal • Potential increased risk of cardiovascular mortality with sulfonylureas: Inform Indications and Usage, patient population restrictions 05/2014 patients of risks, benefits and treatment alternatives. (5.12) removal (1) Dosage and Administration (2) 05/2014 Contraindications (4) 05/2014 ------------------------------ ADVERSE REACTIONS -----------------------------­ Warnings and Precautions, Cardiac Failure (5.1) 05/2014 Common adverse reactions (≥5%) reported in clinical trials for AVANDARYL Warnings and Precautions, Major Adverse Cardiovascular 05/2014 without regard to causality were headache, hypoglycemia, and nasopharyngitis. Events (5.2) (6.1) Warnings and Precautions, Rosiglitazone REMS (Risk 05/2014 Evaluation and Mitigation Strategy) Program removal To report SUSPECTED ADVERSE REACTIONS, contact (formerly 5.4) GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or Warnings and Precautions, Weight Gain (5.5) 05/2014 www.fda.gov/medwatch. Warnings and Precautions, Hypersensitivity Reactions (5.9) 03/2015 ------------------------------ DRUG INTERACTIONS -----------------------------­ ----------------------------INDICATIONS AND USAGE ---------------------------­ • Inhibitors of CYP2C8 (e.g., gemfibrozil) may increase rosiglitazone levels. (7.1) AVANDARYL is a combination antidiabetic product containing a • Inducers of CYP2C8 (e.g., rifampin) may decrease rosiglitazone levels. (7.1) thiazolidinedione and a sulfonylurea indicated as an adjunct to diet and exercise • Inhibitors and inducers of CYP2C9 may affect glycemic control by altering to improve glycemic control in adults with type 2 diabetes. (1) glimepiride plasma concentrations. (7.1) Important Limitations of Use: • Certain medications may affect glucose metabolism, requiring glimepiride • Should not be used in patients with type 1 diabetes or for the treatment of dose adjustment and close monitoring of blood glucose. (7.2) diabetic ketoacidosis. (1, 4) • Miconazole: Severe hypoglycemia can occur when glimepiride and oral • Coadministration with insulin is not recommended. (1, 5.1, 5.2) miconazole are used concomitantly. (7.3) • Colesevelam: Coadministration may reduce glimepiride absorption. AVANDARYL should be administered at least 4 hours prior to colesevelam. ----------------------- DOSAGE AND ADMINISTRATION ----------------------­ (2.1, 7.4) • Individualize the starting dose based on the patient’s current regimen. (2.1) • Administer AVANDARYL at least 4 hours prior to colesevelam. (2.1) • Dose increases should be accompanied by careful monitoring for adverse ----------------------- USE IN SPECIFIC POPULATIONS ----------------------­ events related to fluid retention. (2.2) • Pregnancy: No adequate and well-controlled studies in pregnant women. Use • Do not exceed the maximum recommended daily dose of 8 mg rosiglitazone during pregnancy only if the potential benefit justifies the potential risk to the and 4 mg glimepiride. (2.3) fetus. (8.1) • Do not initiate if the patient exhibits clinical evidence of active liver disease • Nursing Mothers: Discontinue drug or nursing. (8.3) or increased serum transaminase levels. (2.4) • Safety and effectiveness in children younger than 18 years have not been established. (8.4) • Elderly patients may be particularly susceptible to hypoglycemic effects. (8.5) --------------------- DOSAGE FORMS AND STRENGTHS --------------------­ Rounded triangular tablets containing rosiglitazone/glimepiride: 4 mg/1 mg, See 17 for PATIENT COUNSELING INFORMATION and Medication 4 mg/2 mg, 4 mg/4 mg, 8 mg/2 mg, and 8 mg/4 mg (3) Guide. Revised: 03/2015 ------------------------------- CONTRAINDICATIONS ------------------------------­ • Initiation in patients with established NYHA Class III or IV heart failure. (4) 2.3 Maximum Dose FULL PRESCRIBING INFORMATION: CONTENTS* 2.4 Specific Patient Populations WARNING: CONGESTIVE HEART FAILURE 3 DOSAGE FORMS AND STRENGTHS 1 INDICATIONS AND USAGE 4 CONTRAINDICATIONS 2 DOSAGE AND ADMINISTRATION 5 WARNINGS AND PRECAUTIONS 2.1 Starting Dose 5.1 Cardiac Failure With Rosiglitazone 2.2 Dose Titration 5.2 Major Adverse Cardiovascular Events 1 Reference ID: 3715877 5.3 Hypoglycemia 8.2 Labor and Delivery 5.4 Edema 8.3 Nursing Mothers 5.5 Weight Gain 8.4 Pediatric Use 5.6 Hepatic Effects 8.5 Geriatric Use 5.7 Macular Edema 10 OVERDOSAGE 5.8 Fractures 11 DESCRIPTION 5.9 Hypersensitivity Reactions 12 CLINICAL PHARMACOLOGY 5.10 Hematologic Effects 12.1 Mechanism of Action 5.11 Hemolytic Anemia 12.2 Pharmacodynamics 5.12 Increased Risk of Cardiovascular Mortality With 12.3 Pharmacokinetics Sulfonylureas 12.4 Drug-drug Interactions 5.13 Diabetes and Blood Glucose Control 13 NONCLINICAL TOXICOLOGY 5.14 Ovulation 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 6 ADVERSE REACTIONS 13.2 Animal Toxicology and/or Pharmacology 6.1 Clinical Trial Experience 14 CLINICAL STUDIES 6.2 Laboratory Abnormalities 14.1 Patients Inadequately Controlled on Diet and Exercise 6.3 Postmarketing Experience 14.2 Patients Previously Treated With Sulfonylureas 7 DRUG INTERACTIONS 15 REFERENCES 7.1 Drugs Metabolized by Cytochrome P450 16 HOW SUPPLIED/STORAGE AND HANDLING 7.2 Drugs Affecting Glucose Metabolism 17 PATIENT COUNSELING INFORMATION 7.3 Miconazole *Sections or subsections omitted from the full prescribing information are not 7.4 Concomitant Administration of Colesevelam listed. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 2 Reference ID: 3715877 ______________________________________________________________________ FULL PRESCRIBING INFORMATION WARNING: CONGESTIVE HEART FAILURE ● Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions (5.1)]. After initiation of AVANDARYL®, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of AVANDARYL must be considered. ● AVANDARYL is not recommended in patients with symptomatic heart failure. Initiation of AVANDARYL in patients with established NYHA Class III or IV heart failure is contraindicated. [See Contraindications (4), Warnings and Precautions (5.1).] 1 INDICATIONS AND USAGE AVANDARYL is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Important Limitations of Use: • Due to its mechanism of action, rosiglitazone is active only in the presence of endogenous insulin. Therefore, AVANDARYL should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. • Coadministration of AVANDARYL with insulin is not recommended [see Warnings and Precautions (5.1, 5.2)]. 2 DOSAGE AND ADMINISTRATION Therapy with AVANDARYL should be individualized for each patient. The risk-benefit of initiating monotherapy versus