• Coadministration of AVANDIA and insulin is not recommended. (1.2, HIGHLIGHTS OF PRESCRIBING INFORMATION 5.3) These highlights do not include all the information needed to use • Use of AVANDIA with nitrates is not recommended. (1.2, 5.2) AVANDIA safely and effectively. See full prescribing information for AVANDIA. ----------------------- DOSAGE AND ADMINISTRATION ---------------- • Start at 4 mg daily in single or divided doses; do not exceed 8 mg daily. AVANDIA (rosiglitazone maleate) Tablets (2) Initial U.S. Approval: 1999 • Dose increases should be accompanied by careful monitoring for adverse WARNING: CONGESTIVE HEART FAILURE AND MYOCARDIAL events related to fluid retention. (2) ISCHEMIA • Do not initiate AVANDIA if the patient exhibits clinical evidence of ● Thiazolidinediones, including rosiglitazone, cause or exacerbate active liver disease or increased serum transaminase levels. (2.4) congestive heart failure in some patients (5.1). After initiation of AVANDIA, --------------------- DOSAGE FORMS AND STRENGTHS -------------- and after dose increases, observe patients carefully for signs and symptoms of Pentagonal, film-coated tablets in the following strengths: heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). • 2 mg, 4 mg and 8 mg (3) If these signs and symptoms develop, the heart failure should be managed -------------------------------CONTRAINDICATIONS------------------------ according to current standards of care. Furthermore, discontinuation or dose Initiation of AVANDIA in patients with established NYHA Class III or IV reduction of AVANDIA must be considered. heart failure is contraindicated. (4) ● AVANDIA is not recommended in patients with symptomatic heart failure. Initiation of AVANDIA in patients with established NYHA Class III ----------------------- WARNINGS AND PRECAUTIONS ---------------- or IV heart failure is contraindicated. (4, 5.1) • Fluid retention, which may exacerbate or lead to heart failure, may occur. ● A meta-analysis of 42 clinical studies (mean duration 6 months; 14,237 Combination use with insulin and use in congestive heart failure NYHA total patients), most of which compared AVANDIA to placebo, showed Class I and II may increase risk of other cardiovascular effects. (5.1, 5.3) AVANDIA to be associated with an increased risk of myocardial ischemic • Increased risk of myocardial ischemic events has been observed in a meta- events such as angina or myocardial infarction. Three other studies (mean analysis of 42 clinical trials (incidence rate 2% versus 1.5%). (5.2) duration 41 months; 14,067 patients), comparing AVANDIA to some other • Use of AVANDIA with nitrates is not recommended. (1.2, 5.2) approved oral antidiabetic agents or placebo, have not confirmed or excluded • Coadministration of AVANDIA and insulin is not recommended. (1.2, this risk. In their entirety, the available data on the risk of myocardial 5.3) ischemia are inconclusive. (5.2) • Dose-related edema (5.4), weight gain (5.5), and anemia (5.9) may occur. ---------------------------RECENT MAJOR CHANGES -------------------- • Macular edema has been reported. (5.7) Boxed Warning (5.2, 5.3) X/2007 • Increased incidence of bone fracture in female patients. (5.8) Indications and Usage (1) X/2007 ------------------------------ ADVERSE REACTIONS ----------------------- Contraindications (4) 8/2007 Common adverse reactions (>5%) reported in clinical trials without regard to Warnings and Precautions, Cardiac Failure (5.1) 8/2007 causality were upper respiratory tract infection, injury, and headache. (6.1) Warnings and Precautions, Myocardial Ischemia(5.2) X/2007 To report SUSPECTED ADVERSE REACTIONS, contact Warnings and Precautions, Fractures (5.8) 3/2007 GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or ----------------------------INDICATIONS AND USAGE--------------------- www.fda.gov/medwatch. AVANDIA is a thiazolidinedione antidiabetic agent indicated as an adjunct to -------------------------------DRUG INTERACTIONS------------------------ diet and exercise to improve glycemic control in patients with type 2 diabetes Inhibitors of CYP2C8 (e.g., gemfibrozil) may increase rosiglitazone levels; mellitus. (1) inducers of CYP2C8 (e.g., rifampin) may decrease rosiglitazone levels. (7.1) Important Limitations of Use: See 17 for PATIENT COUNSELING INFORMATION and FDA- • AVANDIA should not be used in patients with type 1 diabetes mellitus or approved Patient Information. for the treatment of diabetic ketoacidosis. (1.2) Revised: Month 200x AVD:XXPI 7 DRUG INTERACTIONS FULL PRESCRIBING INFORMATION: CONTENTS* 7.1 CYP2C8 Inhibitors and Inducers FULL PRESCRIBING INFORMATION 8 USE IN SPECIFIC P OPULATIONS WARNING: CONGESTIVE HEART FAILURE AND 8.1 Pregnancy MYOCARDIAL ISCHEMIA 8.2 Labor and Deliver y 1 INDICATIONS AND USAGE 8.3 Nursing Mothers 1.1 Monotherapy and Combination Therapy 8.4 Pediatric Use 1.2 Important Limitations of Use 8.5 Geriatric Us e 2 DOSAGE AND ADMIN ISTRATION 10 OVERDOSAGE 2.1 Monotherapy 11 DESCRIPTION 2.2 Combination With Sulfonylurea or Metformin 12 CLINICAL PHARMACOLOGY 2.3 Combination With Sulfonylurea Plus Metformin 12.1 Mechanism of Action 2.4 Specific Patient Populations 12.2 Pharmacodynamics 3 DOSAGE FORMS AND STRENGTHS 12.3 Pharmacokinetics 4 CONTRAINDICATIONS 12.4 Drug-Drug Interactions 5 WARNING S AND PRECAUTIONS 13 NONC LINICAL TOXICOLOGY 5.1 Cardiac Failure 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.2 Myocardial Ischemia 13.2 Animal Toxicology 5.3 Congestive Heart Failure and Myocardial Ischemia 14 CLINICAL STUDIES During Coadministration of AVANDIA With Insulin 14.1 Monotherapy 5.4 Edema 14.2 Combination With Metformin or Sulfonylurea 5.5 Weight Gain 14.3 Combination With Sulfonylurea Plus Metformin 5.6 Hepatic Effects 15 REFERENCES 5.7 Macular Edema 16 HOW SUPPLIED/STORAGE AND HANDLING 5.8 Fractures 17 PATIENT COUNSELING INFORMATION 5.9 Hematologic Effects 17.1 Patient Advice 5.10 Diabetes and Blood Glucose Control 17.2 FDA-Approved Patient Labeling 5.11 Ovulation *Sections or subsections omitted from the full prescribing information are not 6 ADV ERSE REACTIONS listed. 6.1 Clinical Trial Experience 6.2 Laboratory Abnormalities 6.3 Postmarketing Experience 1 ______________________________________________________________________ FULL PRESCRIBING INFORMATION WARNING: CONGESTIVE HEART FAILURE AND MYOCARDIAL ISCHEMIA ● Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions (5.1)]. After initiation of AVANDIA, 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 AVANDIA must be considered. ● AVANDIA is not recommended in patients with symptomatic heart failure. Initiation of AVANDIA in patients with established NYHA Class III or IV heart failure is contraindicated. [See Contraindications (4) and Warnings and Precautions (5.1).] ● A meta-analysis of 42 clinical studies (mean duration 6 months: 14,237 total patients), most of which compared AVANDIA to placebo, showed AVANDIA to be associated with an increased risk of myocardial ischemic events such as angina or myocardial infarction. Three other studies (mean duration 41 months; 14,067 total patients), comparing AVANDIA to some other approved oral antidiabetic agents or placebo, have not confirmed or excluded this risk. In their entirety, the available data on the risk of myocardial ischemia are inconclusive. [See Warnings and Precautions (5.2).] 1 INDICATIONS AND USAGE 1.1 Monotherapy and Combination Therapy AVANDIA is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. [See Clinical Studies (14).] 1.2 Important Limitations of Use • Due to its mechanism of action, AVANDIA is active only in the presence of endogenous insulin. Therefore, AVANDIA should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. • The coadministration of AVANDIA and insulin is not recommended. • The use of AVANDIA with nitrates is not recommended. 2 DOSAGE AND ADMINISTRATION The management of antidiabetic therapy should be individualized. All patients should start AVANDIA at the lowest recommended dose. Further increases in the dose of AVANDIA should be accompanied by careful monitoring for adverse events related to fluid retention [see Boxed Warning and Warnings and Precautions (5.1)]. AVANDIA may be administered either at a starting dose of 4 mg as a single daily dose or in 2 divided doses. For patients who respond inadequately following 8 to 12 weeks of treatment, 2 as determined by reduction in FPG, the dose may be increased to 8 mg daily as monotherapy or in combination with metformin, sulfonylurea, or sulfonylurea plus metformin. Reductions in glycemic parameters by dose and regimen are described under Clinical Studies (14.1). AVANDIA may be taken with or without food. The total daily dose of AVANDIA should not exceed 8 mg. 2.1 Monotherapy The usual starting dose of AVANDIA is 4 mg administered either as a single dose once daily or in divided doses twice daily. In clinical trials, the 4-mg twice-daily regimen resulted in the greatest reduction in FPG and HbA1c. 2.2 Combination With Sulfonylurea or Metformin When AVANDIA is added to existing therapy, the current dose(s)