1. 1 One Year Post Exclusivity Adverse Event Review: Glimepiride Pediatric Advisory Committee Meeting November 16, 2006 Hari Cheryl Sachs, MD, FAAP Medical Officer Pediatric and Maternal Health Staff Office of New Drugs Center for Drug Evaluation and Research Food and Drug Administration

2. 2 Background Drug Information Drug: Amaryl ® (glimepiride) Therapeutic Category: oral hypoglycemic agent Sponsor: Sanofi Aventis US Original Market Approval: November 30, 1995 Pediatric Exclusivity Granted: June 9, 2005 Related combination products: –Avandaryl™ (glimepiride and rosiglitazone, approved 11/05) –Duetact™ (glimepiride and pioglitazone, approved 7/06) Mechanism of action: stimulates insulin release from beta cells

3. 3 Background Drug Information Indication: adjunct to diet and exercise to lower blood glucose in patients with type 2 diabetes mellitus –As monotherapy –Concomitantly with metformin or insulin Dosage: –Adults only: initial dose 1 to 2 mg daily with first main meal, maximum 8 mg maintenance

4. 4 Glimepiride: Pediatric Exclusivity Labeling Changes Data are insufficient to recommend pediatric use Both pK and clinical trials for pediatric patients are described Single dose study (ages 10 to 17, n=30) 24 week clinical trial (n= 272, aged 8 to 17 years) Profile of adverse events similar to that in adults Comparative risk of hypoglycemia Hypoglycemia (BG < 36) observed in 4% of patients treated with glimepiride, 1% metformin

5. 5 Glimepiride: Outpatient Use Total dispensed prescriptions for glimepiride and related antihyperglycemic agents (glipizide, glyburide, metformin and combinations of these) increased: –Overall: 8% from 73.6 to 79.4 million 1 (pre- and post- exclusivity; July 2004 to June 2005 vs. June 2005 to June 2006) –glimepiride: 7% from 6.7 to 7.2 million (same time period) 1 Amaryl (glimepiride) 4 th most commonly dispensed product 1 Pediatric use: < 1%, decreased from 5,890 to 4,210 (pre and post-exclusivity) 1 1 Verispan LLC, Vector One® National (VONA), Jul 2003 – Jun 2006, Data extracted Sep 2006

6. 6 Glimepiride: Adverse Events Pediatric AEs < 1 % of total –Since Approval: 8/1494 –No pediatric deaths –During post-exclusivity period: 2/290 Two confounded, non-fatal, serious adverse events identified in pediatric patients during the post-exclusivity period: –17 year old with Trisomy 21 on amitryptiline who experienced behavioral abnormalities after 2 doses of glimepiride –Infant with congenital anomalies (VSD, microcephaly, dysmorphic facies) after in utero exposure to mother with history of multiple miscarriages and 2 children with congenital anomalies; consanguinity Labeling: Pregnancy category C; change to insulin. Not recommended for use in pregnancy

7. 7 Summary: Glimepiride As a result of exclusivity studies, labeling indicates there are insufficient data to recommend pediatric use No new pediatric AEs identified during one-year post-exclusivity period This completes the one-year post-exclusivity adverse event reporting as mandated by BPCA The FDA recommends routine monitoring of glimepiride for AEs in all populations Does the Advisory Committee concur?

8. 8 Acknowledgements OSE Laura Governale Lanh Green Joslyn Swann Rosemary Johann-Liang PMHS Lisa Mathis Kristin Phucas Jean Temeck DPEP Robert Misbin David Orloff OPT Dianne Murphy Ann Myers