1. 1 One Year Post-Exclusivity Adverse Event Review: Rosiglitazone 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 Outline Background Drug Information Drug Use Trends Pediatric Exclusivity Studies Pediatric Exclusivity Labeling Changes Additional Relevant Safety Labeling Adverse Events –Since approval –One-year post exclusivity Summary

3. 3 Background Drug Information Drug: Avandia ® (rosiglitazone) Therapeutic Category: Oral hypoglycemic agent (thiazolidinedione) Sponsor: GlaxoSmithKline Original Market Approval: May 25, 1999 Pediatric Exclusivity Granted: Dec 9, 2004 –No pediatric approval Mechanism of action: increases insulin sensitivity

4. 4 Background Drug Information Indication: adjunct to diet and exercise to improve glycemic control in type II DM (monotherapy or combination therapy) in adults Dosage: –Adults: 4 to 8 mg qd or divided bid Related combination products: –Avandamet® (rosiglitazone and metformin), approved 10/2002 –Avandaryl™ (rosiglitazone and glimepiride), approved 11/2005

5. 5 Drug Use Trends (Outpatient Settings): rosiglitazone Dispensed prescriptions for Avandia ® and Avandamet ® have been increasing (Jan 2003 to Dec 2006) 1 –Avandia ® increased by estimated 33 % (~7.8 to 10.4 million) –Avandamet ® increased almost 2 fold (~935K to 1.9 million) Avandia ® and Avandamet ® together accounted for > 55 % of total thiazolidinediones dispensed during one year post-exclusivity period 1 Pediatric patients who received prescription < 1 / 10 % (approximately 2,200 prescriptions/year) 2 –Majority of this use in patients 12-16 years 3 –Only diagnosis: Diabetes Mellitus 4 1 Verispan LLC, Jan 2003 to Dec 2005, Data extracted Feb 2006 2 Verispan LLC, Total Patient Tracker, Jan 2003 to Dec 2005, Data extracted Feb 2006 3 Verispan LLC, Vona Vector One, Jan 2003 to Dec 2005, Data extracted Feb 2006 4 IMS National Disease and Therapeutic Index TM, 3yr Jan 2003 to Dec 2005, Data extracted Feb 2006

6. 6 http://www.fda.gov/cder/pediatric/Summaryreview.htm

7. 7 Pediatric Exclusivity Studies: Rosiglitazone Population pharmacokinetic (pk) and safety study Efficacy and safety in children with type II DM

8. 8 Pediatric Exclusivity Study: Pharmacokinetic Population pK study –n = 96 adolescents, age 10-17 years (subset of efficacy trial) –Exposures were similar to exposure estimates reported for adults Labeling change: –Pharmacokinetics: parameters in children consistent with adults

9. 9 Pediatric Exclusivity Study: Efficacy 24 week active-controlled trial of adolescents with type II DM (ages 8-17) (n = 200, randomized 1:1 rosiglitazone: metformin) Treatment naive patients with HgbA1c 7.1-10, failed diet and exercise alone, no evidence type I DM Primary endpoint: within group change in HbA1c from baseline Secondary endpoint: between groups, non- inferiority of change in HbA1c from baseline

10. 10 Pediatric Exclusivity Study: Efficacy Unable to detect meaningful difference in HbA1c between treatment groups (rosiglitazone vs. metformin) Weight gain higher for rosiglitazone (+2.8 kg) compared with metformin (+0.2 kg) Labeling change: –Precautions: weight gain –Pediatric Use: description of clinical study –Dosage and administration: special populations: Data are insufficient to recommend pediatric use of Avandia®”

11. 11 Pediatric Exclusivity Study: Safety No deaths Serious AEs- –Rosiglitazone (1): mild DKA requiring insulin rescue –Metformin (6): hyperglycemia requiring insulin rescue (3), suicidal ideation (1), status asthmaticus (1), menorrhagia (1) AE resulting in withdrawal from the study –Rosiglitazone (6): hyperglycemia requiring insulin rescue (5), bronchitis, gastroenteritis, rectal hemorrhage, and facial/hand edema (1) –Metformin (7): hypoglycemia (2); hyperglycemia requiring insulin rescue (2), elevated LFTs (2), nausea and diarrhea (1)

12. 12 Pediatric Exclusivity Study: Labeling Changes Clinical Pharmacology: Pediatric Pk findings described, consistent with adults Precautions: Pediatric Use: Clinical trial results described Weight gain described under pediatric use Adverse Reactions Adverse events experienced during the trial described DKA AE reported by > 5 % in either rosiglitazone or metformin group

13. 13 Contraindications: hypersensitivity Warning: Cardiac failure and other cardiac events, fluid retention. Precautions: –Hypoglycemia –Edema –Weight gain –Decreased hemoglobin and hematocrit –Ovulation (pregnancy risk) –Elevations in liver enzymes, potential liver failure, need to monitor Additional Relevant Safety Labeling

14. 14 Pregnancy Category C: “Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies as well as increased increased neonatal morbidity and mortality, most experts recommend that insulin monotherapy be used during pregnancy to maintain blood glucose levels as close to normal as possible.” Dosage and Administration: use lowest dose, monitor for fluid retention Overdosage- limited data, manage per clinical statusOverdosage- limited data, manage per clinical status Additional Relevant Safety Labeling

15. 15 Adverse Event Reports since Market Approval (May 1999): Rosiglitazone Raw counts*All reports (US)Serious (US)Death (US) All Ages9072 (7687)3841 (2502)365 (200) Adults (> 17)6496 (5318)3058 (1923)319 (175) Pediatrics (0-16)14 (13)10 (9)1 (1) *may include duplicates and unknown ages

16. 16 Pediatric Adverse Event Reports Adverse events prior to granting of pediatric exclusivity on December 9, 2004 (n=12) Adverse events during the one-year post exclusivity period (n=2)

17. 17 Fatal Serious AE since approval: Rosiglitazone (n= 1) 6 month old male twin A died from “respiratory failure” secondary to ascites from liver failure/biliary atresia –In-utero exposure to metformin, clomiphene and rosiglitazone –Premature birth (29 weeks gestational age) –Multiple medical problems –Twin B with multiple medical problems survived –Causality difficult to ascertain Underlined events are not specifically labeled

18. 18 Non Fatal AEs Prior to December 9, 2004 (n=11) Accidental ingestion (n=6) –Hypoglycemia (2), seizures (1), hypoglycemia/seizures (1), emesis (1), choking (1) In utero exposures (n=3) –Male twin B with multiple medical problems survived –Twins with fetal stress and 33 week preterm delivery to 40 year old with PCO on multiple medications –Female with developing left breast tissue and elevated hormone levels (discovered at 6-month checkup) Liver enzyme abnormalities (n=2) –11 year old, multiple medical problems- abnormal liver enzymes associated with EBV and fatty infiltration on sonogram, decreased after discontinuation –16-year-old obese (weight 420 pounds) with abnormal LFTs. Normalized upon discontinuation

19. 19 Adverse Event Reports One Year Post Exclusivity Period: Rosiglitazone Raw counts*All reports (US)Serious (US)Death (US) All ages1389 (1076)679 (371)50 (21) Adults (> 17)907 (657)487 (242)41 (17) Pediatrics (0-16)2 (2)00 * may include duplicates and unknown ages

20. 20 Summary: Rosiglitazone Labeling updated after exclusivity studies describing the pk and clinical studies and to reflect that data are insufficient to recommend use in pediatric patients AEs incorporated into labeling include weight gain. hyperglycemia or DKA risk No new pediatric AEs identified during one-year post-exclusivity period This completes the one-year post-exclusivity AE reporting as mandated by BPCA The FDA recommends routine monitoring of rosiglitazone for AEs in all populations Does the Advisory Committee concur?

21. 21 Acknowledgements OSE Andrea Feight Lanh Green Toni Piazza-Hepp Solomon Iyasu Kendra Worthy Jo Wyeth PMHT Lisa Mathis Kristin Phucas Jean Temeck DMEP David Orloff Joanna Zawadzki OPT Ann Myers Dianne Murphy