1. 1 One Year Post-Exclusivity Adverse Event Review: Insulin Aspart Recombinant 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: NovoLog ® (insulin aspart recombinant) Therapeutic Category: human insulin analog Sponsor: Novo Nordisk Inc Original Market Approval: June 7, 2000 Pediatric Exclusivity Granted: May 24, 2005 Mechanism of action: regulation of glucose metabolism –Binds to insulin receptors on muscle and fat –Facilitates cellular uptake of glucose –Inhibits output of glucose from liver

3. 3 Background Drug Information Indication: treatment of patients with diabetes mellitus, for the control of hyperglycemia –Normally with regimen of intermediate or long-acting insulin –May be infused via external insulin pumps –May be used intravenously under medical supervision Dosage: –Individualized, immediately prior to a meal

4. 4 Drug Use Trends (Outpatient Settings): Insulin Aspart Recombinant Dispensed prescriptions for NovoLog have been increasing (June 2004 to May 2006) 1 –Total NovoLog ® and NovoLog ® Mix 70/30 prescriptions increased by estimated 29% (~ 2.4 to 3.4 million) 1 –Relative increase in pediatric patient count: 22% (~47,000 to 57,000) 2 Pediatric patients accounted for ~13% of prescriptions 2 Majority of pediatric NovoLog ® prescriptions to patients ages 12-16 years 1 1 Verispan LLC, Vector One National, Jun 2003 to May 2006, Data extracted Jul 2006 2 Verispan LLC, Vector One National: Total Patient Tracker, Data Extracted 7/2006 Excludes NovoLog® Mix 70/30

5. 5 Pediatric Exclusivity Labeling changes: Insulin Aspart Recombinant Indicated for use in pediatric patients Pk and clinical studies described, including those in children ages 2 to 6 years Glycemic control and adverse events, particularly hypoglycemia comparable to regular insulin

6. 6 Adverse Event Reports since Market Approval (June 2000): Insulin Aspart All reports (US)Serious (US)Death (US) All Ages*1338 (1056)616 (341)36 (8) Adults (> 17)1051 (828)491 (275)30 (8) Pediatrics (0-16)154 (117)72 (35)5 (0) *may include duplicates and unknown ages Serious outcomes per regulatory definition include death, hospitalization, life-threatening, disability, congenital anomaly, requiring intervention, and other

7. 7 Fatal Serious AE since approval: Insulin Aspart (n= 4, unduplicated) Infants born to participants in post-marketing clinical trial in pregnant women with diabetes: 4 month old female with truncus arteriosus communis 4 day old male with hypoxic ischemic encephalopathy and seizures Direct exposures 14 year old male with type I DM and remote history of asthma found dead in bed, treated for 4-5 months with insulin detemir and aspart; post mortem: “consistent with acute asthma attack, although patient had not had attack in 8 years.” 9 year old male with type 2 DM on insulin glargine for 6 months and aspart for unknown period, died, “possible alcohol overdose” Underlined events are not specifically labeled

8. 8 Adverse Event Reports One Year Post Exclusivity Period: Insulin Aspart Raw counts*All reports (US)Serious (US)Death (US) All ages284 (169)249 (135)15 (1) Adults (> 17)230 (135)202 (108)12 (1) Pediatrics (0-16)28 (18)24 (14)3 (0) * may include duplicates and unknown ages

9. 9 Adverse Event Reports during One-Year Post Exclusivity Period: Unlabeled Serious Non-fatal cases: Insulin Aspart. In utero exposure (n =4) –Newborn with neonatal hypoglycemia and ankyloglossia, first trimester exposure insulin lispro, regular insulin, NovoLog® –37 week with urinary retention, neonatal asphyxia, and hypoxic-ischemic lesion of the central nervous system, first trimester exposure multiple drugs –Neonate with dysmorphy of the right frontal lobe, increased frontal subarachnoid space, and assymetry of lateral ventricle –32 week preterm with neonatal hypoglycemia (blood glucose 24 mg/dl) Underlined events are unlabeled

10. 10 Summary: Insulin Aspart Labeling updated after exclusivity studies –Treatment of type I DM > 2 years –Most frequent AE is hypoglycemia During post exclusivity period –Although AEs related to in utero exposure observed, no pattern –No new pediatric AEs identified This completes the one-year post-exclusivity AE reporting as mandated by BPCA. The FDA recommends routine monitoring of insulin aspart recombinant for AEs in all populations. Does the Advisory Committee concur?

11. 11 Acknowledgements OSE Andrea Feight Lanh Green Solomon Iyasu Rosemary Johann-Liang David Moeny Joslyn Swann DMEP David Orloff Joanna Zawadzki PMHS Lisa Mathis Kristin Phucas Jean Temeck