One Year Post-Exclusivity Adverse Event Review: Ondansetron Pediatric Advisory Committee Meeting November 16, 2006

1. One Year Post-Exclusivity Adverse Event Review: OndansetronPediatric Advisory Committee Meeting November 16, 2006 Felicia L. Collins, MD, MPH, FAAPMedical Officer Pediatric and Maternal Health Staff Office of New Drugs Center for Drug Evaluation and Research Food and Drug Administration

2. Background Drug Information: Ondansetron Drug: Zofran® (ondansetron hydrochloride) Therapeutic Category: SerotoninHT3 receptor antagonist Sponsor: GlaxoSmithKline Original Market Approval: January 4, 1991 Pediatric Exclusivity Granted: December 1, 2004

3. Background Drug Information: Ondansetron • Indications: • Prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including high dose cisplatin [chemotherapy induced nausea and vomiting (CINV)] • Prevention of postoperative nausea and/or vomiting [PONV]

4. Drug Use Trends in Outpatient Settings: Ondansetron • 1.6 million dispensed prescriptions for all age groups during the 12-month post-exclusivity period • 107,000 (6.6%) were dispensed for the pediatric population 0 - 16 years old • 11% increase in prescriptions for all age groups between the 12-month pre and post-exclusivity periods • 39% increase for the pediatric population Verispan, LLC, 2003 – 2006, Data Extracted January 2006

5. Drug Use Trends in Outpatient Settings: Ondansetron • OB/GYN was the most frequent prescriber specialty during the 12-month post-exclusivity period • OB/GYN: 23% (369,000) • Pediatrics: 4% (68,000) • Malignant neoplasm of the brain was the diagnosis most frequently associated with ondansetron use in the pediatric population: 18% (20,000) Verispan, LLC, 2003 – 2006, Data Extracted January 2006

6. Drug Use Trends in Inpatient Settings: Ondansetron • ~390,000 discharges associated with ondansetron use for all age groups during the 6-month post-exclusivity period • ~12,400 (3.2%) for the pediatric population 0 - 16 years old • 2.7% decrease in the discharges associated with ondansetron use for all age groups between the 6-month pre and post-exclusivity periods • 7.3% decrease for the pediatric population Premier Informatics Extracted 2-2-06

7. Pediatric Exclusivity Studies: Ondansetron • PONVPK study in 1 month to 2 year olds: 51 pediatric surgical patients utilized ondansetron prophylactically (24 hour observation period) • PONV efficacy and safety study in 1 month to 2 year olds: 670 pediatric surgical patients utilized ondansetron or placebo prophylactically (24 hour observation period) • CINV efficacy and safetystudy in 6 month to 4 year olds: 76 pediatric cancer patients receiving moderately to highly emetogenic chemotherapy utilized ondansetron prophylactically (24 hour observation period)

8. Pediatric Exclusivity Studies: PK Study (n=51) • Design: Multi-center, two-arm, single dose (0.1 mg/kg or 0.2 mg/kg IV) • Results: Drug clearance was lower and half-life was prolonged in patients 1 to 4 months old compared to those > 4 months to 2 years old

9. Pediatric Exclusivity Studies: Population PK Analysis (n=127) • Design: Combined data from PK and CINV studies • Results: 0.15 mg/kg/dose IV every 4 hours x 3 doses in cancer patients, aged 6 months to 4 years, results in systemic exposure levels similar to those achieved in older pediatric cancer patients at similar doses

10. Pediatric Exclusivity Studies: PONV (n=670) • Design: Multi-center, double-blind, placebo-controlled, randomized study of a single dose of 0.1 mg/kg ondansetron IV administered within 5 minutes following anesthesia induction

11. Pediatric Exclusivity Studies: PONV Efficacy • Endpoints: • Primary: Proportion of patients experiencing at least one episode of emesis during the 24 hour assessment phase • Secondary: • Time to first emetic episode • Time to first rescue medication • Incidence of emetic episodes • Proportion of patients receiving rescue medications • Proportion of patients with emetic episodes after the receipt of rescue medications

12. PONV Exclusivity Study: Efficacy Results • Fewer patients experienced at least one emetic episode in the drug group (11%) compared to the placebo group (28%) • The drug performed better than placebo in 4 of the 5 secondary endpoints • Time to first emetic episode • Incidence of emetic episodes • Proportion of patients receiving rescue medications • Proportion of patients with emetic episodes after the receipt of rescue medications

13. Pediatric Exclusivity Studies: CINV Efficacy (n=76) • Design: Multi-center, open-label, 3 doses of 0.15 mg/kg IV • Primary Endpoints: • Incidence of emesis • Proportion of patients who received supplemental antiemetic medication during the 24-hour assessment period • Time to first rescue antiemetic medication • Parent/guardian overall satisfaction

14. CINV Exclusivity Study: Efficacy Results • More than half of the patients had no emetic episodes • More than half of the patients did not require rescue medications • 80% of parents/guardian were satisfied with drug use

15. Pediatric Exclusivity Studies: Safety Results(n=797) (drug group = 463, placebo group = 334) • No deaths • 1% of patients had non-fatal serious adverse reactions in both the drug (5) and placebo (3) groups • Drug group: convulsions (1), dehydration (1), respiratory depression (1), staphylococcal infection (1), nodal arrhythmia, hypocapnia, & hypoxia (1) • Placebo group: tachycardia (1), bronchospasm (1), exacerbated pain (1)

16. Pediatric Exclusivity Study: Labeling Changes • Clinical Pharmacology – Pharmacodynamics: • Population PK analysis of PK and CINV studies • Clinical Studies: • CINV & PONV studies • Precautions – Pediatric Use: • Little information available about the use in pediatric surgical patients <1 month old and pediatric cancer patients younger than 6 months old • Slower drug clearance and half-life ~2.5 fold longer in pediatric patients 1 to 4 months old compared to older children > 4 months to 2 years old

17. Pediatric Exclusivity Study: Labeling Changes • Dosage and Administration: • CINV in 6 month to 4 year old patients: • 3 doses of 0.15 mg/kg IV • PONV in 1 month to 2 year old patients: • Single 0.1 mg/kg IV dose for patients weighing 40 kg or less • Single 4 mg dose for patients weighing more than 40 kg

18. Adverse Event Reports Since Market Approval and Prior to Pediatric Exclusivity1/4/91 – 12/1/04 *May include duplicates and unknown ages †Crude count is 18 with 14 unduplicated cases

19. Pediatric Deaths Since Market Approval and Prior to Pediatric Exclusivity • 18 crude count reports • 14 unduplicated cases • 7 cases excluded due to confounding or insufficient information • 1 - Erroneous classification of death • 1 - Unspecified cause of death in infant with in utero exposure • 2 - Significant time delay between symptoms and/or death and last ondansetron dose (17 hrs, 12 days) • 3 - Complicated underlying medical conditions, some with concomitant medications (stage IV neuroblastoma with multi-organ failure and chemotherapy, medulloblastoma with radiation and chemotherapy, idiopathic pneumonitis with progressive germ cell disease)

20. Deaths Since Market Approval and Prior to Pediatric Exclusivity (continued) • 7 remaining cases also confounded by complicated underlying medical conditions, concomitant medications, and/or insufficient details • 14 y.o. female with asthma, 1 day s/p scoliosis surgery, with decreased RR, BP, SaO2 after morphine and 1 hour after 4 mg ondansetron IV for nausea (concomitant meds: cyclizine, albuterol, beclomethasone, terfenadine) • 10 y.o. male on chemotherapy for rhabdomyosarcoma with dizziness and collapse after 0.15 mg/kg ondansetron IV for vomiting (concomitant meds: methylprednisolone mesna, ifosfamide, etoposide) • 9 m.o. male with bone marrow allografts developed acidosis, bundle branch block, and cardiac arrest with QT prolongation after cisapride and 6 mg ondansetron for nausea (concomitant meds: cyclosporin, ganciclovir, omeprazole, amikacine, hydrocortisone, cyclophsphamide, foscarnet, alizapride, tienam, and ornidazole)

21. Deaths Since Market Approval and Prior to Pediatric Exclusivity (continued) • 16 y.o. female with disseminated lupus developed septic shock or cardiomyopathy 3 days after ondansetron IV [unknown dose] to prevent nausea (concomitant meds: prednisone, cyclophosphamide, mesna, dextropropoxyphene/paracetamol combination, furosemide, alizapride, ergocalciferol) • 2 y.o. male with h/o renal failure and renal hypoplasia with unknown cause of death after 17 days of 3 mg ondansetron po for nausea and vomiting (concomitant meds: sodium polystyrene sulfonate, alfacalcidol, erythropoietin, calcium, growth hormone) • 11 y.o. female with congenital heart disease on antibiotics developed decreased SaO2, headache, dizziness, and respiratory failure 1 hour after 4 mg ondansetron IV for nausea of unknown etiology (concomitant meds: clarithromycin, cefuroxime. PMH: allergy to amoxicillin and codeine) • 16 y.o. male with end stage cystic fibrosis developed decreased SaO2 and arrested minutes after 2 mg ondansetron IV for nausea (numerous allergies to foods and medications, especially antibiotics)

22. Adverse Event Reports During the Post-Exclusivity Period12/1/04 – 1/1/06 *May include duplicates and unknown ages

23. Pediatric Death During the Post-Exclusivity Period (n=1, 0 US) • 1 death case with insufficient information to assess causality • 3 year old male with unreported cause of death receiving 4 mg ondansetron po (unknown indication and duration)

24. Serious Adverse Events During the Post-Exclusivity Period (n=16, 5 US) • 1 respiratory case (respiratory depression with bradycardia) • 2 hepatic cases (1- increased aspartate aminotransferase; 1- increased alanine aminotransferase with ascites) • 3 allergic reactions/anaphylaxis cases (1 - cyanosis, hypotension, and urticaria; 1- dyspnea, hypotension, and pruritus; 1- anaphylactic shock) • 5 neurologic cases (1- dystonia and agitation; 1 - auditory hallucinations, headache, and blurred vision; 1 - seizure, hypotonia, musculoskeletal stiffness, and urinary incontinence; 1- extrapyramidal reaction, speech impairment, clenched jaw; 1- seizure and oculogryic crisis) • 5 other cases (2 - birth defects, 1- drug precipitation in IV, 2 - drug ineffectiveness) Unlabeled events are unlined

25. Unlabeled Serious Adverse Events • 1 year old child (gender unspecified) with respiratory depression and bradycardia after receiving 2 mg ondansetron IV x 1 dose to treat an unknown condition (foreign case with very little information) • 9 year old boy with neuroblastoma experienced increased alanine aminotransferase, ascites, and pleural effusion after receiving several cancer chemotherapy agents and 4 mg ondansetron qd (duration and route of administration unknown) • Infant (age and gender unspecified) whose mother had used ondansetron during pregnancy experienced a foot/limb malformation (ondansetron dose, duration and route of administration unknown) • Infant (age and gender unspecified) whose mother had used ondansetron during pregnancy experienced tracheomalacia (ondansetron dose, duration, and route of administration unknown)

26. Summary: Ondansetron • This completes the one-year post-exclusivity adverse event reporting as mandated by BPCA. • FDA recommends routine monitoring of ondansetron for adverse events in all populations. • Does the Advisory Committee concur?

27. Acknowledgements OSEDGP Ann Corken Mackey Lolita Lopez Lanh Green Ruyi He Rosemary Johann-Liang Joyce Korvick Mark Avigan Michael Evans OCP Laura Governale Suliman Al-Fayoumi Sigal Kaplan Suresh Doddapaneni Toni Piazza-Hepp