One Year Post-Exclusivity Adverse Event Review for Tamiflu ® (oseltamivir)

1. One Year Post-Exclusivity Adverse Event Review forTamiflu® (oseltamivir) Pediatric Advisory Committee Meeting November 18, 2005 Melissa M. Truffa, R.Ph. Safety Evaluator Team Leader Division of Drug Risk Evaluation Office of Drug Safety Center for Drug Evaluation and Research

2. Overview • Background/Regulatory History • Tamiflu® Drug Use Data • AERS Adverse Event Reports for oseltamivir during post-exclusivity (Mar. 22, 2004 to Apr. 22, 2005) • Japanese Experience with Tamiflu® • Summary

3. Background • Drug: Tamiflu® (oseltamivir phosphate) capsules and oral suspension • Therapeutic Class: Neuraminidase inhibitor • Sponsor: Roche Pharmaceuticals • Indications: • Treatment of influenza in adults and pediatrics ( ≥1 yr) • Prophylaxis of influenza in adults and pediatrics (≥ 13 yrs)

4. US Regulatory History

5. Drug Use Data: Outpatient Prescription Data Verispan, LLC • Verispan’s VONA measures retail dispensing of prescriptions. Prescriptions are captured from a sample of approximately 51,000 pharmacies throughout the U.S. • The pharmacies in the database account for nearly all retail pharmacies and represent approximately 55% of retail prescriptions dispensed nationwide.

6. Drug Use Data: Tamiflu® Source: Verispan, LLC Vector One National, Extracted 9-2005,

7. Drug Use Data: Tamiflu® Source: Verispan, LLC Vector One National, Extracted 9-2005

8. Raw Count of Adverse Event Reports for Tamiflu®* from approval through April 22, 2005 * Includes duplicate reports

9. Raw Count of Adverse Event Reports for Tamiflu®* from March 22, 2004 –April 22, 2005 *includes duplicate reports

10. Pediatric AE Reports for Tamiflu®March 22, 2004 - April 22, 2005 • Total of 75 unduplicated AERS reports • Location: Japan-69, US-5, Canada-1 • 8 Deaths (all from Japan) • 67 Non-Fatal Reports • 32 CNS Reports • 12 Skin/Hypersensitivity Reports • 23 Other events: • GI-6, musculoskeletal-5, abnormal lab values-4, vascular-2, infections-2, hypothermia-2, cardiac-1, overdose-1

11. Pediatric Deaths (n=12) • Total of 12 deaths in AERS database eight of which were reported in the 1-year post-exclusivity period • 10 males, 2 females • Mean age: 4.4 years • Age Range: 2-14 years • Relevant Labeling: Death is not mentioned and there were no deaths in clinical trials.

12. Source of Pediatric Deaths • All 12 deaths are from Japan • Year of Event by Flu Season: • 1999-00 (1), 2001-02 (1), 2002-03 (5), 2003-04 (1), 2004-05 (4) • 4 reports of “sudden death” from 2002-2003 Flu season are from a Japanese newspaper article concerning children that died suddenly in their sleep.

13. Reports of Pediatric Sudden Death and Cardiopulmonary Arrest • 2-yr-old healthy male with influenza suddenly died in his sleep 1-2 days after starting Tamiflu®. Autopsy revealed brain and pulmonary edema. • 2-yr-old male with asthma and influenza suddenly died in his sleep 1-2 days after starting Tamiflu®. No autopsy results. • 3-yr-old male with asthma and influenza suddenly died in his sleep 1-2 days after starting Tamiflu®. Autopsy revealed pulmonary edema.

14. Reports of Pediatric Sudden Death and Cardiopulmonary Arrest (cont) • 3-yr-old healthy male with influenza suddenly died in his sleep 1-2 days after starting Tamiflu®. No autopsy results. • 2-yr-old male with influenza and mild “pseudo-croup” developed difficulty breathing and was taken to hospital. En route suffered cardiopulmonary arrest and died. Encephalopathy and myocarditis were suspected. Patient received one dose of Tamiflu. No autopsy was performed. • 4-yr-old female in good general condition was diagnosed with fever and influenza. She received one dose of Tamiflu and the next day suddenly developed cardiopulmonary arrest and died.

15. Pediatric Deaths with Confounding Factors and Limited Information • 2-yr-old male with multiple medical problems was diagnosed with influenza and suffered cardiopulmonary arrest with pulmonary and brain edema 3 days after starting Tamiflu®. He died of sepsis over 2 months later. • 3-yr-old male was hospitalized in ICU with encephalopathy. Influenza test was positive so Tamiflu® and amantadine were started. Patient died 6 weeks later of pneumonia. • 4-yr-old male with fever and suspected influenza suffered cardiopulmonary arrest and became brain dead. He died 2 months later, no autopsy.

16. Pediatric Deaths with ConfoundingFactors and Limited Information (cont) • 5-yr-old female started Tamiflu® and cefdinir and next day developed asphyxiation and vomiting. Cefdinir was stopped and 3 days later the Tamiflu® was stopped. Died of asphyxiation on unknown date. • 9-yr-old male with mental retardation, CP, and methylmalonic acidemia (often with severe acidosis) was diagnosed with fever and influenza. Patient developed acute pancreatitis with cardiopulmonary arrest and died 4 days after starting Tamiflu®.

17. Pediatric Deaths with Confounding Factors and Limited Information (cont) • Initial AERS report stated that a14-yr-old male with influenza “took one dose of Tamiflu® and took his own life in an hour”. Follow-up information from Roche updated the report to read that a14-yr-old male with influenza took one dose of Tamiflu and 2 hours later fell off the 9th floor of his apartment building. He died of hemorrhagic shock 5 hours later. No autopsy was performed. At his clinic visit earlier in the day he showed no disturbances of consciousness or mental disorders. There were no witnesses to the circumstances of his fall.* *There is a report in AERS of a death of a 17-yr-old adult patient with a similar clinical picture. Note that the US definition of pediatrics is 0-16 years of age.

18. Pediatric Deaths: Conclusions • Co-morbidity and confounding factors in many of the cases. • Limited and missing data in majority of cases makes if difficult to assess cause of death. • Issues with translated reports and limited access to follow-up information make interpreting foreign reports challenging. • At this time, based on available data, it is difficult to establish a direct causal relationship between the use of oseltamivir and the reported deaths.

19. PediatricSerious Skin and Hypersensitivity Reactions (n=12) March 22, 2004 –April 22, 2005 • 4 males, 8 females • Mean age 6 yrs, Range 2-14 yrs • 3-hospitalizations, 1-life-threatening, 8 -medically significant • Japan-11, US-1 • Type of Reaction: • Stevens-Johnson Syndrome (SJS)-3, SJS/Toxic epidermal necrolysis (TEN)-1, anaphylaxis/anaphylactoid-3, Erythema multiforme (EM)-2, urticaria-2, eczema-1

20. Relevant Tamiflu® Labeling for Serious Skin and Hypersensitivity Reactions: • Adverse Reactions: lists dermatitis under Treatment Studies in Pediatric Patients (Table 4) • Observed During Clinical Practice for Treatment (General): lists rash, swelling of the face or tongue and TEN

21. Summary of Pediatric Serious Skin/Hypersensitivity Reactions March 22, 2004 –April 22, 2005 • Majority of SJS, TEN, and EM cases were confounded by concomitant medications. • 3 additional cases had limited information to adequately assess the adverse event. • However there were 4 notable cases (SJS-1, anaphylaxis-1 and urticaria-2) from the 1-year post-exclusivity period. • These cases and cases identified from a review of adverse events from 2004-05 flu season prompted a further investigation of all serious skin and hypersensitivity reports in the AERS database.

22. Reports of Serious Skin and Hypersensitivity Reactions* from approval through Apr 22, 2005 *Includes duplicate reports

23. Pediatric CNS Events (n=32)March 22, 2004 –April 22, 2005 • 20 males, 12 females • Mean age 8 yrs, Range 5 months -15 yrs • 12-hospitilizations, 2-life-threatening, 1-Disability, 17-medically significant • Japan-31, US-1

24. Relevant Tamiflu® Labeling for CNS Events • Observed During Clinical Practice for Treatment (Neurologic): lists seizure, confusion

25. General Categories ofPediatric CNS Events (n=32) • Convulsions (7) • Depressed level of consciousness (6) • Visual disturbances and hallucinations (5) • Delirium (4) • Mixed events(4): tremor, excitability, somnolence, fontanelle bulging • Abnormal behavior (6)

26. CNS Events: Example Cases from Abnormal Behavior Category Case #1: “hours after the 2nd dose of oseltamivir, patient jumped from the second floor of his house. His lower body was deep in snow; he got out of the snow and rang the doorbell and entered his house. He repeatedly said “I am no half asleep” and went back to his room and slept. He remembered the incident but did not know why he jumped. Case #2: “patient complained he was suffering from “abnormal look” and jumped from upstairs window of his house” Case #3: “patient experienced hallucinations and showed abnormal behavior. He seemed frightened by something and rushed outside into the street”

27. Steps Taken to Address Differential Reporting of Adverse Events • Established a working group with representatives from ODS, OND, OCTAP, and OC. • Requested additional information from Roche • Obtained a copy of the English version of Japanese product labeling for oseltamivir • Formally contacted the Japanese Ministry of Health, Labor, and Welfare (MHLW) for additional information

28. FDA Inquiries to Japanese Regulators • Have there been reports in pediatric patients of deaths, CNS toxicity or serious skin/hypersensitivy reactions with the use Tamiflu® in Japan? Are these labeled events? • Are there differences in the manifestation of influenza in Japanese patients, especially regarding CNS or neurological effects? Could these adverse events be due to disease (influenza) vs. drug?

29. FDA Inquiries to Japanese Regulators cont. • How is Tamiflu® prescribed to pediatric patients in Japan? • How are adverse events reported in Japan? • What is the usage data of Tamiflu® in Japan? If there is increased use of Tamiflu® in Japan, could it be resulting in a potential early safety signal that has not been seen in US pediatric patients?

30. Japanese Response to FDA Inquiries • In Japan’s Tamiflu® label, shock, anaphylactoid/ serious skin reactions, and psychoneurological symptoms are labeled under PRECAUTIONS/Adverse Reactions/Clinically significant adverse reactions. • Influenza-associated encephalopathy has been a concern in Japan for over a decade. • There is widespread use of test kits for influenza and awareness to treat influenza early especially in pediatrics. • Mass media reports of positive effects of Tamiflu®

31. Japanese Response to FDA Inquiries • Increased postmarketing surveillance in Japan that coincided with US post-exclusivity period; retrospective study (2003-2004) to evaluate CNS effect in infants (< 1 yr of age). • Tamiflu® is readily available in Japan resulting in tremendous use compared to US. • Prescriptions for 2001-2005 (all ages): Approximately 24.5M (Japan) vs. 6.5M (US) • Prescriptions for 2001-2005 (≤ 16 years): Approximately 11.6M (Japan) vs. 872,386 (US) (Source: Nov. 18th Pediatric Advisory Committee Executive Summary for Tamiflu® prepared by Hoffman-La Roche)

32. Summary • US adverse event reports do not show deaths or comparable CNS effects in the pediatric age group as seen in the Japanese data. • Serious skin/hypersensitivity reactions for adults and pediatrics are currently under review by ODS. • CDER will continue to closely monitor all serious adverse event reports for oseltamivir. • FDA will continue to meet with CDC for the 2005-2006 flu season to discuss serious U.S. adverse events with antivirals used to treat influenza.

33. Acknowledgements • Evelyne Edwards, Pharm.D. • Rosemary Johann-Liang, M.D. • David Moeny, R.Ph.