Tamiflu ® (oseltamivir) Safety Update

1. Tamiflu® (oseltamivir) Safety Update Pediatric Advisory Committee Meeting November 16, 2006 Rosemary Johann-Liang, M.D., FAAP Deputy Director Andrew Mosholder, M.D., M.P.H. Epidemiologist Division of Drug Risk Evaluation FDA Center for Drug Evaluation and Research

2. Overview • Background/Regulatory History • Brief Summary of 11/05 PAC • Safety Update • Drug Use Data • Skin/Hypersensitivity Reactions • Pediatric Death Reports • Neuropsychiatric Events

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

4. US Regulatory History (with DDRE post-marketing reviews)

5. PAC 11/05 Summary/Conclusions • FDA presentations of clinical trials safety data, pediatric post-marketing adverse event review, and literature review. • Presentations from CDC and Roche. • Unclear if neuropsychiatric AEs represent a safety signal associated with oseltamivir. • Pattern of neuropsychiatric AEs more suggestive of increased AE reporting from Japan, and disease manifestations of influenza. • Severe skin reactions less likely to be manifestation of influenza, more concern for drug-related AE.

6. PAC 11/05 Committee’s Charge • FDA is to return after 1 influenza season with a brief update to the PAC on any new developments in either adverse events or new information that may have developed within the next year. • In 2 years the PAC would expect a complete review of 2 influenza seasons and to have additional information from the sponsor from their U.S. United Health Care Claims Database and any other studies or databases to which they have access.

7. Update: Drug Use Data

8. Drug Use Data: Tamiflu® Source: Verispan Vector One® : National, MAT 2000-2006, data extracted 08-04-2006

9. Data courtesy of Hoffmann-La Roche, Inc. Japan : IMS Quarterly Rx Data until June 2005, Biannual data until June 2006 United States : IMS Weekly prescriptions until September 2006 Rest of World : IMS MIDAS Quarterly Retail data (Germany, France UK, Brazil, Canada, Argentina) until June 2006

10. Safety Update: Serious Skin and Hypersensitivity Reactions

11. AERS Update: Serious Skin and Hypersensitivity Reactions • December 19, 2005 postmarketing safety review identified 43 cases of serious skin reactions in FDA’s Adverse Event Reporting System (AERS), including 3 fatalities (all adults). • 16 of 43 were in pediatric patients • 24 cases of Stevens-Johnson Syndrome, 14 cases of erythema multiforme, 4 cases of toxic epidermal necrolysis, and 1 case of pemphigus • In addition to serious skin reactions, 75 other hypersensitivity reactions were identified from AERS and the literature. • This includes 6-anaphylactic reactions, 6-anaphylactoid reactions and 17-anaphylactic shock reports

12. Tamiflu®Labeling Update: 12/05 Precautions and Postmarketing sections of Tamiflu® (oseltamivir) Label updated December 21, 2005 • Precautions: Serious Skin/Hypersensitivy Reactions • “Rare cases of anaphylaxis and serious skin reactions including toxic epidermal necrolysis, Stevens-Johnson Syndrome, and erythema multiforme have been reported in postmarketing experience with Tamiflu. Tamiflu should be stopped and appropriate treatment instituted if an allergic-like reaction occurs or is suspected.” • Observed During Clinical Practice: Dermatologic: dermatitis, rash, eczema, urticaria, erythema multiforme, Stevens-Johnson Syndrome, and toxic epidermal necrolysis, (see Precautions)

13. Safety Update: Pediatric Death Reports

14. PAC 11/05: AERS Pediatric deaths • A total of 12 pediatric (<17 y/o) death reports in AERS as of Nov. 18, 2005 • Plus a 13th report of a 17 y/o boy • All reports from Japan • Co-morbidity and confounding factors in many of the cases. • Limited and missing data in majority of cases; difficult to assess cause of death. • Issues with translated reports and limited access to follow-up information make interpreting foreign reports challenging. • Based on available data, it is difficult to establish a direct relationship between the use of oseltamivir and the reported deaths.

15. Pediatric deaths reported with Tamiflu®: AERS update through 10/23/06 • Examined all pediatric AERS reports with fatal outcome irrespective of causality, age ≤17 y/o • 5 additional deaths reported since 11-18-05 • 2 US cases • 3 y/o healthy girl with flu with reported altered mental status. Diagnosis of “severe strep pneumonia” died due to sudden respiratory and cardiac arrest. • 8 y/o girl with history of SJS, TEN and anxiety after the use of oseltamivir and ibuprofen, needed prolonged and extensive rehabilitation, died 8-9 months after use of the drugs from unstated reasons.

16. Pediatric deaths reported with Tamiflu®: AERS update through 10/23/06 • 5 additional deaths reported since 11-18-05 • 3 Japanese cases • 7 y/o boy with Down’s Syndrome and flu. Difficulty breathing then sudden death (cardio-pulmonary arrest) with GI hemorrhage. • 3 y/o boy with influenza A and cardio-pulmonary arrest. Death possibly due to encephalopathy or cardiomyopathy. • 12 y/o boy with fever to 40 degree C, took 1 capsule of his brother’s Tamiflu and several hours later died in fall from high rise apartment building.

17. Pediatric deaths reported with Tamiflu®: AERS update through 10/23/06 • We noted that 3 out of 18 reported deaths in patients <17 y/o involved unusual traumatic injuries. • 14-year-old boy after 1 dose of Tamiflu fell off the 9th floor • 17-year-old boy after 1 dose of Tamiflu jumped over a concrete wall and leapt in front of a truck • 12-year-old boy after 1 dose of Tamiflu found in parking lot presumably due to a fall. • From available data, difficult to establish a direct relationship between the use of Tamiflu and the reported deaths; however, concerned about the pattern.

18. Safety Update: Neuropsychiatric Adverse Events

19. Safety Update: Neuropsychiatric events (Dec 2005 Review) • December 19, 2005 postmarketing safety review with supplement for prophylaxis indication identified 126 cases of neuropsychiatric events in AERS including 3 fatalities. • 17 of 126 categorized as cases of abnormal behavior including 2 deaths in Japanese patients < 18 yrs of age (14 and 17 yr olds) • Conclusions: not to label at this time, continue monitoring AEs for 2005-2006 influenza season, and reassess safety profile at end of the influenza season

20. Update: Postmarketing surveillance of oseltamivir neuropsychiatric events Purpose of this review: to update analysis of postmarketing reports of neuropsychiatric events with oseltamivir following the 2005-2006 influenza season

21. Update: Postmarketing surveillance of neuropsychiatric events • Methods • Search of FDA’s Adverse Event Reporting System (AERS) database • Reports received during time frame = 8-29-05 to 7-6-06 • MedDRA terms searched • HLT “Suicidal and Self-injurious Behaviour” • 30 additional preferred terms representing neuropsychiatric events • Suspect Drug = oseltamivir • Age = any • Case categories derived from manual review of reports

22. Results: Neuropsychiatric events • 129 AERS reports returned • 26 excluded • Narrative did not support • Medication errors • Confounded by concurrent medical or psychiatric disorders • 103 cases included in review • 95 from Japan, 5 from U.S., 3 from other countries • Median age = 12 yrs (range 1½ - 90) • Only 3 involved prophylactic use • 69 M, 32 F

23. Results: Categories and # of reports 1.Delirium with Prominent Behavioral Disturbances – 60 (US-1) 2. Suicidal events – 6 (US-1) 3. Panic Attack – 3 4. Delusions – 3 5. Convulsions – 12 (US-1) 6. Depressed Level of Consciousness – 6 7. Loss of Consciousness – 4 (US-1) 8. Miscellaneous – 9 (US-1)

24. Results: Fatal Cases 8/05-7/06 • Additional information received on 14 y/o boy found dead from 9-story fall after one dose, apparently had been hanging from balcony railing. • 44 y/o man received oseltamivir 75mg twice daily for influenza; 2 days later he committed suicide (fall); “open verdict” by coroner. • 51 y/o man hospitalized with tuberculosis; treated at 7 pm with one dose of oseltamivir for influenza A.  Next morning committed suicide by jumping from hospital room; left suicide note. 

26. Oseltamivir AERS reports of delirium with prominent behavioral disturbance, 8/05-7/06 • N = 60 • US: n=1 • 75% male • 17+ yrs: n=8 • 12-16 yrs n=14 • 6-11 yrs n=31 • 2-5 yrs n=7 • Median number of doses to onset = 1 • 1 dose n=38 • 1 or 2 doses n=52 • Dechallenge 35 pos, 6 neg • Reports confirming negative brain imaging studies (n=25) • Median fever = 39 deg C, n=11 with fever <38 • 1 report with prophylaxis

27. Oseltamivir AERS reports of delirium with prominent behavioral disturbance Examples • 11 y/o boy after two doses fell from landing, fractured skull and femur • 7 y/o boy 30 min post first dose ran from house screaming, later found at neighbor’s • 13 y/o, after one dose, apparently hallucinating and screaming about being chased, ran towards a 9th floor window • Literature report (Koide, 2006) of 8 y/o boy, ~90 min post first dose, agitated, growling, tried to run outdoors, memory impaired • 6 y/o boy got out of bed several hours after first dose, said a huge Pokemon told him to get up; minimal fever at the time

28. Additional Points on Neuropsychiatric Events Why so many reports from Japan? • Pediatric use >> than in U.S. • As yet unknown genetic risk factors could be more prevalent in Japanese population • More sensitive postmarketing surveillance system in Japan • Combination of all these factors

29. Additional Points on Neuropsychiatric Events • Influenza itself can be associated with delirium, and in some cases frank encephalitis • Relative contribution of drug versus viral illness difficult to define in the absence of systematic data • Degree to which oseltamivir crosses blood-brain barrier during acute illness unclear • Influenza is associated with serious morbidity and mortality • Drug risk evaluation always a balance of benefit/risk • Need for monitoring of patients emphasized

30. Additional Points on Neuropsychiatric Events • Characteristics of reports in this follow-up review make it uncertain that this is a disease-only process. • Temporality (1 – 2 doses to event) • “Drug –effect” as per reporting physician • Lack of negative sequelae after de-challenge • Absence of frank influenza encephalitis • Peculiar pattern (“abnormal behavior”) of adverse events, differs from the typical flu related CNS symptoms • Prudent to update the US labeling to be similar in scope to the current Japanese labeling. • Concern that if US drug use becomes similar to Japan use, there may be increasing AE consequences as well.

31. Labeling Recommendations: Neuropsychiatric events • Section under Precautions • Post-marketing reports (mostly from Japan) of self-injurious behavior and delirium with the use of Tamiflu. • Primarily among pediatric and adolescent patients with influenza • Relative contribution of the drug to these events is not known • Monitor for signs of abnormal (or unusual) behavior immediately after starting Tamiflu and throughout the duration of treatment. • If abnormal behavior, healthcare provider should be contacted immediately to determine appropriate treatment including whether Tamiflu should be discontinued.

32. Tamiflu® (oseltamivir) Safety Update : Summary/Plan • Labeling Updated • Serious Skin and Hypersensitivity Reactions • Drug utilization last year similar to previous several years • Updated review of pediatric AERS fatal reports with possible pattern of traumatic injury from “abnormal behavior” on drug • Follow-up neuropsychiatric AEs: cannot rule out drug – disease adverse effect. Predominantly in children and adolescents. • Labeling recommended on • neuropsychiatric events to be similar in scope to the Japanese current labeling • Need to closely monitor patient in order to prevent any attempt at unsafe behavior • Return next year for full report. 11/05 committee suggested that Roche report on studies which address this safety issue.

33. Acknowledgements • Evelyne T. Edwards, Pharm.D., M.A. • Melissa M. Truffa, R.Ph. • Jeff O’Neill, A.C.R.N. • Scott Proestel, M.D. • Vicky Borders-Hemphill, Pharm.D. • Hoffmann-La Roche, Inc.