1. Pediatric Advisory Committee November 16, 2006 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. Pediatric Advisory Committee November 16, 2006 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. Pediatric Advisory Committee November 16, 2006 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. Pediatric Advisory Committee November 16, 2006 4 US Regulatory History (with DDRE post-marketing reviews) Approval DateIndicationPopulation Oct. 27, 1999 Tamiflu ® capsules Treatment of influenza Adults Nov. 17, 2000Prophylaxis of influenza Adults and Pediatrics ≥ 13 Dec. 14, 2000 Tamiflu ® Suspension Treatment of influenza Adults and Pediatrics ≥ 1 March 22, 2004 November 18, 2005 December 19, 2005 Pediatric Exclusivity Granted BPCA Section 17 AE Review Follow-up post-marketing reviews December 21, 2005Prophylaxis of influenza Pediatrics 1-12 September 2006 Review2005-06 Flu Season AE surveillance

5. Pediatric Advisory Committee November 16, 2006 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. Pediatric Advisory Committee November 16, 2006 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. 7 Update: Drug Use Data

8. Pediatric Advisory Committee November 16, 2006 8 Drug Use Data: Tamiflu ® Source: Verispan Vector One® : National, MAT 2000-2006, data extracted 08-04-2006

9. Pediatric Advisory Committee November 16, 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. 10 Safety Update: Serious Skin and Hypersensitivity Reactions

11. Pediatric Advisory Committee November 16, 2006 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. Pediatric Advisory Committee November 16, 2006 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. 13 Safety Update: Pediatric Death Reports

14. Pediatric Advisory Committee November 16, 2006 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 13 th 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 Advisory Committee November 16, 2006 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 Advisory Committee November 16, 2006 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 Advisory Committee November 16, 2006 17  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 9 th 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. Pediatric deaths reported with Tamiflu ® : AERS update through 10/23/06

18. 18 Safety Update: Neuropsychiatric Adverse Events

19. Pediatric Advisory Committee November 16, 2006 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. Pediatric Advisory Committee November 16, 2006 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. Pediatric Advisory Committee November 16, 2006 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. Pediatric Advisory Committee November 16, 2006 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. Pediatric Advisory Committee November 16, 2006 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. Pediatric Advisory Committee November 16, 2006 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.

25. Pediatric Advisory Committee November 16, 2006 25

26. Pediatric Advisory Committee November 16, 2006 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. Pediatric Advisory Committee November 16, 2006 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 9 th 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. Pediatric Advisory Committee November 16, 2006 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. Pediatric Advisory Committee November 16, 2006 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. Pediatric Advisory Committee November 16, 2006 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. Pediatric Advisory Committee November 16, 2006 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. Pediatric Advisory Committee November 16, 2006 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. Pediatric Advisory Committee November 16, 2006 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.