Safety of Tamiflu in Pediatric Patients – Review of Clinical Trials Data and the Scientific Literature

1. Safety of Tamiflu in Pediatric Patients – Review of Clinical Trials Data and the Scientific Literature Linda L. Lewis, M.D. Medical Officer Division of Antiviral Products, FDA

2. Outline • Recap of ODS BPCA safety consult and some possible explanations for pattern of Adverse Events (AEs) • For each topic – deaths, neuropsychiatric AEs, serious skin reactions • Re-analysis of pediatric data from clinical trials • Review of scientific literature – influenza in children • FDA conclusions

3. ODS BPCA Pediatric Safety Review - Tamiflu • ODS reviewed AERS database for cases of AEs in pediatric patients over the year following granting Tamiflu pediatric exclusivity • Total of 12 deaths reported in pediatric patients using Tamiflu since approval date • All deaths reported from Japan • Total 75 pediatric AE cases in database during review period (3/04-4/05) • 69 reports from Japan, 5 U.S. and 1 Canada • Neuropsychiatric events and serious skin reactions were most common

4. Possible Explanations for Adverse Event Pattern • Difference in absorption, distribution, metabolism, or elimination of Tamiflu in Japanese leading to different PK profile? • Difference in dose/use of Tamiflu? • Difference in AE reporting in Japan? • Difference in manifestations of influenza? • Identification of a safety signal associated with Tamiflu in children due to greater use of drug in Japan?

5. Re-analysis of pediatric clinical trial data • Original NDA 21-246 for Tamiflu for oral suspension, 2 randomized pediatric studies • WV15758 – Tamiflu vs placebo in treatment of influenza in healthy pediatric patients 1-12 years of age, 2 mg/kg BID x 5 days, 342 received Tamiflu and 353 received placebo • WV15759/15871 - Tamiflu vs placebo in treatment of influenza in patients 6-12 years of age with asthma, 2 mg/kg BID x 5 days, 170 Tamiflu and 164 placebo

6. Re-analysis of pediatric clinical trial data • sNDA to extend prophylaxis indication to patients 1-12 years of age - under review • WV16193 – Ill index cases treated with Tamiflu and households randomized to receive Tamiflu prophylaxis QD x 10 days or treatment if ill; 138 households Tamiflu QD and 139 households treatment if needed (total 1104 active subjects) • 534 patients 1-18 years of age – 181 as index cases (all treated), 353 as contacts randomized to Tamiflu prophylaxis or no prophylaxis • Roche asked to provide post-marketing safety update for serious hepatic, renal, skin, and CNS AEs in all ages as part of supplement review

7. Re-analysis of pediatric clinical trial data • Electronic study datasets were reviewed for events of interest (by preferred term and body system) • All neurologic and psychiatric adverse events selected and compiled • Dermatologic and hypersensitivity events selected and compiled • Prophylaxis study – Selected patients 1-18 years of age, patients receiving Tamiflu prophylaxis or Tamiflu treatment were pooled • All studies evaluated separately, then pooled • All pediatric patients receiving Tamiflu compared to all those receiving either placebo or no treatment

8. Pediatric Deaths

9. Pediatric Deaths • No pediatric deaths reported in any clinical trials • Case summaries of 12 AERS death reports variable in level of detail, confounded by other conditions and use of other medications, difficult to assign causality • Young children have higher morbidity and mortality with influenza • Excess rates of hospitalization for children < 1 year of age and excess number of deaths from cardiopulmonary conditions during flu season (Neuzil et al, 2000) • CDC reported 152 influenza-associated deaths during 2003-04 flu season in patients < 18 years

10. Neuropsychiatric Adverse Events

11. Integrated Neuropsychiatric Adverse Events in Pediatric Patients in Clinical Trials of Tamiflu (1-18 years of age)

12. Re-analysis of clinical trial data in children • In treatment trials one neuropsychiatric serious AE reported • 9 year old male with confirmed influenza B, hospitalized with “viral encephalitis”, received placebo • In prophylaxis trial, 2 adolescents reported with psychiatric events • 18 year old male with “psychological disorder” noted present for one month prior to study, received Tamiflu prophylaxis • 17 year old female with “nervous breakdown”, history of depression, hospitalized (reported as SAE), received Tamiflu as index case

13. Literature review of influenza-associated encephalitis and encephalopathy in children • Increased reports of influenza-associated encephalitis and encephalopathy from Japan beginning in 1990s • Prompted nationwide surveillance efforts in Japan • Medical community and public education of CNS complications of influenza

14. Literature review of influenza-associated encephalitis and encephalopathy in children • Morishima et al, 2002 – Retrospective study of 1998-99 flu season, • National survey of every local health care center in Japan • Definition of encephalitis/encephalopathy clinical (altered consciousness or loss of consciousness), diagnosis of influenza based on positive culture, antigen test, PCR, or increased HAI titers • 148 cases met their definition of encephalopathy with documented influenza

15. Literature review of influenza-associated encephalitis and encephalopathy in children • Typical course (Morishima et al, 2002) • Onset of high fever, seizures, and altered consciousness, rapid progression to comatose state within 1-2 days of flu symptoms • Few patients with Reye’s syndrome (4%) • Associated with influenza A (88%) • CSF findings frequently normal, brain imaging suggestive of cerebral edema and localized areas of low density, some with bilateral symmetric thalamic low densities (acute necrotizing encephalopathy, ANE) • Very high mortality (32%) and “disability” (28% total, 9% with severe sequelae)

16. Literature review of influenza-associated encephalitis and encephalopathy in children • No accepted explanation for difference in rate/pattern of CNS complications in Japan compared to other countries • Japanese report continued high rates of influenza-related encephalitis and encephalopathy in recent flu seasons but mortality rates have decreased • Some suggest decreased mortality due to increased awareness and rapid diagnosis and treatment of influenza among children

17. Literature review of influenza-associated encephalitis and encephalopathy in children • Isolated case reports and small series of encephalitis and encephalopathy from U.S. • Largest series from Houston during 2003-04 flu season (Maricich et al, 2004) • 478 laboratory-confirmed cases of influenza A at Texas Children’s Hospital • 8 patients hospitalized with neurologic symptoms • Antiviral use after admission – 4 received rimantidine and one received Tamiflu • One with significant neurologic sequelae (ANE)

18. Additional Information • DAVP/ODS requested additional information from Japanese regulatory authority and Roche regarding neuropsychiatric events • Japanese undertook active surveillance of influenza-associated encephalitis and encephalopathy beginning in late 1990s • Japanese national health service facilitates rapid diagnostic testing for influenza in children and subsequent treatment • Roche/Chugai solicited AE reporting from 70,000 Japanese physicians during 2003-04 flu season

19. Dermatologic Adverse Events

20. Integrated Dermatologic Adverse Events in Pediatric Patients in Clinical Trials of Tamiflu (1-18 years of age)

21. Literature review of influenza-associated dermatologic events in children • Rare case reports of dermatologic manifestations of influenza in children • Survey of respiratory viruses in Great Britain (Hope-Simpson and Higgins, 1969) note “rash” was present in approximately 2% of influenza A and 8% of influenza B cases, not further described • Pediatric and infectious diseases textbooks do not describe skin reactions related to influenza

22. FDA Conclusions Regarding Adverse Event Reports • Search of the AERS database identified deaths, an unusual pattern of neuropsychiatric AEs, and serious skin reactions reported with Tamiflu use in children • Re-analysis of the pediatric clinical trials data failed to identify differences in skin and neuropsychiatric AEs between children receiving Tamiflu and placebo/no treatment

23. FDA Conclusions Regarding Adverse Event Reports • Further investigation into possible reasons for pattern of AEs in Japanese children • Syndrome of influenza-associated encephalitis and encephalopathy described in pediatric literature prior to approval of Tamiflu • Increased awareness of CNS complications in Japan • Increased use of Tamiflu in children in Japan • Probable increased levels of AE reporting from Japan during review period

24. Questions?

25. Extra Slides

26. Integrated Neuropsychiatric Adverse Events in Pediatric Treatment Trials of Tamiflu (1-12 years of age)

27. Neuropsychiatric Adverse Events in Prophylaxis Trial of Tamiflu (1-18 years of age)