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

Linda L. Lewis, M.D.Linda L. Lewis, M.D.

Medical OfficerMedical Officer

Division of Antiviral Products, FDADivision of Antiviral Products, FDA

OutlineOutline

Recap of ODS BPCA safety consult and Recap of ODS BPCA safety consult and some possible explanations for pattern some possible explanations for pattern of Adverse Events (AEs)of Adverse Events (AEs)

For each topic – deaths, For each topic – deaths, neuropsychiatric AEs, serious skin neuropsychiatric AEs, serious skin reactionsreactions– Re-analysis of pediatric data from clinical Re-analysis of pediatric data from clinical

trialstrials– Review of scientific literature – influenza in Review of scientific literature – influenza in

childrenchildren FDA conclusionsFDA conclusions

ODS BPCA Pediatric ODS BPCA Pediatric Safety Review - TamifluSafety Review - Tamiflu ODS reviewed AERS database for cases ODS reviewed AERS database for cases

of AEs in pediatric patients over the year of AEs in pediatric patients over the year following granting Tamiflu pediatric following granting Tamiflu pediatric exclusivity exclusivity

Total of 12 deaths reported in pediatric Total of 12 deaths reported in pediatric patients using Tamiflu since approval patients using Tamiflu since approval datedate– All deaths reported from Japan All deaths reported from Japan

Total 75 pediatric AE cases in database Total 75 pediatric AE cases in database during review period (3/04-4/05)during review period (3/04-4/05)– 69 reports from Japan, 5 U.S. and 1 Canada69 reports from Japan, 5 U.S. and 1 Canada– Neuropsychiatric events and serious skin Neuropsychiatric events and serious skin

reactions were most commonreactions were most common

Possible Explanations for Possible Explanations for Adverse Event PatternAdverse Event Pattern

Difference in absorption, distribution, Difference in absorption, distribution, metabolism, or elimination of Tamiflu in metabolism, or elimination of Tamiflu in Japanese leading to different PK profile?Japanese leading to different PK profile?

Difference in dose/use of Tamiflu?Difference in dose/use of Tamiflu? Difference in AE reporting in Japan? Difference in AE reporting in Japan? Difference in manifestations of influenza?Difference in manifestations of influenza? Identification of a safety signal associated Identification of a safety signal associated

with Tamiflu in children due to greater with Tamiflu in children due to greater use of drug in Japan?use of drug in Japan?

Re-analysis of pediatric Re-analysis of pediatric clinical trial dataclinical trial data Original NDA 21-246 for Tamiflu for oral Original NDA 21-246 for Tamiflu for oral

suspension, 2 randomized pediatric suspension, 2 randomized pediatric studiesstudies– WV15758 – Tamiflu vs placebo in treatment WV15758 – Tamiflu vs placebo in treatment

of influenza in healthy pediatric patients 1-of influenza in healthy pediatric patients 1-12 years of age, 2 mg/kg BID x 5 days, 342 12 years of age, 2 mg/kg BID x 5 days, 342 received Tamiflu and 353 received placeboreceived Tamiflu and 353 received placebo

– WV15759/15871 - Tamiflu vs placebo in WV15759/15871 - Tamiflu vs placebo in treatment of influenza in patients 6-12 treatment of influenza in patients 6-12 years of age with asthma, 2 mg/kg BID x 5 years of age with asthma, 2 mg/kg BID x 5 days, 170 Tamiflu and 164 placebodays, 170 Tamiflu and 164 placebo

Re-analysis of pediatric Re-analysis of pediatric clinical trial dataclinical trial data sNDA to extend prophylaxis indication to sNDA to extend prophylaxis indication to

patients 1-12 years of age - under reviewpatients 1-12 years of age - under review– WV16193 – Ill index cases treated with Tamiflu WV16193 – Ill index cases treated with Tamiflu

and households randomized to receive Tamiflu and households randomized to receive Tamiflu prophylaxis QD x 10 days or treatment if ill; prophylaxis QD x 10 days or treatment if ill; 138 households Tamiflu QD and 139 138 households Tamiflu QD and 139 households treatment if needed (total 1104 households treatment if needed (total 1104 active subjects)active subjects)

– 534 patients 1-18 years of age – 181 as index 534 patients 1-18 years of age – 181 as index cases (all treated), 353 as contacts randomized cases (all treated), 353 as contacts randomized to Tamiflu prophylaxis or no prophylaxisto Tamiflu prophylaxis or no prophylaxis

– Roche asked to provide post-marketing safety Roche asked to provide post-marketing safety update for serious hepatic, renal, skin, and CNS update for serious hepatic, renal, skin, and CNS AEs in all ages as part of supplement reviewAEs in all ages as part of supplement review

Re-analysis of Re-analysis of pediatric clinical trial pediatric clinical trial datadata Electronic study datasets were reviewed for Electronic study datasets were reviewed for

events of interest (by preferred term and body events of interest (by preferred term and body system)system)– All neurologic and psychiatric adverse events selected All neurologic and psychiatric adverse events selected

and compiledand compiled– Dermatologic and hypersensitivity events selected and Dermatologic and hypersensitivity events selected and

compiledcompiled Prophylaxis study – Selected patients 1-18 years Prophylaxis study – Selected patients 1-18 years

of age, patients receiving Tamiflu prophylaxis or of age, patients receiving Tamiflu prophylaxis or Tamiflu treatment were pooled Tamiflu treatment were pooled

All studies evaluated separately, then pooledAll studies evaluated separately, then pooled All pediatric patients receiving Tamiflu All pediatric patients receiving Tamiflu

compared to all those receiving either placebo compared to all those receiving either placebo or no treatment or no treatment

Pediatric DeathsPediatric Deaths

Pediatric DeathsPediatric Deaths

No pediatric deaths reported in any clinical trials No pediatric deaths reported in any clinical trials Case summaries of 12 AERS death reports Case summaries of 12 AERS death reports

variable in level of detail, confounded by other variable in level of detail, confounded by other conditions and use of other medications, difficult conditions and use of other medications, difficult to assign causality to assign causality

Young children have higher morbidity and Young children have higher morbidity and mortality with influenzamortality with influenza– Excess rates of hospitalization for children < 1 year of Excess rates of hospitalization for children < 1 year of

age and excess number of deaths from age and excess number of deaths from cardiopulmonary conditions during flu season (Neuzil cardiopulmonary conditions during flu season (Neuzil et al, 2000) et al, 2000)

CDC reported 152 influenza-associated deaths CDC reported 152 influenza-associated deaths during 2003-04 flu season in patients < 18 during 2003-04 flu season in patients < 18 yearsyears

Neuropsychiatric Neuropsychiatric Adverse EventsAdverse Events

Clinical AE Preferred Term

Tamiflu(N=903)

Placebo/Not Treated(N=660)

Anxiety 1 0

Balance impaired NOS

0 1

Confusion 0 1

Hallucinations 2 1

Headache 35 (4%) 34 (5%)

Insomnia 2 1

Migraine 0 2

Mood swings 0 1

Nervous breakdown 1 0

Nightmares 1 4

Psychiatric disorder 1 0

Taste disturbance 0 1

Vasovagal attack 1 0

Total Patients with Neuropsych AEs

44 (5%) 44 (7%)

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

Re-analysis of clinical Re-analysis of clinical trial data in childrentrial data in children In treatment trials one neuropsychiatric In treatment trials one neuropsychiatric

serious AE reportedserious AE reported– 9 year old male with confirmed influenza B, 9 year old male with confirmed influenza B,

hospitalized with “viral encephalitis”, hospitalized with “viral encephalitis”, received placeboreceived placebo

In prophylaxis trial, 2 adolescents In prophylaxis trial, 2 adolescents reported with psychiatric events reported with psychiatric events – 18 year old male with “psychological 18 year old male with “psychological

disorder” noted present for one month prior disorder” noted present for one month prior to study, received Tamiflu prophylaxisto study, received Tamiflu prophylaxis

– 17 year old female with “nervous 17 year old female with “nervous breakdown”, history of depression, breakdown”, history of depression, hospitalized (reported as SAE), received hospitalized (reported as SAE), received Tamiflu as index caseTamiflu as index case

Literature review of influenza-Literature review of influenza-associated encephalitis and associated encephalitis and encephalopathy in childrenencephalopathy in children

Increased reports of influenza-Increased reports of influenza-associated encephalitis and associated encephalitis and encephalopathy from Japan encephalopathy from Japan beginning in 1990sbeginning in 1990s

Prompted nationwide surveillance Prompted nationwide surveillance efforts in Japanefforts in Japan

Medical community and public Medical community and public education of CNS complications of education of CNS complications of influenzainfluenza

Literature review of influenza-Literature review of influenza-associated encephalitis and associated encephalitis and encephalopathy in childrenencephalopathy in children

Morishima et al, 2002 – Retrospective Morishima et al, 2002 – Retrospective study of 1998-99 flu season, study of 1998-99 flu season, – National survey of every local health care National survey of every local health care

center in Japan center in Japan – Definition of encephalitis/encephalopathy Definition of encephalitis/encephalopathy

clinical (altered consciousness or loss of clinical (altered consciousness or loss of consciousness), diagnosis of influenza consciousness), diagnosis of influenza based on positive culture, antigen test, based on positive culture, antigen test, PCR, or increased HAI titersPCR, or increased HAI titers

– 148 cases met their definition of 148 cases met their definition of encephalopathy with documented encephalopathy with documented influenza influenza

Literature review of influenza-Literature review of influenza-associated encephalitis and associated encephalitis and encephalopathy in childrenencephalopathy in children Typical course (Morishima et al, 2002)Typical course (Morishima et al, 2002)

– Onset of high fever, seizures, and altered Onset of high fever, seizures, and altered consciousness, rapid progression to consciousness, rapid progression to comatose state within 1-2 days of flu comatose state within 1-2 days of flu symptomssymptoms

– Few patients with Reye’s syndrome (4%) Few patients with Reye’s syndrome (4%) – Associated with influenza A (88%)Associated with influenza A (88%)– CSF findings frequently normal, brain CSF findings frequently normal, brain

imaging suggestive of cerebral edema and imaging suggestive of cerebral edema and localized areas of low density, some with localized areas of low density, some with bilateral symmetric thalamic low densities bilateral symmetric thalamic low densities (acute necrotizing encephalopathy, ANE)(acute necrotizing encephalopathy, ANE)

– Very high mortality (32%) and “disability” Very high mortality (32%) and “disability” (28% total, 9% with severe sequelae)(28% total, 9% with severe sequelae)

Literature review of influenza-Literature review of influenza-associated encephalitis and associated encephalitis and encephalopathy in childrenencephalopathy in children No accepted explanation for difference No accepted explanation for difference

in rate/pattern of CNS complications in in rate/pattern of CNS complications in Japan compared to other countries Japan compared to other countries

Japanese report continued high rates Japanese report continued high rates of influenza-related encephalitis and of influenza-related encephalitis and encephalopathy in recent flu seasons encephalopathy in recent flu seasons but mortality rates have decreased but mortality rates have decreased

Some suggest decreased mortality due Some suggest decreased mortality due to increased awareness and rapid to increased awareness and rapid diagnosis and treatment of influenza diagnosis and treatment of influenza among children among children

Literature review of influenza-Literature review of influenza-associated encephalitis and associated encephalitis and encephalopathy in childrenencephalopathy in children

Isolated case reports and small series of Isolated case reports and small series of encephalitis and encephalopathy from U.S. encephalitis and encephalopathy from U.S.

Largest series from Houston during 2003-Largest series from Houston during 2003-04 flu season (Maricich et al, 2004)04 flu season (Maricich et al, 2004)– 478 laboratory-confirmed cases of influenza A at 478 laboratory-confirmed cases of influenza A at

Texas Children’s HospitalTexas Children’s Hospital– 8 patients hospitalized with neurologic 8 patients hospitalized with neurologic

symptomssymptoms– Antiviral use after admission – 4 received Antiviral use after admission – 4 received

rimantidine and one received Tamiflurimantidine and one received Tamiflu– One with significant neurologic sequelae (ANE)One with significant neurologic sequelae (ANE)

Additional InformationAdditional Information

DAVP/ODS requested additional DAVP/ODS requested additional information from Japanese regulatory information from Japanese regulatory authority and Roche regarding authority and Roche regarding neuropsychiatric eventsneuropsychiatric events– Japanese undertook active surveillance of Japanese undertook active surveillance of

influenza-associated encephalitis and influenza-associated encephalitis and encephalopathy beginning in late 1990s encephalopathy beginning in late 1990s

– Japanese national health service facilitates Japanese national health service facilitates rapid diagnostic testing for influenza in rapid diagnostic testing for influenza in children and subsequent treatmentchildren and subsequent treatment

– Roche/Chugai solicited AE reporting from Roche/Chugai solicited AE reporting from 70,000 Japanese physicians during 2003-04 70,000 Japanese physicians during 2003-04 flu seasonflu season

Dermatologic Dermatologic Adverse EventsAdverse Events

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

Clinical AE Preferred Term

Tamiflu(N=903)

Placebo/Not Treated(N=660)

Dermatitis atopic 0 1

Dermatitis NOS 7 11 (2%)

Dry skin 1 0

Eczema NOS 3 3

Eczema seborrheic 0 1

Erythema multiforme 1 0

Facial or periorbital edema

3 0

Localized exfoliation 1 0

Petechiae 1 0

Pruritus 1 2

Rash erythematous 0 2

Red face 0 1

Urticaria 5 2

Total Patients with Dermatologic AEs

29 (3%) 22 (3%)

Literature review of influenza-Literature review of influenza-associated dermatologic events associated dermatologic events in childrenin children Rare case reports of dermatologic Rare case reports of dermatologic

manifestations of influenza in childrenmanifestations of influenza in children Survey of respiratory viruses in Great Survey of respiratory viruses in Great

Britain (Hope-Simpson and Higgins, Britain (Hope-Simpson and Higgins, 1969) note “rash” was present in 1969) note “rash” was present in approximately 2% of influenza A and approximately 2% of influenza A and 8% of influenza B cases, not further 8% of influenza B cases, not further describeddescribed

Pediatric and infectious diseases Pediatric and infectious diseases textbooks do not describe skin textbooks do not describe skin reactions related to influenzareactions related to influenza

FDA Conclusions FDA Conclusions Regarding Adverse Event Regarding Adverse Event ReportsReports Search of the AERS database identified Search of the AERS database identified

deaths, an unusual pattern of deaths, an unusual pattern of neuropsychiatric AEs, and serious skin neuropsychiatric AEs, and serious skin reactions reported with Tamiflu use in reactions reported with Tamiflu use in childrenchildren

Re-analysis of the pediatric clinical Re-analysis of the pediatric clinical trials data failed to identify differences trials data failed to identify differences in skin and neuropsychiatric AEs in skin and neuropsychiatric AEs between children receiving Tamiflu between children receiving Tamiflu and placebo/no treatment and placebo/no treatment

FDA Conclusions FDA Conclusions Regarding Adverse Event Regarding Adverse Event ReportsReports Further investigation into possible reasons Further investigation into possible reasons

for pattern of AEs in Japanese childrenfor pattern of AEs in Japanese children– Syndrome of influenza-associated encephalitis Syndrome of influenza-associated encephalitis

and encephalopathy described in pediatric and encephalopathy described in pediatric literature prior to approval of Tamifluliterature prior to approval of Tamiflu

– Increased awareness of CNS complications in Increased awareness of CNS complications in Japan Japan

– Increased use of Tamiflu in children in JapanIncreased use of Tamiflu in children in Japan– Probable increased levels of AE reporting from Probable increased levels of AE reporting from

Japan during review periodJapan during review period

Questions?Questions?

Extra SlidesExtra Slides

Clinical AE Preferred Term

Tamiflu(N=512)

Placebo(N=517)

Anxiety 1 0

Balance impaired NOS

0 1

Confusion 0 1

Hallucinations 2 1

Headache 14 (3%) 17 (3%)

Insomnia 1 1

Migraine 0 1

Mood swings 0 1

Nightmares 1 4

Taste disturbance 0 1

Vasovagal attack 1 0

Total Patients with Neuropsych AEs

20 (4%) 26 (5%)

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

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

Clinical AE Preferred Term

Tamiflu QD(N=168)

Tamiflu BID

(N=212)

No Treatment(N=143)

Headache NOS 14 (8%) 6 (3%) 17 (12%)

Headache aggravated

1 0 0

Insomnia 1 0 0

Migraine 0 0 1

Nervous breakdown 0 1 0

Psychiatric disorder 1 0 0

Total Patients with Neuropsych AEs

17 (10%) 7 (3%) 18 (13%)