One Year Post-Exclusivity Adverse Event Review for Tamiflu

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
Approval Date Indication Population
Oct. 27, 1999 Tamiflu capsules Treatment of influenza Adults
Nov. 17, 2000 Prophylaxis of influenza Adults and Pediatrics 13
Dec. 14, 2000 Tamiflu Suspension Treatment of influenza Adults and Pediatrics 1
Pending Prophylaxis of influenza Pediatrics 1-12
Pediatric Exclusivity granted March 22, 2004 Pediatric Exclusivity granted March 22, 2004 Pediatric Exclusivity granted March 22, 2004
5
Drug Use Data Outpatient Prescription Data
Verispan, LLC

• Verispans 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

Age All reports (U.S.) Serious (U.S.) Death (U.S.)
All Ages (includes age not specified) 1184 (514) 1149 (480) 71 (25)
Adults ( 17 years) 778 (291) 764 (278) 58 (23)
Pediatrics (0-16) 190 (28) 190 (28) 12 (0)
Includes duplicate reports
9
Raw Count of Adverse Event Reports for Tamiflu
from March 22, 2004 April 22, 2005

Age All reports (U.S.) Serious (U.S.) Death (U.S.)
All Ages (includes age not specified) 349 (37) 342 (30) 23 (3)
Adults ( 17 years) 248 (14) 248 (14) 15 (2)
Pediatrics (0-16) 76 (6) 76 (6) 8 (0)
includes duplicate reports
10
Pediatric AE Reports for TamifluMarch 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 (n12)

• 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
Pediatric Serious Skin and Hypersensitivity
Reactions (n12) 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/anaphyla
  ctoid-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/Hypersensitivi
ty 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

Age Serious Skin Anaphylaxis Death
All Ages (includes age not specified) 43 (7 US) 111 (36 US) 11
Adults ( 17 years) 24 86 11
Pediatrics (0-16) 16 18 0
Includes duplicate reports
23
Pediatric CNS Events (n32) 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 (n32)

• 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 Japans 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 (lt 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.