# Presentation: 524321

## 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

## Overview

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

## 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)

## US Regulatory History (with DDRE post-marketing reviews)

| 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 |
| March 22, 2004
November 18, 2005
December 19, 2005 | Pediatric Exclusivity Granted
BPCA Section 17 AE Review
Follow-up post-marketing reviews |  |
| December 21, 2005 | Prophylaxis of influenza | Pediatrics 1-12
 |
| September 2006 Review | 2005-06 Flu Season AE surveillance
 |  |

## 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.

## 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.

## Update: 

**Drug Use Data**

## Drug Use Data: Tamiflu®

- Source:   Verispan Vector One® : National, MAT 2000-2006, data extracted 08-04-2006

## Data courtesy of Hoffmann-La Roche, Inc. 

- 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

**Notes:**
Source Files: A060284-D060309 VONA 8-4-06 tamiflu age2.qry

## Safety Update: 

**Serious Skin and Hypersensitivity Reactions**

## 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

## 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****)*

## Safety Update: 

**Pediatric Death Reports**

## 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.

## 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.*

## 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.*

## 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.

- 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.

**Pediatric deaths reported with ****Tamiflu****®****: ****AERS update through 10/23/06**

## Safety Update: 

**Neuropsychiatric **
**Adverse Events**

##  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

## 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

## 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

## 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 11⁄2 - 90)
- Only 3 involved prophylactic use
- 69 M, 32 F

## 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)

## 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.

## Slide 25

## 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

## 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

## 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

## 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

## 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.

## 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.

## 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.

## 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.