Intended for healthcare professionals

Rapid response to:


Guidelines on neuraminidase inhibitors in children are not supported by evidence

BMJ 2004; 328 doi: (Published 22 January 2004) Cite this as: BMJ 2004;328:227

Rapid Response:

New type of influenza-related encephalopathy or new adverse drug reaction?

EDITOR- In addition to the efficacy issue of neuramidase inhibitors
that Symmonds pointed out, I would like to mention a new possibility of
adverse reaction to the drug.

In Japan, influenza-associated acute encephalopathy among children is
a substantial public health problem; in the winter of 1998-99, for
example, a total of 148 cases of encephalitis/encephalopathy associated
with influenza were reported [1]. But after warnings and restriction of
non-steroidal anti-inflammatory drugs (NSAIDs) not to use as antipyretics
in influenza infection for children, reports of influenza related
encephalopathy apparently decreased. Few such cases had been reported in
the United States [2] after restriction of salicylates not to use as
antipyretics for children.

However, cases of sudden death associated influenza in previously
healthy children were reported in the United States during 2002-03 seasons
[2]. Center of Disease Control (CDC) began to investigate severe morbidity
and mortality associated with influenza in children and young adults. 93
cases were reported since October 2003 to January 2004 [3]. The median age
of the 93 children was 4 years (range: 4 weeks-17 years), with 55 (59%)
children aged <_5 years="years" and="and" _24="_24" _26="_26" aged="aged" _6-23="_6-23" months.="months." _41="_41" _54="_54" of="of" the="the" _76="_76" children="children" whose="whose" medical="medical" history="history" was="was" known="known" were="were" reported="reported" to="to" have="have" had="had" no="no" underlying="underlying" conditions.="conditions." _55="_55" for="for" whom="whom" location="location" death="death" _15="_15" _27="_27" died="died" at="at" home="home" _3.="_3." p="p"/> On the other hand Shiomi [4] reported Japansese six cases of sudden
death during the 2002-03 seasons. All of these cases found dead during
sleep; three were during nap and three were at night. Four of 6 cases were
autopsied and found that all of their brains were swollen. Taking account
of these findings Shiomi proposed a new type of influenza-associated
encephalopathy: acute brain swelling type (ABS type) [4]. Among six cases
five aged 3 years or less. Of the five infants four suddenly died during
sleep after taking the first single dose of oseltamivir, while one took
amantadine (8 year old child) and one infant took none of drug[4]. One of
them, for example, was found dead during two hours nap after the first
dose of oseltamivir [4]. Oseltamivir for pediatric use was first marketed
in July 2002. Japanese market share of oseltamivir is outstandingly the
largest in the world. Shiomi reffered that several similar sudden death
cases during sleep (not known whether oseltamivir were taken) were
reported in US [4].

According to the BPCA Executive Summary of oseltamivir in US [5], the
data that were submitted on June 15, 2000 for new drug application shows
Cmax and AUC of oseltamivir in brain tissue were 1500 or more (3000 for
Cmax) fold higher in 7-day old pups compared to the 42-day old (adult)
rats. I wonder these experiments might be the same as the new experiments
on which Roche Laboratories cited when they cautioned health care
professionals about using oseltamivir in infants under one year of age in
December 2003 [6].

Roche Laboratories say it is likely that these high exposures are
related to an immature blood-brain barrier (BBB) and that these data do
not affect the use of oseltamivir in children of one year or older and in
adults [6]. But I am very much afraid that even the well developed BBB of
previously healthy children might be affected and disordered by cytokines
during influenza.

According to the Japanese NAP of oseltmivir [7,8], more precise data
are available: in an experiment, 18 (8 males and 10 females) among 24 rats
administered with 1000mg/kg of oral oseltamivir died within 7 hours after
the first dose of oseltamivir except two male rats. Cyanosis was observed
in 6 rats but no abnormality was observed at autopsy [7]. In the other
experiment [8] two of 14 rats in 700mg/kg group and three of 14 rats in
1000mg/kg group died. The body temperature decreased, spontaneous movement
decreased and respiration rate decreased and get irregular in 6 among 14
of 700mg/kg group and in 12 among 14 of 1000mg/kg group, while none of
these signs and symptoms was observed either in 14 rats in control group
or in 500 mg/kg of oseltamivir group. In the 1000mg/kg group tremor and
collapse were also observed. These signs and symptoms indicate that major
cause of those animals may be respiratory suppression due to general
central nervous system suppression which resembles the toxicity profile of
barbiturate and/or other sedatives. 500mg/kg is about 125 times the
recommended dose in children (about 4mg/kg/day) in US and in Japan too, by
mg/kg base, but it is only 20 times the recommended dose by peak plasma
concentration base that is preferable for this type of toxicity.

Considering the similarity between the signs and symptoms of the four
sudden death children during sleep reported by Shiomi [4] and the juvenile
animals reported by Roche laboratories [7,8], isn't it rational to doubt
about the possibilities of causal relation to oseltamivir administered.

At least we have to bear in mind that sudden death during sleep after
taking oseltamivir (especially after the first dose) for the treatment of
influenza might be related to the drug. Such cases should be reported as
adverse reactions (adverse events of which relationship cannot be ruled
out) and should not be excluded as non-drug-related adverse events.

HAMA, Rokuro MD


1. Morishima T, Togashi T, Yokota S, et al. Encephalitis and
encephalopathy associated with an influenza epidemic in Japan. Clin Infect
Dis 2002;35:512-7.

2. CDC. Severe Morbidity and Mortality Associated with Influenza in
Children and Young Adults--Michigan, 2003 MMWR 2003; 52(35); 837-840

3. CDC. Update: Influenza-Associated Deaths Reported Among Children
Aged <_18 xmlns:http="urn:x-prefix:http" years--united="years--united" states="states" _2003-04="_2003-04" influenza="influenza" season.="season." mmwr="mmwr" _2004="_2004" _5253="_5253" _1286-1288="_1286-1288" http:_="http:_""" preview="preview" mmwrhtml="mmwrhtml" mm5253a4.htm="mm5253a4.htm" p="p"/> 4. Shiomi S. Clinical spectrum of influenza-related encephalopathy.
Pediatric internal medicine (in Japanese). 2003: 34(10) ; 1676-1681.

5. BPCA Executive Summary NDA 21-087/NDA 21-246 �gTamiflu capsules
and for oral suspension�h submitted June 15, 2000, review completed
December 14, 2000,21246_Tamiflu_clinical_BPCA.pdf

6. Roche Pharmaceuticals. Dear Health Care Professional (December
2003) �@

7.New drug approval package (NAP) of oseltmivir (in Japanese);
Tamiflu dry syrup (2002):

8.New drug approval package (NAP) of oseltmivir (in Japanese);
Oseltamivir capsule for prevention (2004)

Competing interests:
None declared

Competing interests: No competing interests

28 February 2005
Rokuro Hama
Chairman of
Room 502 Osaka 2-3-1, Tennoji-ku Osaka, Japan 543-0062@