Limited benefit and potential harm of oseltamivir including sudden death and death from abnormal behavior
EDITOR- In response to experts' question, Roche [1] showed very rough
data which, they claimed, supports an improvement in mortality with
oseltamivir. Although I could not have access to the datasets at
<www.eswi.org>, data they showed (32 % and 90 % risk reduction of
pneumonia and death respectively) may not be easily believed by those who
know the limited benefits shown in the randomized controlled trials
(RCTs), potentially harmful effects of the drug shown below and that flu
is a self-limiting disease for previously healthy people.
In the RCT for treatment of adult flu in Japan [2], Kaplan-Meier
curves for proportion of patients without freedom from illness of both
groups were almost completely the same in patients with H3N2 influenza A,
although oseltamivir improved the symptoms of those with H1N1 influenza A
significantly faster than placebo. In the RCT [3] in which chronic asthma
children with influenza were tested, oseltamivir did not improve symptoms
significantly (average duration of illness is rather 14.7 hours less in
placebo group than that in oseltamivir group: p value was not stated).
Oseltamivir did not significantly decrease the proportion of patients with
flu-like symptoms based on data from an RCT for prevention of flu in Japan
(proportion of patients with symptom was 21.9 % in the oseltamivir group
and 23.5 % in the placebo group), although the proportion of patients both
with symptoms and test-proven flu virus was significantly reduced in the
oseltamivir group than in the placebo group[4,5].
Additionally, I have reported three death cases closely related to
the use of oseltamivir recently at a scientific meeting in Japan [6]. One
of the leading Newspaper reported my presentation [7]. Of these only one
case (a 14-year-old male) is included in the 12 pediatric death cases all
from Japan that FDA reported in November 18 [8]. It was concluded that co-
morbidity and confounding factors in many of the cases, limited and
missing data in majority of cases makes it difficult to establish a direct
causal relationship between the use of oseltamivir and the reported deaths
[8].
However, according to my history taking that I presented in Japanese
[6], neither fever nor other drugs could be the causes of his abnormal
behavior and death of a 14-year-old boy. He was one of the two boys
reported by the newspaper [7]. Japanese MHLW (Ministry of Health, Labour,
and Welfare) reported a case of teenage girl as a warning that oseltamivir
could cause hallucination and abnormal behavior [8]. She tried to rush out
of the window as soon as her body temperature went down. Fever was not the
cause of the strange behavior in this case either. This case was not
mentioned in the reports by FDA.
I also reported a previously healthy 2-year-old boy who became breathless
suddenly during afternoon nap and had very low body temperature [6].
Another 2-year-old boy whose parents noticed his abnormal breathing and
took him to a hospital by their car, stopped breathing in the car before
he arrived at the hospital [10]. This case is not included in the 12
Japanese pediatric death cases reported by FDA [8]. These cases strongly
suggest that the infants died from respiratory suppression.
As I mentioned [11], four other sudden infant deaths during sleep
were reported [12]. In total, six infants of sudden death during sleep or
death from abnormal breath were previously healthy and did not take
antipyretics. Causality to such sudden death was considered as follows in
the memorandum of FDA-CDER [13]: "the contribution of the drug to the
death of these patients, especially with the case of sudden death and
cardio-pulmonary arrest, cannot be excluded based upon the information
available."
Previously reported cases of influenza-related encephalopathy (IRE),
especially fatal cases, were closely related to non-steroidal anti-
inflammatory drug (NSAIDs) antipyretics such as diclofenac and/or
mefenamic acid, and the incidence of the fatal cases has decreased since
warnings about NSAIDs antipyretics for flu children were issued in 2000.
Even fatal cases of classical type of IRE did not cause death so suddenly
as the six cases above. So Shiomi called his cases as a new type of IRE
[12]. The new type of IRE cases have started to be reported in the winter
season just after marketing of oseltamivir for children had begun in July
2002.
It should be stressed that the mechanism of sudden death from
respiratory suppression in human infants is confirmed by at least three
animal toxicity studies conducted by Roche [2-4]. Ten minutes to seven
hours (mainly 2 to 3 hours) after the first dose of Tamiflu, many 7-day
old rats died from respiratory suppression, exhibiting spontaneously
decreased movement, weakened respiration which subsequently became
irregular [2-4]. Considering the similarity between the signs and symptoms
in human infants and the juvenile rats, and rather low safety index; only
26 to 40 times based on the peak plasma concentration, close causal
relationship should be suspected between oseltamivir and the infant sudden
death from respiratory suppression during sleep.
Central nervous system suppressants including sedatives, hypnotics
and anesthetics may induce death from respiratory suppression at high
dose, and may induce hallucination, delirium and abnormal behavior by
disinhibition or dyscontrol of the central nervous system at a certain
dose. They are well-known adverse reactions to barbiturate and
benzodiazepins and so on.
It should be noted that FDA did not discuss the animal toxicity
studies indicating suppressive effects of oseltamivir on central nervous
system, the similarity of clinical course of human and animal, and
disinhibition or dyscontrol action of oseltamivir as a central nervous
system suppressant at all.
Number needed to Harm (NNH) of vomiting at the first day of
oseltamivir commencement in the RCT for treatment of children is 15 [3,6].
NNH of headache, nausea and vomiting in the RCT of preventative use of
oseltamivir for adults is 25, 24 and 55 respectively [4,6]. These results
and the evidence of bulged fontanel in the 5 month-old baby adminidtered
oseltamivir for flu prevention [13] indicate that unchanged oseltamivir
alone could increase intracranial pressure even in adults.
If we take into account of these well-known pharmacological actions
of central nervous system suppressants and the effect on intracranial
pressure, full spectrum of psychiatric and neurological adverse effects of
oseltamivir could be well understood.
We should not overlook these potentially harmful effects in addition
to the limited benefit of oseltamivir not only in daily practice but also
in stockpiling oseltamivir.
References
1. James R Smith and Regina Dutkowski Stockpiling oseltamivir: Roche
clarifies data for improved mortality with oseltamivir BMJ, Nov 2005; 331:
1203
5. Kashiwagi S, Kudoh S, Watanabe A, Yoshimura I. Efficacy and safety
of the selective oral neuraminidase inhibitor oseltamivir for prophylaxis
against influenza- -placebo-controlled double-blind multicenter phase III
trial. Kansenshogaku Zasshi (J Infection). 2000 Dec; 74(12): 1062-76 (in
Japanese).
6. Hama R. Discussion of the causal relationship between Oseltamivir
phosphate (Tamiflu), and sudden death and death from abnormal
behavior(presentation at a session of Japanese Society for Pediatric
Infectious Diseases in Tsu, Mie Prefecture November 12 2005) available at: http://www.npojip.org/sokuho/051112.html (in Japanese) and http://www.npojip.org/english/no59.html (in English)
7.Mainichi Daily News: Abnormal reaction to Tamiflu medicine tied to
deaths of two boys; http://mdn.mainichi-
msn.co.jp/national/news/20051112p2a00m0na030000c.html
10. Fujii F et al. A death case of influenza-related encephalopathy
without showing neurological signs and symptoms. Infection and Immunity in
childhood (2004) 16(2) : 231-232 (in Japanese)
Rapid Response:
Limited benefit and potential harm of oseltamivir including sudden death and death from abnormal behavior
EDITOR- In response to experts' question, Roche [1] showed very rough
data which, they claimed, supports an improvement in mortality with
oseltamivir. Although I could not have access to the datasets at
<www.eswi.org>, data they showed (32 % and 90 % risk reduction of
pneumonia and death respectively) may not be easily believed by those who
know the limited benefits shown in the randomized controlled trials
(RCTs), potentially harmful effects of the drug shown below and that flu
is a self-limiting disease for previously healthy people.
In the RCT for treatment of adult flu in Japan [2], Kaplan-Meier
curves for proportion of patients without freedom from illness of both
groups were almost completely the same in patients with H3N2 influenza A,
although oseltamivir improved the symptoms of those with H1N1 influenza A
significantly faster than placebo. In the RCT [3] in which chronic asthma
children with influenza were tested, oseltamivir did not improve symptoms
significantly (average duration of illness is rather 14.7 hours less in
placebo group than that in oseltamivir group: p value was not stated).
Oseltamivir did not significantly decrease the proportion of patients with
flu-like symptoms based on data from an RCT for prevention of flu in Japan
(proportion of patients with symptom was 21.9 % in the oseltamivir group
and 23.5 % in the placebo group), although the proportion of patients both
with symptoms and test-proven flu virus was significantly reduced in the
oseltamivir group than in the placebo group[4,5].
Additionally, I have reported three death cases closely related to
the use of oseltamivir recently at a scientific meeting in Japan [6]. One
of the leading Newspaper reported my presentation [7]. Of these only one
case (a 14-year-old male) is included in the 12 pediatric death cases all
from Japan that FDA reported in November 18 [8]. It was concluded that co-
morbidity and confounding factors in many of the cases, limited and
missing data in majority of cases makes it difficult to establish a direct
causal relationship between the use of oseltamivir and the reported deaths
[8].
However, according to my history taking that I presented in Japanese
[6], neither fever nor other drugs could be the causes of his abnormal
behavior and death of a 14-year-old boy. He was one of the two boys
reported by the newspaper [7]. Japanese MHLW (Ministry of Health, Labour,
and Welfare) reported a case of teenage girl as a warning that oseltamivir
could cause hallucination and abnormal behavior [8]. She tried to rush out
of the window as soon as her body temperature went down. Fever was not the
cause of the strange behavior in this case either. This case was not
mentioned in the reports by FDA.
I also reported a previously healthy 2-year-old boy who became breathless
suddenly during afternoon nap and had very low body temperature [6].
Another 2-year-old boy whose parents noticed his abnormal breathing and
took him to a hospital by their car, stopped breathing in the car before
he arrived at the hospital [10]. This case is not included in the 12
Japanese pediatric death cases reported by FDA [8]. These cases strongly
suggest that the infants died from respiratory suppression.
As I mentioned [11], four other sudden infant deaths during sleep
were reported [12]. In total, six infants of sudden death during sleep or
death from abnormal breath were previously healthy and did not take
antipyretics. Causality to such sudden death was considered as follows in
the memorandum of FDA-CDER [13]: "the contribution of the drug to the
death of these patients, especially with the case of sudden death and
cardio-pulmonary arrest, cannot be excluded based upon the information
available."
Previously reported cases of influenza-related encephalopathy (IRE),
especially fatal cases, were closely related to non-steroidal anti-
inflammatory drug (NSAIDs) antipyretics such as diclofenac and/or
mefenamic acid, and the incidence of the fatal cases has decreased since
warnings about NSAIDs antipyretics for flu children were issued in 2000.
Even fatal cases of classical type of IRE did not cause death so suddenly
as the six cases above. So Shiomi called his cases as a new type of IRE
[12]. The new type of IRE cases have started to be reported in the winter
season just after marketing of oseltamivir for children had begun in July
2002.
It should be stressed that the mechanism of sudden death from
respiratory suppression in human infants is confirmed by at least three
animal toxicity studies conducted by Roche [2-4]. Ten minutes to seven
hours (mainly 2 to 3 hours) after the first dose of Tamiflu, many 7-day
old rats died from respiratory suppression, exhibiting spontaneously
decreased movement, weakened respiration which subsequently became
irregular [2-4]. Considering the similarity between the signs and symptoms
in human infants and the juvenile rats, and rather low safety index; only
26 to 40 times based on the peak plasma concentration, close causal
relationship should be suspected between oseltamivir and the infant sudden
death from respiratory suppression during sleep.
Central nervous system suppressants including sedatives, hypnotics
and anesthetics may induce death from respiratory suppression at high
dose, and may induce hallucination, delirium and abnormal behavior by
disinhibition or dyscontrol of the central nervous system at a certain
dose. They are well-known adverse reactions to barbiturate and
benzodiazepins and so on.
It should be noted that FDA did not discuss the animal toxicity
studies indicating suppressive effects of oseltamivir on central nervous
system, the similarity of clinical course of human and animal, and
disinhibition or dyscontrol action of oseltamivir as a central nervous
system suppressant at all.
Number needed to Harm (NNH) of vomiting at the first day of
oseltamivir commencement in the RCT for treatment of children is 15 [3,6].
NNH of headache, nausea and vomiting in the RCT of preventative use of
oseltamivir for adults is 25, 24 and 55 respectively [4,6]. These results
and the evidence of bulged fontanel in the 5 month-old baby adminidtered
oseltamivir for flu prevention [13] indicate that unchanged oseltamivir
alone could increase intracranial pressure even in adults.
If we take into account of these well-known pharmacological actions
of central nervous system suppressants and the effect on intracranial
pressure, full spectrum of psychiatric and neurological adverse effects of
oseltamivir could be well understood.
We should not overlook these potentially harmful effects in addition
to the limited benefit of oseltamivir not only in daily practice but also
in stockpiling oseltamivir.
References
1. James R Smith and Regina Dutkowski Stockpiling oseltamivir: Roche
clarifies data for improved mortality with oseltamivir BMJ, Nov 2005; 331:
1203
2. New drug approval package (NAP) of oseltmivir (in Japanese);
Tamiflu capsule (2000):
http://211.132.8.246/shinyaku/g0012/07/53039900_21200AMY00238.html
3. NAP of oseltmivir (in Japanese); Tamiflu dry syrup (2002):
http://211.132.8.246/shinyaku/g0201/11/5303990_21400AMY00010.html?
4. NAP of oseltmivir (in Japanese); Tamiflu capsule for prevention
(2004) : http://211.132.8.246/shinyaku/g0407/g040703/index.html
5. Kashiwagi S, Kudoh S, Watanabe A, Yoshimura I. Efficacy and safety
of the selective oral neuraminidase inhibitor oseltamivir for prophylaxis
against influenza- -placebo-controlled double-blind multicenter phase III
trial. Kansenshogaku Zasshi (J Infection). 2000 Dec; 74(12): 1062-76 (in
Japanese).
6. Hama R. Discussion of the causal relationship between Oseltamivir
phosphate (Tamiflu), and sudden death and death from abnormal
behavior(presentation at a session of Japanese Society for Pediatric
Infectious Diseases in Tsu, Mie Prefecture November 12 2005) available at:
http://www.npojip.org/sokuho/051112.html (in Japanese) and
http://www.npojip.org/english/no59.html (in English)
7.Mainichi Daily News: Abnormal reaction to Tamiflu medicine tied to
deaths of two boys; http://mdn.mainichi-
msn.co.jp/national/news/20051112p2a00m0na030000c.html
8. Truffa MM. One Year Post-Exclusivity Adverse Event Review
forTamiflu® (oseltamivir)
http://www.fda.gov/ohrms/dockets/ac/05/slides/2005-4180s_03_truffa.ppt#17
9. Japanese FDA MHLW. Pharmaceuticals and Medical Devices Safety
Information No.202 (June 2004; in Japanese )
http://www.mhlw.go.jp/houdou/2004/06/h0624-2/index.html#gai2
10. Fujii F et al. A death case of influenza-related encephalopathy
without showing neurological signs and symptoms. Infection and Immunity in
childhood (2004) 16(2) : 231-232 (in Japanese)
11. Hama R. New type of influenza-related encephalopathy or new
adverse drug reaction? BMJ Rapid Response, 28 February 2005.
http://bmj.bmjjournals.com/cgi/eletters/328/7433/227#98374
12. Shiomi S. Clinical spectrum of influenza-related encephalopathy.
Pediatric internal medicine (in Japanese). 2003: 34(10); 1676-1681.
13. Memorandum of FDA CDER: Tamiflu AE �EReviewed.
http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-
4180b_06_01_Tamiflu%20AE_reviewed.pdf
Competing interests:
None declared
Competing interests: No competing interests