2005.11. 25

Web-Kusuri-no-Check : English version of No59

3 boys died from adverse reactions probably related to Tamiflu:
Presentation at a scientific meeting

I presented two cases of teenagers who died from abnormal behavior and one case of infant sudden death during afternoon nap at a session of Japanese Society for Pediatric Infectious Diseases in Tsu, Mie Prefecture November 12 2005. This is the English version of No 59 (Nov 13, 2005) [1] of "Web-Kusuri-no-Check". As Mainichi Daily News [2] reported in the morning, many mass media came to the venue to report our presentation.

Poster Presentation

Discussion of the causal relationship between oseltamivir phosphate (Tamiflu), and sudden death and death from abnormal behavior

Kusuri-no-Check (NPOJIP) Rokuro Hama MD

(revised after the presentation at a session of Japanese Society for Pediatric Infectious Diseases in Tsu, Mie Prefecture November 12 2005). [3]


Discussion of the causal relationship between oseltamivir phosphate(Tamiflu), and sudden death and death from abnormal behavior


I analyzed three death cases for which I made expert opinions, reviewing similar cases with neurological and psychiatry reactions including four infant sudden death cases in a paper written by Shiomi [4] which a pediatrician introduced to me. I have searched Japan Medical Abstracts and PubMed to find literatures and the web of PMDA (Pharmaceuticals and Medical Devices Agency) [5] from 2000 to May 31 2005 to find adverse drug reaction cases gathered and listed in the national adverse drug reaction monitoring system.

For the further discussion of causal relationship between Tamiflu and death, NAP (New Drug Approval Package) [6-8] and standard textbook of pharmacology such as "Goodman & Gilman's The Pharmacological Basis of Therapeutics" [9] were used.

Case reports

A sudden death during nap

Case 1:A 2-year and 9-month-old boy who was usually healthy. He had 38.3 degrees centigrade (100.8 F) of body temperature and consulted his family doctor on February 5 this year. He was influenza A positive by rapid testing.

He was alert and not so ill in the morning. He took one dose of Tamiflu dry syrup with one dose each of other drugs including antihistamines, mucolytics and antitussives when his temperature was 39.2 degrees centigrade (102.6 F). He did not complain of vomiting and headache when he fell asleep ten minutes after taking medicines. One and half hours after taking the medicines, he woke up crying and complained of headache. He did not stop crying even when his mother took him in her arms fondling. It took forty to fifty minutes for him to stop crying and to fall asleep again. That was two hours and 20 minutes after taking medicines. His mother noticed that he turned over in his sleep two hours and 45 minutes after taking the medicines. Just ten minutes after the turn over, she touched him and found him flaccid and breathless. She called an ambulance and about thirty minutes after she noticed him breathless, he was taken to a hospital. His body temperature was 34 degrees centigrade (93.2 F)then. He was resuscitated and only his heartbeat came back, but he died next day (28 hours after admission to the hospital). His AST/ALT/LDH/CK were slightly elevated at admission and extremely increased just before death which was the result of hypoxic organ failure due to cardiopulmonary arrest.

Two boys with strange behavior and death in accidents:

Death in an accident from abnormal behavior after taking only Tamiflu without fever suggests causal relationship to neither fever-delirium nor other medicines.

Case 2:A 14-year-old boy with a body temperature 39.4 degrees centigrade (102.9 F) and other flu symptoms was diagnosed as influenza A by rapid testing. After he came back home and slept for about 3.5 hours, his body temperature went down to 37.5 degrees centigrade. After he took the first dose of Tamiflu only, he watched a video on TV for about 1.5 hours with his elder sister. About 30 minutes after he went to bed in his room, her mother could not find him there. She noticed that the entrance door was opened. She looked outside of the door and heard a shout "a boy has fallen". His house is on the ninth floor of a condominium. She came down to the ground and found that the boy was her son.

His fingerprints were found on the guardrail of steps outside of the condominium. It showed that he grasped the guardrail from outside of the steps. So it was thought that he once grasped and hung down from the guardrail and then fell to the ground. His body was severely damaged except his head and died from massive bleeding.

Case 3: A 17-year-old high school boy with high fever (39 degrees C or 102.2 F) in February 2004 consulted his home doctor. He was initially treated with amantadine, though rapid flu testing was negative. In the next morning he had 39.7 degrees C (103.5 F) and again consulted the doctor and was tested positive to influenza A. He took a Tamiflu capsule at home around noon. And one and half hours later, he complained of nausea. His body temperature was 39.2 degrees C (102.6 F) before his father left home. This was about two hours after the boy took Tamiflu. While all his family members were away from home, he suddenly jumped over the fence around his house. He ran on the snow, then jumped over a concrete fence, crossed a railway and jumped over a guardrail of a high way with smile on his face. Then he dived into an oncoming truck and died about 3 and a half hours after taking Tamiflu.

Summary of Sudden death cases and deaths from abnormal behavior:

Sudden death during sleep 5

Sudden death from respiratory suppression 1[ref 10]

Death in accidents after abnormal behavior 2

In all but one (of death case in accidents after abnormal behavior), causal relationship was denied by doctors[5].

Besides above cases two sudden death cases from unknown cause were registered in PMDA [5] as adverse reaction to Tamiflu. Eight non-fatal abnormal behavior cases were also registered in PMDA[*a].

[*a: Three cases I reported are not included in the 12 pediatric death cases all from Japan that FDA reported in November 18 [11]].

Definition of Adverse reaction:

If causal relation is not denied the adverse event should be called adverse reaction.

It is very recent that Tamiflu was first marketed in Japan. Sudden death and death from abnormal behavior were previously unknown adverse events. Nobody can deny the causal relationship. So it should be diagnosed as adverse reaction according to the definition.

Discussion of causal relationship:

There have been discussions over the possible causal relationship between Tamiflu and sudden deaths during sleep or due to abnormal respiration. The following ten reasons are the main points of the arguments:

  1. Severe and fatal influenza-related encephalopathy has become rare after NSAIDs antipyretics became to be rarely used for children.

  2. The progress of influenza-related encephalopathy normally takes at least a half or one day even in the severest cases. But in the cases of the new type of encephalopathy, infants may stop breathing within ten minutes to an hour. This is one of the most important differences between the previous influenza-related encephalopathy and the new one.

  3. This new type of encephalopathy was first found in the 2002/2003 winter right after the marketing of Tamiflu for children started.

  4. Mechanism of sudden death is confirmed by at least three animal toxicity studies conducted by Roche[6-8]. 10 minutes to seven hours (mainly 2 to 4 hours) after the first dose of Tamiflu, 7-day old rats spontaneously decreased movement, had weakened respiration which subsequently became irregular, and died probably from respiratory suppression. All of the six human infants died within two to several hours after taking their first dose of Tamiflu during sleep at night or afternoon nap. One infant died within an hour after his parents found abnormal respiration [10]. The clinical courses of the infants and the rats are very similar to each other.

  5. The major cause of death of these rats is probably respiratory suppression due to a very high concentration (about 3000 times higher peak concentration than that of mature rats) of Tamiflu in the brain tissue [8]. Non-fatal dose in rats (500mg/kg) is about 125-167 times the recommended human dose in children (about 2-3 mg/kg/day) in US, on mg/kg base, but it is only 26-40 times the recommended dose in terms of peak plasma concentration based on the comparison that is preferable for this type of toxicity.

  6. Even in mature individuals the function of blood-brain barrier may deteriorate if one has influenza, and there are several data that show Tamiflu causes increased pressure inside the brain (intra-cranial pressure): a 5-month-old baby who was treated with Tamiflu for prevention of flu, showed fontanel bulging that is a firm sign of increased pressure in brain [11].

  7. It is clearly suggested that these abnormal behaviors are different from the fever delirium. For instance, in the case reported to the MHLW (Ministry of Health, Labor and Welfare) a girl suddenly rushed and tried to jump out of the window just as her body temperature was coming down [12]. Also, the temperature of the 14-year-old boy (the case 2) had already gone down to 37.5 C(or 99.5F) before taking Tamiflu. And in another case of the sudden death the temperature of a 2-year-old infant was 34 degrees C ( 93.2 degrees F) when he was taken to a hospital.

  8. If fever was present, it and Tamiflu would synergistically affect individuals and may induce abnormal behaviors and hallucinations more easily. Thus fever does not deny the contribution of Tamiflu.

  9. We know several patients who took no drugs other than Tamiflu and had no high fever. This shows that their symptoms were not induced by other drugs or these patients are not the cases of fever delirium.

  10. Central nervous suppressants such as sedatives, hypnotics, anesthetics and alcohol often induce delirium, hallucination by disinhibition or dyscontrol [9]. High doses of this class of agents suppress respiratory center in the brain and may induce respiratory arrest and death. Thus, a wide range of various reactions (sudden death, abnormal behavior or hallucination) caused by these agents are the different aspect of the actions normally known with this class of agents. Therefore, suggesting fever and/or other drugs as a possible reason to deny the causal relationship between Tamiflu and sudden death and abnormal behaviors, has no rational ground.


  1. Oseltamivir (Tamiflu) itself has central nervous system suppressive action that resembles hypnotics, sedatives and anesthetics.

  2. It induces the following serious adverse reactions very early especially after the first dose;

  3. Sudden death during sleep from respiratory suppression especially in infants and

  4. Death in accidents after abnormal behavior in older children and adolescents.

  5. The extent may be substantial because observing 5 cases in Osaka in one season means that about 50 to 60 death cases per year might occur in Japan.

  6. These are the important and serious adverse reactions that should be investigated epidemiologically.

  7. In addition to the sudden or accidental death from respiratory suppression and abnormal behavior, serious skin reaction such as SJS/TEN (26cases) and anaphylaxis (33 cases) should be taken into account for the harm/benefit balance of Tamiflu.

  8. Japanese way of medical care for influenza by which almost 80 percent of world Tamiflu has been consumed in Japan should be reconsidered.


  1. http://www.npojip.org/sokuho/051112.html
  2. http://mdn.mainichi-msn.co.jp/national/news/20051112p2a00m0na030000c.html
  3. http://www.npojip.org/sokuho/no59-1.html
  4. Shiomi S. Clinical spectrum of influenza-related encephalopathy. Pediatric internal medicine (in Japanese). 2003: 34(10) ; 1676-1681.
  5. http://www.info.pmda.go.jp/fsearch/jsp/menu_fukusayou_base.jsp
  6. Tamiflu capsule:
  7. Tamiflu dry syrup:
  8. Tamiflu capsule for prevention:
  9. Hardman JG and Limbird LE. "Goodman & Gilman's The Pharmacological Basis of Therapeutics" 10th ed, McGraw-Hill 2001.
  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. Memorandum of FDA CDER: Tamiflu AE - Reviewed
  12. Japanese FDA MHLW. Pharmaceuticals and Medical Devices Safety Information No.202 (June 2004; in Japanese )