Of the three, a boy without fever died in an accident after taking one tablet of Tamiflu and showing strange behavior which well suggests causal relationship to the medicine
Flu is a kind of common cold and a self-limiting disease Warm drink/food/room and good sleep are essential for flu patients Neither Tamiflu nor anti-inflammatory antipyretics is needed with an exception of acetaminophen (paracetamol)
According to our analysis [1,2], Tamiflu shows no treatment effect against influenza in children with asthma. Although the drug significantly lowered the percentage of people who had positive test results for flu virus, it did not lower the number of people who showed flu-like symptoms [1,2]. Thus we conclude that Tamiflu does not prevent flu.
A pharmaceutical company (Roche Laboratories) issued a warning in December 2003 to health care professionals that oseltamivir should not be used in infants under one year of age [3,4]. We analyzed some papers on which this warning was based. During the analysis, we found one paper [5] that reported the sudden deaths of 6 children during sleep or afternoon nap. 4 of these six children had one dose of Tamiflu just 2 to several hours before their death.
We wrote papers warning about the possible adverse effects of Tamiflu. They were published in Kusuri-no-Check [1] and TIP (The Informed Prescriber) [2] and e-bmj [6].
After we wrote these articles, I was consulted by bereaved family members of other three children who had died after taking Tamiflu. I reported these cases [7] at a session of the Japanese Society for Pediatric Infectious Diseases in Tsu, Mie Prefecture on 12th November 2005. The many mass media reported it subsequently.
Pediatric specialists say that fever or various drugs may cause delirium and only little scientific evidence exists about causal relation between Tamiflu and the events. These comments are not correct, because there are several cases in which the patients had no fever (after temperature went down to almost normal or even lower) or took no medicine other than Tamiflu.
A 14-year boy is a typical case: his body temperature went down to 37.5 centigrade (or 99.5 F) just before taking Tamiflu. He took only Tamiflu.
Strange behaviors and sudden death during sleep are types of symptoms apparently different to each other. But these are the reactions categorized into the same pharmacological spectrum as alcohol-like agents such as hypnotics, sedatives and anesthetics.
The fatal reactions to this type of agents include respiratory suppression. This class of agents may cause disinhibition or dyscontrol reaction in some individuals at certain doses.
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:
It was revealed that most of the influenza-related encephalopathy cases were caused by the use of non-steroidal anti-inflammatory antipyretics like aspirin which was proven to be a major cause of Rey's syndrome in Western countries. Since this possible causal relation was recognized, NSAIDs antipyretics have been rarely used for children and the occurrence of fatal influenza-related encephalopathy has become rare. On the other hand, the proportion of non-fatal encephalopathy cases has increased. The causal agents of these cases include theophyllins and antihistamins that induce severe seizure with subsequent sequels, and antihistamins and carbocystein that cause hypoglycemia that leads to seizure and brain damage with sequels.
The progress of influenza-related encephalopathy (IRE) is not as rapid as reported with the recent fatal cases. It normally takes at least a half or one day for patient's condition to deteriorate even in the severest cases. But in the cases of the new type of encephalopathy, infants could stop breathing within ten minutes to one hour. This is one of the most important differences between the previous influenza-related encephalopathy and the new one.
This new type of encephalopathy was first found in the 2002/2003 winter right after the marketing of Tamiflu for children started.
Mechanism of sudden death is confirmed by at least three animal toxicity studies conducted by Roche company[8-10]. 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. In one experiment, of the 24 rats administered with 1000mg/kg of oral oseltamivir 18 died within 7 hours after the first dose of oseltamivir. Cyanosis was observed in 6 rats but no abnormality was found at autopsy. In another experiment two of the 14 rats in the 700mg/kg group and three of the 14 rats in the 1000mg/kg group died. Their body temperatures, spontaneous movement and respiration rates decreased, and the respiration became irregular in 6 among 14 of the 700mg/kg group and in 12 among 14 of the 1000mg/kg group, while none of these signs and symptoms was observed either in 14 rats in the control group or in 500 mg/kg group. In the 1000mg/kg group tremor and collapse were also observed. These signs and symptoms indicate that a major cause of the death of those animals is respiratory suppression due to central nervous system suppression which resembles the pharmacological/toxicological profile of barbiturate and/or other sedatives and sleeping pills.
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 one hour after his parents found abnormal respiration [11]. The clinical courses of the infants and the rats are very similar to each other.
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. Non-fatal dose in rats (500mg/kg) is about 125 to 167 times the recommended human dose in children (about 2-3mg/kg/day) in US, on a mg/kg base, but it is only 26 to 40 times the recommended dose in terms of peak plasma concentration based on the comparison that is preferable for comparison of this type of toxicity.
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 [12] that is a firm sign of increased pressure in brain. And a randomized controlled trial of Tamiflu for prevention of adult flu shows that the drug induces headache, nausea and vomiting in one in 25, 24 and 55 people who were treated with the drug (number needed to Harm is 25, 24 and 55 respectively). This indicates that oseltamivir increases pressure inside the brain too.
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 going down [13]. Also, the temperature of a 14-year-old boy, who jumped from 9th floor of his condominium and died, had already gone down to 37.5 degrees C (or 99.5 F) 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 F) when he was taken to a hospital.
If fever was present, fever and Tamiflu would synergistically affect individuals and may induce abnormal behaviors and hallucinations more easily. Thus fever does not deny the causality of Tamiflu.
We know several patients who had no high fever and took no drugs other than Tamiflu. This shows that these patients are not the cases of fever delirium or their symptoms were not induced by other drugs.
Central nervous suppressants such as sedatives, hypnotics, anesthetics and alcohol often induce delirium, hallucination by disinhibition or dyscontrol [14]. 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.
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 [12,15].
Most of the severe influenza-related encephalopathy cases feared by people are related to some drugs such as non-steroidal anti-inflammatory drugs, theophylin and antihistamines. Influenza is not a dangerous infection but a self-limiting disease like common cold for previously healthy people. Patients recover spontaneously and more easily without using drugs than with above mentioned drugs.
Please keep warm, take hot drinks and foods, and take good rests if you catch cold or influenza.
If you read Japanese, please refer to Kusuri-no-Check No.12 (revised) and The Informed Prescriber (February 2005), Web-Kusuri-no-Check No.49 (March 1 2005) and No.59 (November 13 2005). After the media reports of our presentation at the scientific conference, we have been consulted by many people who have experienced similar cases. Please let us know if you have experienced or know similar cases.
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