Sunday, July 26, 2009

Are you more likely to die of Tamiflu than of Swine Flu?

With the expiry dates on Tamiflu extended by the European Medicines Agency, the UK holds sufficient stocks for over 28 million UK residents to receive a course of treatment.

The government would argue that it has through the NHS a duty to prevent illness in the general population, and that dosing almost half the population with self-prescribed Tamiflu is a part of fulfilling this duty. Is it? As already discussed, the apparent mortality rate for swine flu is between 1 in 4,000 and 1 in 12,000. Using the governments own suggestion that up to 30% of the UK population might eventually be infected, that means that the odds of dying from swine flu are between 1 in 15,000 and 1 in 40,000 for each member of the UK population. To put this into perspective, you stand more chance of dying of electrocution (1 in 5,000), drowning (1 in 8,943) or even dying in a plane crash (1 in 20,000) over your lifetime than you do of dying of swine flu. It is only slightly more risky than your chances of dying of capital punishment in the US (1 in 58,618) or dying in a tornado (1 in 60,000).

Be that as it may, it still leaves us with potentially over 28 million people taking Tamiflu. The question must then be whether or not Tamiflu is worse than swine flu: are you more likely to die of the cure than you are to die of the disease?

In Japan, Tamiflu is used extensively, and estimates indicate that over 30 million Japanese citizens have received doses. It is recognised that as with any drug, there are Adverse Drug Reactions (ADRs) inherent in taking Tamiflu, the most common (occuring in over 1% of patients in clinical trials) being nausea, vomiting, abdominal pain, diarrheoa and headaches. Uncommon ADRs included cardiac arrythmia, hepatitis, skin rashes including Stevens-Johnson syndrome and allergic reactions. All of these, or at least most of them, are listed on the labelling indications accompanying doses of Tamiflu sold in the European Union, as directed by the European Medicines Agency (EMEA).

However, an increasing body of medical evidence has raised concerns about other ADRs, including severe neuropsychiatric reactions, including self-harm, hallucinations, abnormal behaviour, impaired consciousness and, in infants and babies, Sudden Infant Death Syndrome, or Cot Death as it is more commonly known.

These reactions were most prominent in young adults, adolescents and children, and in fact so seriously was it taken by the Japanese Ministry of Health, Labour and Welfare (MHLW) that in 2007 manufacturers were required to alter the packaging to reflect this increased risk and to list the potential neuropsychiatric problems. The Japanese government also issued a warning that recommended Tamiflu should not be given to those aged 10 to 19 after studies showed that between 2004 and March 2007, fifteen people aged 10 to 19 have been injured or killed by jumps or fallen from buildings after taking Tamiflu, and one 17-year-old died after he jumped in front of a truck. A renewed investigation of the Japanese data was completed in April 2007. It found that 128 patients had been reported to behave abnormally after taking Tamiflu since 2001. Forty-three of them were under 10 years old, 57 patients were aged 10 to 19, and 28 patients were aged 20 or over. Eight people, including five teens and three adults, had died from these actions.

To determine whether to lift the 2007 ban, a research team from the Japanese MHLW studied 10,000 children under the age of 18 who had been diagnosed with influenza since 2006. The study was finalised in April 2009. Taking into account all degrees of abnormal behaviour, including minor behavioural problems such as incoherent speech, the study found that children who took Tamiflu were 54 per cent more likely to exhibit abnormal behaviour than those who did not take the drug. When the team limited its analysis to children who had displayed serious abnormal behaviour that led to injury or death, it found those who had taken Tamiflu were 25 per cent more likely to behave unusually.

So seriously were these findings taken that in November 2006, the US Food & Drug Administration (FDA) amended the warning label to include the possible side effects of delirium, hallucinations, or other related behavior. This went further than the FDA's previous pronouncement, from a year before, that there was insufficient evidence to claim a causal link between Tamiflu use and the deaths of 12 Japanese children (only two were from neurological problems, although more have died since then). The change to a more cautionary stance was attributed to 103 new reports that the FDA received of delirium, hallucinations and other unusual psychiatric behavior, mostly involving Japanese patients, received between August 29, 2005 and July 6, 2006. This was an increase from the 126 similar cases logged between the drug's approval in 1999 and August 2005. It should be noted that the increase of 103 fresh reports was likely to be because of greater understanding of potential neuropsychiatric ADRs, and could raise considerably the incidence of reported ADRs of this type, particularly since the 2007 studies conducted by the Japanese MHLW.

The US FDA report largely concurred with the findings of the Japanese MHLW, noting that from the date of marketing authorisation of tamiflu until 31st May 2007, it had recorded 2004 serious (ie life threatening or otherwise medically significant) ADRs out of a total of 2064 ADR reports, including 157 deaths, 43 in the US alone. More significantly, in the period 23rd April 2005 to 31st May 2007, it had recorded 939 serious ADRs worldwide, of which over 43% were in paediatric cases involving patients under 16, leading to 15 deaths out of a total of 82 recorded for all ages. Statistical analysis showed the average age of those paediatric cases as a whole was just under 9 years, while if neuropsychiatric ADRs were excluded, the average age fell to 5 years although the death rate was much higher: out of 112 cases, there were 12 deaths reported - all described as sudden death - an almost 11% mortality rate for those infants who suffered severe non-neuropsychiatric ADRs.

So what was the EU's EMEA doing during all this? In February 2007, it warned that patients receiving Tamiflu should be 'closely observed' and did move to include warnings on documentation accompanying the drug that neuropsychiatric problems could occur. However, it stopped short of restricting the prescribing of Tamiflu to young people, deciding instead that 'the benefits outweigh the risks' and that it would 'monitor closely' continued research into reports of abnormal behaviour.

With the inception of the governments self-prescription service via a telephone hotline, fresh questions have arisen. I phoned the helpline myself and was prescribed Tamiflu for myself and my children, and despite asking specifically about any dangers was re-assured that Tamiflu was 'perfectly safe', an assertion which flies in the face of studies and medical evidence. Dr Stephen Maxwell, a senior lecturer at the Clinical Pharmacology Unit of the University of Edinburgh, in an editorial in the British Medical Journal in 2007, noted that since the impact of the common flu is usually so modest in otherwise healthy people, patients should be encouraged to use instead "conservative strategies such as resting, increasing fluid intake, and taking simple analgesics and over the counter symptomatic remedies", and warned that serious side effects of a drug sometimes only come to light after the drug is launched.

"Although common adverse effects of a drug may emerge in prelicensing studies, the detection of rarer and potentially more serious events has to await exposure of large numbers of patients."

In response to Dr Maxwells editorial, Rokuro Hama, the Chairman of the Japan Insitute of Pharmacovigilance, wrote to the BMJ citing in some detail the Japanese findings. Researchers there had discovered 1,377 cases of ADRs by May 31st 2007, of which 567 were serious neuropsychiatric cases, 211 of which involved abnormal behaviour. There were also 80 reported deaths, of which 18 were sudden deaths in those aged under 10: some of these had apparently yet to reach the FDA when it conducted its paediatric review into Tamiflu ADRs, hence the slight discrepency in numbers. Most of these deaths were in infants and resembled Sudden Infant Death Syndrome, and research on young rats suggested that it was caused by a build up of Tamiflu in the brain because the Brain Blood Barrier (BBB) is not sufficiently developed in babies and young infants. From research findings already published at the time of writing, he suggested that the spectrum of action and toxicity of oseltamivir is very similar to that of central nervous system suppressants such as benzodiazepines, barbiturates and general anesthetics.

The government is faced with a considerable problem politically - it is stuck with millions of doses of date expired Tamiflu. The current hysteria surrounding swine flu provides an excellent opportunity to rid itself of these stocks, worth almost a quarter of a billion pounds, without having to admit it is throwing them away. However, by using Tamiflu against a relatively innocuous virus in the form of swine flu without fully considering the potential outcomes in terms of deaths caused by ADRs, is it putting the population at a greater risk than the miniscule risk of dying of swine flu? It is not possible to quote the odds of dying of Tamiflu, because (a) no-one knows how many people have taken it in total and (b) as knowledge of the potential ADRs becomes more widely known, more cases of ADRs are reported: the US FDA reports show graphically the exponential increase in reported ADRs over time.

It is possible to draw several conclusions. The first relates to the monitoring of patients, particulary adolescents and young adults, for neuropsychiatric effects. If my personal experience of the Swine Flu hotline is replicated elsewhere, then the government is allowing the prescribing of Tamiflu without making patients aware of the possible side effects or the need to monitor behavioural patterns for abnormalities. Without adequate medical supervision, this is clearly absurd, and could statistically place the most at risk groups at a higher risk of death or serious illness from Tamiflu than they face, statistically, from swine flu.

Secondly, the authorisation for Tamiflu to be used in 'pandemic' circumstances, issued by the World Health Organisation in June, allowed the EMEA to remove restrictions on the prescribing of Tamiflu to babies under 1 year of age. There exists a body of evidence to suggest that because of insufficient maturity of the BBB in the very young, those babies dosed with Tamiflu run a significantly higher risk of dying of Sudden Infant Death Syndrome or suffering respiratory distress than they do of dying of swine flu.

Thirdly, the suggestion that Tamiflu acts upon the brain in the same fashion as benzodiazepans, barbituates and general anaesthetics must surely give cause for concern to parents: would you really countenance giving your baby Diazepan because he or she had flu?

My own opinion, for what it's worth, is this. The government is saving itself a political problem regarding the wasted £250m it has so far spent on Tamiflu, but is probably risking the lives of more UK residents through ADRs than are at risk of death from Swine Flu. We must all make such decisions for ourselves, but neither I nor my children will be taking Tamiflu any time soon. Of course, to a certain extent, what the British government thinks is immaterial: even if it was minded to, it could not suspend or withdraw Tamiflu, nor withdraw its market authorisation in the UK, as such power resides at a European level, and only the European Commission, on the recommendation of the European Medicines Agency, could authorise such an action. Indeed, were the British government to act to protect its citizens, it could face action for disrupting the 'free market' in pharmaceutical products. Can we expect to see the Commission take action? Hardly. Governments across the EU are in the same position as the UK, sitting on huge stockpiles of date expiring antiviral drugs purchased at the behest of the European Commission in the first place. Which will volunteer to be the first to tell its citizens that it is throwing away £200m + because they are useless and potentially dangerous? Exactly.

Reference Information

US FDA Briefing Document on Paediatric ADRs to Tamiflu:

EMEA Tamiflu Warning:

Dr Simon Maxwell, Tamiflu and neuropsychiatric problems in adolescents, British Medical Journal:

Rokuro Hama, response to editorial above:

CTV Canada, repeating Dr Maxwells' comments for those without BMJ subscription:

International Journal of Risk & Safety in Medicine - Fatal neuropsychiatric reactions to oseltamivir: Case series and overview of causal relationships, Rokuro Hama:

The Odds of Dying:

Does the use of Tamiflu decrease the chance of sucessfully using it during a future epidemic of something that is actually dangerous? This and other questions answered later today or tomorrow, depending on time! Please subscribe to this blog for automatic updates!


  1. Dear Mark,

    Here in Brazil it is impossible to buy Tamiflu due to government control. The government is desperate to DO NOT give Tamiflu because the stocks are at a very low level. So, are our government much more scientific and efficient than the British one?

  2. Yes, Osame, I think they probably are. There is a real problem with excessive prescribing of oseltamivir (Tamiflu) for what are really minor virii such as the current Swine Flu strain of H1N1 which is related to viral resistance to drugs. I've got more on this to say later on, so I'll keep you in suspense until then! As to tamiflu stocks in Brazil, there has been a major problem (as there is with the vaccine currently in development) of the richest countries buying all the available stocks, while the rest of the world is left to manage the best it can. If you look at the two issues combined, I'd have said that the Brazilian governments response is not just more scientific and more efficient that the British, but also eminently more sensible!

    Best regards,


  3. thankyou mark for out lining the risks of taking this drug i my self phoned the advise line as was feeling like crap i had all the symptoms of flu a few days ago and after reading this i am glad that the person on the other end of the phone who i assume had no medical experience told me i was not at risk as i dd not have the flu how she could tell without even seeing me is beyond me but it left me thinking about how many people are miss diagnosed by the use of this hotline thanks again for a job well done. jeff and family

  4. Excellent article. Have you started to investigate the swine flu vaccine that, according to reports, is due to have only 5 days clinical trials before it is used on the public?

    Regards Paul