Fifty sudden deaths may be related to central suppression

In his editorial on the association between oseltamivir phosphate (Tamiflu or oseltamivir-P) and neuropsychiatric disturbance in adolescents Maxwell says that the case is not proved but caution is advisable.1 On 16 June 2007 the Japanese Ministry of Health Labour and Welfare announced that by 31 May 2007 it had received 1377 reports of adverse reactions since 2001, when marketing of oseltamivir started in Japan.2

Of these, 567 were serious neuropsychiatric cases, 211 showing abnormal behaviour. The number of deaths reported was 71. These are not only “adverse events” but also “adverse reactions” to oseltamivir because many doctors classed and reported them as probably related or that causality could not be ruled out. However, the ministry classed all but four as “rather negative,” believing that the four were allergic in origin.

In addition to these 71 deaths, there were nine sudden deaths which the ministry did not recognise as adverse reactions.

Of the total 80 deaths, 50 were sudden deaths or deaths from sudden cardiopulmonary arrest (18 in those <10 years old, 32 in those aged 20 or over), while eight were accidental deaths from abnormal behaviour (five in teenagers, three in those aged 20 or over). All 58 deaths were classed as “rather negative” by the ministry—totally different from many doctors' classifications. Four deaths were from sepsis following pneumonia after possible respiratory suppression, 10 were possibly related to exacerbation of mainly pneumonia, and eight were from hepatic failure, pancytopenia, gastrointestinal bleeding, etc.

Thus adverse reactions to oseltamivir may be roughly classified into three groups: (a) sudden onset reactions related to central suppressive action of oseltamivir-P during cytokine storm, including sudden death, abnormal behaviours, and other sudden neuropsychiatric disorders3 4; (b) late onset reactions such as pneumonia, sepsis, hyperglycaemia, and late onset neuropsychiatric disorders possibly related to inhibition of human cytosolic neuraminidase (sialidase) activity by oseltamivir carboxylate5; and (c) allergic reactions and others.