Abstract
Background: Infection-associated encephalopathies such as Reye's syndrome have been one of the major public health problems in many countries. The not dissimilar neuropsychiatric adverse reactions, including deaths, observed with Tamiflu (oseltamivir phosphate: OP) have been another current problem especially in Japan.
Methods: Among the cases with neuropsychiatric adverse reactions to Tamiflu on which I was consulted, those cases in which medical charts, autopsy records and/or prescription certificates were available were analyzed and described. In order to obtain a complete view of the spectrum of neuropsychiatric adverse reactions attributed to Tamiflu and of existing knowledge of the causal relationship, adverse reaction case reports and accounts of personal experiences were collected using PubMed, Japonica Centra Revuo Medicina, the websites of MHLW, PMDA and FDA and other Internet sources. Information on animal toxicity and clinical trial findings was derived from the texts of the officially approved data sheet for Tamiflu.
Results and discussion: This paper reports eight cases in total: five of these died and three survived. Two died as a result of accidents resulting from abnormal behaviour. Three others died suddenly during sleep (two infants and one adult). One of the infants and the adult were found at autopsy to have severe lung oedema. A 14-year-old boy experienced agitation, cyanosis, loss of consciousness and seizures but recovered completely, while a 10-month-old girl showed retarded development and mental retardation after initially appearing to recover from the acute event involving loss of consciousness and seizure. A 15-year-old boy had a delayed onset of complications but developed prolonged neuropsychiatric adverse reactions after taking an almost complete course of Tamiflu; in this case the symptoms lasted for two weeks.
Following our review of known clinical cases of this type, which included 80 fatalities (among them 50 instances of sudden death and 8 cases of accidental death consequential upon abnormal behaviour, and in the light of our study of animal experiments and the latest laboratory findings, we propose to classify adverse reactions to Tamiflu as follows:
(1) Sudden onset adverse reactions typically occurring after taking one or two doses of Tamiflu; these result from the central nervous system suppressant action of oseltamivir, a pro-drug of oseltamivir carboxylate (OCB: an active metabolite). The group includes cases of sudden death during sleep or associated with respiratory suppression, sudden onset of abnormal behaviour and occurrence of other neuropsychiatric disorders having an acute onset but a short duration.
(2) Delayed onset adverse reactions occurring after taking several doses or a full course of Tamiflu, probably caused by OCB. Examples include delayed onset neuropsychiatric reactions with prolonged duration, pneumonia, sepsis, bleeding and hyperglycemia.
(3) Allergic and miscellaneous reactions involving various organs.
The mechanisms underlying the adverse reactions to oseltamivir and the causal relationships may be summarized as follows:
(1) Oseltamivir has a depressant effect on the central nervous system (CNS); the signs, symptoms and pathological findings are similar to those induced by hypnotics and sedatives (decreased body temperature, decreased spontaneous movements, slow/irregular breathing, cyanosis and pulmonary oedema). Severe sequels may reflect delayed neuronal damage resulting from temporary cardiopulmonary arrest.
(2) Abnormal behaviour, delirium, hallucinations and even suicide could be the consequences of disinhibition or loss of control induced by the CNS depressant effect.
(3) Delayed onset reactions to Tamiflu may be related to its inhibitory action on sialidase (neuraminidase), a key enzyme for antiviral activity and involved in a wide variety of mammalian physiological processes including immune functions, cell apoptosis and glucose metabolism reflecting its ability to influence the conformation of glycoproteins and gangliosides that are important components of cell structure and function.
Conclusion: Three sudden deaths during sleep and two near deaths with or without sequels, as well as two deaths from accidents resulting from abnormal behaviour in older children and adolescents shortly after taking Tamiflu are probably related to the central depressant action of oseltamivir. Late onset neuropsychiatric symptoms after taking a full dose of Tamiflu, which we observed in one case, may be related to the inhibition of human neuraminidase by OCB, an active metabolite of Tamiflu.