Fatal neuropsychiatric adverse reactions to oseltamivir: Case series and overview of causal relationships

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 ...

Neuraminidase inhibitors for preventing and treating influenza in adults and children

“…Adamantanes are well known centrally active agents and may be more harmful than oseltamivir and zanamivir. Anti-inflammatory antipyretics (except paracetamol) may be more toxic than NIs (Hama 2008). Hence, the other NIs, adamantanes and anti-inflammatory antipyretics may not be alternatives to oseltamivir and zanamivir.…”

“…Antibody suppression seems stronger for oseltamivir than zanamivir, probably due to the difference in bioavailability. It may be that evidence of other effects, such as hyperglycaemia and renal impairment (though significance was marginal) in the prophylaxis trials may be due to inhibition of the host's endogenous neuraminidase, which impairs the cell function of various organs (Hama 2008). Overall, the significance of oseltamivir for nasal shedding is unclear but problems with sampling and culture undermine any claims as to its secondary prophylactic properties, as the FDA made clear in its response (FDA 1999c).…”

“…Overall, the significance of oseltamivir for nasal shedding is unclear but problems with sampling and culture undermine any claims as to its secondary prophylactic properties, as the FDA made clear in its response (FDA 1999c). The dose-response increase in psychiatric events in the "pivotal" oseltamivir treatment trials and the increase in vomiting only on day one in treatment trials in children may be due to the sudden onset of the central action of unchanged oseltamivir (Hama 2008). Brain concentration of unchanged oseltamivir increases during the early phase of influenza in juvenile animals (Freichel 2009), due to a reduced or low function of p-glycoprotein, a major transporter of oseltamivir at the blood-brain barrier (Hama 2008; Kimura 2012).…”

“…Influenza is mostly a mild, self limiting infection of the upper airways with local symptoms, including sniffles, nasal discharge, dry cough and sore throat, and systemic symptoms such as fever, headache, aches and pains, malaise and tiredness. Occasionally patients with influenza develop complications such as pneumonia, otitis media and dehydration or encephalopathy with or without liver failure, which may be due to the effects of the influenza virus itself or associated secondary bacterial infections and/or adverse effects of drugs such as antipyretics (including salicylates and other non-steroidal anti-inflammatory drugs) (Hama 2008…”

Risk of adverse events following oseltamivir treatment in influenza outpatients, Vaccine Safety Datalink Project, 2007–2010

“…Two secondary risk intervals were also defined in sensitivity analyses. For all AEs except syncope, the risk interval was extended to 1-14 days following the treated patient's dispensing, to account for the possibility of delayed presentation or diagnosis 34,35 and for consistency with prior studies. 9,10 For all AEs, the risk interval was also shortened to 1-2 days following the treated patient's dispensing, because reports of neuropsychiatric events have largely had an abrupt onset and rapid resolution, 1 and onset has frequently occurred after a single oseltamivir dose.…”