Oseltamivir (Tamiflu®, Roche) is an antiviral agent licensed by HSA in October 2000 for the treatment of uncomplicated acute illness due to influenza infection (influenza A & B) in adults and children ≥ 1 year old who have been symptomatic for no more than two days and for the prophylaxis of influenza in adults and children ≥ 13 years old.

The Health Sciences Authority (HSA) has reviewed the data from the 103 post-marketing reports of neuropsychiatric adverse events suspected to be associated with oseltamivir received from August 2005 to July 2006. These include events such as delirium with prominent behavioural disturbances (n=60) and suicidal events (n=6) including self-injury and suicidal ideation.

The majority of the cases were reported from Japan (92%) and were predominantly for the treatment of influenza (97%). These were primarily among paediatric patients (67%) with an age range of 1.5 to 17 years old. There were three deaths: a 14 year-old boy and two adults who fell to their deaths. The patients who died were healthy before contracting influenza and receiving oseltamivir. Most of the adverse events occurred during the first day of oseltamivir use (1 to 2 doses).

Our assessment of the reports was that many of the cases lacked sufficient detail for causality assessment and largely originated from one country. Therefore, it is unclear at the present time whether these events were the outcomes of the direct adverse effect of the drug, genetic differences in metabolic handling of oseltamivir, an unusual manifestation of influenza infection in Japanese patients, higher usage of oseltamivir in Japan or a coincident period of intensive monitoring of adverse events in Japan or a combination of any of these possible factors. Additionally, many events such as convulsions, delirium and depressed levels of consciousness are complications of viral encephalitis secondary to influenza making a direct causal link to Tamiflu® administration very difficult.

Nonetheless, considering the rapid temporal relationship of adverse event to the use of oseltamivir, and cases which reported positive de-challenge (n=65) where there was rapid and full recovery from neuropsychiatric adverse effects once oseltamivir was discontinued and/or lack of positive neuro-imaging findings in the reviewed reports (n=25), the local prescribing information of Tamiflu® will be updated to warn of the potential for the occurrence of neuropsychiatric adverse events. In addition, it also advised that patients with flu, particularly children may be at an increased risk of self injury and confusion shortly after taking Tamiflu® and should be closely monitored for signs of unusual behaviour.

HSA has received three adverse drug reactions suspected with use of oseltamivir. They are one report of hepatitis and another of nausea and urticaria. There is also one report of a middle-aged male who committed suicide by falling to his death. He was prescribed oseltamivir at 75mg twice a day for flu and the adverse event was reported to have occurred on the 7th day. The causality however could not be established as it was reported that the patient was also taking other medications.

HSA will continue to closely monitor this emerging safety concern and update our healthcare professionals as and when necessary. All healthcare professionals are encouraged to report all serious side effects including neuropsychiatric adverse events suspected to be associated with oseltamivir to the Pharmacovigilance Unit of HSA.

1. US FDA Medwatch 2006 Safety Alerts.   http://www.fda.gov/medwatch/safety/2006/safety06.htm#tamiflu
   
   
2. Tamiflu® Adverse Event Review by the FDA Paediatric Advisory Committee.
   http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4254b_09_01_Tamiflu%20AE%20Review%202006%20Redacted_D060309_092.pdf