Local experience with oseltamivir (Tamiflu®)

HSA would like to update healthcare professionals on the local ADR reports associated with oseltamivir (Tamiflu®, Roche) since the issuance of the Dear Healthcare Professional Letter on 31 July 2009 on the same subject (please log on to http://www.hpp.moh.gov.sg for details of letter).

Background

HSA had earlier published a report on oseltamivir and neuropsychiatric events in its December 2006 Vol. 8 No. 3 issue of the HSA ADR News Bulletin. In the article, it was reported that the majority of the cases originated from Japan. They were primarily among paediatric patients (67%) with an age range of 1.5 to 17 years old. Most of the adverse events occurred during the first day of oseltamivir use (1 to 2 doses).

As a result of these findings, the local prescribing information of Tamiflu® was updated to include warnings on the potential of the occurrence of neuropsychiatric adverse events. It cautioned that patients with influenza, 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.

Since the start of the Influenza A/H1N1 (2009) pandemic, there has been a sharp increase in the usage of oseltamivir. A corresponding increase in the number of adverse drug reactions (ADR) associated with oseltamivir, notably neuropsychiatric events, was reported. On 31 July 2009, HSA issued a Dear Healthcare Professional Letter (DHCPL) to remind healthcare professionals to closely monitor patients prescribed Tamiflu® for the development of neuropsychiatric events as these events, although rare, are often unpredictable and potentially fatal.

Recent local reports of central nervous system (CNS) disorders

As of 1 October 2009, HSA's Vigilance Branch received a total of 42 ADR reports suspected to be associated with Tamiflu® (36 were received after 1 July 2009). Out of the 42 reports, 23 were CNS related. They include the following ADR terms:

agitation (1), anxiety (1), cognitive function abnormal (1), confusion (2), crying abnormal (1), delirium (3), disorientation (2), disturbance in social behaviour (3),

dreaming abnormal(1), drowsiness (1), giddiness (1), hallucination (2), hallucination auditory (1), headache (1), hypoactivity (2), insomnia (1),

involuntary movement oral (1), lethargy (1), mental state abnormal (1), nightmares (3), nodding of head (1), panic reaction (2), psychotic state (1),

simple partial seizures (1), sleep walking (1), staring (2), status epilepticus (1), suicidal tendency (2) suicide (1).

_{*An ADR report may describe more than one ADR term.}

Majority of these patients were young patients (74%) (17 patients were <17 years and six were >18 years). 15 (65%) were males and eight (35%) were females.

The remaining 19 ADR reports received include hepatitis (1); G6PD hemolytic anaemia (1); epistaxis in an elderly patient (1); severe stomach pain & vomiting (2); aggravation of diabetes in a diabetic patient (1); increase in INR (1) and non serious reports of rash, allergy, periorbital swelling, nausea (12).

Many events such as convulsions, delirium and depressed levels of consciousness may be possible complications of viral encephalitis secondary to influenza. Influenza infection itself can also be associated with a variety of neurologic and behavioural symptoms such as abnormal behaviour, hallucinations, agitation, anxiety and nightmares. It therefore remains unclear whether these neuropsychiatric events were the outcomes of the direct adverse effect of the drug, genetic differences in metabolic handling of oseltamivir, unusual manifestation of the underlying infection or a combination of any of these possible factors.

Conclusion

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

Published: 23 Dec 2009

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