HSA Updates on Neuropsychiatric Adverse Events Suspected to be Associated with Oseltamivir (Tamiflu®)

The Health Sciences Authority (HSA) is issuing this public document to share the background and local situation leading to its recent action to issue a Dear Healthcare Professional Letter (DHCPL)* on 31 Jul 2009, where the latter reminds healthcare professionals to be aware of possible neuropsychiatric adverse reactions arising from the use of Tamiflu in patients with influenza.

[Note: * Dear Healthcare Professional letter (DHCPL) is one of HSA's important communication tools to healthcare professionals (doctors, dentists, pharmacists) to advise and keep them updated on important safety issues relating to health products in a timely manner.]

2      As a precautionary measure, healthcare professionals were advised in the DHCPL to inform their patients and caregivers of young patients, who are prescribed Tamiflu, of the remote possibility of the development of neuropsychiatric adverse events such as hallucinations and delirium, and that these patients be monitored closely.

3      The public is advised not to be unduly alarmed as these reports are rare and to consult their doctor should they experience any adverse reaction during treatment with Tamiflu.

Background

4      HSA has been closely monitoring the international developments of neuropsychiatric events suspected to be associated with Tamiflu since the alert was first raised in November 2005 by Japan's Ministry of Health and Labour Welfare. Events such as delirium with abnormal behaviour, suicidal ideation, panic attacks, hallucinations, convulsions, lowered level of consciousness and loss of consciousness with isolated cases resulting in fatal outcomes have also been reported globally. These events were reported to occur primarily in children and adolescent patients.

5      Many of these serious neuropsychiatric cases were reported in Japan. Presently, establishing a direct cause-effect relationship between Tamiflu and such events is difficult due to incompleteness of the reports and the presence of confounding factors such as concomitant drugs and the presence of influenza illness. Also, such neuropsychiatric events were reported in patients with influenza who were not taking Tamiflu. Neuropsychiatric adverse events are known to occur during influenza, especially in but not confined to those with more severe forms of the illness.

6      HSA's assessment of the global reports to-date is that the association between the neuropsychiatric events and Tamiflu remains unclear. Given the worldwide number of patients who have taken Tamiflu (estimated at about 58 million) since it was first marketed, it has also been assessed that the incidence of reports of serious neuropsychiatric disturbances with Tamiflu is very rare.

7      In 2006, HSA communicated the above safety issue via the HSA Adverse Drug Reaction Bulletin** (Dec 2006 issue) and worked with Roche, the drug company selling Tamiflu to send a DHCPL reflecting the above safety concern to all healthcare professionals.

[Note: ** HSA Adverse Drug Reaction Bulletin is a newsletter sent to all healthcare professionals every four monthly to update them on new and emerging or major drug safety concerns and to promote the reporting of adverse drug reactions to HSA.]

Local Situation To-date

8      HSA has received 6 reports of neuropsychiatric events including reports of disorientation, incoherent speech, hallucination and suicidal ideation suspected to be associated with Tamiflu from 2005 to 2009, 4 of which were reported recently. After our investigations into these reports, the causality of these adverse events with Tamiflu usage still remains unclear due to the presence of confounding factors such as the presence of influenza illness and concomitant medicines. It is to be noted that in 5 out of the 6 cases, the neuropsychiatric symptoms resolved after its first manifestation and in 3 of them, the patients continued to take Tamiflu without recurrence of the symptoms.

9      As a continuing follow-up on the situation, HSA has issued another DHCPL on 31 Jul 2009 to remind healthcare professionals to be aware of possible neuropsychiatric adverse reactions arising from the use of Tamiflu in patients with influenza. As a precautionary measure, healthcare professionals were advised to inform their patients and caregivers of young patients of the remote possibility of the development of neuropsychiatric adverse events and that these patients be monitored closely.

Public Advisory

10      "As pharmacological agents, medicines bring with them beneficial effects and may cause side effects in certain patients. HSA has assessed that the benefits of using Tamiflu to treat early symptoms for patients at risk of serious influenza complications outweigh the potential risks that the medicine may cause. The wider prescribing of these medicines in a pandemic situation may reveal rare effects that have not previously been detected. HSA will continue to closely monitor the safety profile of Tamiflu and take the necessary actions to safeguard public health should the situation warrant", says Ms Chan Cheng Leng, Division Director of HSA's Pharmacovigilance and Compliance Division.

11      The public is advised not to be unduly alarmed and to consult their doctor should they experience any adverse reaction during treatment with Tamiflu. The common side effects of Tamiflu which may occur in patients taking the drug include headache, nausea, vomiting, stomachache and diarrhoea. The frequency of these side effects is reduced if Tamiflu is taken with food.

12      As patients with influenza, particularly children and adolescents, may be at an increased risk of seizures, confusion or abnormal behaviour early during their illness, the caregivers of adolescent and young children are advised to monitor closely these patients or family members who are prescribed Tamiflu for signs of abnormal behaviour, and to contact their doctor immediately should such abnormal behaviour arise.

13      A list of Frequently Asked Questions is attached in Annex A (in pdf version) to address some common concerns.

HEALTH SCIENCES AUTHORITY
SINGAPORE
6 AUGUST 2009

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