Tamiflu and neuropsychiatric disturbance in adolescents

Abstract

The case is not proved but caution is advisable

In March 2007 the Japanese authorities advised against prescribing oseltamivir (Tamiflu, Roche) to adolescents aged 10-19 years.¹ This unusually severe measure resulted from the separate suicides of two 14 year olds who jumped to their deaths while taking oseltamivir; 52 other deaths (14 in children or adolescents) have been associated with the same drug. So far, similar action has not followed in Europe. When a regulatory authority warns doctors not to prescribe a drug but decides not to retract its marketing authorisation prescribers and patients are entitled to be concerned and a little confused.

Oseltamivir is a sialic acid analogue that inhibits influenza type A and type B neuraminidase, the viral enzyme that allows the release of virus from infected cells. Its main licensed indications are the treatment of flu, short term postexposure prophylaxis after contact with a diagnosed case of flu, and more prolonged (up to six weeks) “seasonal” prophylaxis when flu is circulating in the community. The licence was extended in 2005 to include children aged 1-12 years.

When used to treat otherwise healthy people, oseltamivir reduces the duration of symptoms by 1-1.5 days if started within 48 hours of first symptoms, irrespective of vaccination status, although it may be less effective in those with chronic diseases.^{2 3 4 5} It also provides a modest reduction in complications such as pneumonia, otitis media in children, and hospital admission.^{4 5} As postexposure prophylaxis, the protective efficacy of oseltamivir was 80-90% in the family contacts of index cases.^{2 3 6 7} As seasonal prophylaxis, the protective efficacy was 74% in healthy people aged 18-65⁶ and even higher in frail elderly people in residential care.⁸

The National Institute for Health and Clinical Excellence advises that oseltamivir should not be prescribed for otherwise healthy people because the health gain in this group is modest.^{4 6} However, oseltamivir is recommended for treatment and postexposure prophylaxis in people who are at increased risk of complications because of age or comorbid conditions (box). This restricted recommendation in the United Kingdom has limited prescription of oseltamivir to only a few thousand people.⁹ In contrast, an estimated 45 million patients have received oseltamivir worldwide.¹ This has been partly boosted by encouragement from the World Health Organization, as a way to gain familiarity with antiviral agents before the outbreak of a pandemic.¹⁰ Several governments have been stockpiling supplies in preparation for such an event.

Patients at high risk of complications after flu

• People over 65 years of age

• People with chronic respiratory disease (including asthma and chronic obstructive pulmonary disease)

• Patients with cardiovascular disease (excluding those with hypertension only)

• Patients with chronic renal disease

• Immunocompromised patients

• People with diabetes mellitus

So far, oseltamivir has been thought to be well tolerated and safe. The most common adverse effect is dose related nausea, which occurs twice as frequently as with placebo when used as prophylaxis.⁵ Postlicensing monitoring has revealed very rare reports of raised liver enzymes and hepatitis and of serious skin reactions, including Stevens-Johnson syndrome and erythema multiforme.¹¹ However, the recent events in Japan have prompted a reappraisal.

Before 2007, there had already been more than 100 reports of neuropsychiatric events (including delirium, convulsions, and encephalitis) with oseltamivir in children, almost entirely from Japan, which has the highest usage of oseltamivir worldwide. However, these disturbing events had to be seen in the context of the millions of prescriptions worldwide and the fact that abnormal behaviour could also be due to flu or disease related complications. Indeed, a Food and Drug Administration (FDA) review of clinical trial and postmarketing data concluded that these events were not clearly drug related but might be related to higher rates of flu related encephalitis in Japan.¹² Since last November, the FDA has required that doctors be warned that patients should be closely monitored for signs of abnormal behaviour throughout the treatment period and the European Medicine Evaluation Agency (EMEA) took similar steps in February.

The controversy about oseltamivir is a further reminder that, although common adverse effects of a drug may emerge in prelicensing studies, the detection of rarer and potentially more serious events has to await exposure of large numbers of patients. In the UK, oseltamivir is a “black triangle” drug, so it remains under more intensive surveillance. Doctors and other healthcare professionals should report all minor as well as serious adverse events via the yellow card scheme.

In the light of these concerns how should prescribers proceed? There seems little doubt that oseltamivir reduces the number and seriousness of flu episodes when used as treatment and prophylaxis. However, the impact of such events in otherwise healthy people is usually modest and of short duration. They should be encouraged to use conservative strategies such as resting, increasing fluid intake, and taking simple analgesics and over the counter symptomatic remedies. In people at higher risk of serious complications the potential benefit of treatment seems greater, although convincing evidence about reductions in hospital admission or mortality is still awaited. In these groups, vaccination still offers a cost effective first line of defence.⁶