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Adverse drug reactions: Neuraminidase inhibitors: widespread use for influenza may reveal more adverse effects

The neuraminidase inhibitors (NAIs), oseltamivir (Tamiflu) andzanamivir (Relenza), are indicated for prophylaxis and treatment ofinfluenza. Both antivirals are included within the current UK HealthProtection Agency guidance for the treatment and prophylaxis ofinfection from the novel swine influenza A (H1N1) virus

by Anthony Cox and Deborah Layton

Roche tablet (Science Photo Library)The neuraminidase inhibitors (NAIs), oseltamivir (Tamiflu) and zanamivir (Relenza), are indicated for prophylaxis and treatment of influenza.

Both antivirals are included within the current UK Health Protection Agency guidance for the treatment and prophylaxis of infection from the novel swine influenza A (H1N1) virus. These drugs are more effective and safer than older antivirals, such as the amantanes (amantidine and rimantadine).

In the event of a global pandemic the NAIs will be administered to a large proportion of the population.

Common adverse effects

A recent review of the safety of NAIs for influenza examined the treatment and prophylactic dosing schedules in both children and adults.1

In addition, the Cochrane Collaboration reviewed the use of NAIs in both adults2 and children.3 For treatment of influenza, limited trial evidence indicates adverse events do not occur with a frequency greater than with placebo.

Oseltamivir

Clinical trials of oseltamivir for influenza prophylaxis in adults have shown nausea (10.5 per cent), vomiting (3 per cent), bronchitis, insomnia and vertigo to be common, and reported at similar rates to placebo. Nausea occurred at a statistically significant higher rate than placebo (5.6 per cent) and is dose related.1

When used to treat children, oseltamivir caused similar reactions to those in adults. Vomiting occurred in 14.8 per cent of children, and was statistically different from placebo (9.3 per cent).1

In children receiving the once daily prophylactic dose, the incidence of vomiting is halved.3 Few children withdraw from therapy because of adverse events. There is no evidence that oseltamivir affects respiratory function or triggers asthma exacerbations.

Skin reactions may be associated with oseltamivir. Dermatitis, rash, urticaria, and eczema have been reported, although some reports were confounded by other drugs known to be associated with hypersensitivity reactions.4

The summary of product characteristics (SPC) of oseltamivir also notes rare serious skin reactions, including Stevens-Johnson syndrome, erythema multiform, toxic epidermal necrolysis and angioneurotic oedema, although the frequency is unknown.

Zanamivir

Studies of zanamivir report primarily minor transient upper respiratory tract and gastrointestinal symptoms (ie, nausea, diarrhoea and sinusitis) as common adverse effects occurring with similar frequency to placebo in both adults and children.2,3

A Cochrane review did not identify any reports of zanamivir-related bronchospasm in children,3 although the zanamivir SPC describes rare reports of acute bronchospasm or serious declines in respiratory function, or both. These mainly occurred in patients with a previous history of respiratory disease.

Zanamivir is not currently recommended in children or adults with severe asthma or chronic pulmonary disease because of the perceived risk of bronchospasm associated with its use. Short-acting bronchodilators should be available if it is used in those with less severe respiratory disease.5

 

Neuropsychiatric effects

Concern has been expressed about the risk of neuropsychiatric events associated with both NAIs. Concerns first arose in Japan, where 76 per cent of all prescribed oseltamivir worldwide was used between 1999 and 2007.

Cases (mostly from Japan) of delirium and abnormal behaviour leading to injury have been reported in patients with influenza who were receiving oseltamivir, in some cases resulting in fatal outcomes. Toovey et al reviewed 3,051 spontaneous reports of neuropsychiatric events (in 2,466 patients) received by Roche between 1999 and 2007.6

They estimated that 48 million doses of the drug had been prescribed worldwide during that period, with 91 per cent of adverse effect reports originating from Japan. Most events were in males (78 per cent) and within the first two days of treatment; 73 per cent of events occurred in those under 16 years of age.

The most commonly reported events were abnormal behaviour (n=1,160), delusions or perceptual disturbances (n=661), miscellaneous psychiatric reactions, depressed levels of consciousness (n=183), delirium (n=176) and convulsions (n=138).

Of 16 suicidal events reported, 14 occurred in people over 16 years old. Of three successful suicide attempts, all occurred in adults with significant confounding factors.

Epidemiological studies have shown no association with neuropsychiatric events. A retrospective study of patients with influenza comparing those prescribed oseltamivir for treatment of influenza (n=3,211), with those not (n=19,985), found no association with neuropsychiatric events.7

Three epidemiological studies using US databases have also shown no association between oseltamivir and neuropsychiatric events.6

However, as with any observational pharmacoepidemiological study, the limitations in terms of confounding and bias should be considered.

Ascertaining whether NAIs are associated with neuropsychiatric events is
confounded by the neuropsychiatric symptoms of influenza, which can have a similar onset as the case reports of problems with these drugs. A UK General Practice Research Database study showed increased risk of delusions, panic attacks, depressed consciousness and cognition disturbances in influenza patients compared with the general population.7

Regulators have taken a cautious approach. In February 2007 the European Medicines Agency’s Committee for Medicinal Products for Human Use recommended an update of the product information for oseltamivir to inform healthcare professionals and patients about the risk of neuropsychiatric side effects.8

Similar action was taken by the US Food and Drug Administration in February 2008. Currently, the UK SPC for oseltamivir notes the risk of neuropsychiatric disorders with influenza and the occurrence of post-marketing reports of convulsions and delirium, which have in some cases led to accidental injuries and death.9

It is also noted that most reports were in children and adolescents, with a rapid onset and resolution or adverse reactions. The lack of clear causality is stressed. A similar warning exists in the zanamivir SPC.10

 

Summary

Both oseltamivir and zanamivir are safe drugs with relatively few adverse effects based on clinical trial data.

A theoretical risk of bronchospasm with the use of inhaled zanamivir is of concern in those with respiratory disease and there is an unknown risk of very rare skin reactions to oseltamivir.

Despite the concerns about neuropsychiatric events with the use of NAIs, and the inclusion of these in product literature, pharmacoepidemiogical studies and case report analysis cast doubt on such an association.

Influenza infection is arguably the more plausible cause of neuropsychiatric events. Widespread use of NAIs, either for treatment or prophylaxis, may uncover further rare adverse reactions.

Oseltamivir is currently a black triangle drug, under intensive surveillance by the Medicines and Healthcare products Regulatory Agency. All suspected adverse reactions, including non-serious ones, should be reported, even if the reaction is well recognised, or if the reporter is uncertain that the drug has caused it.

In addition, any suspected adverse reactions in children to either drug should be reported to the MHRA via the Yellow Card Scheme.

The MHRA website can be visited for the latest advice.

 

Anthony Cox, Aston Pharmacy School, Birmingham, and Deborah Layton, Drug Safety Research Unit, Southampton.

References

1.    Jones M, Del Mar C. Safety of neuraminidase inhibitors for influenza. Expert Opinion on Drug Safety 2006;5:603–8.

2.    Jefferson T, Demicheli V, Di Pietrantonj C, Jones M, Rivetti D. Neuraminidase inhibitors for preventing and treating influenza in healthy adults. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No. CD001265. DOI: 10.1002/14651858.CD001265.pub2.

3.    Matheson NJ, Harnden A, Perera R, Sheikh A, Symmonds-Abrahams M. Neuraminidase inhibitors
for preventing and treating influenza in children. Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No. CD002744. DOI: 10.1002/14651858.CD002744.pub2.

4.    Dutkowski R, Thakrar B, Froehlich E, Suter P, Oo C Ward P. Safety and pharmacology of oseltamivir in clinical use. Drug Safety 2003; 26:787–801.

5.    British National Formulary 55. BMJ Group and RPS Publishing; London: 2009.

6.    Toovey S, Rayner C, Prinssen E, Chu T, Donner B, Thakrar B et al. Assessement of neuropsychiatric adverse events in influenza patient treated with oseltamivir: a comprehensive review. Drug Safety 2008; 31:1097–114.

7.    Enger C, Nordstrom BL, Thakrar B, Sacks S, Rothman KJ. Health outcomes among patients receiving oseltamivir. Pharmacoepidemiology and Drug Safety 2004; 3:227–37.

8.    European Medicines Agency statement on
safety of Tamiflu. Press Release 23. Available at www.emea.europa.eu (accessed on 7 May 2009).

9.    Tamiflu summary of product characteristics. 17/02/2009 revision. Roche Products Limited.

10.    Relenza Summary of Product Characteristics. 10/11/2008 revision. GlaxoSmithKline UK.

Citation: The Pharmaceutical Journal URI: 10964880

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