Amantadine was the first specific therapy effective against the influenza A virus but has been superseded by the neuraminidase inhibitors oseltamivir and zanamivir.

Antiviral drugs now form one important part of plans to prevent and contain epidemics of influenza infection.

However, it is important to consider that use of antivirals in the management of influenza infection (for individuals and in populations) should be selective and appropriate. Effective use of antivirals should be consistent with the efficacy of the drugs currently available and with co-ordinated disease control strategies.

Indications

Antivirals for influenza are currently recommended for:^1,2

• The treatment of influenza infection in at-risk adults (oseltamivir and zanamivir) and children (oseltamivir).
• Post-exposure prophylaxis (PEP) in at-risk adults and adolescents over the age of 13 years, who are not protected by vaccination and can commence treatment (oseltamivir) ideally within 48 hours of exposure to influenza infection, but benefit has been shown up to seven days.³

Antiviral drugs available

Oseltamivir

• Well tolerated.
• Effective against influenza types A and B.
• Inhibits neuraminidase enzyme (which promotes release and spread of virus from infected cells).
• Taken orally (capsules or suspension, once-daily dosage for up to six weeks during an epidemic for post-exposure prophylaxis (PEP) in at-risk groups or at twice-daily dosage for five days in the treatment of infection). Available as Tamiflu®.
• Recommended for PEP in at-risk adults and adolescents over the age of 13 years, not protected by influenza vaccination.
• Should be started within 48 hours of close contact with someone suffering from influenza-like symptoms in PEP.
• Should be started within 48 hours of the onset of symptoms in the treatment of influenza infection in at-risk children over the age of 1 year and adults.
• Not recommended for treatment of influenza infection, seasonal prophylaxis or PEP in otherwise healthy individuals.
• Only for NHS prescription according to the notes above and National Institute for Health and Clinical Excellence (NICE) guidance. The prescription should be endorsed 'SLS'.

Zanamivir

• Effective against influenza types A and B.
• Inhibits neuraminidase enzyme.
• Taken by inhalation of powder twice daily (disks contain four blisters, five disks per pack of Relenza®). There is a risk of bronchospasm in asthma, and relieving inhalers should be kept available. It is best avoided in severe asthma.⁵
• Standard treatment dose of zanamivir is 10 mg bd for five days (inhaled) and is more suitable for pregnant patients and those with renal failure.²
• Licensed for use in influenza infection affecting at-risk adults and adolescents aged over 12 years.
• Should be started within 48 hours of the onset of symptoms.
• Not recommended for PEP even in at-risk groups (unlike oseltamivir).
• Not recommended for treatment of influenza infection or seasonal prophylaxis in otherwise healthy individuals.
• The prescription should be endorsed 'SLS'.

Adverse effects

• Oseltamivir may cause nausea and vomiting in about 10% of people.
• Rarely, zanamivir precipitates bronchospasm or a decline of respiratory function in people with chronic respiratory diseases (including asthma).

Clinical scenarios

Antivirals should be used as early as possible, ideally within first 48 hours (36 hours in children), but benefit has been shown up to seven days.^3,6 Give priority to people in higher-risk groups.

At-risk patients

Influenza in healthy people

Do not prescribe antiviral drugs for people with influenza who are otherwise healthy. Reassure the person that the worst symptoms of uncomplicated influenza resolve after about one week, although other symptoms (such as cough, headache, insomnia, weakness, and loss of appetite) may take longer than two weeks to resolve.
Evidence for the efficacy of antivirals comes mainly from studies on otherwise healthy subjects. These studies have shown:⁷

• Zanamivir reduces the duration of symptoms in influenza by 1.26 days.
• Zanamivir reduces the rate of some complications compared with placebo and reduces antibiotic prescribing.
• There is no evidence to show a reduction in serious complications requiring hospital admission, or a reduction in deaths.

Influenza infection in at-risk patients

• Oseltamivir and zanamivir can be used in adults, and oseltamivir in children.
• It must be started within 48 hours of the onset of flu symptoms. Oseltamivir is taken orally at a dose of 75 mg, twice daily, for five days. Lower doses should be used in children aged 1-12 years and people with severe renal impairment (chronic kidney disease stages 4 and 5).
• Zanamivir is administered as a dry powder and inhaled through the lungs using a Diskhaler®, and is suitable for people of 5 years of age and older at a dose of 10 mg, twice daily, for five days.
• Zanamivir is the preferred drug for pregnant women. Oseltamivir is recommended when zanamivir is contra-indicated. If an antiviral drug is prescribed for a pregnant woman, ask the woman for permission to pass on her contact details to the UK Teratology Information Service (0844 892 0909).
• Oseltamivir or zanamivir can be used when the woman is breast-feeding.

Follow-up

• Consider follow-up (particularly in frail people) after about one week, to confirm symptoms are improving and to exclude the development of secondary complications.
• Advise the person that they should seek urgent medical attention if they develop shortness of breath or pleuritic chest pain, or if they start to cough up blood.
• Arrange a follow-up appointment if there is no improvement after one week (that is, they are still significantly ill), or if they are deteriorating.
• Have a lower threshold for seeking help if they are caring for a young child or baby with influenza, as children cannot accurately communicate their symptoms.

Post-exposure prophylaxis (PEP) in at-risk patients

• Oseltamivir is recommended in adults and adolescents over the age of 13 for up to six weeks.
• Oseltamivir is taken orally at a dose of 75 mg, once daily, for 10 days. Lower doses should be used in children aged 1-12 years and people with severe renal impairment (chronic kidney disease stages 4 and 5).
• Zanamivir is administered as a dry powder and inhaled through the lungs using a Diskhaler®, and is suitable for people of 5 years of age and older at a dose of 10 mg, once daily, for 10 days.
• They must be started within 48 hours of close contact with patients suffering from influenza symptoms.

If an antiviral drug is prescribed for a pregnant woman, ask the woman for permission to pass on her contact details to the UK Teratology Information Service (0844 892 0909). Oseltamivir or zanamivir can be used when the woman is breast-feeding.

Swine flu

The World Health Organization (WHO) has predicted that human swine influenza A virus (H1N1v) will be evident again this season (2011-2012). It can be treated with the antiviral oseltamivir (Tamiflu®) and zanamivir (Relenza®).⁵ Give priority to early treatment with antivirals of people in higher-risk groups, but also:⁸

• Young children under 5 years old. Children below 1 year of age may be treated with low-dose oseltamivir (seek paediatric advice if there are any concerns).
• Pregnant women - patients with uncomplicated influenza should be offered antivirals. Zanamivir is preferred (inhaled, hence less systemic exposure), although either can be used and oral may be better if there is respiratory disease or difficulty with inhalers.⁹

Evidence of efficacy

It remains an unproven hypothesis that antiviral drugs will reduce the rate of serious complications either in at-risk or healthy subjects in the event of another flu pandemic, or indeed a flu epidemic. There is consensus about the strategy for use of antivirals outlined above.^4,10,11

Document references

1. Pandemic flu: clinical management of patients with an influenza-like illness during an influenza pandemic, British Infection Society et al (2007); Provisional guidelines from the British Infection Society, British Thoracic Society, Health Protection Agency in collaboration with the Dept of Health
2. Influenza - zanamivir, amantadine and oseltamivir (review), NICE Technology Appraisal (February 2009); Amantadine, oseltamivir and zanamivir for the treatment of influenza (review of existing guidance No. 58)
3. Pandemic H1N1 2009 influenza: clinical management guidelines for adults and children, Dept of Health (Dec 2009)
4. Mayor S; Review says oseltamivir and zanamivir should be kept for epidemics of flu; BMJ. 2006 Jan 28;332(7535):196.
5. Summary of Product Characteristics (SPC) - Relenza® 5 mg/dose inhalation powder (zanamivir), GlaxoSmithKline UK, electronic Medicines Compendium. Updated May 2011
6. Guidelines on the Management of Communicable Diseases: Influenza, Health Protection Agency
7. Turner D, Wailoo A, Nicholson K, et al; Systematic review and economic decision modelling for the prevention and treatment of influenza A and B. Health Technol Assess. 2003;7(35):iii-iv, xi-xiii, 1-170. [abstract]
8. New H1N1v Influenza: Current situation and next steps. Chief Medical Officer, Dept of Health CEM/CMO/2009/16, 2 July 2009
9. Pandemic H1N1 2009 influenza: clinical management guidelines for pregnancy, Dept of Health, 2009
10. Lynd LD, Goeree R, O'Brien BJ; Antiviral agents for influenza: a comparison of cost-effectiveness data. Pharmacoeconomics. 2005;23(11):1083-106. [abstract]
11. Groeneveld K, van der Noordaa J; Use of antiviral agents and other measures in an influenza pandemic. Neth J Med. 2005 Oct;63(9):339-43. [abstract]

Internet and further reading

• Jamieson DJ, Honein MA, Rasmussen SA, et al; H1N1 2009 influenza virus infection during pregnancy in the USA. Lancet. 2009 Aug 8;374(9688):451-8. Epub 2009 Jul 28. [abstract]
• Influenza - seasonal, Prodigy (August 2009)
• Immunizations - seasonal influenza, Prodigy (September 2011)
• Seasonal Influenza, Health Protection Agency (2011)