Antivirals for Influenza

Amantadine was the first specific therapy effective against the influenza A virus but has been superseded by the neuraminidase inhibitors oseltamivir and zanamivir.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

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 age 13 years who are not protected by vaccination and can commence treatment (oseltamivir) within 48 hours of exposure to influenza infection.

Cochrane recommends the use of neuraminidase inhibitors be restricted to epidemics and pandemics.³

Oseltamivir

• Well tolerated
• Effective against influenza types A and B
• Inhibits neuramidase enzyme (which promotes release and spread of virus from infected cells)
• Taken orally (capsules or suspension, once daily dosage for up to 6 weeks during an epidemic for PEP in at-risk groups or at twice daily dosage for 5 days in the treatment of infection)
• Recommended for PEP in at-risk adults and adolescents over age 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 age 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 NICE guidance. The prescription should be endorsed “SLS” (selected list scheme)

Zanamivir

• Effective against influenza types A and B
• Inhibits neuramidase enzyme
• Taken by inhalation of powder twice-daily (disks contain 4 blisters, 5 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
• Licensed for use in influenza infection affecting at-risk adults and adolescents 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

• 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.

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 1 week, although other symptoms (such as cough, headache, insomnia, weakness, and loss of appetite) may take longer than 2 weeks to resolve.
Evidence for the efficacy of antivirals comes mainly from studies on otherwise healthy subjects. These studies have shown:⁴

• 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 death.

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 a day, for 5 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 a day, for 5 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 1 week to confirm symptoms are improving and to exclude the development of secondary complications.
• Advise the person 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 1 week (that is, they are still significantly ill), or 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.

PEP in at-risk patients

• Oseltamivir is recommended in adults and adolescents over age 13 for up to 6 weeks.
• Oseltamivir is taken orally at a dose of 75 mg, once a day, 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 a day, for 10 days.
• They must be started within 48 hours of close contact with patients suffering from influenza symptoms.

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.

Pandemic flu

Antiviral drugs are likely to be important in the event of another flu pandemic, both for treatment and prevention of infection. Vaccines may not be available or supply may be limited.^5,5
However:

• Effectiveness at reducing mortality has not been established
• Current recommendations for use may change during a pandemic. For example, the UK plan has identified groups likely to be a priority, but which are to be reviewed and possibly changed according to expert advice about the epidemiology and other information of an emerging pandemic. Priority groups are likely to be:
  • Healthcare workers (to maintain the health service response)
  • Essential service workers (to maintain key services)
  • Un-immunised high-risk groups (to reduce complications, hospital admissions and deaths)
  • Immunised people if it emerges that the vaccine is ineffective
• Resistance to drugs may become significant

It remains an unproven hypothesis that antiviral drugs will reduce the rate of serious complications in either 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.^3,6,7

The diagnosis of flu is made on clinical grounds. Influenza surveillance data can aid clinical diagnosis⁸. Surveillance of flu is a year-round global activity. The UK is part of an international network of flu surveillance involving 112 laboratories in 83 countries. In the UK the Health Protection Agency co-ordinates flu surveillance and will inform decisions about antiviral strategy across the UK.

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 Department 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. Mayor S; Review says oseltamivir and zanamivir should be kept for epidemics of flu.; BMJ. 2006 Jan 28;332(7535):196.
4. 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]
5. Pandemic Influenza Contingency Plan, Health Protection Agency (2009)
6. Lynd LD, Goeree R, O'Brien BJ; Antiviral agents for influenza: a comparison of cost-effectiveness data. Pharmacoeconomics. 2005;23(11):1083-106. [abstract]
7. 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]
8. Burls A, Clark W, Stewart T, et al; Zanamivir for the treatment of influenza in adults: a systematic review and economic evaluation. Health Technol Assess. 2002;6(9):1-87.

• HPA - Guidelines on the Management of Communicable Diseases: Influenza, Health Protection Agency
• Influenza, Clinical Knowledge Summaries (August 2009)
• Immunizations - seasonal influenza, Clinical Knowledge Summaries (July 2009)
• Summary of prescribing guidance for the treatment and prophylaxis of influenza-like illness: Treatment Phase. Health Protection Agency (7 July 2009)
• 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 Department of Health)
• Ward P, Small I, Smith J, et al; Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic. J Antimicrob Chemother. 2005 Feb;55 Suppl 1:i5-i21. [abstract]