Indications

Complicated influenza

This is influenza needing hospital admission and/or with symptoms and signs of lower respiratory tract infection, central nervous system involvement and/or a significant exacerbation of an underlying medical condition.^[1]

• Severe immunosuppression: inhaled, nebulised or intravenous (IV) zanamivir.
• No immunosuppression: oral or nasogastric oseltamavir first-line. Inhaled, nebulised or IV zanamivir as second-line.

Patients at greater risk of developing complicated influenza include:

• Pregnant women (including up to two weeks postpartum).
• Patients over 65 years.
• Patients with chronic cardiac, pulmonary, renal, hepatic or neurological disease.
• Patients with diabetes mellitus.
• Patients who are immunosuppressed. This may be either primary immune suppression, or secondary to treatment (such as chemotherapy or high-dose steroids) or HIV infection.
• Patients who are morbidly obese (BMI ≥40).

Treatment should be started as soon as possible for these groups.

All patients with complicated influenza should receive treatment, usually in hospital. Treatment should be commenced as soon as possible but should always be given, no matter how long after onset of illness. Treatment should not be delayed for laboratory confirmation of results. Length of treatment will be dictated by clinical response.

Uncomplicated influenza

• Previously healthy individuals: Oral oseltamivir is indicated if the physician feels the patient is at risk of developing complications.
• At risk groups:
  • Severely immunocompromised: inhaled zanamivir (as Diskhaler®), or (if unable to take an inhaled preparation) oral oseltamivir. Follow up clinically to assess response to treatment and whether resistance has developed.
  • Immune-competent: oral oseltamivir within 48 hours of symptom onset, or later at clinical discretion.

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.

NB: please remember to endorse prescriptions 'selected list scheme' (SLS); otherwise, community pharmacies will not be able to dispense on the NHS.

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, twice-daily (bd) dosage for five days in the treatment of infection. Available as Tamiflu®.
• 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.
• 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'.

Dosing

• 0-1 month: 2 mg/kg/dose bd.
• 1-3 months: 2.5 mg/kg/dose bd.
• 3-12 months 3 mg/kg/dose bd.
• 1-13 years:
  • <15 kg 30 mg bd.
  • 15-23 kg 45 mg bd.
  • 23-40 kg 60 mg bd.
  • >40 kg 75 mg bd.
• Adults (13 years and over) 75 mg bd.
• In critical care units the dose may be increased to 150 mg to maximise drug levels in the lungs, reduce shedding and prevent viral rebound.

Oseltamivir oral suspension (Tamiflu® 12 mg/ml) should be used only for children under the age of one. This is an off-label use but is advised by the British National Formulary for Children. The syringe that is supplied is too large for infant dosing so a small-volume syringe should also be supplied to ensure an accurate dose. Children aged over 1 year, adults with swallowing difficulties and those receiving nasogastric oseltamivir, should use capsules which are opened and mixed into an appropriate liquid.

Zanamivir

• Effective against influenza types A and B.
• Inhibits neuraminidase enzyme.
• Taken by inhalation of powder bd (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.^[2]
• Inhaled (INH) zanamivir via Diskhaler® may not be an effective delivery route in some patients, including those unable to administer the Diskhaler® and patients with severe underlying respiratory disease. It is not licensed for use in children aged under 5 years.
• Zanamivir solution for IV or nebulised administration is an unlicensed medication and is available on a compassionate use basis for named patients in the UK.
• IV zanamivir is indicated for patients who have already failed to respond to nebulised zanamivir, or patients who have developed respiratory conditions affecting nebuliser delivery, such as airways disease or pulmonary oedema and patients who have multi-organ involvement or are in intensive care.
• The 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.^[3]
• It should be started within 48 hours of the onset of symptoms.
• The prescription should be endorsed 'SLS'.

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.

Efficacy

Evidence for the efficacy of antivirals comes mainly from studies on otherwise healthy subjects. These studies have shown:^[4][5]

• 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.

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).

Post-exposure prophylaxis

Exposure to circulating influenza virus

• Previously healthy people: no prophylaxis is advised.
• At risk of complicated influenza (includes pregnant women): oseltamivir PO for ten days if it can be started within 48 hours of contact.
• Severely immunosuppressed patients (excluding children aged under 5 years): zanamivir INH for ten days if therapy can be started within 36 hours of contact. If unable to take zanamivir, oseltamivir PO for 10 days (if therapy can be started within 48 hours of contact).
• Children under 5 years old who are at risk or immunocompromised: oseltamivir PO for 10 days if it can be started within 48 hours of contact.

Exposure to confirmed oseltamivir-resistant influenza

• Previously healthy people: no prophylaxis is advised.
• At risk of complicated influenza (includes pregnant women): zanamivir INH for 10 days if therapy can be started within 36 hours of contact.
• Severely immunosuppressed patients (excluding children aged under 5 years): zanamivir INH for 10 days if therapy can be started within 36 hours of contact. If unable to administer, discuss with a specialist and consider nebulised aqueous zanamivir (unlicensed) after individual risk assessment.
• Children under 5 years old who are at risk or immunocompromised: discuss with a specialist. Consider nebulised aqueous zanamivir (unlicensed) after individual risk assessment.

Dosing

• 0-1 month: 2 mg/kg/dose od.
• 1-3 months: 2.5 mg/kg/dose od.
• 3-12 months 3 mg/kg/dose od.
• 1-13 years:
  • <15 kg 30 mg od.
  • 15-23 kg 45 mg od.
  • 23-40 kg 60 mg od.
  • > 40 kg 75 mg od.
  • Adults (aged over 13 years) 75 mg od.

NB: see notes on syringe size for infant dose, as detailed under 'Dosing' in 'Antiviral drugs available' section, above.

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.

Special precautions

Renal dysfunction

Oral oseltamivir:

• Haemodialysis: 30 mg after each session for treatment; every 2nd session for prophylaxis.
• Peritoneal dialysis: single 30 mg dose for treatment; weekly 30 mg dose for prophylaxis.
• Creatinine clearance ≤10 ml/min: avoid for treatment or prophylaxis
• Creatinine clearance 10-30 ml/min: 30 mg od for treatment; 30 mg every 48 hours for prophylaxis.
• Creatinine clearance 30-60 ml/min: 30 mg: bd for treatment and od for prophylaxis.
• Creatinine clearance ≥60 ml/min: standard dosing.

Inhaled zanamivir is as per standard dosing.

Pregnancy

For both oseltamivir and zanamivir, use is advised only if benefit outweighs the risk as above.

Breast-feeding

For both oseltamivir and zanamivir, amounts are thought to be too small to be harmful. However, use is advised only if benefit outweighs the risk as above.