Clinical Notes : Pharmacology

171. Antiviral agents for the treatment of seasonal influenza

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Definitions

Uncomplicated influenza

Influenza presenting with fever, coryza, generalised symptoms (headache, malaise, myalgia, arthralgia) and sometimes gastrointestinal symptoms, but without any features of complicated influenza

 

Complicated influenza

Influenza requiring hospital admission and/or with symptoms and signs of lower respiratory tract infection (hypoxaemia, dyspnoea, lung infiltrate), central nervous system involvement and/or a significant exacerbation of an underlying medical condition.

 

Risk factors for complicated influenza

  • neurological, hepatic, renal, pulmonary and chronic cardiac disease

  • diabetes mellitus

  • severe immunosuppression

  • age over 65 years

  • pregnancy (including up to two weeks post partum)

  • children under 6 months of age

  • morbid obesity (BMI ≥40)

Severe immunosuppression

Examples of severe immunosuppression relevant to this guidance are given below.

Degrees of immunosuppression are difficult to quantify and individual variation exists, therefore this list is not comprehensive:

  • severe primary immunodeficiency

  • current or recent (within 6 months) chemotherapy or radiotherapy for malignancy

  • solid organ transplant recipients on immunosuppressive therapy

  • bone marrow transplant recipients currently receiving immunosuppressive treatment, or within 12 months of receiving immunosuppression

  • patients with current graft-versus-host disease

  • patients currently receiving high dose systemic corticosteroids (equivalent to ≥40 mg prednisolone per day for >1 week in an adult, or ≥2 mg/kg/day for ≥1 week in a child), and for at least 3 months after treatment has stopped

  • HIV infected patients with severe immunosuppression (CD4 <200/μl or <15% of total lymphocytes in an adult or child over 5; CD4 <500/μl or <15% of total lymphocytes in a child aged 1–5; expert clinical opinion in a child aged under 1)

  • patients currently or recently (within 6 months) on other types of highly immunosuppressive therapy or where the patient’s specialist regards them as severely immunosuppressed

 

Treatment of suspected or confirmed influenza

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p.o.= by mouth

NG = nasogastric (administration via a nasogastric tube)

INH = inhaled

NEB = nebulised

i.v. = intravenous


Note: Commencing oseltamivir and zanamivir treatment more than 48 hours after symptom onset (36 hours for zanamivir use in children) is an off-label use.

 

* for treatment of suspected or confirmed oseltamivir-resistant influenza, see section 1.3.3 in the full guideline


clinical follow-up—advise patient to seek medical attention if illness worsens. Patient may need to be reswabbed for influenza testing if this occurs, noting on the form that they are already on antiviral treatment. The circulating influenza strain can be checked via the National Flu Report (UK only)


‡  The following hospitalised patients may be considered for IV zanamivir:

  • patients who have already failed to respond to nebulised zanamivir

  • patients who have developed respiratory conditions affecting nebuliser delivery (e.g. airways disease, pulmonary oedema)

  • patients who have multi-organ involvement or who require intensive care

 

Treatment of adults and children in community/A&E with uncomplicated influenza

All patients should be advised of the symptoms of complicated influenza and told to seek medical help should their condition worsen.

Previously healthy people (excluding pregnant women)

No antiviral treatment, or if physician feels patient is at serious risk of developing serious complications from influenza, then oseltamivir by mouth (p.o.)

 

At risk population, including pregnant women (but excluding the severely immunosuppressed)

Oseltamivir (p.o.).

Do not wait for laboratory confirmation.

Treatment should be started as soon as possible, ideally within 48 hours of onset.

There is evidence that treatment may reduce the risk of mortality even if started up to five days after onset.

Treatment after 48 hours is an off-label use of oseltamivir and clinical judgement should be exercised

 

Severely immunosuppressed patients

Some influenza subtypes are associated with a greater risk of developing oseltamivir resistance, and the selection of first line antivirals in severely immunosuppressed individuals should take account of the dominant circulating strain of influenza.

The risk of resistance is highest in people who are severely immunosuppressed and have complicated influenza, who are given antivirals.

Oseltamivir p.o. is the first line treatment, unless the dominant circulating strain is influenza A(H1N1) which has a higher risk for developing oseltamivir resistance, in which case use inhaled zanamivir (INH)

Treatment should start as soon as possible.

If clinical condition does not improve, continue with Zanamivir, take a specimen for resistance testing and consider other possible causes for a failure to improve. 

When oseltamivir is indicated based on the above advice (Table 1), the manufacturer recommends a longer treatment course of 75 mg p.o. twice daily for 10 days for immunosuppressed patients (amended 2019).

 

Suspected or confirmed oseltamivir resistant influenza in a patient who requires treatment

Zanamivir (INH).

Treatment should be started as soon as possible

 

Management of patients for whom zanamivir is indicated, who are unable to self-administer inhaled zanamivir

Some patients who would normally receive inhaled zanamivir are unable to use it, either due to underlying severe respiratory disease or inability to effectively self-administer the Diskhaler® (this includes children under 5, for whom zanamivir is unlicensed).

Patients who are severely immunosuppressed and cannot take inhaled zanamivir should receive oseltamivir p.o.

As they are at increased risk of developing oseltamivir resistant influenza, they should be reviewed clinically to assess response to therapy.

Patients who have suspected or confirmed oseltamivir resistant infection and cannot take inhaled zanamivir should be considered for nebulised aqueous zanamivir.

This is an unlicensed medication and the dose is provided on the manufacturer’s guidance supplied with the drug (see full guideline)

The selection of first line antivirals in uncomplicated influenza

 
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The selection of first line antivirals in severely immunosuppressed individuals

The selection of first line antivirals in severely immunosuppressed individuals should take account of the subtype of influenza causing infection, or if not yet known, the dominant strain of influenza that is circulating during the current influenza season (obtainable from the national weekly influenza reports). 

In general, influenza A (H1N1) is considered to be a higher risk for the development of oseltamivir resistance, whilst influenza A(H3N2) and influenza B are considered lower risk.

Further advice on the risk of individual subtypes can be obtained from a Consultant Microbiologist or Consultant Virologist

The selection of first line antivirals in severely immunosuppressed individuals

 
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Use of antivirals in pregnancy

  • Oseltamivir remains the first line option for the vast majority of pregnant women with influenza, including during seasons that are dominated by influenza A(H1N1)

  • For pregnant women who meet additional criteria for requiring zanamivir first line, further assessment (i.e. rapid diagnostics) and antiviral treatment should be discussed with a local infection specialist

  • Oseltamivir is generally well tolerated in patients with influenza, but side effects can occur. There are no data suggesting tolerability differs between pregnant and non-pregnant adults

  • Recent studies suggest there is no evidence of harm in pregnant women treated with oseltamivir or zanamivir

  • Please see the summaries of product characteristics for oseltamivir and zanamivir for more guidance regarding safety of use in pregnancy

 

Use of antivirals in patients with renal dysfunction (amended 2018)

 

  • The information provided here on dosing in renal impairment and renal failure is intended specifically for consideration when patients have an existing history of chronic kidney disease (CKD) and renal failure results have been previously documented for the purpose of managing CKD. As with other groups, it is essential to give the first dose as soon as possible 

 

  • Clinical judgement will be required where renal function is unstable (i.e. in acute renal failure)

 

  • For full recommendations about using creatinine clearance (CrCl) and estimated glomular filtration rate (eGFR) to guide treatment in patients with stable renal function, please see the full guideline

Recommended oseltamivir treatment dosing in relation to renal function

(adults and those aged 13 years or over)

 
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Note: it is acknowledged that the some of the advice for dosing in renal impairment presented here may differ to the renal drug handbook; however, the dosage information presented above is consistent with the summary of product characteristics provided by the manufacturer, at the time of writing

For adult zanamivir i.v. dosing in relation to renal function, see full guideline

 

Treatment of adults and children with complicated influenza

All patients with complicated influenza should receive treatment, often in hospital.

Rapid testing for respiratory viruses including influenza virus is recommended for all patients fulfilling the clinical criteria for complicated infection.

Treatment should be started as early as possible; do not wait for laboratory confirmation of influenza virus infection

Therefore. in OOH setting, refer all complicated influenza to A+E

 
GIP.png

Antiviral agents for the prophylaxis of seasonal influenza

Guidelines in Practice

22 January 2019

Access

 

PHE guidance on use of antiviral agents for the treatment and prophylaxis of seasonal influenza.

Public Health England. Gov.UK
Last updated 24 January 2019

Access

Flu vaccination: increasing uptake

NICE guideline [NG103]

Published date: August 2018

Access

Influenza: the green book, chapter 19

Gov.UK

Published 20 March 2013
Last updated 23 April 2019

Access

Influenza (Flu). April 2018.

Centers for Disease Control and Prevention (CDC).

April 2018.

Access

Recommendations for Prevention and Control of Influenza in Children, 2018–2019

Committee on Infectious Diseases, American Academy of Pediatrics

Pediatrics

October 2018, VOLUME 142 / ISSUE 4

Access

Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenza.

Uyeki TM, Bernstein HH, Bradley JS, et al.

Clin Infect Dis. 2018 Dec 19.

Access

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Ireland notes.png

Oseltamivir is available in Ireland as Tamiflu

Zanamivir is available in Ireland as Relenza

 

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