Guidance

Guidance on use of antiviral agents for the treatment and prophylaxis of seasonal influenza

Updated 4 November 2025

This guidance provides treatment and prophylaxis recommendations for seasonal influenza and is primarily intended for use by healthcare professionals and health protection teams in England. This guidance does not provide comprehensive guidance on the general clinical or infection prevention and control (IPC) management of suspected or confirmed influenza.

Initial advice on the management of people with influenza should be provided by local infection specialists, and further support is available from clinical virologists based in regional public health laboratories, or UK Health Security Agency (UKHSA) Colindale through the usual channels. Local health protection teams should be contacted about localised influenza-related outbreaks, and separate guidance is provided for care homes and ‘prisons and prescribed places of detention’(1,2).

This guidance is based on available current information from a range of data sources including a literature review, other guidelines, product literature, as well as expert opinion. Formal cost-benefit analysis was not performed, however the relative costs of antivirals and expected ability to achieve clinical endpoints are taken into consideration (see licensed treatments section).

Some of the recommendations included in this guidance involve the off-label use of licensed medications, or use of unlicensed medications, for which there may be limited safety and efficacy data. In these instances, such recommendations are the views of the writing group and not of the manufacturer. This guidance should be used by clinicians in conjunction with the summary of product characteristics (SPC) for these medicines, particularly with reference to the contraindications, interactions, and adverse events.

Introduction

Clinical suspicion of influenza virus infection and influenza like illness

Fever with cough is typically considered relatively specific for clinical diagnosis of influenza during the influenza season when influenza is highly prevalent. Therefore influenza-like-illness, and its presumption of infection with influenza virus, appropriately remains a clinical diagnosis, especially for non-severe illness in primary care. However, the potential for co-circulation and similarity in clinical presentation of other respiratory viruses can make influenza diagnosis challenging on clinical-epidemiological grounds alone. Coinfection of a patient with influenza and other respiratory viruses is possible, more commonly in children, and may be associated with increased mortality (3). Secondary bacterial infection further increases morbidity and mortality (4).

Influenza virus infection should be considered in the differential diagnosis of other presentations such as:

• community acquired pneumonia
• hospital acquired pneumonia
• severe acute respiratory infection
• exacerbations of chronic lung disease (such as asthma and chronic obstructive pulmonary disease)
• sepsis
• acute myocardial infarction
• encephalitis
• transverse myelitis
• aseptic meningitis
• Guillain Barré syndrome
• myocarditis
• rhabdomyolysis

(5)

A history of influenza immunisation does not exclude influenza as a possible diagnosis.

Therefore, depending on the epidemiological picture, severity of illness, experience of the clinician, clinical setting and the infection prevention and control (IPC) requirements, an increased use of virological testing to guide case management and outbreak response may be warranted. UKHSA supports the use of validated point-of-care/near-patient influenza tests (POCTs) in patients presenting with acute respiratory infection symptoms to improve diagnostic certainly and support timely clinical management and IPC when influenza is suspected.

Severity of influenza illness

There are different ways of describing severity of influenza disease, with a high degree of overlap. ‘Complicated’ and ‘uncomplicated’ were previously used to describe the severity of influenza infections in this guidance and is used by the National Institute of Health and Care Excellence (NICE) Clinical Knowledge Summaries). The terms ‘severe’ and ‘non-severe’ are used by the European Centre for Disease Control (ECDC) and World Health Organization (WHO) (6), and from Version 12 of this guidance the terms severe and non-severe are used to align with these international definitions (6).

Non-severe influenza (illness)

Non-severe influenza illness is most commonly characterised by symptoms such as:

• sudden onset cough
• sore throat
• rhinorrhoea (runny nose),
• fever
• headache
• muscle and joint pain
• severe malaise (feeling tired and unwell)

Most people recover from the fever and other symptoms within a week, without requiring medical attention (6). This was previously referred to as ‘uncomplicated’. If antiviral treatment of non-severe infection is warranted, this can typically be done in the community.

Gastrointestinal (particularly in children) and less commonly ocular (eye) symptoms (photophobia, conjunctivitis, lacrimation and pain upon eye movement) have been described in association with influenza infection (7).

Severe influenza (illness)

Severe influenza illness is characterised by evidence of clinical complications directly resulting from influenza virus infection, such as pneumonia, sepsis, multi-organ-failure, encephalopathy or exacerbation of chronic disease, which warrant management in a hospital or critical care setting (such as a high dependency unit (HDU) or intensive care unit (ICU) (6). However, not all patients who are hospitalised primarily for other reasons with an incidental finding of influenza detection have severe influenza and clinical judgement should be exercised.

Risk factors for severe influenza and hospitalisation

Certain patient groups are at increased risk of progression to severe influenza (3,5).

Patients considered at-risk include those with:

• chronic neurological, hepatic, renal, respiratory and cardiovascular diseases
• diabetes mellitus
• (potential) immunosuppression [note 1]
• morbid obesity (BMI ≥40)
• age over 65 years
• current pregnancy (including up to 2 weeks post-partum)
• children under 6 months of age

Note 1: For oseltamivir and zanamivir treatment, NICE includes any who might be immunosuppressed within its at-risk criteria (TA168).

See the Green Book influenza chapter for mortality risk in clinical risk groups, and details of clinical risk groups and other risk groups. An updated evidence review quantifying the risk of hospitalisation from influenza was commissioned by the WHO for their 2024 influenza clinical guidelines and remain consistent with risk factors found in previous versions of this guidance, the Green Book and NICE Technology Appraisal (TA) guidance (6,8,9).

Severe immunosuppression

The risk of developing severe illness, and the risk of developing resistance to antivirals is higher in people with severe immunosuppression (further details are found in ‘Diagnostic testing and antiviral resistance’ section).  This is a subset of patients with immunosuppression and a narrower definition than those used in assessment of whether a patient is ‘at-risk’ (see ‘Risk factors for severe influenza and hospitalisation’ section). Degrees of immunosuppression are difficult to quantify, and individual variation exists, therefore this list is not comprehensive (6,10).

Examples of severe immunosuppression include:

• 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 ≥ 2mg/kg/day for ≥1 week in a child), and for at least 3 months after treatment has stopped
• people living with HIV 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 to 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

The influenza season

The influenza ‘season’ is the period of the year when influenza virus is known to be circulating in the community and is determined by UKHSA based on information from a range of influenza surveillance systems. It follows that the influenza season is a period of the year when there is a substantial likelihood that patients presenting with an influenza-like illness are infected with influenza virus (high pretest probability), and usually occurs in the autumn to spring in the northern hemisphere. Antiviral treatment should be considered for cases of virologically confirmed influenza and for influenza-like illness when the national influenza surveillance weekly report indicates that flu is circulating above baseline levels or where there is evidence of increased influenza circulation locally.

At the time of writing of this guidance, the influenza viruses known to circulate in humans on a seasonal basis are influenza A(H1N1)pdm09, A(H3N2), and B/Victoria. Detection of influenza virus out of season, unsubtypeable samples, or unexpected discrepancies between typing and subtyping assays may indicate a non-seasonal or zoonotic influenza and should prompt referral of the influenza-positive specimen to the local public health laboratory or the UKHSA national respiratory virus reference unit (RVU Colindale) for characterisation, following current UKHSA sample referral guidance.

Consideration of other influenza antivirals guidance

In 2024, the WHO published ‘Clinical practice guidelines for influenza’. Other public health agencies have also published guidelines on the use of antivirals for managing influenza, including within the UK devolved administrations. Furthermore, NICE have published TAs on seasonal influenza prophylaxis and treatment with oseltamivir and zanamivir, however, baloxavir marboxil is not included in any NICE TA to date because no evidence submission was provided by the manufacturer. Clinicians should note that the recommendations in the NICE TA for use of oseltamivir and zanamivir are covered in the NHS Constitution.

These UKHSA guidelines make use of both randomised trials and observational evidence, consider NICE TAs, cost effectiveness, and expert option.

Treatment of suspected or confirmed influenza

General advice

The 2 classes of direct acting antivirals (DAA) licenced in the UK for the treatment of seasonal influenza include neuraminidase inhibitors (NAI) (oral (PO) oseltamivir and inhaled (INH) or intravenous (IV) zanamivir) which target the NA glycoprotein; and cap-dependent endonuclease inhibitors (CENi) (PO baloxavir marboxil) (11,12,13,14) which act on the polymerase acidic (PA) protein.

A comprehensive approach to prevent severe influenza-related morbidity and mortality includes annual seasonal influenza vaccination and IPC practices, in addition to antiviral agents (6,15). A comprehensive approach to prevent severe influenza-related morbidity and mortality includes annual seasonal influenza vaccination and infection prevention and control practices, in addition to antiviral agents (6,15).

Inform all patients of the symptoms of severe influenza and to seek medical help should their condition worsen as patients with severe influenza should receive treatment in hospital in most cases.

DAAs have the greatest impact on influenza viral replication at the beginning of illness onset, or as post-exposure prophylaxis. Treatment should therefore be started  promptly, without waiting for results of testing, if severe influenza is suspected based on clinical presentation and/or epidemiological information.

Testing for influenza is recommended for all patients with severe respiratory illness (as defined above), as soon as possible, but should not delay initiation of antiviral treatment. Treatment with antivirals may be stopped if not clinically indicated following testing.

All influenza positive patients in critical care should have an influenza subtyping test (to differentiate A(H1N1) and A(H3N2)) to support IPC, national surveillance and identification of zoonotic infections (see sample referral guidance).

Co-infection with other pathogens is not a contraindication to prescribing influenza antivirals where prompt initiation for suspected or confirmed influenza is required.

Consider ‘follow up’ sampling and testing for antiviral resistance in patients who do not respond after 5 days of treatment especially if they are immunosuppressed or critically ill.

Principles of antiviral stewardship apply when prescribing antivirals in the treatment of influenza. In most cases this involves adhering to the recommendations of antiviral agent choice and duration. Further advice for specific circumstances is provided in the ‘Poor clinical response to first line treatment’ section and is available from specialists.

There remains a need to strengthen the evidence base for the relative effectiveness of different approaches to managing influenza. Considering patients for ethically approved randomised controlled trials will strengthen the knowledge base and is a decision for clinicians and their consenting patients.

The optimum antiviral choice is based on several considerations: clinical aspects included antiviral efficacy and cost, patient factors (see ‘Antiviral Resistance: Reduced Susceptibility to Antiviral Treatments’ section), and acceptable routes of administration.

All treatment recommendations in this section assume there is no confirmed antiviral resistance. The international evidence on risks of and from antiviral resistance are also part of the evidence considerations in development of these recommendations. See ‘Antiviral Resistance: Reduced Susceptibility to Antiviral Treatments’ section below for further details.

Treatment of adults and children in community or A&E with non-severe influenza

Non-severe influenza, previously healthy patient (excluding pregnant women):

• no antiviral treatment

or:

• if an independent prescriber believes that the patient is at risk of developing serious complications from influenza, then manage as per at risk population, below. See also [note 2]

Non-severe influenza, at risk population (as per the ‘Risk factors for severe influenza and hospitalisation’ section) (any circulating strain)

1st line: oseltamivir (PO/NG)

2nd line (where oseltamivir cannot be given): zanamivir (INH)

Note 2: Treatment may also be considered in order to reduce transmission to severely immunosuppressed household contacts. Antiviral treatment has been shown to reduce transmission from influenza case-patients to others, giving a potential role in indirect protection of at-risk household contacts (see also post-exposure prophylaxis recommendations) (78).

Refer also to section ‘Essential treatment considerations and contraindications, and when to use 2nd and 3rd line treatments’.

Key evidence to inform clinical decision making

• NICE TA168.
• an individual patient meta-analysis of the oseltamivir treatment trials suggests approximately 60% reduction in risk of all-cause hospital admissions (0.6% vs 1.7%, risk difference -1.1% (95%CI -1.4 to -0.3)) (16)

Treatment of adults and children with severe influenza

Severe influenza, any dominant circulating strain:

1st line: oseltamivir PO/NG

2nd line (where oseltamivir cannot be given): zanamivir INH

3rd line (Poor clinical response or concern about oseltamivir resistance development):  Consider adding baloxavir PO/NG [note 3] or switching to zanamivir IV [note 3]

Note 3: that there is a limited evidence base for adding CENi to NAI, and a limited evidence base on clinical outcomes from zanamivir intravenous (IV) use. Seek specialist advice. See below and ‘Antiviral Resistance: Reduced Susceptibility to Antiviral Treatments’ section.

If PO, NG or INH routes are unsuitable, IV zanamivir can be considered.

Refer also to section ‘Essential treatment considerations and contraindications, and when to use 2nd and 3rd line treatments’.

Key evidence to inform clinical decision-making

A meta-analysis summarised evidence from randomised controlled trials on treatment of severe influenza (17).

Whilst randomised clinical trials of antivirals (oseltamivir, zanamivir and baloxavir) administered to patients presenting to hospitalised settings have commonly been underpowered on key endpoints such as survival, observational data indicate NAI antivirals have clinical benefit including reduction of mortality and length of stay.

Starting antivirals early, within 48 hours of illness onset, shows the greatest benefit. Treatment beyond 48 hours is off label but also valuable. An individual level meta-analysis of patients hospitalised with A(H1N1)pdm09 found that initiation up to 5 days from onset was associated with mortality reductions (adjusted odds ratio 0.81, 95%CI 0.70 to 0.93), with early initiation providing the greatest reduction (aOR 0.50, 95%CI 0.37 to 0.67)(18).

Essential treatment considerations and contraindications, and when to use 2nd and 3rd line treatments

Oseltamivir

Standard dose oseltamivir PO or NG is adequately absorbed in critical illness (19,20) (see section on ‘Enteral absorption and absorption difficulties’ for further details). If the patient has already started PO oseltamivir, discuss with local infection specialists before changing to 2nd line or 3rd line antiviral recommendation.

Inhaled and Intravenous zanamivir

Consider inhaled zanamivir instead of PO/NG oseltamivir if:

• poor clinical response to oseltamivir

• confirmed strain with potential for oseltamivir resistance

• evidence of gastrointestinal dysfunction requiring discontinuation

• oseltamivir cannot be given for other reasons

Patients with good respiratory function despite their illness should use the Diskhaler® to deliver zanamivir, if able. Inhaled therapy is not appropriate for systemic disease with other organ dysfunction that could be directly caused by influenza. Prescribers should be mindful that some patients will not be able to use zanamivir Diskhaler® even with direct support by a pharmacist or specialist nurse. Feasibility of zanamivir Diskhaler® inhalation may be limited in patients with severe influenza. It is not licensed for use in children less than 5 years. Never administer zanamivir powder preparation for the Diskhaler® by nebuliser or to a mechanically ventilated patient.

Treatment of severely immunosuppressed patients with severe influenza with zanamivir is only recommended in circumstances where oseltamivir is unable to be administered or is unlikely to be effective. There is a greater body of evidence to support use of oseltamivir in severe influenza. Monitor clinically and if a clinician has concern about poor clinical response (see ‘Poor clinical response to first line treatment’ section) and/or suspicion of resistance, consider switching to 2nd or 3rd line options, see ‘Antiviral Resistance: Reduced Susceptibility to Antiviral Treatments’ section. Risk of treatment-emergent oseltamivir resistance is higher in A(H1N1)pdm09 infection.

Baloxavir marboxil

Baloxavir is licensed in the UK but has not undergone a NICE health technology appraisal (see ‘Note on other influenza antivirals guidance’ section), therefore prescribers should assess availability and supply where usage is planned, including Trust formulary inclusion and non-formulary processes. Do not delay initiation of antiviral treatment due to supply - start an alternative available treatment option. Early treatment of influenza is where the greatest benefit is seen.

See ‘Licensed treatments’ section for more information on the evidence base for baloxavir.

Baloxavir marboxil may be administered PO (film coated tablet) (SPC, BNF).

Due to increased risk of developing baloxavir-resistant influenza in severe immunosuppression and in children, monitor clinically to assess response to therapy. If poor clinical response (see ‘Poor clinical response to first line treatment’ section) and/or suspicion of resistance, see ‘Antiviral Resistance: Reduced Susceptibility to Antiviral Treatments’ section.

Risk of treatment-emergent baloxavir resistance appears higher in A(H3N2) infection.

The FLAGSTONE trial of baloxavir plus NAI vs NAI did not find difference in time to clinical improvement (13), though one post-hoc analysis of selected risk groups suggests some may benefit from dual therapy (77).

Prescribing antivirals for treatment

Tables 1a to c. Antiviral dosage and schedules: NAIs   

Table 1a. Treatment dosage of Oseltamivir PO
(treatment course: 5 days) [note 4]

Age group	dose
Premature (less than 36 weeks post conceptional age)	1mg/kg/dose BD Off-label [note 5]
Infants under 12 months (36 weeks post conceptional age or greater)	3mg/kg/dose BD
Children 1 to 12 years: 10 to 15kg	30mg BD
Children 1 to 12 years: more than 15 to 23kg	45mg BD
Children 1 to 12 years: more than 23 to 40kg	60mg BD
Children 1 to 12 years: over 40kg	75mg BD
Adults (13 years and over)[note 6]: up to 41 kg	60mg BD
Adults (13 years and over)[note 6]: 41kg and above	75mg BD

Table 1b. Treatment dosage of Zanamivir INH
(treatment course: 5 days)

Age group	dose
Children under 5 years old	Not licensed
Children 5 to 17 years	10mg BD
Adult	10mg BD

Table 1c. Treatment dosage of Zanamivir IV
(treatment course 5 to 10 days)

Age group	dose
Children 6 months to 5 years	14mg/kg BD
Children 6 to 17 years	12mg/kg BD (max 600mg per dose)
Adult	600mg BD

Note 4: Recommendation from manufacturer regarding treatment length for immunosuppressed patients. Source: Summary of Product Characteristics updated May 2021 (15).

Note 5: This is an off-label use of oseltamivir, and is based on evidence from the literature, and expert opinion (21,22,23).

Note 6: If a person in this age group weighs 40kg or less, it is suggested that the more than 23 to 40kg dose for those aged 1 to 12 years, is used.
Dosing in renal impairment is described in ‘Dosing of antivirals in patients with renal dysfunction’ section.

Duration

• Oseltamivir PO may be given for 5 days and extended to 10 days in immunosuppressed patients
• Zanamivir INH may be given for 5 days
• Zanamivir IV may be given for up to 10 days for the treatment of severe influenza

See ‘Continuing antiviral therapy beyond 5 days’ section for further advice on when to extend treatment.

Oseltamivir oral suspension

Oseltamivir oral suspension should be prioritized for those unable to use capsules (as described below), such as for children under the age of 1 year. It is available as Tamiflu® oral suspension (Roche, 6mg/mL oral suspension reconstituted from powder). The pack includes an oral dispenser, which is marked in milliliters (mLs), since prescriptions for Tamiflu® 6 mg in 1 mL powder for oral suspension should state the dose in mLs. Children over 1 year of age and adults with swallowing difficulties, and those receiving nasogastric oseltamivir, should use capsules which are opened and mixed into an appropriate sugary liquid as oseltamivir has a very bitter taste. If the powder for suspension is used for children over 1 year of age and/or adults, there may not be adequate quantities of the powder for suspension to meet demand for the less than 1 year age group. It is important that the powder for suspension is reserved for the under 1 year age group.

Dosing for extremes of weight

No dose adjustment is needed in obese patients for oseltamivir, and zanamivir (INH and IV) (24,25). See Table 1, note 6 for dosing related to adults weighing 40kg or less.

The dose of IV zanamivir is not weight adjusted for adults and adolescents with actual body weight 50kg or greater, the dose is not weight adjusted.

For specific dosing information, please refer to the summary of product characteristics (26).

Antiviral dosage and schedules: CENi

Table 2. Treatment dosage of baloxavir marboxil according to weight

Body weight	< 20 kg	20 kg to 79 kg	80 kg and over
Dose of baloxavir marboxil	2 mg/kg	40 mg (tablet)	80 mg (tablet)

Duration: baloxavir marboxil is licensed as a single dose. There is insufficient evidence that increasing the duration of treatment provides an additional benefit. However, there are examples of repeated dosing being used safely in clinical trial settings (20,27).

No change of dosing is required in renal or hepatic dysfunction.

Further Information: Baloxavir marboxil has been studied in treatment trials involving patients older than 5 years, with adverse events similar to those observed in adults (19). There are limited data available for patients aged 5 years or younger (14). The pharmacokinetics of baloxavir marboxil in paediatric patients under 1 year of age have not been established (12).

Dosing in paediatric populations

The British National Formulary (BNF) reports weight based dosage recommendations for children from 12 to 17 years, of 40mg for 1 dose for body weight up to 79kg, and 80mg for 1 dose for body weight 80kg and above (28). The European Medicines Agency has produced further information about dosing in paediatric patients (29). Seek further dosing advice from local pharmacists.

Baloxavir marboxil is not currently recommended for use in pregnant individuals due to insufficient safety and efficacy data for treating pregnant and postpartum patients; see section ‘Use of antivirals in pregnancy, breastfeeding and the neonatal period’ for treatment of pregnant patients (30).

Dosing of antivirals in patients with renal dysfunction

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. For older adults in care homes and similar settings where renal function may be unknown (not available in clinical records or through urea and electrolytes testing in time to inform prescribing), see the UKHSA care home guidance (1).

The choice of dose in renal failure is complicated by the different measures available to describe degree of renal impairment, as well as a lack of specific data in some circumstances. Creatinine Clearance (CrCl) is used in this document as it is a more accurate measure upon which to make dosing recommendations and is congruent with the manufacturers prescribing information for both oseltamivir and zanamivir. The limitations for using estimated glomerular filtration rate (eGFR) are described in the British National Formulary (‘Prescribing in renal impairment’). CrCL can be estimated in adults by utilising the Cockcroft and Gault equation. Both eGFR and CrCl (using Cockcroft and Gault) assume the patient’s renal function is stable. Clinical judgement will be required where renal function is unstable (in acute renal failure).

It is recognised that eGFR may be more readily available at the outset of therapy. If this is the only value available, then do not delay therapy and prescribe a dose according to eGFR (substituting eGFR for the CrCL figure in the tables 4 and 5). Some patients may receive a larger oseltamivir dose as a result, but this is unlikely to be harmful as clinical experience reveals a wide margin of safety. The use of IV zanamivir is anticipated to only occur in hospitals, and as such all the data necessary to make a CrCl calculation will be available, so do not use eGFR in this setting.

Table 3. Recommended oseltamivir treatment dosing in relation to renal function (adults and young people aged 13 years or over)

CrCL (mL/min)	Oseltamivir PO treatment for 5 Days
Greater than 60mL/min [note 7]	75mg BD
31 to 60 mL/min [note 7]	30mg BD
11 to 30mL/min [note 7]	30mg OD
Haemo-dialysis (HD) [note 8]	30mg ONCE and then 30mg after every HD session
Continuous Ambulatory Peritoneal Dialysis [note 7] (refer to Summary of Product Characteristics for advice in relation to automated peritoneal dialysis [APD] mode)	30mg ONCE
Haemo(dia)filtration [note 8] 1 to 1.8L/hr exchange rate	30mg OD
Haemo(dia)filtration [note 8] 1.9,3.6L/hr exchange rate	30mg BD
Haemo(dia)filtration [note 8] Greater than 3.6L/hr exchange rate	75mg BD

Note 7: Source: Summary of Product Characteristics updated April 2020.

Note 8: The recommendations for haemo-dialysis, haemo(dia)filtration and established renal failure are based on expert opinion.

Note: It is acknowledged that the some of the advice for dosing in renal impairment presented in Table 3 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.

Table 4. Adult zanamivir IV dosing for adults and children (6 years and over with a body weight of ≥50kg) in relation to renal function

CrCl (mL/min)	Dose
Greater than or equal to 80mL/min or haemo(dia)filtration greater than 4.7L/hour exchange rate	Initial dose: 600mg and 12 hours later, maintenance dose: 600mg BD
50 to 79 or haemo(dia)filtration 3.0 to 4.7L/hour exchange rate	Initial dose: 600mg and 12 hours later, maintenance dose: 400mg BD
30 to 49 or haemo(dia)filtration 1.8 to 2.9L/hour exchange rate	Initial dose: 600mg and 12 hours later, maintenance dose: 250mg BD
15 to 29 or Haemo(dia)filtration 1 to 1.7L/hour exchange rate	Initial dose: 600mg and 24 hours later, maintenance dose: 150mg BD
less than 15	Initial dose: 600mg and 48 hours later, maintenance dose: 60mg BD

Source: Adapted from the SPC (31)

Details of administering IV zanamivir are provided in the SPC which specifies that “the dose can be infused as supplied or diluted in sodium chloride 9 mg/mL (0.9%) solution for injection down to any concentration greater than or equal to 0.2 mg/mL”(26) .

Details of use of IV zanamivir for patients under 18 years can be found in the SPC (31) (#R16) Further dosing information on dosing in haemodialysis, if needed, can be found in the SPC.

For children with renal dysfunction aged less than 13 years, adjust the oseltamivir dose as per the Oseltamivir chapter in the BNF for children.

Some patients receiving renal replacement therapy in critical care will also have some residual renal function, and renal replacement therapy itself may be interrupted for a variety of reasons. Critical care units should discuss further dose adjustments with their pharmacist.

There is no dose adjustment required for baloxavir marboxil in renal dysfunction.

Dosing of antivirals in patients with hepatic dysfunction

Changes in dosage for patients with hepatic dysfunction should be made in reference to Table 5.

Table 5. Recommended dosage for hepatic dysfunction

	Liver dysfunction
Oseltamivir PO	Standard dosing SPC
Zanamivir INH (Diskhaler®)	Standard dosing SPC
Zanamivir IV	Standard dosing SPC
Baloxavir marboxil PO	No dose adjustment is required for patients with mild or moderate hepatic impairment (Child-Pugh class A or B). The safety and efficacy of baloxavir marboxil has not been established in patients with severe hepatic impairment (Child-Pugh class C). SPC

Use of antivirals in pregnancy, breastfeeding and the neonatal period

Use in pregnancy

Antivirals are recommended in pregnancy due to the adverse clinical outcomes that have been observed for influenza infection in this group.

1st line: oseltamivir PO

2nd line: zanamivir INH

Oseltamivir is the first line option for the vast majority of cases of influenza in pregnancy, including during seasons that are dominated by influenza A(H1N1)pdm09. For pregnant patients who meet additional criteria for requiring zanamivir first line, further assessment (that is, 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 is no data suggesting tolerability differs between pregnant and non-pregnant patients. Recent studies suggest there is no evidence of harm in pregnant patients treated with oral oseltamivir or inhaled zanamivir (32,33,34). However, published data is limited.

The use of oseltamivir may be considered during pregnancy if necessary and after considering the available safety and benefit information, including the pathogenicity of the circulating influenza virus strain. For manufacturer’s information on use in pregnancy please refer to SPC sections 4.6 ‘Pregnancy’ and 5.1 ‘Treatment of influenza in pregnant women’  (35)

Zanamivir: for manufacturer’s information on use of inhaled Relenza® (zanamivir) in pregnancy please refer to SPC section 4.6 ‘Pregnancy’, and for IV zanamivir use section 4.6 of the Dectova® SPC (26,36).

Baloxavir marboxil: the BNF advises to avoid use in pregnancy due to limited information available (37). The SPC advises that as a precautionary measure, it is preferable to avoid the use of baloxavir during pregnancy, noting there are no or limited data from the use of baloxavir marboxil in pregnant women but that animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (38)

Use during breastfeeding

NAIs: The UK Drugs in Lactation Advisory Service (UK DILAS) has published advice on the use of Oseltamivir and Zanamivir while breastfeeding.

Baloxavir marboxil

Seek specialist advice. Baloxavir is present in animal studies in milk. Baloxavir is licensed from 3 weeks of age and if there is lactational transfer this may not be disadvantageous to infants exposed to maternal influenza, though is unlikely to be protective, with oseltamivir required for at risk infants if post exposure prophylaxis (PEP) is indicated (see 3.3) (38) 

Management of neonates exposed after birth

Clinicians may be faced with situations where a pregnant patient is diagnosed with laboratory confirmed seasonal influenza shortly before the onset of labour. The potential mode of influenza transmission in this situation is via direct contact from infected respiratory secretions rather than via breastmilk itself.

There are limited data on seasonal influenza infection in neonates. Severe outcomes were reported in 9.3% of children aged under 12 months in the UK who were hospitalised with Influenza A(H1N1pdm09) during the 2009 to 2010 pandemic (14). More recent infant influenza mortality data record 18 deaths in the less than 1 year old age group (12 of whom were under 6 months of age) during 2009 to 2017 seasons in Spain, with an admission rate of 156 admissions per 100,000 (95% CI 152.4-160.6) from the Spanish Surveillance System for Hospital Data (39).

According to the SPC for Tamiflu® (oseltamivir):

• for post-exposure prophylaxis for the prevention of influenza infection, oral suspension may be given only to infants aged over 1 year, use in younger infants is an off-label use
• treatment of seasonal influenza is with Oseltamivir is licensed for children including full term neonates using capsules and Tamiflu® (oseltamivir) 6mg/mL powder for oral suspension
• Relenza® (zanamivir) inhalation powder is not licensed for treatment or prophylaxis in children under 5 years

In addition antiviral treatment of pregnant or postpartum patients, the following options may be considered for management of the neonate:

1. Oseltamivir oral suspension for post-exposure prophylaxis in the neonate, as an off-label indication.
2. Physical separation of the symptomatic mother and asymptomatic neonate until 5 days after the onset of symptoms:
   • discuss with parents the risk of neonate infection and the potential impacts of separation including loss of benefits from breastfeeding-related transfer of immune factors to help protect neonate, loss of nutrients for development from breastfeeding, and loss of maternal-neonate contact
   • if physical separation is chosen, encourage the mother to express breastmilk so that the neonate can receive the benefits of breastmilk, and to maintain the mother’s milk supply so that breastfeeding can continue once they are reunited. More detailed advice on use in breastfeeding should be sought from the SPC and the UK Drugs in Lactation Advisory Service (DILAS) advice.
3. No prophylaxis for the neonate and no separation of neonate and mother. This will require:
   • careful monitoring for symptoms of influenza
   • a discussion in advance with the mother about prompt antiviral treatment of the neonate
   • arrangements made in advance for rapidly accessing oseltamivir oral suspension (as this is more readily available via hospital pharmacies than community pharmacies)
   • consideration of laboratory testing of a symptomatic neonate, as per existing local practice
   • giving the mother advice on non-pharmaceutical measures to reduce transmission, including advice to wash their hands with soap and water, particularly before breast feeding or touching any other item that the neonate will have contact with. If expressing breast milk using a pump, this should be cleaned as per the manufacturer’s instructions

UKHSA recognises that the decision on which action to take is likely to involve a detailed discussion between the parents or guardians and their clinicians about the relative advantages and disadvantages of each potential option in relation to their own individual situation. This advice does not constitute a specific endorsement of the routine use of oseltamivir oral suspension for prophylaxis in neonates but recognises that this may occur as an off-label use in specific circumstances.

These scenarios highlight the importance of seasonal influenza vaccination in pregnancy. Previous research has shown that this was 71% effective in preventing influenza infection in infants aged less than 6 months in England (37,40).

Poor clinical response to first line treatment

Definitions

A poor clinical response may manifest as failure to improve, progressive lower respiratory tract signs or symptoms, or new or progressive multi-organ dysfunction in a patient receiving first line antiviral treatment.

Failure to improve or clinical deterioration may be explained because of uncontrolled viral infection, made worse by resistance to treatment. However, non-virological phenomena may cause failure to improve such as the natural progression of acute lung injury and the inflammatory response seen in influenza illness, or by secondary infections for example bacterial co-infection. Therefore, the assessment of whether a patient has a poor clinical response can only be made by the treating clinician.

The main points for consideration regarding resistance to antivirals are:

• N1-containing influenza viruses such as A(H1N1)pdm09 virus are more likely to develop reduced susceptibility if treated with oseltamivir (14)
• A(H3N2) influenza infections in children are more likely to lead to emergence of resistance to CENi drugs

Other scenarios where resistance development should be considered include:

• severely immunosuppressed patients
• contacts of treated cases
• infancy and young age
• patients who have switched antivirals, particularly if they have received non-concurrent antiviral treatments in the same illness episode
• patients who become influenza positive whilst, or shortly after, receiving antiviral prophylaxis
• influenza positive contacts of confirmed cases of NAI or CENi resistance

These patients are at a greater risk of developing influenza that is resistant to treatment and might be explained by the prolonged durations of infection and/or greater viral burden seen in these groups compared with others. Rapid emergence of oseltamivir resistance (as early as 48h after starting treatment) has been described, particularly in severely immunosuppressed patients. (42) Emergence of resistance to baloxavir has been found to be more prevalent in children in data from clinical trials and routine use in Japan (see ‘Antiviral Resistance: Reduced Susceptibility to Antiviral Treatments’ section).

Influenza testing for antiviral resistance

Influenza antiviral susceptibility surveillance is performed (using whole genome sequencing) by the national reference laboratory (Respiratory Virus Unit (RVU) Colindale) to identify substitutions associated with resistance, whilst meeting reporting requirements to the WHO which informs treatment guidance.

Treatment interruption should be avoided (for example when awaiting results of follow-up testing), since interruption itself may be associated with the development of antiviral resistance.

If urgent testing is required for impacting clinical decisions during the acute illness period, laboratories should contact the UKHSA RVU reference laboratory (telephone: 020 8327 7125 / 7002) before sending samples for sequencing with the explicit purpose of antiviral genotypic testing. The routine turnaround time for results on these samples is such that the results are unlikely to be able to impact on patient management, unless specific arrangements are made.

If samples are sent to RVU for antiviral resistance testing, follow up swabs should also be taken and sent. Both pre-treatment and post-treatment samples will allow assessment of whether resistance is de novo or treatment associated, and comparing estimated viral load between the initial and repeat sample can help determine the antiviral effect. (41)

Provide as much clinical information as possible on the laboratory request form including patient’s background, history of immune suppression, exposure history, with dates and details about the course of antiviral medications received. Further information is found in the ‘Antiviral Resistance: Reduced Susceptibility to Antiviral Treatments’ section).

Use of oseltamivir if zanamivir resistance is suspected

Recent antiviral resistance surveillance data for seasonal influenza viruses demonstrates that resistance to oseltamivir remains far more common than resistance to zanamivir. (14) Several mutations that confer resistance to zanamivir are also associated with resistance or reduced susceptibility to oseltamivir.

If zanamivir resistance is believed to be a possibility, then continue zanamivir treatment and arrange urgent resistance testing. Advice should be sought from local infection specialists, who may wish to seek additional advice from virologists at regional public health laboratories. In cases of influenza with confirmed dual oseltamivir and zanamivir resistance, virologists at the regional public health laboratory or the RVU Colindale will offer advice to the local team. Adding in or switching to therapy with baloxavir may be considered in these cases.

Antivirals for post-exposure prophylaxis against influenza

Eligible groups and selection of antivirals for prophylaxis

Oseltamivir and zanamivir may be used for prophylaxis of persons in at-risk groups following exposure to a person in the same household or residential setting with influenza-like illness when influenza is circulating in the community. NICE provides information on post-exposure prophylaxis of influenza (8,43). Use of prophylaxis outside the NICE recommendations is a matter for individual clinical judgement within local governance and operational arrangements. See ‘Diagnostic Testing for Influenza Virus’ section for advice on diagnostic testing. Special considerations and guidelines may apply to localised incident situations and outbreaks, such as in care homes and ‘prisons and prescribed places of detention’ (1,2). Seek specialist advice from local health protection teams in relation to specific incidents.

Prescribe an antiviral drug for post-exposure prophylaxis (PEP) if all the following circumstances apply:

• the person has had contact with a person strongly suspected (on basis of community prevalence) and clinical features) or known to have influenza.
• the person is in an ‘at risk’ group and has not been adequately protected by vaccination because:
  • they have not been vaccinated within the same influenza season
  • there has been less than 14 days between vaccination and date of contact with influenza
  • there is low confidence the vaccine gives good protection against the influenza strain they are known or suspected to have been infected with based on testing of the case or national surveillance of circulating strains (for example where national surveillance indicates that a drifted strain is circulating)
  • Note: if the person has been exposed due to a localised outbreak for example in a care home PEP can be considered regardless of vaccination status
• the person can start PEP within 48 hours of this contact for oseltamivir or 36 hours for zanamivir
  • PEP after 48 hours for oseltamivir or 36 hours for zanamivir is off-label use but can be done in consultation with a local infection specialist, such as a virologist, or a consultant in health protection. Note that in institutional outbreaks, ongoing exposures may occur due to new-onset cases and may support initiation beyond 48 or 36 hours from exposure to the index or primary cases

For neonatal exposure, see advice for neonates exposed to influenza.  

Selection of antivirals for post exposure prophylaxis

Previously healthy patient (excluding pregnant women)

No prophylaxis.

At risk population (see ‘Risk factors for severe influenza and hospitalisation’ section)

Any dominant strain, except where exposure is to confirmed oseltamivir resistant influenza:

• 1st line oseltamivir PO once daily for 10 days should be offered if therapy can be started within 48 hours of last exposure (or after 48 hours on advice of a consultant in health protection or other local infection specialist)
• 2nd line: zanamivir INH once daily for 10 days if therapy can be started within 36 hours of last exposure (or after 36 hours on advice of a consultant in health protection or other local infection specialist), except in children aged less than 5 years

Where exposure is to confirmed oseltamivir resistant influenza:

• 1st line: zanamivir INH once daily for 10 days if therapy can be started within 36 hours of last exposure (or after 36 hours on advice of a consultant in health protection or other local infection specialist), except in children aged less than 5 years.

• 2nd line:

  • baloxavir marboxil single dose if therapy can be started within 48 hours of exposure (or after 48 hours on advice of a consultant in health protection or other local infection specialist), except in pregnant women or infants under 3 weeks old (see ‘Antiviral dosage and schedules: CENi’ section) or

  • monitor closely and begin treatment promptly if ILI symptoms develop

Baloxavir marboxil is not the first choice for post-exposure prophylaxis but may be considered in circumstances where its properties are most suitable for the specific situation, (such as where oseltamivir resistance has been confirmed and zanamivir cannot be administered) in discussion with an infectious disease specialist, see ‘Treatment of suspected or confirmed influenza’ section.

Antiviral dosage and schedules for prophylaxis: NAI  

Table 6a. Antiviral dosage and schedules for post-exposure prophylaxis: Oseltamivir PO (prophylaxis course: 10 days)

Age group	Dose
Premature (less than 36 weeks post conceptional age)	Seek advice from an infection specialist [note 9]
Infants under 12 months (36 weeks post conceptional age or greater)	3mg/kg od
Children 1 to 12 years: less than or equal to 15kg	30mg od
Children 1 to 12 years: more than 15 to 23kg	45mg od
Children 1 to 12 years: more than 23 to 40kg	60mg od
Children 1 to 12 years: more than 40kg	75mg od
Adults (13 years and over) [note 10]	75mg od

Table 6b. Antiviral dosage and schedules for post-exposure prophylaxis: Zanamivir INH (prophylaxis course: 10 days)

Age group	Dose
Children under 5 years old	Not licensed
Children aged 5 and above	10mg od
Adults (13 years and over) [note 10]	10mg od

Note 9: Although it may be possible to provide half the treatment frequency, each day for 10 days, there is currently no publicly available dosing information for oseltamivir prophylaxis in pre-term infants, and so is outside the product licence (source: expert advice).

Note 10: If a person in this age group weighs 40kg or less, it is suggested that the greater than 23 to 40kg dose for those aged 1 to 12 years, is used.

Further information

Oseltamivir oral suspension is available as Tamiflu® oral suspension (Roche, 6mg/mL powder for oral suspension). This preparation replaces the 12 mg in 1 mL suspension. The new pack includes an oral dispenser, which is marked in millilitres (mLs), since prescriptions for Tamiflu® 6 mg in 1 mL powder for oral suspension should state the dose inmLs. Check the BNF for Children for further information on dosing. Children over 1 year and adults with swallowing difficulties, and those receiving nasogastric oseltamivir, should use capsules which are opened and mixed into an appropriate sugary liquid as oseltamivir has a very bitter taste. If the powder for suspension is used for children over 1 year of age and/or adults, there may not be adequate quantities of the powder for suspension to meet demand for the under 1 year age group. It is important that the powder for suspension is reserved for the less than 1 year age group. Inhaled zanamivir is not licensed for children aged under the age of 5 years and is unlikely to be an effective delivery route in these patients. Some other patients, such as those with severe underlying respiratory disease or impaired cognition, may also be unable to use the Diskhaler® effectively.

Severely immunosuppressed patients who cannot use the Diskhaler®, including severely immunosuppressed children under 5 years, who require prophylaxis after exposure to currently circulating antiviral sensitive strains of influenza should receive oral oseltamivir, with advice to seek immediate medical attention if symptoms develop subsequently.

Patients in this group who are exposed to suspected or confirmed oseltamivir resistant influenza should be discussed with a specialist. These individuals should receive close clinical monitoring following exposure with arrangements to receive prompt treatment following onset of influenza like illness symptoms.

Baloxavir marboxil, where available, may be considered with caution on discussion with specialists where there is no other option, such as in instances of dual oseltamivir and zanamivir resistance, other antivirals are unsuitable, and where there is highest risk of morbidity in ‘at risk’ patients such as for severely immunosuppressed patients.

Antiviral dosage and schedules for prophylaxis: CENi

There are limited data available for patients aged 5 years or younger (14). Additionally, the pharmacokinetics of baloxavir marboxil in paediatric patients under 1 year of age have not been established.(12)

Table 7. Prophylaxis dosing of baloxavir marboxil by weight

Body weight	Dose of baloxavir marboxil
< 20 kg	2 mg/kg (as suspension)
20 kg to 79 kg	40 mg (tablet)
80 kg and over	80 mg (tablet)

Antiviral dosage for prophylaxis in patients with renal dysfunction

General considerations about prescribing for renal impairment may also be applicable when prescribing for prophylaxis (see ‘Dosing of antivirals in patients with renal dysfunction’ section), except that the dosage of oseltamivir in Table 8 should be used.

Table 8. Recommended oseltamivir prophylaxis dosing in relation to renal function (adults and those aged 13 years or over)

CrCL (ml/min)	Oseltamivir PO prophylaxis for 10 days
More than 60mL/min [note 11]	75mg OD
31 to 60 mL/min [note 11]	30mg OD
11 to 30mL/min[note 11]	30mg every 48 hours
Less than or equal to 10mL/min [note 12]	30mg ONCE, repeated after 7 days
Haemodialysis (HD) [note 12]	30mg ONCE and then 30mg after every second HD session
Continuous Ambulatory Peritoneal Dialysis [note 11] (refer to Summary of Product Characteristics for advice in relation to automated peritoneal dialysis [APD] mode)	30mg ONCE, repeated after 7 days
Haemo(dia)filtration[note 12] 1-1.8L/hr exchange rate	30mg every 48 hours
Haemo(dia)filtration[note 12] 1.9 to 3.6L/hr exchange rate	30mg OD
Haemo(dia)filtration[note 12] Greater than 3.6L/hr exchange rate	75mg OD

Note 11: Source: Summary of Product Characteristics.

Note 12: The recommendations for haemo-dialysis, haemo(dia)filtration and established renal failure are based on expert opinion.

Note: this dosage information in renal dysfunction is based on expert opinion, with reference to the most recent summary of product characteristics (44) and may differ from the renal drug handbook.

No difference in prophylaxis dosing for high flux and low flux intermittent haemodialysis (HD) is recommended due to a lack of published clinical data on oseltamivir carboxylate levels in high-flux intermittent HD patients. This advice is expert opinion based on information on pore size, oseltamivir carboxylate molecule size and likely length of HD sessions.

For renal dosing in children aged less than 13 years, refer to the oseltamivir monograph in the BNF for children.

Additional clinical scenarios and considerations

Continuing antiviral therapy beyond 5 days

The optimal duration of treatment is not clear for hospitalised patients with influenza. Extending the duration of treatment to at least 10 days may be appropriate in some patients with severe influenza (such as critically ill patients) and management should be discussed with specialists. Prolonged treatment can be associated with the development of antiviral resistance, particularly in immunosuppressed patients, and antiviral resistance monitoring is recommended.

The manufacturer of oseltamivir recommends a longer treatment course of 75mg PO twice daily for 10 days for severely immunosuppressed patients (44). Treatment for longer than 5 days is off-label in other patients.

The recommended duration of IV zanamivir for the treatment of severe influenza in special circumstances is 5 to 10 days.

Repeat dosing of baloxavir can be considered in discussion with a specialist. The FLAGSTONE trial showed repeat doses were well-tolerated (19).

Antiviral prophylaxis in unvaccinated healthcare workers with no underlying illness

Currently, prophylaxis is only given to at-risk groups and is not recommended as an alternative to influenza immunisation. The use of prophylactic antivirals in individuals not in risk-groups as a way of controlling an outbreak in hospital settings is not recommended by the UKHSA Immunisation and Vaccine-Preventable Diseases Division. Healthcare worker contacts of a case who are not in an at-risk group may continue to work, using appropriate personal protective equipment and should rapidly report any illness. They should then be excluded from work promptly if they develop symptoms consistent with influenza-like illness. The importance of seasonal influenza immunisation of healthcare workers needs to be emphasised as does the advice for staff not to come to work if they are ill. 

Influenza-like illness in individuals with a prior influenza infection within the same season

Where a patient presents with influenza-like illness following a prior laboratory confirmed influenza infection within the same season, the 2 infections should be considered separately, and treatment given, if indicated, on both occasions. It is entirely possible that the first infection is with one influenza virus, and the infection later in the season with a different type or subtype so there would not be a protective effect from the first exposure.

Use of higher dose oseltamivir treatment

An increase in dosage is not recommended in patients with severe illness caused by influenza A virus infection, due to a lack of evidence that it is any more effective (5,45,46).

Although it has been previously reported that higher inhibitory concentrations of oseltamivir carboxylate are required to produce an effect on influenza B in in-vitro tests (47), there is insufficient clinical evidence to suggest that double-dosing in patients with influenza B has a clinical benefit (48).

Administering live attenuated influenza vaccine (LAIV) at the same time as influenza antiviral agents

Chapter 19 (Influenza) of ‘Immunisation against Infectious Diseases’ states: “There is a potential for influenza antiviral agents to lower the effectiveness of LAIV. Therefore, influenza antiviral agents and LAIV should not be administered concomitantly. LAIV should be delayed until 48 hours following the cessation of treatment with influenza antiviral agents. Administration of influenza antiviral agents within 2 weeks of administration of LAIV may adversely affect the effectiveness of the vaccine” (6).

Enteral absorption difficulties

When managing critically unwell patients, it is important to differentiate between those with defined absorption defects (such as patients receiving total parenteral nutrition, gastric stasis, malabsorption states, gastrointestinal haemorrhage) and those with dysmotility as a consequence of their critical illness.

In critically unwell patients where there is no defined absorption defect, an increase in oseltamivir dosage is not recommended because there is a lack of evidence of increased efficacy over standard dosing (45,49, 50, 51).

In a cohort of 41 critically unwell patients (70% of whom had nasogastric (NG) or nasojejunal (NJ) tube in situ but with no documented absorption defect) the dosage of oseltamivir 75mg twice daily achieved plasma levels far in excess of concentrations required to maximally inhibit neuraminidase activity, regardless of NG/NJ feeding status.(52,53). 

For patients with defined absorption defects, therapeutic concentrations of oseltamivir may not be achieved with oral or NG administration at standard PO dosing. IV zanamivir may be considered in special circumstances, though clinicians should note that the evidence base for IV zanamivir is more limited than that of oseltamivir for reducing mortality and severity in the treatment of severe influenza. There is also limited evidence to support increasing the dose of orally or nasogastrically delivered oseltamivir in cases of reduced gastric absorption, though administering oseltamivir at an increased dose is unlikely to be harmful (5). Specialist advice should be sought on a case-by-case basis.

Influenza associated encephalopathy

Influenza associated encephalopathy (IAE), and in particular acute necrotizing encephalopathy (ANE) are rare complications of influenza infection that predominantly affect children, may be more associated with A(H1N1)pdm09 (although ANE has been seen in both A(H1N1) and A(H3N2)), and are generally considered to be caused by host immune response. In Japan during 2010 to 2015, the case fatality rate for IAE in those under 18 years of age was 8%. (5,54,55). Further consensus definitions for infection triggered encephalopathy syndromes including the above are found in this reference (57).

Influenza positive patients should be treated with antivirals as per routine guidance. However, efficacy of antivirals on the outcome of neurological sequalae is unknown, and evidence is lacking on penetration of antivirals to the central nervous system.

In one adult case series from Hong Kong, CSF (cerebrospinal fluid) was sampled in a three unwell elderly patients with influenza and encephalopathy. The concentration in CSF of the active drug oseltamivir carboxylate (OC) was 12% to 13% of the OC plasma concentration. No direct evidence of viral neuroinvasion was found, cytokines were raised in CSF and blood (55).

Diagnostic testing and antiviral resistance

Diagnostic Testing for Influenza Virus

Recommendations on the use of diagnostic tests when considering antiviral initiation in at-risk patients

Where available, multiplex reverse transcriptase polymerase chain reaction (RT-PCR), lateral flow antigen tests, and other validated diagnostic tests for SARS-CoV-2, influenza A, influenza B and potentially other respiratory viruses can be used to strengthen diagnosis and support prompt initiation of influenza antivirals where appropriate.

POCT are molecular or antigen based diagnostic tests, performed at or near the site of patient care to support clinical decision making, undertaken by healthcare professionals who may not be trained laboratory staff and for which the results can be available in real time, usually in less than 90 minutes. In general, antigen tests, including lateral flow devices, have lower sensitivity than RT-PCR for influenza detection but good specificity. The positive predictive value (PPV) of tests with this profile can be high in times of high prevalence, during the influenza season. Users should note that prevalence impacts PPV and negative predictive value (NPV) of tests and exert judgement where antigen testing is used to guide clinical treatment and IPC decisions, given clinical evidence base for their use is currently limited.

Key principles in the use of diagnostic tests to inform treatment decisions:

• testing for influenza is recommended in all patients admitted to hospital with severe influenza, but should not delay initiation of antiviral treatment
• if POCTs or rapid RT-PCR for respiratory viruses are unavailable, prompt NAI initiation prior to virological testing is recommended, as early initiation of therapy is associated with clinical benefit
• reassess indication for antiviral treatment once test results are available
• during the ‘out-of-season’ period when influenza is not circulating, treatment is usually guided by influenza diagnostic tests - however, if the patient has onset during a virologically confirmed influenza outbreak in a closed setting, then this would be indication for empirical initiation of treatment

The suspicion or confirmation of another respiratory virus is not a contraindication to antiviral initiation where suspected or confirmed influenza is part of the differential diagnosis. However, diagnostic evidence should be attempted for influenza virus infection. There can be prolonged detection by RT-PCR of respiratory viruses after the acute illness.

For empirically initiated influenza treatment, clinicians may continue with treatment where there is strong clinical suspicion despite a negative influenza result, guided by factors such as an epidemiological link to a case, notification of high community incidence of influenza and/or absence of an alternative diagnosis.

In community or primary care settings antivirals should be provided through a suitable commissioned service for prophylaxis in- or out-of-season.

Performing diagnostic sampling for influenza when commencing antiviral post-exposure prophylaxis

Considerations on the need for diagnostic testing to inform antiviral post-exposure prophylaxis depend on influenza epidemiology at the time of exposure and the type of index case:

• during the ‘in-season’ period when influenza is circulating, undertake testing for influenza in the index cases alongside other respiratory viruses if available, but testing is not required for antiviral initiation and should not delay initiation of therapy
• during the ‘out-of-season’ period when influenza is not circulating, NAI use is usually guided by prompt influenza testing of the index cases
• for contacts of an immunosuppressed or critically ill patient with confirmed influenza, diagnostic sampling is recommended due to the possible risk of exposure to an influenza virus that is resistant to antivirals - do not postpone prophylaxis while the results of influenza testing are awaited

If testing reveals that a patient commenced on a prophylactic dose of an antiviral is infected with influenza virus, then stop prophylaxis, and commence a treatment course of antivirals immediately. Do not count any prophylactic doses received when determining the duration of treatment antivirals. Infection control measures should be implemented. In the absence of influenza symptoms, cessation of these infection control measures will need to be considered locally by an infection specialist, on a case-by-case basis.

Specialist advice is available from local health protection teams and public health virologists for prophylaxis in healthcare settings where repeated or ongoing exposure is suspected.

An alternative to prophylaxis in some clinical settings may be to monitor persons exposed to an influenza case and start antiviral treatment promptly when symptoms of influenza start. It is recommended that such an arrangement is undertaken only when:

• the patient (or their carer) has been provided with information on symptoms prompting antiviral use, potential adverse events, and has decided to take antiviral medicines for treatment rather than prophylaxis

and

• the clinician has made arrangements in advance with a relevant pharmacy for the patient to promptly receive and start antiviral treatment within 48 hours of symptom onset (or 36 hours for zanamivir treatment)

Follow-up laboratory testing in patients receiving antivirals

In most cases of illness, a single testing episode is sufficient to confirm a diagnosis of influenza virus infection and multiple ‘follow-up’ tests are not required. However, it can be challenging to assess clinical improvement in specific patient groups because they may have atypical or minimal clinical signs and symptoms or be unable to describe symptoms. Consider ‘follow-up’ sampling and diagnostic testing if the patient:

• is immunosuppressed, unconscious or ventilated
• deteriorates or has a non-resolving illness after at least 5 days of treatment dose antivirals
• develops an influenza illness whilst receiving prophylactic-dose antivirals of any duration

Follow-up sampling should also be undertaken if the clinician suspects the possibility of antiviral resistance.

Comparing estimated viral load between the initial and repeat sample can be helpful in determining the antiviral effect in these cases.

When follow-up testing has been performed because of suspected treatment failure, consider antiviral resistance testing  on any positive sample and is recommended in the context of immunosuppression (see ‘Poor clinical response to first line treatment’ section). If oseltamivir resistance is clinically suspected and further treatment is required, then consider switching to zanamivir before the results of resistance testing are known. Avoid treatment interruption (for example when awaiting results of follow-up testing), since it can be associated with the development of antiviral resistance.

Clinicians should be mindful of the potential need for continued infection control measures for inpatients if repeat testing provides positive results.

Antiviral Resistance: Reduced Susceptibility to Antiviral Treatments

In testing for antiviral resistance, reduced inhibition (RI) or highly reduced inhibition (HRI) are the terms for when viruses are inhibited less by the specified agents, more commonly known as resistance to antiviral agents.

Globally, frequencies of Influenza that showed resistance to NAIs and/or baloxavir marboxil were low (<1%) for seasons 2018-2023, although prevalence may vary in different healthcare systems, depending on prescribing practices and circulating subtype, and ongoing surveillance is required for changes in prevalence (15,57).

NAI resistance (oseltamivir, zanamivir)

NA-H275Y is the most common amino acid substitution that has been associated with RI or HRI to oseltamivir. This substitution and RI/HRI phenotype has been associated most with the influenza A (H1N1)pdm09 viruses since its emergence in 2009, with sporadic outbreaks of resistant virus, as well as global circulation of an oseltamivir resistant H275Y variant in 2007/8.

WHO global surveillance of seasonal influenza in years 2020 to 2023 found that the global frequency of all seasonal influenza viruses with RI/HRI by NAIs or carrying NA markers associated with RI/HRI phenotypes was low (<0.25%), which is lower than the pre COVID-19 pandemic periods (14).

In England in 2024/25, when A(H1N1)pdm09 was the predominant circulating influenza A subtype, of the 1,102 influenza A(H1N1)pdm09 viruses characterised in the reference laboratory, there were 16 detections of  the H275Y substitution, and 12 of those were in immunosuppressed individuals (see annual influenza epidemiological report).

Amino acid substitutions producing RI/HRI by zanamivir were very rarely seen in a global surveillance of isolates from 2021-2023 (14).

CENi resistance (baloxavir marboxil)

The most common amino acid position that has been associated with reduced susceptibility to baloxavir is PA-I38X (58).  The frequency of seasonal influenza viruses with reduced susceptibility to baloxavir marboxil or carrying PA markers globally was between 0.05%-0.12% of the isolates tested in 2022 to 2023. However, the rate is higher in Japan where baloxavir marboxil has been used more frequently. In Japan, the frequency of the relevant PA markers for reduced susceptibility was 4.5% in 2018 to 2019 and 3.3% in 2022 to 2023(14). Between 2018/19 and 2022/23, the rate of clinical use of baloxavir marboxil in Japan was reduced as a consequence of the detection of resistant viruses (59). There has been suggestion of community transmission of viruses with PA change based baloxavir resistance in Japan as several cases were not associated with antiviral treatment administration (14,54,60,61).

Several clinical trials have also reported development of baloxavir marboxil resistance to varying degrees, across a variety of patient ages and degrees of comorbidity, with rates between 2% to 23%.

Further information on specific studies available at time of writing includes:

• in non-severe influenza, patients who are otherwise healthy, under 12 years of age, recruited from the US, European and South American countries: 13.5% (11/81) patients developed treatment emergent PA/I38X substitutions after a single dose of baloxavir marboxil (5)
• in non-severe influenza patients, under 12 years of age, with no comorbidity information, recruited from Japan: 23.4% (18/77) patients developed I38T/M substitutions after a single dose of baloxavir marboxil. (9)
• in non-severe influenza patients, at risk of developing severe influenza, 12 years of age or over, globally recruited: 5% (15/290) of patients with comorbidities developed I38X substitutions after a single dose of baloxavir marboxil. (10)
• in non-severe influenza patients, 20-64 years of age, otherwise healthy: 9.7% of (36/370) baloxavir marboxil treated patients developed mutations at PA/I38, compared with 0% of 95 placebo recipients (20)
• in severe influenza patients, aged 12 years or older, with limited information about patient characteristics: 2% (3/134) baloxavir marboxil-treated patients developed I38X mutations, all of which were in A(H1N1) virus - treatment course in this trial was 2 to 3 administrations of baloxavir marboxil, which is more than the single dose that the manufacturer recommends (35)

Data suggest that a higher prevalence of influenza A viruses with PA/I38X substitutions is associated with childhood infection, infection with H3N2 virus, and higher rates of use of baloxavir marboxil in the community, and there is insufficient data on expected rates of resistance in immunosuppressed groups. For baloxavir marboxil recipients with I38T/M substitution, median time to alleviation of symptoms was longer (60) and time to cessation of viral shedding observed to be prolonged in children (62).

Further information on pharmacotherapy for influenza

Licensed antiviral treatments

Oseltamivir

Oseltamivir is the recommended first line for treatment of influenza where possible. The evidence base is largest for oseltamivir, and includes both randomized controlled trials and observational data, with a diversity of clinical endpoints. (13, 18, 63, 64 ).

There remains a need to strengthen the evidence base for the relative effectiveness of different approaches to managing influenza. Nausea and/or vomiting are the most commonly reported side effects. In clinical trials, these episodes were typically reported on a single occasion on either the first or second treatment day and resolved spontaneously within 1 to 2 days; it is not usually required to discontinue use.

Zanamivir solution for infusion:

Dectova® was launched in the UK in November 2019. Nebulised use of this product is not included in the marketing authorization. The SPC recommends IV zanamivir is commenced as soon as possible and usually within 6 days of the onset of symptoms of influenza. IV zanamivir is renally excreted and requires dose modification for patients with renal dysfunction including those on renal replacement therapy, see Table 3 and the SPC. Further details on use of IV zanamivir for patients under 18 years can be found in the SPC (26).

Dectova® should only be considered in patients for whom zanamivir is indicated but who cannot use inhaled zanamivir or have severe systemic illness such as multi-organ failure. The evidence base for IV zanamivir for severe influenza treatment is very limited. Recommendations for when to consider use of intravenous delivery are stated in the ‘Treatment of suspected or confirmed influenza’ section. Although the WHO clinical guidance 2024 includes a conditional recommendation against use of zanamivir for severe influenza (evaluated by WHO as very low-quality evidence based on consideration of RCT data), this is because of small net benefit, or little difference between alternatives. There are no major concerns regarding safety/potential harms.

Scenarios where IV zanamivir may be indicated include:

1. Patients with severe influenza in whom antivirals delivered by oral, nasogastric tube, or inhaled methods would be ineffective, are contraindicated or cannot be administered.
2. Patients with suspected or confirmed oseltamivir resistance AND, in whom inhaled zanamivir is contraindicated or cannot be administered.
3. Patients with severe influenza and poor clinical response during course of oseltamivir and inhaled zanamivir cannot be administered.

In scenarios 2 and 3, baloxavir marboxil may be an alternative treatment option in certain patient groups. Seek specialist advice.

Zanamivir: contraindications

Zanamivir powder for inhalation should not be nebulised by dissolving the capsules in water. This practice has been linked to deaths in ICU believed to be due to blockage of ventilator tubes. Nebulisation of zanamivir aqueous solution is no longer recommended by UKHSA for any patient group, and the marketing authorisation of zanamivir aqueous solution in Europe is for IV administration only; if a patient requires zanamivir, but inhaled zanamivir via a Diskhaler is inappropriate (for example, the patient has critical illness and/or severe respiratory disease), IV zanamivir should be used.

Baloxavir Marboxil

Baloxavir marboxil (PO) is a single-dose, oral agent that has antiviral activity against influenza A and B viruses. It is a cap-dependent endonuclease inhibitor (CENi) and therefore has a different mode of action from the neuraminidase inhibitors. Baloxavir marboxil received regulatory approval in Japan in February 2018 and from the US FDA in October 2018. It was approved by the European Medicines Agency in January 2021 and by the MHRA in June 2021 and is procurable in the UK where available.

At the time of writing, baloxavir marboxil is licenced in the UK in tablet form, although granules are available in other territories. The manufacturer does not recommend crushing the tablet. Preparation of oral solutions/suspensions of baloxavir is off-label and should be done in a pharmacy or in close consultation with a pharmacist. In particular, paediatric dosing should be discussed with a pharmacist. The advice in the RECOVERY Trial Pharmacy FAQ V21.0 18 Jun 2022 is that a baloxavir tablet should not be crushed but can be dissolved in 50ml of water for irrigation in a 100ml medicine bottle by shaking for 10 minutes. For oral administration, 50ml ORA-Blend as a flavour masker should then be added (other masking agents, food or juice should not be used) and the bottle shaken further. For enteric feeding tube use, such as nasogastric (NG), a further 50ml of water for irrigation should be added instead of ORA-Blend and the bottle shaken further. No drug-tubing interactions are expected; in the USA baloxavir suspension is licensed for enteric tube administration.

The approach taken in this guideline is that baloxavir marboxil should be reserved for where oral oseltamivir or inhaled zanamivir are not appropriate, or cases of known NAI resistance, which will enable clinicians to exercise clinical judgement in light of its favourable aspects: reduction viral load, ease of dosing and minimal side effect profile.(20,65,60). This is based upon comparative efficacy/effectiveness data, comparative cost (see ‘Licensed treatments’ section) and consideration of the risk of antiviral resistance in A(H3N2) and other types/subtypes (details in ‘Antiviral Resistance: Reduced Susceptibility to Antiviral Treatments’ section).

The WHO clinical guidance 2024 (6) included a conditional recommendation on use of baloxavir marboxil in patients with non-severe influenza at risk of deterioration and takes into consideration ease of administration/patient convenience, whilst acknowledging the low certainty of evidence regarding any effect on reduction in hospitalisation. The estimated effect of baloxavir on reduction in hospitalisations in a risk groups was 16 per 1000 (95%CI: 4 more to 20 less). Cost-effectiveness, risk of resistance, stock availability and data from observational studies were not considered in the WHO recommendation.

In non-severe influenza, baloxavir marboxil likely reduces time to alleviation of symptoms by 1.02 fewer days (1.41 days lower to 0.63 days lower, with moderate certainty). For severe influenza, the sole RCT on the subject reports no significant differences in outcomes comparing baloxavir marboxil plus an NAI with NAI alone (18,20).

There is risk of developing resistance to baloxavir marboxil, noting rates of community resistance in Japan during periods of high usage and data from clinical trials. The risk of developing resistance is higher in children and patients with immune suppression. In recent years in Japan, rates of baloxavir resistance have remained low in Japan despite use of baloxavir. Further details in ‘Antiviral Resistance: Reduced Susceptibility to Antiviral Treatments’ section.

There are limited studies comparing the outcomes in immunosuppressed patients receiving baloxavir or oseltamivir. An underpowered retrospective study in this group was unable to discern a difference in clinical outcomes between the 2 agents (17). A phase 2 clinical trial is currently comparing the different treatments further Baloxavir and Oseltamivir for the Treatment of Severe Influenza Infection in Immunocompromised Patients).

Evidence from a RCT suggests that baloxavir marboxil can reduce transmission in households when administered to an index case by an adjusted odds ratio of 0.68 (95% CI, 0.50 to 0.93; P = 0.01) which is a relative risk reduction of 29% (95% CI, 12 – 45). (Of note the second primary endpoint of reduction of transmission of symptomatic influenza did not reach significance). Additionally, no transmitted baloxavir marboxil resistance was detected in the 7 household contacts who developed influenza infection from 15 index patients with known PA I38X substitutions, and more broadly from any of the 1268 household contacts whose index cases had received baloxavir as treatment (66).

Cost of licensed influenza antivirals

Table 9. licensed antiviral drugs, formulations and current (Oct 2025) NHS list prices for a typical course

Drug	Formulation and dose	Price per course
Oseltamivir	Tamiflu 75mg capsules	£15.41
Oseltamivir	Tamiflu 45mg capsules	£15.41
Oseltamivir	Tamiflu 30mg capsules	£7.71
Oseltamivir	Tamiflu 6mg/ml suspension (nominal 50ml bottle, 390mg in 65ml)	£10.27
Zanamivir	Relenza 5mg diskhaler inhaler	£16.36
Zanamivir	Dectova IV (£27.83 per 200mg) 600mg BD for 10 days	£1669.80
Zanamivir	Dectova IV (£27.83 per 200mg)  600mg BD for 5 days	£834.90
Baloxavir	Xofluza 80mg stat	£100
Baloxavir	Xofluza 40mg stat	£100

Unlicensed treatments

All of the following influenza treatments are unlicensed in the UK. The prescription of unlicensed medicines is the clinical responsibility of the prescribing physician. It is part of the prescribing responsibility of the physician to return the case data requested by the manufacturer as this is an important source of safety monitoring data. Always seek specialist advice before initiating an unlicensed treatment for influenza.

Peramivir

Peramivir (IV) is a neuraminidase inhibitor which does not current have marketing authorisation in the UK. Peramivir is administered as a single dose of 600mg by intravenous infusion for the treatment of non-severe influenza in adults and children (from 2 years of age) within 2 days of onset of acute influenza symptoms. The dose should be adjusted according to the manufacturer’s instructions for children weighing less than 50 kg. A dose adjustment is also required in renal impairment as peramivir is renally excreted. Evidence of efficacy is limited to mainly influenza A infection but there is no evidence to support the routine use of peramivir in treating serious influenza requiring hospitalisation.

There is also no robust evidence for improved outcomes in combination therapy with oseltamivir, though there are recent case reports and retrospective cohort series of survival when used as salvage therapy. Peramivir is not recommended for severe symptomatic influenza because of uncertainty of evidence of efficacy over oseltamivir or zanamivir. (17, 67, 68, 69).

Several neuraminidase mutations, including the H275Y amino acid substitution, confer reduced susceptibility or resistance to peramivir in addition to oseltamivir (14, 70). Peramivir should not be used in patients with known oseltamivir resistance unless susceptibility to peramivir has been demonstrated by laboratory tests.

The common adverse reactions in adults and children in clinical trials were decreased neutrophil counts (3.2%) and nausea (2.4%). Common adverse reactions in children not reported in adults were injection site rash, pyrexia, tympanic membrane hyperaemia, psychomotor hyperactivity, and pruritus. There is no information available in terms of safety of use in pregnancy or in breastfeeding. Peramivir is not licensed for prophylaxis.

Ribavirin

Ribavirin (IV) is unlicensed for the treatment of influenza and should only be used in combination with other antivirals only in the context of an approved research protocol. It should never be used for treatment or prophylaxis of influenza in pregnancy.

Favipiravir

Favipiravir (PO) inhibits RNA-dependent RNA polymerase of viruses. This has been investigated for influenza and other viruses and has been approved for use in Japan, only in patients infected with novel or re-emerging influenza viruses (that is, in the event of a pandemic), and only when that virus is resistant to other influenza antivirals. It is not licensed for use in the UK and is not recommended currently for therapeutic use, and should only be used in the context of an approved research protocol. (6, 69, 50). Concerns about teratogenicity have been raised based on information from animal models. Favipiravir resistant emergent influenza viruses have been reported in an in vitro study (71).

Laninamivir

Laninamivir (INH) is a neuraminidase inhibitor which has been licensed in Japan for the treatment and prophylaxis of influenza. It is not licensed for use in the UK and should only be used in the context of an approved research protocol. Although the WHO allows for its use as a conditional recommendation after exposure to seasonal influenza virus, (27)  it is not recommended for prophylaxis of influenza as there are other alternatives, it is not licensed for use in the UK, and is not widely available.

Adamantanes

Adamantanes (amantadine and rimantadine) are not recommended for treatment of seasonal influenza because of widespread global resistance for M2 ion channel inhibitors. (72)

Umifenovir

Umifenovir (arbidol) is not recommended for administration. Some limited efficacy data is available.  (73, 74)

Onradivir

Onradivir is not recommended for administration because the phase 3 clinical results are not available. Phase 2 clinical trial data are available (75) and a phase 3 clinical trial has not been registered on clinicaltrials.gov.

Other therapeutic agents

These guidelines do not consider other therapeutics beyond antiviral agents, including immune modulators such as dexamethasone or other corticosteroids.

Adjunctive corticosteroid therapy has been associated with an increased risk of mortality in observational studies, however there is a strong possibility of confounding by indication in these studies and further evidence from clinical trials is needed.(76)

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