Other Treatment Considerations

Timing. Treatment should be started as soon as possible. Laboratory confirmation of influenza virus infection is not necessary for the initiation of treatment and a negative laboratory test for H1N1 does not exclude the diagnosis in all patients, therefore early, empiric treatment is strongly recommended. The evidence from clinical trials in uncomplicated seasonal influenza suggests most patients benefit from antiviral treatment commencing within 48 hours of onset of symptoms, but experience from use in patients with H5N1 virus infection and severe lower respiratory tract disease suggests that later initiation of treatment may also be effective, whenever viral replication is present or strongly suspected.

Dose and duration. Higher doses of oseltamivir and longer duration of treatment may be appropriate, although there is no available clinical trial evidence to inform recommendations. An adult dose of 150 mg twice daily has been administered to some critically ill patients. When treating patients with renal impairment, consideration needs to be given to the likely higher systemic exposure to oseltamivir (see Section 6.7 below).

Where the clinical course remains severe or progressive, despite 5 or more days of antiviral treatment, monitoring of virus replication and shedding, and antiviral drug susceptibility testing is desirable. Antiviral treatment should be maintained without a break until virus infection is resolved or there is satisfactory clinical improvement.

Antiviral resistance. Zanamivir is the treatment of choice for all patients where oseltamivir resistance is demonstrated or highly suspected. Intravenous zanamivir may be considered where available.

Drug delivery. Patients who have severe or progressive clinical illness, but who are unable to take oral medication may be treated with oseltamivir administered by nasogastric or orogastric tube (e.g. mechanically ventilated patients).

Remarks

This recommendation takes account of:

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That the prescribing information (5 day treatment course) is based on clinical studies in outpatient settings, and with uncomplicated influenza virus infection.

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Evidence from case reports and case series of prolonged virus replication in the lower respiratory tract of severely ill patients.

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The concern about the increased risk of severe complications or death from influenza in this context.

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The evidence from observational studies that demonstrates a reduction in progression to severe disease and hospitalization in patients treated early (within 2 days of illness onset) with antivirals.

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The ease of use and suitability of oseltamivir compared to other currently available neuraminidase inhibitors, i.e. oral administration versus inhaled.

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Limited data from observational studies that indicate that oseltamivir delivered by nasogastric tube achieves adequate serum levels in critically ill patients.

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The opportunity cost of providing antivirals to these patients is considered low.

Other Treatment Considerations

Drug delivery. Zanamivir containing lactose (powder for inhalation) should not be administered by nebulizer (see Recommendation 18).

Remarks

This recommendation takes account of:

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The need to offer alternative treatment to patients with severe or progressive illness in the absence of oseltamivir or if the virus is known to be resistant to oseltamivir.

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The practical difficulties in administering inhaled zanamivir to severely ill patients in its current commercially available dosage form, and the need for caution in use of inhaled zanamivir in patients with underlying respiratory disease.

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Intravenous zanamivir or peramivir may be considered if available (see Recommendation 17).

Severe or complicated influenza virus infections attributable at least in part to severe immunosuppression have been most frequently described in transplant patients (including hematopoetic stem cell recipients, bone marrow transplant patients, and other transplant patients on immunosuppressive chemotherapy). Other patients with severe immonosuppression include those with graft versus host disease, or with haematological malignancies.

Other cancer patients undergoing chemotherapy and patients infected with HIV, who have developed severe immunodeficiency, may also need to be treated in accordance with the recommendations below.

Other Treatment Considerations

Prevention of infection in this patient group should be a prime objective. This is considered further in the recommendations for chemoprophylaxis below (Recommendation 04).

Duration. Regular monitoring of on-going viral replication and antiviral drug susceptibility is strongly recommended in this patient group. Antiviral treatment should be maintained without a break until virus infection is resolved (as indicated by clinical improvement or sequentially negative results for virus in the respiratory tract).

Antiviral resistance. Zanamivir is the treatment of choice for all patients where oseltamivir resistance has been demonstrated or is highly suspected (see pediatric section; inhaled zanamivir is not approved for use in children aged less than 5 years).

Alternative treatments. Intravenous zanamivir should be considered where available and is recommended for those with serious or progressive illness. If not available, intravenous peramivir may be considered, athough oseltamivir-resistant viruses are reported to have reduced susceptibility in vitro to peramivir.

Remarks

These recommendations take account of:

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The impaired host immune response, such that standard antiviral regimens may not be as effective in clearing virus.

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The higher probability of emergence of oseltamivir-resistant virus in these patients.

Other Treatment Considerations

Infection control procedures should be rigorously applied in this context, including vaccination against seasonal and pandemic influenza in all persons who have direct contact with these patients. Other infection control procedures include hand hygiene, gloves, gowns and masks the use of which is described in full in WHO interim guidance for infection prevention and control in health care for confirmed or suspected cases of pandemic (H1N1) 2009 and influenza-like illnesses¹².

Antiviral resistance. Zanamivir may be the preferred option for chemoprophylaxis for those patients able to take inhalation medicine, due to the known risk of development of oseltamivir resistance in this patient group.

Dose and duration. In severely immunosuppressed persons, there needs to be on-going weekly monitoring for evidence of prolonged viable viral replication, and chemoprophylaxis continued until there is no evidence of on-going viral replication in any patient in the same room or healthcare unit. Where exposure to infection may have occurred and the individual may be within the incubation period, consideration should be given to presumptive treatment (i.e. through the use of treatment doses).

Remarks

This recommendation takes account of:

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The importance of preventing infection in this vulnerable patient group.

Other Treatment Considerations

Antiviral resistance. Zanamivir, where available, is the treatment of choice for all patients where oseltamivir resistance is demonstrated or highly suspected.

Remarks

This recommendation takes account of:

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The concern about the higher risk of severe complications or death from influenza in these patient groups.

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The evidence from observational studies that demonstrates a reduction in progression to severe disease and hospitalization in patients treated with antivirals.

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The importance of clinical judgment in deciding whether to initiate antiviral treatment for uncomplicated illness in persons not in a group known to be at higher risk for influenza complications.

Other Treatment Considerations

There are generally fewer data available on the safety and efficacy of antiviral medicines in very young children (especially from birth to 1 year). In particular, there are insufficient efficacy or safety data to support guidelines on the use of intravenous zanamivir or peramivir in children.

The validity of recently recommended oseltamivir doses in children has been independently evaluated for WHO (Abdel-Rahman and Kearns, Part II, Annex 7). This evaluation was based on an assessment of the available literature, including knowledge of the drug's disposition and knowledge of pathological and physiological characteristics of the target population. On the basis of this evaluation, the Guidelines Panel made the following recommendations with regard to oseltamivir doses for young children:

Other Treatment Considerations

Timing of treatment. Evidence indicates that the greatest benefit is derived from early oseltamivir treatment. Therefore, suitable preparations of oseltamivir need to be available at the point of care.

Drug delivery. Where capsules containing the appropriate oseltamivir dose are available but cannot be swallowed, the contents can be added to a sweet liquid or soft food immediately before administration to disguise bitter taste. Where different doses are required, the following methods may be used:

Powder for oseltamivir oral suspension, where available, is the preferred formulation for children unable to take the capsules, when capsules of appropriate strength are not available or where the smaller capsule of 30 mg is greater than the calculated dose. Where this is not available, an oseltamivir suspension or solution can be produced by extemporaneous preparation from the contents of capsules, or by preparation from bulk powder (also referred to as Active Pharmaceutical Ingredient, or API). WHO recommends that local guidance be developed that takes into account local availability of oseltamivir capsules or API, local facilities, and availability of suitable suspending agents or diluents.

The following points need to be considered in the development of such local guidance (see also Part II, Annex 8, report by A Nunn):

Extemporaneous preparation of oseltamivir treatment course. Preparation of a full oseltamivir treatment course is best done where commercially available suspending agents, containing antimicrobial preservatives, are available. Further information on available suspending agents, and proposed shelf life for suspensions, is provided in Part II Annex 8 (report by A Nunn).

Consideration also needs to be given to availability or provision of suitable measuring devices for individual dose measurement and administration, as well as provision of clear information for the caregiver.

Manipulation of oseltamivir capsules to prepare a solution for immediate use. Where suitable suspending agents or diluents containing preservative are not available and stability and sterility cannot, therefore, be assured, capsules can be opened and mixed with a measured volume of water immediately before administration. Any smaller dose volume required can be calculated and measured for administration.

Local guidance should take into account the availability of materials and measuring devices. User instructions for choice of substrate, dilution, calculation, and measurement of dose should be provided.

Some wastage of drug material is inevitable under these circumstances.

Magistral preparations from API. Preparation of a stable solution from oseltamivir phosphate powder (the API) has been used during the 2009/10 outbreak in the United Kingdom. Further information is provided in Part II, Annex 8 (report by A Nunn).

Remarks

This recommendation takes account of:

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The need for a clear and simple dose schedule.

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The lack of clinical evidence for dosing in this age group and the lack of suitable, commercially available paediatric formulations of oseltamivir.

Other Treatment Considerations

Zanamivir (as inhaled powder) is only indicated for use in persons aged 5 years or above.

Oseltamivir dosing should be as described in Recommendation 07 above.

Other remarks and notes are as given for Recommendation 05 above. In particular, carers of children who do not receive antiviral treatment should be counseled on signs of progression or deterioration of illness and advised to seek medical attention immediately, should the condition deteriorate or persist.

Other Treatment Considerations

Intravenous zanamivir is likely to be the preferred formulation in this setting, (where available and subject to the provisions of Recommendation 15).

Where intravenous zanamivir is not available, intravenous peramivir may be considered (subject to Recommendation 15), although oseltamivir-resistant viruses are reported to have reduced susceptibility in vitro to peramivir.

The panel noted an urgent need for alternative dosage form and products with data to support their use in this population.

Remarks

This recommendation takes account of:

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The need to offer alternative treatment to patients with severe or progressive illness in the absence of oseltamivir or if the virus is known to be resistant to oseltamivir.

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The practical difficulties in administering inhaled zanamivir to severely ill patients in its current dosage form.

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The uncertain activity and clinical efficacy of intravenous peramivir against infection with oseltamivir-resistant pandemic (H1N1) 2009 virus that has the H275Y mutation.

Remarks

This recommendation takes account of:

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The concern about the increased risk of adverse events due to amantadine or rimantadine in pregnant women and lack of evidence supporting use in young children aged <1 year.

Remarks

This recommendation takes account of:

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Reports of oseltamivir resistance following post-exposure prophylaxis failure.

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Severely immunosuppressed persons who may not manifest fever with influenza virus infection or who might have atypical symptoms that do not meet a definition of ILI.