Antiviral treatment of H1N1 influenza

CDC officials report that 99% of all subtyped influenza viruses this season have thus far been 2009 influenza A (H1N1), with very little seasonal influenza reported.

This month’s Pharmacology Consult will discuss the appropriate use of antiviral medications for 2009 influenza A (H1N1) disease in the pediatric population. Treatment recommendations differ from seasonal influenza treatment recommendations from previous years. In addition, new concerns about the appropriate use of the neuraminidase inhibitors in children have risen.

The CDC reported 4,958 laboratory confirmed hospitalizations (all ages) due to 2009 influenza A (H1N1) from Aug. 30 to Oct. 10. Of these, 45% occurred in children 18 years of age and younger. An important distinction between 2009 influenza A (H1N1) and seasonal influenza is the difference in age groups with severe illness requiring hospitalization, with a greater proportion of younger patients affected by 2009 influenza A (H1N1). During this same time, 292 deaths (all ages) due to 2009 influenza A (H1N1) were reported.

In September, data on 36 pediatric deaths associated with influenza A (H1N1) disease from the period April to August were published (MMWR. 2009; 58:941-7). Of these 36 children, seven were younger than 5 years and 24 had one high-risk condition. Nineteen children received antiviral treatment and only four of these received treatment within 48 hours of illness onset (as is recommended). The most recent data on influenza activity and surveillance is available at www.cdc.gov/flu/weekly and www.cdc.gov/h1n1flu/update.htm.

Antiviral medications

Of four commercially available antiviral medications potentially useful for treatment of influenza disease, only two agents are currently recommended for the pharmacotherapy of 2009 influenza A (H1N1) illness – oseltamivir (Tamiflu, Roche) and zanamivir (Relenza, GlaxoSmithKline). These neuraminidase inhibitors are active against influenza A and B viruses, whereas the adamantanes, amantadine and rimantadine are active only against seasonal influenza A viruses.

Neuraminidase inhibitors inhibit the viral enzyme neuraminidase, affecting viral release from infected cells and reducing spread throughout the host’s respiratory tract. This mechanism of action in part explains why these agents are most effective when given early in the disease process, when viral replication is higher. The CDC evaluates 2009 influenza A H1N1 samples for viral drug sensitivity, and between Sept. 1 and Oct. 10, 580 samples were tested. Of these viral samples, 99% have displayed sensitivity to oseltamivir. All were sensitive to zanamivir (N=114).

All viral samples analyzed displayed resistance toward amantadine and rimanatadine. As the respiratory and influenza season progresses, however, it is possible that these resistance patterns may change, and subsequently treatment recommendations may change. Thus, it is important for clinicians to keep abreast of up-to-date resistance patterns and treatment recommendations on the CDC’s website and with their local health departments.

In recent years, seasonal influenza A viruses have commonly demonstrated resistance toward oseltamivir. If oseltamivir-resistant seasonal influenza A activity increases, pharmacotherapeutic options can change. Health care providers should review local or state influenza virus surveillance data to assess circulating virus types and subtypes and drug resistance patterns. If multiple influenza stains are circulating, more information on treatment recommendations is offered by the CDC (Health Advisory, Interim Recommendations for the Use of Influenza Antiviral Medications in the Setting of Oseltamivir Resistance, www.cdc.gov/h1n1flu).

The CDC has published treatment recommendations for the use of antiviral medications for 2009 influenza A (H1N1) disease, including a pediatric supplement at www.cdc.gov/h1n1flu/recommendations_pediatric_supplement.htm.

Key points in these recommendations include a discussion of infants and children most likely to benefit from antiviral pharmacotherapy. Not all children will require specific antiviral pharmacotherapy, and antiviral medication should be reserved for children who are severely ill or for children considered to be at high-risk of complications or severe disease. It is hoped that selective use of antiviral medication will limit increased drug resistance patterns and the potential for antiviral drug shortages.

The pediatric population considered to be at higher risk of complications includes:

1. children younger than 2 years;
2. children and adolescents younger than 19 years receiving long-term aspirin therapy;
3. children with certain comorbidities – chronic pulmonary, cardiovascular (except hypertension), renal, hepatic, hematologic (including sickle cell disease) or metabolic disorders;
4. children with disorders that compromise respiratory function or handling of respiratory secretions (including cognitive dysfunction, spinal cord injuries, seizure disorders or neuromuscular disorders); and
5. children with immunosuppressive disorders (including medication-induced immunosuppression).

Pregnant women (including women up to two weeks postpartum) and adults 65 years of age and older are also at increased risk of complications.

Children aged 2 to 4 years without high-risk medical conditions and mild disease do not necessarily require antiviral therapy. Based on influenza-associated hospitalization rates during April to September, children aged 2 to 4 years had hospitalization rates only 20% higher than older children.

On Oct. 1, the AAP made available additional information describing children considered to be at higher risk of complications from 2009 influenza A (H1N1) disease (www.aap.org/new/swineflu.htm). Conditions described in this document are similar to those listed by the CDC, and this AAP document assists in clarifying comorbidities affecting the pediatric population that can increase disease complications.

If antiviral pharmacotherapy is used, it is important to consider that the neuraminidase inhibitors are most effective when used within 48 hours of symptom onset.

Evidence for the benefit of oseltamivir and zanamivir for seasonal influenza is based primarily on studies of ambulatory subjects with uncomplicated disease. In studies correlating first dose of antiviral pharmacotherapy with symptom onset, earlier therapy was associated with shorter illness duration.

The CDC report that some studies of hospitalized patients with seasonal and 2009 influenza A (H1N1), however, have also shown some benefit when antiviral pharmacotherapy was started more than 48 hours after symptom onset. The FDA has issued emergency use authorizations (EUA) for oseltamivir and zanamivir allowing use of these agents at later time points for treatment (ie, individuals with symptoms for more than 48 hours).

Prophylaxis

The use of oseltamivir or zanamivir for chemoprophylaxis of influenza can be considered for children who have had contact with an individual likely to have been infectious and who are at higher risk of complications (as described above). Chemoprophylaxis should also be considered for health care workers who have had unprotected close contact exposure to an infectious individual. If more than 48 hours have elapsed since contact with an infectious individual, chemoprophylaxis is not recommended. The CDC is recommending that chemoprophylaxis not be used for healthy children and adolescents with exposures in school or in the community. Early recognition of illness and treatment is emphasized as an alternative to chemoprophylaxis.

Potential for error

Oseltamivir is labeled for treatment and prophylaxis for ages 1 year and older.

Oseltamivir is available as an oral capsule and as a fruit-flavored suspension. As 2009 influenza A (H1N1) disease may result in increased morbidity in children younger than 1 year of age, the use of oseltamivir in this age group has been granted approval by the FDA under an EUA.

Labeled treatment and prophylaxis dosing for oseltamivir are weight-based for children 1 year of age and are age-based for infants younger than 1 year of age. Under the EUA, chemoprophylaxis for infants younger than 3 months of age is not recommended unless the clinical situation is judged to be critical, as limited data are available for this age group. Although safety data are limited for oseltamivir use in infants younger than 1 year of age, no data to date indicate an increased risk of severe adverse effects or toxicity in this age group.

Zanamivir is available as an oral inhalation disk. It is labeled for treatment use in 7-year-olds when symptomatic for 48 hours or less, and in ages 5-year-olds for prophylaxis. Zanamivir should not be used for children with underlying airway disease, including asthma, due to risk of serious bronchospasm.

Tamiflu Oral Suspension is commercially available with an oral dosing device that contains graduated markings of 30 mg, 45 mg and 60 mg, and not with volume markings (ie, milliliter or teaspoon).

The FDA has received reports of dosing and administration confusion among caregivers that has resulted in dosing errors, where dosing instructions for Tamiflu have been volume-based and not milligram-based. Prescribers should order Tamiflu in milligram-based doses when possible. For example, for a 20 kg child, an appropriate order would be "Tamiflu Oral Suspension, 12-mg/mL: 45-mg twice daily for five days." If Tamiflu is prescribed as a volume dose only, which ideally it should not be, pharmacists should discard the dosing device packaged with Tamiflu and provide a volume-calibrated dosing syringe to the patient’s caregiver.

If Tamiflu is prescribed for infants younger than 1 year of age (where dosing <30-mg per dose), pharmacists will replace the commercially available oral dosing device calibrated in milligram markings with an oral dosing syringe with volume calibrated markings.

If Tamiflu Oral Suspension is not available, a recipe for a 15-mg/mL-compounded suspension is available (www.cdc.gov/H1N1flu/pharmacist/pharmacist_info.htm). Additional alternative dosing administration for infants and young children includes opening and mixing the contents of Tamiflu oral capsules with various liquids or foods, such as flavored syrups (eg, chocolate, butterscotch), pudding, applesauce or honey (only if the child is >1 year of age).

The FDA has received a fatal report of an individual who received Relenza Inhalation Powder as a solubilized and nebulized (by mechanical ventilation) dosage form. Relenza is commercially available as an oral inhalation device and should only be used with this device. The powder should not be solubilized or given by nebulization.

New investigational antiviral

In October, the FDA issued an EUA for the use of a new (currently unapproved) antiviral agent, intravenous peramivir, that has activity against 2009 influenza A (H1N1) for use in specific pediatric and adult patients. Peramivir should be used only for children and adults ill enough to require hospitalization and: 1) who have not responded to oseltamivir or zanamivir, or 2) who cannot tolerate oseltamivir or zanamivir by enteral or inhaled routes of administration, respectively (www.cdc.gov/h1n1flu/eua/peramivir.htm).

Edward A. Bell, PharmD, BCPS is Professor of Pharmacy Practice at Drake University College of Pharmacy in Blank Children's Hospital and Clinics in Des Moines, Iowa.