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Neuraminidase inhibitor indications, recommendations for treating influenza
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As 2017 closes out, national influenza activity is increasing. All 10 US regions characterized by the CDC have reported elevated outpatient influenza-like illness, i.e., above the national or regional-specific baseline. Of all specimens tested positive for influenza virus by national collaborative laboratories, 81.5% have been confirmed as influenza A; of influenza A specimens tested, the vast majority (approximately 90%) have been subtype H3N2.
Of 470 influenza viral specimens tested, 100% remained sensitive to the neuraminidase inhibitors (NIs) — Tamiflu (oseltamivir, Genentech; and generic), Relenza (zanamivir, GlaxoSmithKline), and Rapivab (peramivir, Seqirus).
At least 12 pediatric deaths attributable to influenza have been reported this influenza season, according to the CDC. Influenza-associated pediatric deaths in recent past seasons have totaled 108 (2016-2017), 92 (2015-2016), and 148 (2014-2015). Within the pediatric population, the risk of influenza-related morbidity and mortality is highest in children aged younger than 6 months; children aged younger than 5 years are at higher risk as well. This month’s column will review and update the role and benefit of the NIs in the treatment of pediatric influenza.
The NIs are the antiviral drugs of choice for the treatment and prophylaxis of influenza. Other antivirals, namely the adamantanes (amantadine, rimantadine), are no longer clinically useful because of high levels of resistance or pharmacologic inactivity by influenza viral isolates (A and B). The NIs function to reduce influenza viral release from host cells, limiting spread, by inhibiting action of influenza viral neuraminidase enzymes. This pharmacologic mechanism explains, in part, the importance and therapeutic benefit of early use of the NIs when treating influenza.
Indications and clinical benefits
The NIs differ primarily by age indications for treatment and prophylaxis, and dosage form availability (Table). Interestingly, all NIs are FDA labeled for treatment of only uncomplicated influenza illness of 48-hour duration or less.
Oseltamivir is labeled for use in ages as young as 2 weeks, and is available as oral capsule and suspension dosage forms. Generic oseltamivir capsules became available in late 2016. Although non-FDA-labeled, oseltamivir dosing regimens for infants aged younger than 2 weeks (including preterm births) have been published by the AAP.
Zanamivir is available as an oral dry powder inhalation, and peramavir is available as an intravenous solution. Oseltamivir is considered the NI of choice for most children with influenza, because it has been evaluated in more clinical studies, is available as enterically administered capsules and suspension and is FDA-labeled for younger ages. Zanamivir may be best used for children unable to tolerate oseltamivir, and peramivir may be best used for children unable to tolerate any oral dosage form because of nausea/vomiting or illness severity.
When given to otherwise healthy children infected with influenza virus who have been ill for 48 hours or less, pharmacotherapy with a NI results in a lessening of symptom duration by approximately 1.25 to 1.5 days, compared with treatment with placebo. It is important to note that in controlled clinical studies used for FDA labeling and approval, NI therapy was begun within 48 hours of symptom onset in actively treated subjects, a scenario that may often be difficult to adhere to. Far fewer pediatric data are available to evaluate the efficacy of NIs in children with underlying medical conditions that increase risk of influenza morbidity and mortality, including cardiovascular, pulmonary, hepatic, renal, metabolic, hematological, neurologic and immunosuppressive comorbidities.
Some data, mostly from retrospective studies, are available to evaluate NI efficacy in treating infants and children with underlying comorbidities or severe illness. Additional data from prospective controlled studies in the pediatric at-risk population are needed.
Antiviral treatment recommendations from the CDC and the AAP are unchanged for the 2017-2018 season, and the NIs continue to be recommended for infants and children with confirmed or suspected influenza requiring hospitalization, complicated illness or severe disease.
Initiation of NI pharmacotherapy is most beneficial when begun within 48 hours of symptom onset; however, observational studies have demonstrated reduced morbidity and mortality when NI pharmacotherapy is begun up to 5 days of symptom onset.
In a recently published study, Louie and colleagues evaluated surveillance data from 784 infants and children aged younger than 18 years hospitalized in intensive care units with laboratory-confirmed influenza over a 3.5-year period (2009-2012). The estimated risk of death was reduced in subjects receiving NIs (OR 0.36), and treatment within 48 hours of illness onset was significantly associated with survival (P < 0.05). The authors of this study additionally discuss the underuse of NI pharmacotherapy in at-risk infants and children not treated (>33% of the study population), and the associated increased morbidity and mortality.
Treatment recommendations
Recommendations by the CDC and the AAP state the NIs “may be considered” for use in the treatment of uncomplicated influenza illness in otherwise healthy infants and children who have been symptomatic for 48 hours or less. This includes infants and children living at home with a sibling or a household contact aged younger than 6 months or an individual with a medical condition that increases risk of disease morbidity or mortality. Additional recommendations by these organizations and others (Infectious Disease Society of America, Pediatric Infectious Disease Society) include NI use (“strongly recommended”) for infants and children with:
Although NI pharmacotherapy begun within 48 hours of symptom onset is most likely to be beneficial, treatment should be initiated for higher risk infants and children, even when symptom onset is later than 48 hours, because some study data demonstrate benefit when treatment is begun within 48 to 120 hours of symptom onset.
Prophylaxis of influenza with the NIs is recommended for the following infants and children with:
Indications for prophylaxis also include unimmunized individuals having close contact with at-risk infants and children, among additional scenarios for prophylaxis.
NIs can significantly reduce morbidity and mortality due to influenza when used judiciously. The NIs are most useful when initiated early (<48 hours of symptom onset) and given to children who are young (<5 years), have at-risk comorbidities, have severe illness or are hospitalized with influenza. The NIs are less useful for older, otherwise healthy children with nonsevere disease, and when begun after 48 hours of symptom onset.
- References:
- Louie JK. Neuraminidase inhibitors for critically ill children with influenza. Pediatrics. 2013;132:e1539-e1545
- Garg S. Antiviral treatment of influenza in children. Pediatr Infect Dis J. 2012;31:e43-e51
- Fiore AE. Antiviral agents for the treatment and chemoprophylaxis of influenza: recommendations of the Advisory Committee on Immunization Practices. MMWR Morbidity and Mortality Weekly Report. 2010;59:1-23
- Committee on Infectious Diseases. Recommendations for prevention and control of influenza in children, 2017-2018. Pediatrics. 2017;140:1-20
- For more information:
- Edward A. Bell, PharmD, BCPS, is a professor of pharmacy practice at Drake University College of Pharmacy and Health Sciences and Blank Children’s Hospital and Clinics, Des Moines, Iowa. He also is a member of the Infectious Diseases in Children Editorial Board. Bell can be reached at ed.bell@drake.edu.
Disclosure: Bell reports no relevant financial disclosures.