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Pharmacotherapy for influenza disease
With influenza season coming up, this month’s Pharmacology Consult will review the prophylaxis and drug treatment of this common infectious disease.
Information on immunization for the coming season is available from the Advisory Committee on Immunization Practices (ACIP) of the CDC at: www.cdc.gov/mmwr/preview/mmwrhtml/rr57e717a1.htm?s_cid=rr57e717a1_e. Significant updates for influenza immunization by the ACIP include recommendations for annual vaccination of all children 5 to 18 years of age and children 6 to 59 months of age (and older children) with conditions that cause them to be at increased risk for complications of influenza.
Among the pediatric population, influenza more significantly affects children younger than 5 years of age. Children in this age group, compared with adults, are more likely to seek emergency department care, become hospitalized, or suffer complications from influenza disease. This includes healthy children as well as children at increased risk of influenza complications.
During an influenza season, young children are equally as likely to be hospitalized as adults 65 years of age and older for influenza-associated illness. Infants younger than 6 months of age are most likely to be hospitalized for influenza in the pediatric population. During active influenza seasons, children younger than 15 are also more likely to use additional medical care services, with an increase of seven to 12 outpatient visits and five to seven antibiotic prescriptions per 100 children.
Antiviral medications
Four antiviral medications are available for treatment and prophylaxis of influenza disease and infection: amantadine, rimantadine, zanamivir (Relenza, GlaxoSmithKline) and oseltamivir (Tamiflu, Roche). Amantadine and rimantadine are classified as adamantanes. As resistance from influenza A virus can develop rapidly to amantadine and rimantadine, the use of these agents for treatment or prophylaxis is not recommended by the ACIP. Neither amantadine nor rimantadine displays antiviral activity toward influenza B virus.
Zanamivir and oseltamivir are classified as neuraminidase inhibitors. They function to prevent release of newly formed virus from host cell membranes.
The ACIP reports that as of June 28, 2008, 7.6% of 1,464 influenza A (H1N1) viruses tested were resistant to oseltamivir. These viruses resistant to oseltamivir have shown resistance toward zanamivir. Resistance to oseltamivir from influenza B has not been reported. Oseltamivir and zanamivir differ in several characteristics (See table), including dosage form availability, FDA-labeled age indications and adverse effects. Neither agent is available generically. Oseltamivir is available as capsule and liquid suspension formulations and zanamivir is available as an orally inhaled diskhaler. Both agents are FDA-labeled for the treatment and prophylaxis of influenza A and B disease. Oseltamivir is labeled for treatment and prevention at ages 1 year and older. Zanamivir is labeled for treatment and prevention at older than 7 years. Zanamivir is contraindicated in children with lactose intolerance and should not be used in children with underlying airway disease, including asthma.
Treatment
Oseltamivir and zanamivir can be used effectively to treat influenza disease in children. Use of these agents should be limited to children with laboratory-confirmed influenza disease. Appropriate diagnostic testing, such as rapid influenza antigen detection tests, should be used prior to prescription of influenza antiviral agents to assure their appropriate use.
Both oseltamivir and zanamivir are most likely to be effective early in the course of disease and should be used within 48 hours of symptom onset. In clinical trials of uncomplicated influenza, initiation of oseltamivir or zanamivir greater than 48 hours after symptom onset resulted in no or only minimal efficacy. No data are available to assess the efficacy of oseltamivir or zanamivir when initiated more than 48 hours after symptom onset in children with severe illness.
As oseltamivir and zanamivir function to inhibit viral release from host cell membranes following replication, it may be logical to consider that antiviral use later in the course of disease onset is not as likely to be effective. In severe cases, however, clinicians may consider use of oseltamivir or zanamivir even when disease onset is greater than 48 hours.
Drug efficacy from clinical trials is based mostly on previously healthy children with uncomplicated influenza. The ACIP recommendations state oseltamivir or zanamivir use can be considered for the following children with laboratory-confirmed influenza, when initiated within 48 hours of illness onset: 1) illness requiring hospitalization; 2) influenza pneumonia; 3) influenza and bacterial co-infection; 4) influenza in children at high risk of complications; 5) children who want to decrease the duration or severity of their symptoms and transmission of influenza to others at high risk for complications. While this last category may be considered all- encompassing, it is important to consider that clinical trials have shown oseltamivir’s and zanamivir’s efficacy to be a reduction in symptoms of one to one-and-a-half days (as compared with placebo), when treatment is initiated within 48 hours.
The AAP published its recommendations on the use of antivirals for the treatment and prophylaxis of influenza in children in 2007. The AAP recommends that antivirals (primarily oseltamivir and zanamivir) be considered for high-risk children with influenza of any severity, and in otherwise healthy children with moderate-severe influenza who may benefit from a decrease in duration of clinical symptoms. The AAP considers the following children to be at high-risk for complications from influenza: 1) babies age 12 to 24 months; 2) children with asthma or other chronic pulmonary diseases; 3) children with hemodynamically significant cardiac disease; 4) children with immunosuppressive disorders or therapy, including HIV infection; 5) children with sickle cell anemia and other hemoglobinopathies; 6) children with conditions requiring long-term aspirin therapy; 7) children with chronic renal dysfunction; 8) children with chronic metabolic disease; 9) and children with neuromuscular disorders that may compromise the handling of respiratory secretions.
Few data are available on the efficacy of oseltamivir or zanamivir in reducing complications of influenza disease. One controlled trial did demonstrate a reduction in acute otitis media in children with influenza receiving oseltamivir. An uncontrolled retrospective trial evaluated children given oseltamivir with untreated children. Results of this study indicated that children receiving oseltamivir were 51.7% less likely to be diagnosed with pneumonia within 14 days of influenza onset and were less likely to be given antibiotics and use ambulatory and emergency department services. This study is limited, however, by a lack of laboratory diagnoses for study inclusion and uncontrolled methodology. A controlled trial of oseltamivir in children with asthma showed that only children given oseltamivir within 24 hours of symptom onset demonstrated a significant reduction in influenza symptoms. All children given oseltamivir demonstrated improved pulmonary function testing and were less likely to experience an asthma exacerbation compared with children receiving placebo.
Prophylaxis
The most effective therapy for prevention of influenza in children is annual vaccination. However, oseltamivir and zanamivir can play an important role. Due to viral resistance, neither amantadine nor rimantidine should be used as prophylaxis. When used for prophylaxis, oseltamivir or zanamivir should be given daily for the duration of influenza activity in the community. Studies of prophylaxis with oseltamivir and zanamivir have demonstrated a reduction of influenza disease in household contacts of index cases of 68% to 89%. The AAP recommends that prophylactic pharmacotherapy be considered for the following children: 1) high-risk children during the two weeks following immunization (if influenza is active in the community); 2) high-risk children when vaccination is contraindicated; 3) unimmunized family members or health care providers in close contact to high-risk unimmunized children or infants younger than 6 months of age; 4) control of influenza outbreaks for unimmunized staff and children in a closed institutional setting with high-risk pediatric residents; 5) supplemental therapy to immunization in high-risk children; 6) post-exposure prophylaxis in a family setting; 7) high-risk children and family members/close contacts when circulating influenza virus strains in the community are not matched with vaccine strains.
Both oseltamivir and zanamivir are well tolerated. Oseltamivir may cause nausea, and although oseltamivir may be taken with or without food, administration with food may lessen the occurrence of nausea.
Adverse effects
Neuropsychiatric effects have been reported with oseltamivir use. Some of these cases have had fatal outcomes. Most case reports of neuropsychiatric effects have occurred in Japanese children. Japan has the highest usage of oseltamivir of any country. The exact cause of these reactions is not currently known, nor is the contribution of oseltamivir, pharmacogenetic characteristics of oseltamivir use in Japanese children, nor underlying influenza CNS illness. Patients and caregivers should be educated to monitor for abnormal behavior with oseltamivir use. Zanamivir has been well tolerated in clinical trials. Because some children with underlying respiratory disease in clinical trials given zanamivir experienced respiratory distress, use of zanamivir is not recommended in these children.
For more information:
- Edward Bell, PharmD, BCPS is professor of pharmacy practice at Drake University College of Pharmacy and Health Sciences, Blank Children’s Hospital in Des Moines, Iowa.
- Advisory Committee on Immunization Practices of the Centers for Disease Control. Prevention and control of influenza. MMWR. 2008;57(early release):1-60
- Barr CE, et al. Effect of oseltamivir on the risk of pneumonia and use of health care services in children with clinically diagnosed influenza. Current Medical Research and Opinion. 2007;23:523-531
- Committee on Infectious Diseases, American Academy of Pediatrics. Antiviral therapy and prophylaxis for influenza in children. Pediatrics. 2007;119:852-60
- Johnsont SL, et al. Oral oseltamivir improves pulmonary function and reduces exacerbation frequency for influenza-infected children with asthma. Pediatr Infect Dis J. 2005;24:225-32
- Whitley RJ, et al. Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J. 2001;20:127-33