With the influenza season upon us, this month's column will focus on the pharmacologic therapy for the prevention and treatment of influenza. Four antiviral agents are available to prevent and/or treat influenza illness. These drugs differ in their pediatric study and Food and Drug Administration (FDA)-approved indications, available dosage forms, adverse effects and cost.
Amantadine and rimantadine (Flumadine, Forest) have been available for the prevention and treatment of influenza for numerous years. Both are approved for use in children aged 1 year and above for the prevention of influenza illness. Amantadine is also approved for the treatment of influenza in children, while rimantadine is approved for treatment only in ages >14 years, although many experts consider it reasonable to use rimantadine for such use in children. Amantadine and rimantadine have activity only toward influenza A strains, which generally are responsible for approximately 75% of infections during a season. Both amantadine and rimantadine are 70%-90% effective in preventing clinical illness.
The 2000 Red Book (Report of the Committee on Infectious Diseases, American Academy of Pediatrics) recommends specific patients which are most likely to benefit from prophylactic therapy. Included are children considered to be at high risk of influenza or complications, such as children with immunosuppressive conditions in which the immune response to vaccination is likely to be poor, children at high risk in whom immunization is contraindicated (e.g., anaphylactic hypersensitivity to egg protein who do not receive desensitization), and any healthy child with age-appropriate development for whom influenza is deemed desirable. Also included are those who are unimmunized and who provide care to high-risk children.
Clinicians and patients should consider that prophylactic therapy is not a substitute for influenza vaccine immunization. Prophylactic therapy with amantadine or rimantadine can also be beneficial in the period between vaccine administration and vaccine response, which is approximately two weeks after vaccine administration, or six weeks after vaccine administration in children immunized for the first time (i.e., two weeks after a two-dose schedule or in between doses). When used, prophylactic therapy should begin when circulation of influenza A in the community has begun, and use of amantadine and rimantadine is most cost-effective when used at the peak of influenza activity in the community.
While all of the available antiviral agents can effectively limit influenza, it is important for clinicians to be aware of several caveats about their use. Because these antiviral agents function by inhibiting viral replication, which is highest early in clinical disease onset, they are most effective if used early (48 hours of symptom onset) in the illness. Most published studies have required patients to be treated within 24-48 hours of symptom onset, and several studies concluded that patients beginning treatment approximately 36-48 hours after symptom onset did not benefit at all. It is also important for clinicians to differentiate influenza from common upper respiratory tract illness or bacterial infection. It maybe helpful for clinicians to make use of influenza surveillance information from state and local health departments to confirm the presence of influenza in the community.
Several rapid diagnostic tests are commercially available that can detect the presence of influenza virus from nasopharyngeal or throat swab specimens within 30 minutes. One, Directigen Flu A (Becton Dickinson Microbiology Systems) tests only for influenza A. The others (Zstat Flu [ZymeTx], FLUOIA[Biostar], QuickVue [Quidel]) detect A and B virus strains, but do not differentiate them.
Several rapid diagnostic tests are commercially available which can detect the presence of influenza virus within 30 minutes. Clinicians should also consider that the treatment benefit seen by most patients in clinical studies has been modest, i.e., an increase to being symptom free by one-two days. None of the antivirals has been shown to prevent serious complications of influenza, and most patients enrolled in clinical efficacy trials had uncomplicated influenza. Data on the use of the antivirals in patients at high risk of serious complications from influenza is limited and inconclusive. The benefit to the average otherwise healthy patient with influenza may be only modest, and it is not clearly known if complications can be avoided in patients with serious underlying illnesses. Also of concern are the cost of widespread use of these agents and the potential for induction of viral resistance.
Both amantadine and rimantadine can be used in the therapy of influenza, but only amantadine is labeled for such use. Many experts, however, consider it appropriate to use rimantadine as well. Both are commercially available in syrup as well as tablet/capsule formulations.
The 2000 Red Book states that antiviral therapy should be considered for children in whom reduction of illness may be important, such as those at risk for:
Once therapy is initiated, it should be continued in immunocompetent children for two to five days or for 24-48 hours after symptom resolution.
Zanamivir (Relenza, GlaxoWellcome) and oseltamivir (Tamiflu, Roche) were approved for use in the treatment of influenza in 1999. These agents represent a new class of antiviral drug called neuraminidase inhibitors. Unlike amantadine and rimantadine, they have activity against both influenza A and B. Oseltamivir was recently approved for prophylaxis of influenza in children aged 13 years and older. Zanamivir is not approved by the FDA for prophylaxis; it is labeled for the treatment of influenza illness in patients 12 years of age and older. Oseltamivir is labeled for the treatment of influenza illness in ages 1 year and older. Zanamivir is available as an oral inhalation device, while oseltamivir is available in capsule and solution dosage forms.
The benefits of treating influenza with zanamivir and oseltamivir are similar to amantadine or rimantadine, i.e., shortening symptoms by one or two days. One important distinction between these classes of antivirals, however, is the expanded activity against influenza B stains. Like amantadine and rimantadine, most of the evidence for their benefit has come from studies in the use of treatment of uncomplicated influenza. As well, they should be used as early as possible within symptom onset, and they may have no benefit if treatment is delayed beyond 48 hours.
Zanamivir's mode of delivery is unique in that it is available as an oral inhalation device. When this product is prescribed, it is important that patients be adequately instructed on appropriate use of the Diskhaler. The product labeling states that the first dose should be given under the direct supervision of a health professional. The manufacturer of zanamivir has given pharmacists demonstration kits to assist with educating patients on the product's use.
Important distinctions among the available antivirals include their adverse effect profiles. Effects upon the central nervous system (CNS) are the most bothersome with use of amantadine and rimantadine. These effects, including nervousness, anxiety, difficulty concentrating, lightheadedness, and insomnia, may be more common with amantadine. Gastrointestinal adverse effects (nausea, vomiting) may also occur with either agent. Administration with food may help. It is also important to note that the seizure threshold may be reduced in patients with a history of seizure disorders. Advantages of the newer antivirals zanamivir and oseltamivir include a reduced adverse effect profile upon the CNS. The most common adverse effects of these agents are gastrointestinal (nausea, vomiting, anorexia). Administration with food may lessen these effects. The most important adverse effect of zanamivir that clinicians should be aware of is its potential adverse effects upon the respiratory system. Adverse reports in pre-approval clinical studies and post-marketing studies have prompted the manufacturer to issue a warning letter and to amend the package labeling. These reports have included cases of bronchospasm and declines in lung function, some serious, in patients receiving zanamivir. While most of these occurred in patients with underlying airway disease (e.g., asthma), some have also occurred in otherwise healthy patients. The manufacturer now recommends that zanamivir should generally not be used in such patients. If it is used, patients should have immediate access to bronchodilator therapy and they should be made aware of the potential for this effect.
Important distinctions among the currently available antiviral agents include differences in adverse effects, available dosage forms, costs and FDA indications. To assure optimal benefit with of any of these agents, it is important for an accurate diagnosis to be made, and for administration to be initiated early in symptom onset.
This information is generally available from state and local health departments. The Centers for Disease Control (CDC) additionally makes information regarding influenza surveillance available through a toll-free number, 888-232-3228.
Choices of Antivirals for the Prophylaxis and Treatment of Influenza
|Drug||Uses*||Dosage Forms||Cost §||Comments|
|Amantadine||Prophylaxis and treatment in
ages >1 year
|Capsule, syrup||$12 per 75cc of syrup¤ (generic)||
|Prophylaxis in ages >1
treatment in ages >14 years
|Tablets, syrup||$17 per 75cc of syrup¤||
(Relenza, Glaxo Wellcome)
|Treatment in ages >12 years||Oral inhalation device (Diskhaler)||$53||
|Treatment and prophylaxis
in ages >13 years
labeled uses by FDA approval
Source: Edward A. Bell, PharmD, BCPS
For more information:
- Edward A. Bell, PharmD, BCPS, is an associate professor of pharmacy practice at Drake University College of Pharmacy, and a clinical specialist at Blank Children's Hospital, Des Moines, Iowa.
- AAP. In: Pickering LK, ed. 2000 Red Book: Report of the Committee on Infectious Diseases. 25th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2000.
- CDC, Advisory Committee on Immunization Practices. Prevention and Control of Influenza. MMWR 2000;49.
- Chapple KJ. Zanamivir in the Treatment and Prevention of Influenza. Ann Pharmacother 2000;34.
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