|Volume 6 Issue 1 Published - 14:00 UTC 08:00 EST 1-Jan-2004 Next Update - 14:00 UTC 08:00 EST 2-Jan-2004||Editor: Susan K. Boyer, RN
© Vidyya., Inc.
All rights reserved.
Information for practitioners: Antiviral agents for influenza
Four prescription medications with antiviral activity against influenza viruses are commercially available in the United States (amantadine, rimantadine, oseltamivir, zanamivir). The four drugs are classified into two categories, the adamantane derivatives and the neuraminidase inhibitors, on the basis of their chemical properties and activities against influenza viruses.
Controlled clinical trials have demonstrated the efficacy of all four antiviral medications in reducing symptom duration when used for treatment of influenza infections. Three of the antiviral drugs have been approved for use as chemoprophylaxis. Table 1 summarizes information about the use of antiviral medications in the United States for influenza.
Neuraminidase Inhibitors (Zanamivir, Oseltamivir)
The neuraminidase inhibitors, zanamivir and oseltamivir, are chemically related drugs that have activity against both influenza A and B viruses.
How do the neuraminidase inhibitor drugs work?
Zanamivir and oseltamivir block the active site of the influenza viral enzyme neuraminidase, which is common to both influenza A and influenza B viruses. This effect results in viral aggregation at the host cell surface and reduces the number of viruses released from the infected cell.
How effective are the neuraminidase inhibitor drugs?
When used within 48 hours of illness onset, both drugs decrease shedding and reduce the duration of influenza symptoms by approximately 1 day compared with placebo. Summary results from randomized, placebo-controlled, double-blinded studies of oseltamivir showed a significant reduction in influenza-related lower respiratory tract complications (pneumonia and bronchitis) associated with antibiotic use and a significant reduction in hospitalizations. These impacts occurred in both healthy and high-risk adolescents and adults. No studies have assessed the impact of antiviral drug therapy on mortality. For both drugs, the recommended duration of treatment is 5 days.
Oseltamivir, but not zanamivir, is approved for chemoprophylaxis of influenza.
Side effects of the neuraminidase inhibitor drugs:
Zanamivir and oseltamivir were approved in 1999, and therefore clinical experience to assess adverse effects is limited.
Antiviral resistance to the neuraminidase inhibitor drugs:
Data are limited on antiviral resistance to the neuraminidase inhibitor drugs.
Adamantane Derivatives (Amantadine, Rimantadine)
The adamantane derivatives, amantadine and rimantadine, are chemically related, orally administered drugs that are approved for treatment and chemoprophylaxis of influenza A. Amantadine and rimantadine specifically inhibit replication of influenza A viruses, but not influenza B viruses.
Antiviral activity: How do the adamantane drugs work?
Amantadine and rimantadine are thought to interfere with influenza A virus M2 protein, a membrane ion channel protein, and inhibit virus uncoating, which inhibits virus replication, resulting in decreased viral shedding.
How effective are the adamantane drugs?
When administered within 48 hours of illness onset, controlled studies have found that both drugs decrease viral shedding and reduce influenza A illness by approximately 1 day compared with placebo. The usual recommended duration of treatment is 5 days.
When used for chemoprophylaxis, amantadine and rimantadine are approximately 70% - 90% effective in preventing symptoms of influenza A illness. The efficacy and effectiveness of amantadine and rimantadine to prevent complications of influenza A are unknown. Both drugs are effective when used for chemoprophylaxis during outbreaks of influenza A in institutions, such as nursing homes .
Side effects of the adamantane drugs:
Chemoprophylactic use of both drugs has been associated with:
Amantadine is teratogenic and embryo toxic in animals. Rimantadine has not been found to be mutagenic. The safety of amantadine and rimantadine when used during pregnancy has not been established.
When used for treatment, amantadine and rimantadine have been associated with the rapid development of resistant viruses.
Adamantanes Compared with Neuraminidase Inhibitors
NOTE: Amantadine manufacturers include Endo Pharmaceuticals (Symmetrel ®--tablet and syrup) and Geneva Pharms Tech (Amantadine HCL--capsule); USL Pharma (Amantadine HCL – capsule and tablet); and Alpharma, Carolina Medical, Copley Pharmaceutical, HiTech Pharma, Mikart, Morton Grove, and Pharmaceutical Associates (Amantadine HCL--syrup). Rimantadine is manufactured by Forest Laboratories (Flumadine (R)--tablet and syrup); Corepharma , Impax Labs (Rimantadine HCL – tablet), and Amide Pharmaceuticals (Rimantadine HCL – tablet). Zanamivir is manufactured by Glaxo Smithkline (Relenza (R) -- inhaled powder). Oseltamivir is manufactured by Hoffman-LaRoche, Inc. (Tamiflu (R) — tablet). Information based on data published by the US Food and Drug Administration at www.fda.gov.
* The drug package insert should be consulted for dosage recommendations for administering amantadine to persons with creatinine clearance < 50 ml/min/1.73m 2.
† 5 mg/kg of amantadine or rimantadine syrup = 1 tsp/22 lbs.
§ Children > 10 years who weigh <40 kg should be administered amantadine or rimantadine at a dosage of 5 mg/kg/day.
¶ A reduction in dosage to 100 mg/day of rimantadine is recommended for persons who have severe hepatic dysfunction or those with creatinine clearance < 10 mL/min. Other persons with less severe hepatic or renal dysfunction taking 100 mg/day of rimantadine should be observed closely, and the dosage should be reduced or the drug discontinued, if necessary.
** Only approved by FDA for treatment among adults.
†† Not applicable.
§§ Rimantadine is approved by FDA for treatment among adults. However, certain experts in the management of influenza consider it appropriate also for treatment among children. (See American Academy of Pediatrics, 2000 Red Book.)
¶ ¶ Older nursing-home residents should be administered only 100 mg/day of rimantadine. A reduction in dosage to 100 mg/day should be considered for all persons aged > 65 years if they experience possible side effects when taking 200 mg/day.
*** Zanamivir administered via inhalation using a plastic device included in the medication package. Patients will benefit from instruction and demonstration of the correct use of the device.
††† Zanamivir is not approved for prophylaxis.
§§§ A reduction in the dose of oseltamivir is recommended for persons with creatinine clearance <30 ml/min.
¶¶¶ The dose recommendation for children who weigh < 15 kg is 30 mg twice a day, for >15 to 23 kg children the dose is 45 mg twice a day, for >23 to 40 kg children the dose is 60 mg twice a day, and for children >40 kg, the dose is 75 mg twice a day.
CDC. Prevention and control of influenza. Recommendations of the Advisory Committee on Immunizations Practices (ACIP). MMWR 2003;52(RR-8):1-34.
CDC. Neuraminidase inhibitors for treatment of influenza A and B infections. MMWR 1999;48:RR-14.
Cooper NJ, Sutton AJ, Abrams KR, Wailoo A, Turner DA, Nicholson KG. Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta-analyses of randomized controlled trials. British Med J 2003;326:1-7.
Demicheli V, Jefferson T, Rivetti D, Deeks J. Prevention and early treatment of influenza in healthy adults. Vaccine 2000;18:957-1030.
Gubareva LV , Kaiser L, Hayden FG. Influenza virus neuraminidase inhibitors. The Lancet 2000;355:827-835.
Jefferson TO, Demicheli V, Deeks JJ, Rivetti D. Amantadine and rimantadine for preventing and treating influenza A in adults (Cochrane Review). In: The Cochrane Library, Issue 1, 2002. Oxford : Update Software.
Jefferson T, Demicheli V, Deeks J, Rivetti D. Neuraminidase inhibitors for preventing and treating influenza in healthy adults (Cochrane Review). In: The Cochrane Library, Issue 1, 2001. Oxford : Update Software.
Kaiser L, Wat C, Mills T, Mahoney P, Ward P, Hayden F. Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations. Arch Intern Med 2003;163:1667-1672.
Uyeki TM. Influenza diagnosis and treatment in children: a review of studies on clinically useful tests and antiviral treatment for influenza. Pediatr Infect Dis J 2003;22:164-177.