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Review: Amantadine and rimantadine effectively prevent and treat influenza in healthy adults, but rimantadine is better tolerated

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Jefferson TO, Demicheli V, Deeks JJ, Rivetti D. Amantadine and rimanta-dine for preventing and treating influenza A in adults. Cochrane Review, latest version 19 Feb 1999. In: The Cochrane Library. Oxford: Update Software.

Question

What are the effectiveness and safety of amantadine and rimantadine for preventing and treating influenza in adults?

Data sources

Studies were identified from the Cochrane Controlled Trials Register, MEDLINE, and EMBASE/Excerpta Medica databases; bibliographies of relevant papers; and contact with authors, researchers, and drug manufacturers.

Study selection

Studies were selected if they were randomized controlled trials (RCTs) or quasi-randomized trials of healthy adults between 14 and 60 years of age. Inclusion criteria were comparison of amantadine, rimantadine, or both with placebo, control antiviral agents, or no intervention; and comparison of doses or schedules of amantadine, rimanta-dine, or both for the prevention or treatment of influenza.

Data extraction

Data were extracted on study and participant characteristics, interventions, number and severity of influenza cases, death, and adverse effects.

Main results

17 prevention trials (15 RCTs; mean number of participants 596; mean length of follow-up 28 d) and 10 treatment trials (9 RCTs; mean number of participants 161; mean length of follow-up 25 d) met the inclusion criteria. Amantadine prevented both clinically and serologically defined influenza better than placebo (Table). Amantadine and rimantadine individually reduced fever in patients with influenza at 48 hours (Table) and shortened the duration of fever by 1.00 day (95% CI 0.73 to 1.29) and 1.27 days (CI 0.77 to 1.77), respectively, more than placebo. Prevention studies showed that compared with amantadine, rimantadine was associated with less risk for adverse effects on the central nervous system {P < 0.001}* and for withdrawals because of adverse effects {P < 0.01}*.

Conclusion

Amantadine and rimantadine are similarly effective in the prevention and treatment of influenza in healthy adults, but rimantadine is associated with fewer adverse effects.

Source of funding: No external funding.

For correspondence: Prof. T. Jefferson, Cochrane Vaccines Field, Ministry of Defence, Army Medical Directorate, Building 21a, Keogh Barracks, Ash Vale, Aldershot, GU12 5RR Hampshire, England, UK. FAX 44-1252-340-368.

*P value calculated from data in article.

Abstract and Commentary also published in ACP Journal Club. 1999;131:68.

Amantadine or rimantadine vs placebo in prevention (P) or treatment (T) studies of adults with influenza at a mean follow-up of 25 to 28 days*

Type of influenza Comparison Weighted event rates RRR (95% CI) NNT (CI)

(study type) Intervention Placebo

CS defined Amantadine (P) 8% 20% 63% (42 to 76) 9 (6 to 17)

C defined Amantadine (P) 28% 33% 23% (11 to 34) 20 (12 to 56)

With fever at 48 h Amantadine (T) 8% 41% 79% (35 to 93) 4 (2 to 7)

Rimantadine (T) 6% 48% 81% (53 to 92) 3 (2 to 4)

*CS = clinically and serologically; C = clinically. All other abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.

Commentary

Outbreaks of influenza occur every winter. Many studies have shown the cost-effectiveness and health benefits of annual influenza immunization (1), which is the primary method of influenza prophylaxis. The meta-analysis by Jefferson and colleagues clearly shows the effectiveness of both amantadine and rimantadine in reducing the risk for influenza in exposed but unaffected persons and in reducing the duration of illness in infected persons.

The major limitation of the studies reviewed is that most of the participants were healthy men in their 20s and 30s. Influenza results in many deaths each year, mostly in persons > 65 years of age. Although anti-viral agents are recommended for use in high-risk adults, such as elderly persons, this recommendation is made mostly on the basis of a few observational studies among nursing home residents (2).

Amantadine and rimantadine shorten clinical illness only by approximately 1 day, need to be taken within 48 hours of symptom onset, and are effective only against influenza A isolates (influenza B causes clinically indistinguishable disease). Zanamivir, a recently approved neuraminidase inhibitor, may be more beneficial because it has activity against both type A and type B influenza viruses (3). Finally, because amantadine's adverse effects (light-headedness and falls) are particularly harmful in elderly persons, rimantadine is preferred in this group despite the higher cost (U.S. $1.75 per capsule vs $0.20 per capsule).

Bradley S. Bender, MD

University of Florida

Gainesville, Florida, USA

References

1. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 1999;48(RR-4):1-28.

2. Drinka PJ, Gravenstein S, Schilling M, et al. Duration of antiviral prophylaxis during nursing home outbreaks of influenza A: a comparison of 2 protocols. Arch Intern Med. 1998;158:2155-9.

3. Monto AS, Robinson DP, Herlocher ML, et al. Zanamivir in the prevention of influenza among healthy adults: a randomized controlled trial. JAMA. 1999;282:31-5.

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