Amantadine and rimantadine for influenza A in children and the elderly

  • Protocol
  • Intervention


  • A Buda,

  • AJL Alves de Cunha

Dr Alessandro Buda, Researcher, Department of Oncology, Istituto Mario Negri, Via Eritrea, 62, Milano, 20157, ITALY.


This is the protocol for a review and there is no abstract. The objectives are as follows:

The aim of this review is to systematically collect evidence about the effectiveness, safety and cost effectiveness of amantadine and rimantadine in children and the elderly for preventing and treating influenza A.


Influenza is an acute usually self limiting respiratory illness affecting the upper and/or the lower respiratory tracts caused by infection with influenza viruses A or B, members of the Orthomyxoviridae family (Nicholson 1992). The illness is characterised by the abrupt onset of specific systemic symptoms such as headache, fever, general aches, weakness and myalgia, accompanied by respiratory tract signs, particularly cough and sore throat. However, a wide spectrum of clinical presentations may occur, ranging from mild, afebrile upper respiratory illness, to illness with severe prostration and respiratory and systemic signs and symptoms.

Uncomplicated influenza generally resolves over a 2 to 5-day period. In a significant minority, however, symptoms of weakness and malaise may persist for several weeks, particularly in the elderly. The most common complication that occurs during outbreaks of influenza is pneumonia (both viral and bacterial pneumonia). In addition a number of extra-pulmonary complications may occur including Reye's syndrome in children (most commonly between 2 and 16), myocarditis, pericarditis and central nervous system disease including encephalitis, transverse myelitis and Guillain-Barrè syndrome (Wiselka 1994).

Influenza virus genome consists of 8 single-stranded segments of viral RNA. Because the genome is segmented, there is a high frequency for rearrangements of the genes and this has been noted to occurs frequently during infection of cells with more than one influenza A virus.
Influenza viruses designation (A, B or C) is based on antigenic characteristics of the nucleoproteins and matrix protein antigens. Influenza A viruses are further subdivided on the basis of the surface hemagglutinin (HA) and neuraminidase (NA) antigens. The hemagglutinin serves as a site by which virus binds to the respiratory epithelium cell receptors, while neuraminidase degrades the receptor and may be play a role in release of the virus from infected cells after replication has taken place (Ahmed 1996).

In the last 110 years there have been five pandemics caused by different influenza A viral subtypes. The Spanish influenza pandemic (1918-1919) is considered to have caused an estimated 40 million deaths world-wide. Pandemics usually arise in China where pigs, ducks and humans live in a very so close proximity and spread westward to the rest of Asia, Europe and America (Bonn 1997). Major variations are referred to as "antigenic shifts", as a result of the re-assortment of genome segments between viral strains. Minor variations likely arising from point mutations are called "antigenic drifts" and cause local or more isolated epidemics (Fleming 1999).

A major determination of severity and spread of outbreaks of influenza is the level of immunity present in the population at risk. When an antigenically novel influenza virus emerges to which little or no antibody is present in a community, extensive outbreaks may occur. When the absence of antibody is world-wide, epidemic disease may spread around the globe, resulting in a pandemic (Claas 1998).

Nowdays there are two main measures for the treatment and prophylaxis of influenza viruses: immunisation by using of inactivated influenza vaccines directly isolated from influenza A and B viruses circulating during the previous season, and specific antiviral agents (Demicheli 2000).
The main antiviral agents are amantadine hydrochloride and rimantadine hydrochloride. Both compounds are reported to be effective by interfering with the replication cycle of type A viruses (but not type B) by affecting ion channel activity through the cell membrane. Amantadine is active only against the influenza A viruses and has been licensed for the prophylaxis and treatment of influenza A virus infection by the FDA in 1976 (Jefferson 2000). Rimantadine has been licensed in the USA in 1993 only for prophylaxis in children as well as for the treatment and prophylaxis of adults (Advisor 1994). Physician are invited to "consider" its use because it appears to be equally efficacious and is associated with less frequent central nervous system side effects than amantadine (Advisor 1994). Five to twenty percent of patients in the course of treatment with amantadine develop side effects that limited the clinical use of this drug (Bryson 1980).

Manifestations of influenza in children and the elderly are different when compared to those in adults. Given the epidemiological form that influenza viruses take and the virulence with which they mutate and replicate among populations, it seems clear that these two subgroups, i.e., children and elderly, are among the most susceptible (Nicholson 1992), and could suffer even more from side effects that could derive from the treatments under study.

The efficacy of amantadine and rimantadine for treatment and prevention of influenza A in adults has already been the topic of a review (Jefferson 2000). Results of this review confirmed that both the compounds had a comparable effectiveness in the prevention and treatment of influenza A in healthy adults, although rimantadine induced fewer adverse effects than amantadine.
Another systematic review investigating the effects of these drugs in children and the elderly is yet unpublished (Burls). Our aim is to carry out a systematic review of the effects and safety of amantadine and rimantadine in children and the elderly, with particular attention to the drug's side effects, in a Cochrane format. Adults aged 14 to 60 are excluded from our review.


The aim of this review is to systematically collect evidence about the effectiveness, safety and cost effectiveness of amantadine and rimantadine in children and the elderly for preventing and treating influenza A.

Criteria for considering studies for this review

Types of studies

Any randomised or quasi-randomised studies comparing amantadine and/or rimantadine in children and the elderly with placebo, control antivirals or no intervention or comparing different doses or schedules of amantadine and/or rimantadine.

Types of participants

Studies where => 75% of the population are <= 16 years or >= 65 years will be included. Studies considering a wider range of age will be included if data by age subgroups will be available.

Types of intervention

Amantadine and/or rimantadine as prophylaxis and/or treatment for influenza A.

Types of outcome measures

Cases of influenza.
Severity of influenza however defined.
Cases of malaise, fever, nausea, arthralgias, rash, headache and more systemic and serious side effects.
Patients well-being.
Admission to hospital
GP's visits
Other drugs used

Search methods for identification of studies

See: Unavailable methods used in reviews.

This review will use the search strategy developed for the Cochrane Acute Respiratory Infections Group. MEDLINE and EMBASE searches will be done for the period 1997-2000. The Cochrane Library now includes searches of MEDLINE 1966-97 and EMBASE 1974-1997, and the most recent issue will be searched. Keywords we will use include amantadine, rimantadine, randomised controlled trial, influenza, random allocation and clinical trial. We will screen the bibliography of retrieved articles and reviews in order to identify further trials. Pharmaceutical companies and researches active in the field will be contacted to seek unpublished trials.

Methods of the review

Two reviewers will independently select the trials to be included in the review.
Disagreements will be resolved by discussion.
The methodological quality of each trial will be assessed by two reviewers.
Details of the randomisation method, blinding of outcome measurement and intention-to-treat analysis will form the main criteria to assess quality. Clinical quality will be also analysed and reported in the results.
Other criteria will include the prognostic balance between the two treatment arms and the completeness and length of follow-up.
Data will be independently extracted by two reviewers and cross-checked and will be combined, if appropriate, using standards statistical computation within RevMan 4.04.
We will test for heterogeneity between trial results and explore the underlying causes of heterogeneity within the limits permitted by the available data.

Potential conflict of interest

None known.


The authors would like to thank Drs Amanda Burls, Rebecca Mears, David Moore, Lisa Gold and Karen Elley for the use of their protocol.
They would also like to thank Prof Tom Jefferson and Mr Richard Stubbs for comments provided on the draft protocol.

Sources of support

External sources of support

  • No sources of support supplied

Internal sources of support

  • No sources of support supplied