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Cochrane Database of Systematic Reviews

آمانتادین و ریمانتادین در درمان آنفلوآنزا A در کودکان و سالمندان

Información

DOI:
https://doi.org/10.1002/14651858.CD002745.pub4Copiar DOI
Base de datos:
  1. Cochrane Database of Systematic Reviews
Versión publicada:
  1. 21 noviembre 2014see what's new
Tipo:
  1. Intervention
Etapa:
  1. Review
Grupo Editorial Cochrane:
  1. Grupo Cochrane de Infecciones respiratorias agudas

Copyright:
  1. Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

Contributions of authors

Márcia G Alves Galvão (MG) selected the trials, extracted data and was responsible of the methodological aspects of the review.
Marilene Augusta Rocha Crispino Santos (MS) selected the trials, extracted data, was responsible of the methodological aspects of the review and supervised the day‐to‐day work of the review.
Antonio Ledo Alves da Cunha (AC) was appointed as an arbitrator to solve disagreements between MG and MS on the selection of the trials. He supervised the work in all phases and provided his experience on the development of the review.

Declarations of interest

Márcia G Alves Galvão: none known.
Marilene Augusta Rocha Crispino Santos: none known.
Antonio Ledo Alves da Cunha: none known.

Acknowledgements

The authors would like to thank Amanda Burls, Rebecca Mears, David Moore, Lisa Gold and Karen Elley for the use of their protocol. We also would like to thank Tom Jefferson and Richard Stubbs for comments provided on the draft protocol. We acknowledge Elizabeth Dooley from the Cochrane Acute Respiratory Infections Group for helping us in all phases of the review process; Ruth Foxlee and Sarah Thorning, for their essential help with the search strategy, the Iberoamerican Cochrane Centre and especially the kindness of Marta Roque, who helped us in the statistical and methodological aspects of the review. We also acknowledge Raimundo Santos, Vladmír Plesnik, Oleg Borisenko and Stuko Nakano for the assessment and translation of the essential topics for this review from the clinical trials published in German, French, Czech, Russian and Japanese. We also thank Jonathan Haliburton for reviewing the English version of this manuscript. The review authors wish to thank Caroline Hall, David Payler and Vladmír Plesnik, who generously provided us with unpublished trial data. Finally, we wish to thank the following referees who gave their permission to be acknowledged for commenting on this review: Maryann Napoli, Nelcy Rodriguez and Tom Jefferson.

Version history

Published

Title

Stage

Authors

Version

2014 Nov 21

Amantadine and rimantadine for influenza A in children and the elderly

Review

Márcia G Alves Galvão, Marilene Augusta Rocha Crispino Santos, Antonio JL Alves da Cunha

https://doi.org/10.1002/14651858.CD002745.pub4

2012 Jan 18

Amantadine and rimantadine for influenza A in children and the elderly

Review

Márcia G Alves Galvão, Marilene Augusta Rocha Crispino Santos, Antonio JL Alves da Cunha

https://doi.org/10.1002/14651858.CD002745.pub3

2008 Jan 23

Amantadine and rimantadine for influenza A in children and the elderly

Review

Márcia G Alves Galvão, Marilene Augusta Rocha Crispino Santos, Antonio JL Alves da Cunha

https://doi.org/10.1002/14651858.CD002745.pub2

2000 Oct 23

Amantadine and rimantadine for influenza A in children and the elderly

Protocol

Alessandro Buda, A JL Alves de Cunha, Antonio JL Alves da Cunha

https://doi.org/10.1002/14651858.CD002745

Differences between protocol and review

Originally in the protocol we planned to study the drug effect on reduction of fever and cough, as they are considered the best predictors of influenza diagnosis. After collecting data, we verified that specific timelines for reduction of signs and symptoms were not reported in the included trials. So, we considered the available data and arbitrarily chose a day of antiviral use to evaluate the response to the treatment. This choice was based on Eccle's study in which clinical manifestations were classified into early and later symptoms (Eccle 2005).

We applied wider age ranges for children than the definition stated in the protocol (participants up to 16 years of age). Trials in older participants who were adolescents by the World Health Organization (WHO) definition were also included (WHO 2007). Data regarding the proportion of the subgroup which strictly fulfilled the age criterion in the protocol were not available in five studies or by contacting the trial authors. The respective age ranges were one to 17 years (Clover 1991), 13 to 19 years (Payler 1984), one to 18 years (Clover 1986; Crawford 1988), and eight to 19 years of age (Finklea 1967).

We planned only to make 12 comparisons. However, whilst analysing data we considered doing an additional comparison and put the two age groups together. As the small samples studied in rimantadine trials for prophylaxis might have influenced the observed results, we tried to overcome this limitation by combining the trials with rimantadine in children and in the elderly. It must be stressed that extraneous characteristics between those groups, other than age or previous immunisations, may have occurred, impairing generalisation of these results.

Keywords

MeSH

PICO

Population
Intervention
Comparison
Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figuras y tablas -
Figure 1

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Figuras y tablas -
Figure 2

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Comparison 1 Amantadine or rimantadine compared to placebo or acetaminophen in the treatment of influenza A in children, Outcome 1 Fever day 3.
Figuras y tablas -
Analysis 1.1

Comparison 1 Amantadine or rimantadine compared to placebo or acetaminophen in the treatment of influenza A in children, Outcome 1 Fever day 3.

Comparison 1 Amantadine or rimantadine compared to placebo or acetaminophen in the treatment of influenza A in children, Outcome 2 Malaise day 6.
Figuras y tablas -
Analysis 1.2

Comparison 1 Amantadine or rimantadine compared to placebo or acetaminophen in the treatment of influenza A in children, Outcome 2 Malaise day 6.

Comparison 1 Amantadine or rimantadine compared to placebo or acetaminophen in the treatment of influenza A in children, Outcome 3 Cough day 7.
Figuras y tablas -
Analysis 1.3

Comparison 1 Amantadine or rimantadine compared to placebo or acetaminophen in the treatment of influenza A in children, Outcome 3 Cough day 7.

Comparison 1 Amantadine or rimantadine compared to placebo or acetaminophen in the treatment of influenza A in children, Outcome 4 Conjunctivitis day 5.
Figuras y tablas -
Analysis 1.4

Comparison 1 Amantadine or rimantadine compared to placebo or acetaminophen in the treatment of influenza A in children, Outcome 4 Conjunctivitis day 5.

Comparison 1 Amantadine or rimantadine compared to placebo or acetaminophen in the treatment of influenza A in children, Outcome 5 Eye symptoms day 5 (pain on movement and visual distortion).
Figuras y tablas -
Analysis 1.5

Comparison 1 Amantadine or rimantadine compared to placebo or acetaminophen in the treatment of influenza A in children, Outcome 5 Eye symptoms day 5 (pain on movement and visual distortion).

Comparison 2 Amantadine and rimantadine compared to placebo and to specific treatment in the prophylaxis of influenza A in children, Outcome 1 Infection.
Figuras y tablas -
Analysis 2.1

Comparison 2 Amantadine and rimantadine compared to placebo and to specific treatment in the prophylaxis of influenza A in children, Outcome 1 Infection.

Comparison 3 Amantadine and rimantadine compared to placebo in the prophylaxis of influenza A in the elderly, Outcome 1 RMT (proved and clinical infection).
Figuras y tablas -
Analysis 3.1

Comparison 3 Amantadine and rimantadine compared to placebo in the prophylaxis of influenza A in the elderly, Outcome 1 RMT (proved and clinical infection).

Comparison 3 Amantadine and rimantadine compared to placebo in the prophylaxis of influenza A in the elderly, Outcome 2 RMT Monto (100 + 200) and Patriarca.
Figuras y tablas -
Analysis 3.2

Comparison 3 Amantadine and rimantadine compared to placebo in the prophylaxis of influenza A in the elderly, Outcome 2 RMT Monto (100 + 200) and Patriarca.

Comparison 3 Amantadine and rimantadine compared to placebo in the prophylaxis of influenza A in the elderly, Outcome 3 RMT 200.
Figuras y tablas -
Analysis 3.3

Comparison 3 Amantadine and rimantadine compared to placebo in the prophylaxis of influenza A in the elderly, Outcome 3 RMT 200.

Comparison 3 Amantadine and rimantadine compared to placebo in the prophylaxis of influenza A in the elderly, Outcome 4 RMT 100.
Figuras y tablas -
Analysis 3.4

Comparison 3 Amantadine and rimantadine compared to placebo in the prophylaxis of influenza A in the elderly, Outcome 4 RMT 100.

Comparison 4 Use of different doses of rimantadine for prophylaxis and treatment of influenza A in the elderly, Outcome 1 Clinical and laboratory infection.
Figuras y tablas -
Analysis 4.1

Comparison 4 Use of different doses of rimantadine for prophylaxis and treatment of influenza A in the elderly, Outcome 1 Clinical and laboratory infection.

Comparison 5 Rimantadine compared to zanamivir in the elderly, Outcome 1 RMT and zanamivir.
Figuras y tablas -
Analysis 5.1

Comparison 5 Rimantadine compared to zanamivir in the elderly, Outcome 1 RMT and zanamivir.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 1 Diarrhoea.
Figuras y tablas -
Analysis 6.1

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 1 Diarrhoea.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 2 Exanthema.
Figuras y tablas -
Analysis 6.2

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 2 Exanthema.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 3 Muscular, limb pain.
Figuras y tablas -
Analysis 6.3

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 3 Muscular, limb pain.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 4 Headache.
Figuras y tablas -
Analysis 6.4

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 4 Headache.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 5 Stimulation/insomnia.
Figuras y tablas -
Analysis 6.5

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 5 Stimulation/insomnia.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 6 Dizziness.
Figuras y tablas -
Analysis 6.6

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 6 Dizziness.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 7 Dyspnoea.
Figuras y tablas -
Analysis 6.7

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 7 Dyspnoea.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 8 Central nervous system symptoms.
Figuras y tablas -
Analysis 6.8

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 8 Central nervous system symptoms.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 9 Change in behaviour.
Figuras y tablas -
Analysis 6.9

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 9 Change in behaviour.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 10 Gastrointestinal symptoms.
Figuras y tablas -
Analysis 6.10

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 10 Gastrointestinal symptoms.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 11 Hyperreactivity.
Figuras y tablas -
Analysis 6.11

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 11 Hyperreactivity.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 12 Tinnitus.
Figuras y tablas -
Analysis 6.12

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 12 Tinnitus.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 13 Cerebellar ataxia.
Figuras y tablas -
Analysis 6.13

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 13 Cerebellar ataxia.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 14 Malaise.
Figuras y tablas -
Analysis 6.14

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 14 Malaise.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 15 Nausea/vomiting.
Figuras y tablas -
Analysis 6.15

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 15 Nausea/vomiting.

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 16 Arrhythmia.
Figuras y tablas -
Analysis 6.16

Comparison 6 Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children, Outcome 16 Arrhythmia.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 1 Stimulation/insomnia.
Figuras y tablas -
Analysis 7.1

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 1 Stimulation/insomnia.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 2 Confusion.
Figuras y tablas -
Analysis 7.2

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 2 Confusion.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 3 Fatigue.
Figuras y tablas -
Analysis 7.3

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 3 Fatigue.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 4 Vomiting.
Figuras y tablas -
Analysis 7.4

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 4 Vomiting.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 5 Headache.
Figuras y tablas -
Analysis 7.5

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 5 Headache.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 6 Impaired concentration.
Figuras y tablas -
Analysis 7.6

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 6 Impaired concentration.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 7 Rash or allergic reaction.
Figuras y tablas -
Analysis 7.7

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 7 Rash or allergic reaction.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 8 Seizures or clonic twitching.
Figuras y tablas -
Analysis 7.8

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 8 Seizures or clonic twitching.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 9 Dry mouth.
Figuras y tablas -
Analysis 7.9

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 9 Dry mouth.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 10 Dizziness.
Figuras y tablas -
Analysis 7.10

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 10 Dizziness.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 11 Anxiety.
Figuras y tablas -
Analysis 7.11

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 11 Anxiety.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 12 Nausea.
Figuras y tablas -
Analysis 7.12

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 12 Nausea.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 13 Depression.
Figuras y tablas -
Analysis 7.13

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 13 Depression.

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 14 Loss of appetite.
Figuras y tablas -
Analysis 7.14

Comparison 7 Adverse effects of rimantadine compared to placebo in the elderly, Outcome 14 Loss of appetite.

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 1 Confusion.
Figuras y tablas -
Analysis 8.1

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 1 Confusion.

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 2 Depression.
Figuras y tablas -
Analysis 8.2

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 2 Depression.

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 3 Impaired concentration.
Figuras y tablas -
Analysis 8.3

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 3 Impaired concentration.

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 4 Insomnia or sleeplessness.
Figuras y tablas -
Analysis 8.4

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 4 Insomnia or sleeplessness.

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 5 Loss of appetite.
Figuras y tablas -
Analysis 8.5

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 5 Loss of appetite.

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 6 Rash or allergic reaction.
Figuras y tablas -
Analysis 8.6

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 6 Rash or allergic reaction.

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 7 Seizure or clonic twitching.
Figuras y tablas -
Analysis 8.7

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 7 Seizure or clonic twitching.

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 8 Dry mouth.
Figuras y tablas -
Analysis 8.8

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 8 Dry mouth.

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 9 Fatigue and drowsiness.
Figuras y tablas -
Analysis 8.9

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 9 Fatigue and drowsiness.

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 10 Headache.
Figuras y tablas -
Analysis 8.10

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 10 Headache.

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 11 Body weakness or debility.
Figuras y tablas -
Analysis 8.11

Comparison 8 Adverse effects related to different doses of rimantadine in the elderly, Outcome 11 Body weakness or debility.

Comparison 9 Additional comparison: RMT compared to placebo in the prophylaxis of influenza A in children and the elderly, Outcome 1 Infection.
Figuras y tablas -
Analysis 9.1

Comparison 9 Additional comparison: RMT compared to placebo in the prophylaxis of influenza A in children and the elderly, Outcome 1 Infection.

Amantadine compared with placebo for prevention and treatment of influenza A in children

Patient or population: children with no influenza A infection (prevention) or with influenza A infection (treatment)

Settings: all

Intervention: amantadine

Comparison: placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Amantadine

Cases of influenza A during prophylaxis

(follow‐up:14 to 18 weeks)

Medium risk population

RR 0.11 (0.04 to 0.3)

773
(2)

⊕⊕⊝⊝
low1,2

10 per 100

1 per 100
(0 to 3)

Fever after initiation of treatment

(follow‐up: 3 days)

Medium risk population

RR 0.37 (0.08 to 1.75)

104
(2)

⊕⊕⊝⊝
low3,4

23 per 100

9 per 100
(2 to 40)

Cough after initiation of treatment

See comment

See comment

Not estimable

0

(0)

See comment

No selected trial

Dizziness

(follow‐up: 7 days)

Medium risk population

RR 6.63 (0.32 to 137.33)

599
(2)

⊕⊝⊝⊝
very low3,4

0 per 100

0 per 100
(0 to 0)

Nausea/vomiting

(follow‐up: 7 days)

Medium risk population

RR 0.54 (0.15 to 2)

599
(2)

⊕⊝⊝⊝
very low3,4,5

13 per 100

7 per 100
(2 to 27)

Stimulation/insomnia

(follow‐up: 7 days)

Medium risk population

RR 0.46 (0.12 to 1.74)

599
(2)

⊕⊕⊝⊝
low3,4

3 per 100

7 per 100
(2 to 27)

CI: confidence interval; RR: risk ratio

GRADE Working Group grades of evidence
High quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.

*The basis for the assumed risk (e.g. median control group risk across studies) was calculated on the basis of control event rate. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

1Allocation concealment not used or unclear.

2Sparse data.

3Allocation concealment unclear.

4Sparse data, confidence intervals do not rule out potential for null effect or harm.

5High heterogeneity unexplained.

Figuras y tablas -

Rimantadine compared with placebo for prevention and treatment of influenza A in children

Patient or population: children with no influenza A infection (prevention) or with influenza A infection (treatment)

Settings: any

Intervention: rimantadine

Comparison: control (placebo or acetaminophen)

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Rimantadine

Cases of influenza A during prophylaxis (follow‐up: 1 to 35 days)

Medium risk population

RR 0.49 (0.21 to 1.15)

178
(3)

⊕⊕⊝⊝
low1,2

24 per 100

12 per 100
(5 to28)

Fever after initiation of treatment

(follow‐up: 3 days)

Medium risk population

RR 0.36 (0.14 to 0.91)

69
(1)

⊕⊕⊕⊝
moderate2

38 per 100

14 per 100
(5 to 34)

Cough after initiation of treatment

(follow‐up: 7 days)

Medium risk population

RR 0.83 (0.63 to 1.1)

69
(1)

⊕⊕⊕⊝
moderate2

81 per 100

67 per 100
(51 to 89)

Dizziness

(follow‐up: 35 days)

Medium risk population

RR 3.21 (0.14 to 75.68)

56
(1)

⊕⊝⊝⊝
very low1,2

0 per 100

0 per 100
(0 to 0)

Nausea/vomiting

(follow‐up: 7 to 35 days)

Medium risk population

RR 0.96 (0.1 to 9.01)

125
(2)

⊕⊕⊝⊝
low2

2 per 100

2 per 100
(0 to 15)

Stimulation/insomnia

See comment

See comment

Not estimable

0
(0)

See comment

No selected trial

CI: confidence interval; RR: risk ratio

GRADE Working Group grades of evidence
High quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.

*The basis for the assumed risk (e.g. median control group risk across studies) was calculated on the basis of control event rate. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

1Allocation concealment unclear.

2Sparse data and confidence intervals do not rule out the potential for no effect or harm

Figuras y tablas -

Amantadine compared with placebo for prevention and treatment of influenza A in the elderly

Patient or population: elderly people with no influenza A infection (prevention) or with influenza A infection (treatment)

Settings: any

Intervention: amantadine

Comparison: control

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Amantadine

Cases of influenza A during prophylaxis

See comment

Not estimable

0
(0)

See comment

No selected trial

Fever after initiation of treatment

See comment

Not estimable

0
(0)

See comment

No selected trial

Cough after initiation of treatment

See comment

Not estimable

0
(0)

See comment

No selected trial

Dizziness

See comment

Not estimable

0
(0)

See comment

No selected trial

Nausea

See comment

Not estimable

0
(0)

See comment

No selected trial

Vomiting

See comment

Not estimable

0
(0)

See comment

No selected trial

Stimulation/insomnia

See comment

Not estimable

0
(0)

See comment

No selected trial

Figuras y tablas -

Patient or population: elderly people with no influenza A infection (prevention) or with influenza A infection (treatment)

Settings: any

Intervention: rimantadine

Comparison: placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Rimantadine

Cases of influenza A during prophylaxis

Medium risk population

RR 0.45 (0.14 to 1.41)

103
(2)

⊕⊝⊝⊝
very low1,2

17per 100

7 per 100
(2 to 23)

Fever after initiation of treatment

See comment

0
(0)

See comment

See comment

No selected trial

Cough after initiation of treatment

See comment

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Dizziness

(follow‐up: 12 weeks)

Medium risk population

12 per 100

11 per 100 (2 to 70)

RR 0.94
(0.15 to 5.97)

35

(1)

⊕⊕⊝⊝
low2,3

Nausea

(follow‐up: 8 to 12 weeks)

Medium risk population

RR 1.99 (0.45 to 8.75)

233
(2)

⊕⊝⊝⊝
very low1,2,4

8 per 100

15 per 100
(3 to 66)

Vomiting

(follow‐up: 8 to 12 weeks)

Medium risk population

RR 0.99 (0.38 to 2.6)

233
(2)

⊕⊕⊝⊝
low1,2

7 per 100

7 per 100
(3 to 17)

Stimulation/insomnia (follow‐up: 8 to 12 weeks)

Medium risk population

RR 1.61 (0.43 to 6.02)

233
(2)

⊕⊕⊝⊝
low1,2

7 per 100

11 per 100
(3 to 40)

CI: confidence interval; RR: risk ratio

GRADE Working Group grades of evidence
High quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.

*The basis for the assumed risk (e.g. median control group risk across studies) was calculated on the basis of control event rate. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

1Allocation concealment unclear and 1 study had high withdrawal rate.

2Sparse data and confidence interval do not rule out no effect or harm.

3Allocation concealment unclear

4High heterogeneity unexplained.

Figuras y tablas -
Comparison 1. Amantadine or rimantadine compared to placebo or acetaminophen in the treatment of influenza A in children

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Fever day 3 Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 AMT

2

104

Risk Ratio (M‐H, Random, 95% CI)

0.37 [0.08, 1.75]

1.2 RMT

1

69

Risk Ratio (M‐H, Random, 95% CI)

0.36 [0.14, 0.91]

2 Malaise day 6 Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 RMT

1

69

Risk Ratio (M‐H, Random, 95% CI)

1.04 [0.63, 1.70]

3 Cough day 7 Show forest plot

1

69

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.63, 1.10]

3.1 RMT

1

69

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.63, 1.10]

4 Conjunctivitis day 5 Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.1 RMT

1

69

Risk Ratio (M‐H, Random, 95% CI)

0.17 [0.01, 3.49]

5 Eye symptoms day 5 (pain on movement and visual distortion) Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

5.1 RMT

1

69

Risk Ratio (M‐H, Random, 95% CI)

0.58 [0.10, 3.24]

Figuras y tablas -
Comparison 1. Amantadine or rimantadine compared to placebo or acetaminophen in the treatment of influenza A in children
Comparison 2. Amantadine and rimantadine compared to placebo and to specific treatment in the prophylaxis of influenza A in children

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Infection Show forest plot

5

951

Risk Ratio (M‐H, Random, 95% CI)

0.25 [0.09, 0.66]

1.1 AMT

2

773

Risk Ratio (M‐H, Random, 95% CI)

0.11 [0.04, 0.30]

1.2 RMT

3

178

Risk Ratio (M‐H, Random, 95% CI)

0.49 [0.21, 1.15]

Figuras y tablas -
Comparison 2. Amantadine and rimantadine compared to placebo and to specific treatment in the prophylaxis of influenza A in children
Comparison 3. Amantadine and rimantadine compared to placebo in the prophylaxis of influenza A in the elderly

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 RMT (proved and clinical infection) Show forest plot

3

191

Risk Ratio (M‐H, Random, 95% CI)

0.74 [0.13, 4.07]

2 RMT Monto (100 + 200) and Patriarca Show forest plot

2

103

Risk Ratio (M‐H, Random, 95% CI)

0.45 [0.14, 1.41]

3 RMT 200 Show forest plot

2

75

Risk Ratio (M‐H, Random, 95% CI)

0.44 [0.12, 1.63]

4 RMT 100 Show forest plot

2

130

Risk Ratio (M‐H, Random, 95% CI)

1.42 [0.10, 21.10]

Figuras y tablas -
Comparison 3. Amantadine and rimantadine compared to placebo in the prophylaxis of influenza A in the elderly
Comparison 4. Use of different doses of rimantadine for prophylaxis and treatment of influenza A in the elderly

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Clinical and laboratory infection Show forest plot

1

54

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.21, 4.20]

1.1 RMT

1

54

Risk Ratio (M‐H, Random, 95% CI)

0.93 [0.21, 4.20]

Figuras y tablas -
Comparison 4. Use of different doses of rimantadine for prophylaxis and treatment of influenza A in the elderly
Comparison 5. Rimantadine compared to zanamivir in the elderly

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 RMT and zanamivir Show forest plot

2

545

Risk Ratio (M‐H, Random, 95% CI)

4.63 [1.46, 14.72]

Figuras y tablas -
Comparison 5. Rimantadine compared to zanamivir in the elderly
Comparison 6. Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Diarrhoea Show forest plot

3

655

Risk Ratio (M‐H, Random, 95% CI)

0.79 [0.42, 1.47]

1.1 AMT

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.81 [0.43, 1.53]

1.2 RMT

1

56

Risk Ratio (M‐H, Random, 95% CI)

0.36 [0.02, 8.41]

2 Exanthema Show forest plot

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.69 [0.21, 2.34]

2.1 AMT

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.69 [0.21, 2.34]

3 Muscular, limb pain Show forest plot

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.85 [0.46, 1.59]

3.1 AMT

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.85 [0.46, 1.59]

4 Headache Show forest plot

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.73 [0.52, 1.03]

4.1 AMT

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.73 [0.52, 1.03]

5 Stimulation/insomnia Show forest plot

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.46 [0.12, 1.74]

5.1 AMT

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.46 [0.12, 1.74]

6 Dizziness Show forest plot

3

655

Risk Ratio (M‐H, Random, 95% CI)

4.69 [0.53, 41.75]

6.1 AMT

2

599

Risk Ratio (M‐H, Random, 95% CI)

6.63 [0.32, 137.33]

6.2 RMT

1

56

Risk Ratio (M‐H, Random, 95% CI)

3.21 [0.14, 75.68]

7 Dyspnoea Show forest plot

1

159

Risk Ratio (M‐H, Random, 95% CI)

0.37 [0.02, 9.02]

7.1 AMT

1

159

Risk Ratio (M‐H, Random, 95% CI)

0.37 [0.02, 9.02]

8 Central nervous system symptoms Show forest plot

1

76

Risk Ratio (M‐H, Random, 95% CI)

0.23 [0.01, 4.70]

8.1 RMT

1

76

Risk Ratio (M‐H, Random, 95% CI)

0.23 [0.01, 4.70]

9 Change in behaviour Show forest plot

1

76

Risk Ratio (M‐H, Random, 95% CI)

0.23 [0.01, 4.70]

9.1 RMT

1

76

Risk Ratio (M‐H, Random, 95% CI)

0.23 [0.01, 4.70]

10 Gastrointestinal symptoms Show forest plot

1

76

Risk Ratio (M‐H, Random, 95% CI)

1.17 [0.08, 18.05]

10.1 RMT

1

76

Risk Ratio (M‐H, Random, 95% CI)

1.17 [0.08, 18.05]

11 Hyperreactivity Show forest plot

1

56

Risk Ratio (M‐H, Random, 95% CI)

0.36 [0.02, 8.41]

11.1 RMT

1

56

Risk Ratio (M‐H, Random, 95% CI)

0.36 [0.02, 8.41]

12 Tinnitus Show forest plot

1

56

Risk Ratio (M‐H, Random, 95% CI)

3.21 [0.14, 75.68]

12.1 RMT

1

56

Risk Ratio (M‐H, Random, 95% CI)

3.21 [0.14, 75.68]

13 Cerebellar ataxia Show forest plot

1

69

Risk Ratio (M‐H, Random, 95% CI)

2.61 [0.11, 61.80]

13.1 RMT

1

69

Risk Ratio (M‐H, Random, 95% CI)

2.61 [0.11, 61.80]

14 Malaise Show forest plot

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.89 [0.41, 1.96]

14.1 AMT

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.89 [0.41, 1.96]

15 Nausea/vomiting Show forest plot

4

724

Risk Ratio (M‐H, Random, 95% CI)

0.61 [0.24, 1.58]

15.1 AMT

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.54 [0.15, 2.00]

15.2 RMT

2

125

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.10, 9.01]

16 Arrhythmia Show forest plot

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

16.1 AMT

2

599

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

Figuras y tablas -
Comparison 6. Adverse effects of amantadine and rimantadine compared to placebo or acetaminophen in children
Comparison 7. Adverse effects of rimantadine compared to placebo in the elderly

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Stimulation/insomnia Show forest plot

2

233

Risk Ratio (M‐H, Random, 95% CI)

1.61 [0.43, 6.02]

1.1 RMT

2

233

Risk Ratio (M‐H, Random, 95% CI)

1.61 [0.43, 6.02]

2 Confusion Show forest plot

2

233

Risk Ratio (M‐H, Random, 95% CI)

0.79 [0.40, 1.56]

2.1 RMT

2

233

Risk Ratio (M‐H, Random, 95% CI)

0.79 [0.40, 1.56]

3 Fatigue Show forest plot

2

233

Risk Ratio (M‐H, Random, 95% CI)

0.81 [0.41, 1.60]

3.1 RMT

2

233

Risk Ratio (M‐H, Random, 95% CI)

0.81 [0.41, 1.60]

4 Vomiting Show forest plot

2

233

Risk Ratio (M‐H, Random, 95% CI)

0.99 [0.38, 2.60]

4.1 RMT

2

233

Risk Ratio (M‐H, Random, 95% CI)

0.99 [0.38, 2.60]

5 Headache Show forest plot

1

198

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.21, 3.38]

5.1 RMT

1

198

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.21, 3.38]

6 Impaired concentration Show forest plot

1

198

Risk Ratio (M‐H, Random, 95% CI)

0.5 [0.10, 2.41]

6.1 RMT

1

198

Risk Ratio (M‐H, Random, 95% CI)

0.5 [0.10, 2.41]

7 Rash or allergic reaction Show forest plot

1

198

Risk Ratio (M‐H, Random, 95% CI)

3.53 [0.18, 67.28]

7.1 RMT

1

198

Risk Ratio (M‐H, Random, 95% CI)

3.53 [0.18, 67.28]

8 Seizures or clonic twitching Show forest plot

1

198

Risk Ratio (M‐H, Random, 95% CI)

2.0 [0.23, 17.54]

8.1 RMT

1

198

Risk Ratio (M‐H, Random, 95% CI)

2.0 [0.23, 17.54]

9 Dry mouth Show forest plot

1

198

Risk Ratio (M‐H, Random, 95% CI)

0.7 [0.23, 2.12]

9.1 RMT

1

198

Risk Ratio (M‐H, Random, 95% CI)

0.7 [0.23, 2.12]

10 Dizziness Show forest plot

1

35

Risk Ratio (M‐H, Random, 95% CI)

0.94 [0.15, 5.97]

10.1 RMT

1

35

Risk Ratio (M‐H, Random, 95% CI)

0.94 [0.15, 5.97]

11 Anxiety Show forest plot

1

35

Risk Ratio (M‐H, Random, 95% CI)

2.83 [0.92, 8.74]

11.1 RMT

1

35

Risk Ratio (M‐H, Random, 95% CI)

2.83 [0.92, 8.74]

12 Nausea Show forest plot

2

233

Risk Ratio (M‐H, Random, 95% CI)

1.99 [0.45, 8.75]

12.1 RMT

2

233

Risk Ratio (M‐H, Random, 95% CI)

1.99 [0.45, 8.75]

13 Depression Show forest plot

2

233

Risk Ratio (M‐H, Random, 95% CI)

1.63 [0.53, 4.98]

13.1 RMT

2

233

Risk Ratio (M‐H, Random, 95% CI)

1.63 [0.53, 4.98]

14 Loss of appetite Show forest plot

2

233

Risk Ratio (M‐H, Random, 95% CI)

1.11 [0.56, 2.17]

14.1 RMT

2

233

Risk Ratio (M‐H, Random, 95% CI)

1.11 [0.56, 2.17]

Figuras y tablas -
Comparison 7. Adverse effects of rimantadine compared to placebo in the elderly
Comparison 8. Adverse effects related to different doses of rimantadine in the elderly

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Confusion Show forest plot

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.41, 1.65]

1.1 RMT

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.41, 1.65]

2 Depression Show forest plot

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.44 [0.12, 1.65]

2.1 RMT

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.44 [0.12, 1.65]

3 Impaired concentration Show forest plot

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.68 [0.11, 3.98]

3.1 RMT

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.68 [0.11, 3.98]

4 Insomnia or sleeplessness Show forest plot

1

262

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.26, 3.97]

4.1 RMT

1

262

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.26, 3.97]

5 Loss of appetite Show forest plot

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.62 [0.27, 1.46]

5.1 RMT

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.62 [0.27, 1.46]

6 Rash or allergic reaction Show forest plot

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.34 [0.04, 3.21]

6.1 RMT

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.34 [0.04, 3.21]

7 Seizure or clonic twitching Show forest plot

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.11 [0.01, 2.07]

7.1 RMT

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.11 [0.01, 2.07]

8 Dry mouth Show forest plot

1

262

Risk Ratio (M‐H, Random, 95% CI)

1.16 [0.43, 3.11]

8.1 RMT

1

262

Risk Ratio (M‐H, Random, 95% CI)

1.16 [0.43, 3.11]

9 Fatigue and drowsiness Show forest plot

1

262

Risk Ratio (M‐H, Random, 95% CI)

1.14 [0.45, 2.87]

9.1 RMT

1

262

Risk Ratio (M‐H, Random, 95% CI)

1.14 [0.45, 2.87]

10 Headache Show forest plot

1

262

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.30, 3.42]

10.1 RMT

1

262

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.30, 3.42]

11 Body weakness or debility Show forest plot

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.91 [0.38, 2.18]

11.1 RMT

1

262

Risk Ratio (M‐H, Random, 95% CI)

0.91 [0.38, 2.18]

Figuras y tablas -
Comparison 8. Adverse effects related to different doses of rimantadine in the elderly
Comparison 9. Additional comparison: RMT compared to placebo in the prophylaxis of influenza A in children and the elderly

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Infection Show forest plot

5

281

Risk Ratio (M‐H, Random, 95% CI)

0.49 [0.27, 0.92]

1.1 RMT

5

281

Risk Ratio (M‐H, Random, 95% CI)

0.49 [0.27, 0.92]

Figuras y tablas -
Comparison 9. Additional comparison: RMT compared to placebo in the prophylaxis of influenza A in children and the elderly