Amantadine and rimantadine for influenza A in children and the elderly

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

doi:10.1002/14651858.CD002745.pub4

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Figure 1

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

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Figure 2

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

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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.

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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.

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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.

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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.

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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).

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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.

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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).

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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.

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Analysis 3.3

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

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Analysis 3.4

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

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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.

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Analysis 5.1

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

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Analysis 6.1

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

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Analysis 6.2

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

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Analysis 6.3

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

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Analysis 6.4

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

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Analysis 6.5

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

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Analysis 6.6

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

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Analysis 6.7

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

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Analysis 6.8

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

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Analysis 6.9

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

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Analysis 6.10

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

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Analysis 6.11

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

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Analysis 6.12

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

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Analysis 6.13

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

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Analysis 6.14

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

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Analysis 6.15

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

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Analysis 6.16

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

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Analysis 7.1

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

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Analysis 7.2

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

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Analysis 7.3

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

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Analysis 7.4

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

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Analysis 7.5

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

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Analysis 7.6

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

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Analysis 7.7

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

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Analysis 7.8

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

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Analysis 7.9

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

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Analysis 7.10

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

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Analysis 7.11

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

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Analysis 7.12

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

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Analysis 7.13

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

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Analysis 7.14

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

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Analysis 8.1

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

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Analysis 8.2

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

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Analysis 8.3

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

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Analysis 8.4

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

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Analysis 8.5

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

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Analysis 8.6

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

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Analysis 8.7

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

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Analysis 8.8

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

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Analysis 8.9

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

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Analysis 8.10

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

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Analysis 8.11

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

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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.

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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)	⊕⊕⊝⊝ low^1,2
	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)	⊕⊕⊝⊝ low^3,4
	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 low^3,4
	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 low^3,4,5
	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)	⊕⊕⊝⊝ low^3,4
	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.

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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)	⊕⊕⊝⊝ low^1,2
	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 low^1,2
	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

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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

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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 low^1,2
	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		0 (0)	See comment	See comment	No selected trial
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)	⊕⊕⊝⊝ low^2,3
Nausea (follow‐up: 8 to 12 weeks)	Medium risk population		RR 1.99 (0.45 to 8.75)	233 (2)	⊕⊝⊝⊝ very low^1,2,4
	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)	⊕⊕⊝⊝ low^1,2
	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)	⊕⊕⊝⊝ low^1,2
	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.

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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]

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

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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]

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

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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]

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

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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]

Comparison 4. Use of different doses of rimantadine for prophylaxis and treatment of influenza A in the elderly

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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]

Comparison 5. Rimantadine compared to zanamivir in the elderly

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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]

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

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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]

Comparison 7. Adverse effects of rimantadine compared to placebo in the elderly

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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]

Comparison 8. Adverse effects related to different doses of rimantadine in the elderly

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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]

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

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