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Meta-Analysis
. 2014 Apr 10;2014(4):CD008965.
doi: 10.1002/14651858.CD008965.pub4.

Neuraminidase inhibitors for preventing and treating influenza in adults and children

Tom Jefferson  1 , Mark A Jones, Peter Doshi, Chris B Del Mar, Rokuro Hama, Matthew J Thompson, Elizabeth A Spencer, Igho Onakpoya, Kamal R Mahtani, David Nunan, Jeremy Howick, Carl J Heneghan
Affiliations
Meta-Analysis

Neuraminidase inhibitors for preventing and treating influenza in adults and children

Tom Jefferson et al. Cochrane Database Syst Rev. .

Abstract

Background: Neuraminidase inhibitors (NIs) are stockpiled and recommended by public health agencies for treating and preventing seasonal and pandemic influenza. They are used clinically worldwide.

Objectives: To describe the potential benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports of published and unpublished randomised, placebo-controlled trials and regulatory comments.

Search methods: We searched trial registries, electronic databases (to 22 July 2013) and regulatory archives, and corresponded with manufacturers to identify all trials. We also requested clinical study reports. We focused on the primary data sources of manufacturers but we checked that there were no published randomised controlled trials (RCTs) from non-manufacturer sources by running electronic searches in the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE (Ovid), EMBASE, Embase.com, PubMed (not MEDLINE), the Database of Reviews of Effects, the NHS Economic Evaluation Database and the Health Economic Evaluations Database.

Selection criteria: Randomised, placebo-controlled trials on adults and children with confirmed or suspected exposure to naturally occurring influenza.

Data collection and analysis: We extracted clinical study reports and assessed risk of bias using purpose-built instruments. We analysed the effects of zanamivir and oseltamivir on time to first alleviation of symptoms, influenza outcomes, complications, hospitalisations and adverse events in the intention-to-treat (ITT) population. All trials were sponsored by the manufacturers.

Main results: We obtained 107 clinical study reports from the European Medicines Agency (EMA), GlaxoSmithKline and Roche. We accessed comments by the US Food and Drug Administration (FDA), EMA and Japanese regulator. We included 53 trials in Stage 1 (a judgement of appropriate study design) and 46 in Stage 2 (formal analysis), including 20 oseltamivir (9623 participants) and 26 zanamivir trials (14,628 participants). Inadequate reporting put most of the zanamivir studies and half of the oseltamivir studies at a high risk of selection bias. There were inadequate measures in place to protect 11 studies of oseltamivir from performance bias due to non-identical presentation of placebo. Attrition bias was high across the oseltamivir studies and there was also evidence of selective reporting for both the zanamivir and oseltamivir studies. The placebo interventions in both sets of trials may have contained active substances. Time to first symptom alleviation. For the treatment of adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval (CI) 8.4 to 25.1 hours, P < 0.0001). This represents a reduction in the time to first alleviation of symptoms from 7 to 6.3 days. There was no effect in asthmatic children, but in otherwise healthy children there was (reduction by a mean difference of 29 hours, 95% CI 12 to 47 hours, P = 0.001). Zanamivir reduced the time to first alleviation of symptoms in adults by 0.60 days (95% CI 0.39 to 0.81 days, P < 0.00001), equating to a reduction in the mean duration of symptoms from 6.6 to 6.0 days. The effect in children was not significant. In subgroup analysis we found no evidence of a difference in treatment effect for zanamivir on time to first alleviation of symptoms in adults in the influenza-infected and non-influenza-infected subgroups (P = 0.53). Hospitalisations. Treatment of adults with oseltamivir had no significant effect on hospitalisations: risk difference (RD) 0.15% (95% CI -0.78 to 0.91). There was also no significant effect in children or in prophylaxis. Zanamivir hospitalisation data were unreported. Serious influenza complications or those leading to study withdrawal. In adult treatment trials, oseltamivir did not significantly reduce those complications classified as serious or those which led to study withdrawal (RD 0.07%, 95% CI -0.78 to 0.44), nor in child treatment trials; neither did zanamivir in the treatment of adults or in prophylaxis. There were insufficient events to compare this outcome for oseltamivir in prophylaxis or zanamivir in the treatment of children. Pneumonia. Oseltamivir significantly reduced self reported, investigator-mediated, unverified pneumonia (RD 1.00%, 95% CI 0.22 to 1.49); number needed to treat to benefit (NNTB) = 100 (95% CI 67 to 451) in the treated population. The effect was not significant in the five trials that used a more detailed diagnostic form for pneumonia. There were no definitions of pneumonia (or other complications) in any trial. No oseltamivir treatment studies reported effects on radiologically confirmed pneumonia. There was no significant effect on unverified pneumonia in children. There was no significant effect of zanamivir on either self reported or radiologically confirmed pneumonia. In prophylaxis, zanamivir significantly reduced the risk of self reported, investigator-mediated, unverified pneumonia in adults (RD 0.32%, 95% CI 0.09 to 0.41); NNTB = 311 (95% CI 244 to 1086), but not oseltamivir. Bronchitis, sinusitis and otitis media. Zanamivir significantly reduced the risk of bronchitis in adult treatment trials (RD 1.80%, 95% CI 0.65 to 2.80); NNTB = 56 (36 to 155), but not oseltamivir. Neither NI significantly reduced the risk of otitis media and sinusitis in both adults and children. Harms of treatment. Oseltamivir in the treatment of adults increased the risk of nausea (RD 3.66%, 95% CI 0.90 to 7.39); number needed to treat to harm (NNTH) = 28 (95% CI 14 to 112) and vomiting (RD 4.56%, 95% CI 2.39 to 7.58); NNTH = 22 (14 to 42). The proportion of participants with four-fold increases in antibody titre was significantly lower in the treated group compared to the control group (RR 0.92, 95% CI 0.86 to 0.97, I(2) statistic = 0%) (5% absolute difference between arms). Oseltamivir significantly decreased the risk of diarrhoea (RD 2.33%, 95% CI 0.14 to 3.81); NNTB = 43 (95% CI 27 to 709) and cardiac events (RD 0.68%, 95% CI 0.04 to 1.0); NNTB = 148 (101 to 2509) compared to placebo during the on-treatment period. There was a dose-response effect on psychiatric events in the two oseltamivir "pivotal" treatment trials, WV15670 and WV15671, at 150 mg (standard dose) and 300 mg daily (high dose) (P = 0.038). In the treatment of children, oseltamivir induced vomiting (RD 5.34%, 95% CI 1.75 to 10.29); NNTH = 19 (95% CI 10 to 57). There was a significantly lower proportion of children on oseltamivir with a four-fold increase in antibodies (RR 0.90, 95% CI 0.80 to 1.00, I(2) = 0%). Prophylaxis. In prophylaxis trials, oseltamivir and zanamivir reduced the risk of symptomatic influenza in individuals (oseltamivir: RD 3.05% (95% CI 1.83 to 3.88); NNTB = 33 (26 to 55); zanamivir: RD 1.98% (95% CI 0.98 to 2.54); NNTB = 51 (40 to 103)) and in households (oseltamivir: RD 13.6% (95% CI 9.52 to 15.47); NNTB = 7 (6 to 11); zanamivir: RD 14.84% (95% CI 12.18 to 16.55); NNTB = 7 (7 to 9)). There was no significant effect on asymptomatic influenza (oseltamivir: RR 1.14 (95% CI 0.39 to 3.33); zanamivir: RR 0.97 (95% CI 0.76 to 1.24)). Non-influenza, influenza-like illness could not be assessed due to data not being fully reported. In oseltamivir prophylaxis studies, psychiatric adverse events were increased in the combined on- and off-treatment periods (RD 1.06%, 95% CI 0.07 to 2.76); NNTH = 94 (95% CI 36 to 1538) in the study treatment population. Oseltamivir increased the risk of headaches whilst on treatment (RD 3.15%, 95% CI 0.88 to 5.78); NNTH = 32 (95% CI 18 to 115), renal events whilst on treatment (RD 0.67%, 95% CI -2.93 to 0.01); NNTH = 150 (NNTH 35 to NNTB > 1000) and nausea whilst on treatment (RD 4.15%, 95% CI 0.86 to 9.51); NNTH = 25 (95% CI 11 to 116).

Authors' conclusions: Oseltamivir and zanamivir have small, non-specific effects on reducing the time to alleviation of influenza symptoms in adults, but not in asthmatic children. Using either drug as prophylaxis reduces the risk of developing symptomatic influenza. Treatment trials with oseltamivir or zanamivir do not settle the question of whether the complications of influenza (such as pneumonia) are reduced, because of a lack of diagnostic definitions. The use of oseltamivir increases the risk of adverse effects, such as nausea, vomiting, psychiatric effects and renal events in adults and vomiting in children. The lower bioavailability may explain the lower toxicity of zanamivir compared to oseltamivir. The balance between benefits and harms should be considered when making decisions about use of both NIs for either the prophylaxis or treatment of influenza. The influenza virus-specific mechanism of action proposed by the producers does not fit the clinical evidence.

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Conflict of interest statement

All review authors have applied for and received competitive research grants. TJ, PD, CDM, MT, RH, MJ and CH are co‐recipients of the NIHR grant to carry out this review ( http://www.nets.nihr.ac.uk/projects/hta/108001 ). In addition:

Prof Jefferson receives royalties from his books published by Blackwell and Il Pensiero Scientifico Editore, Rome. Dr Jefferson is occasionally interviewed by market research companies for anonymous interviews about Phase 1 or 2 pharmaceutical products. In 2011‐2013 Dr Jefferson acted as an expert witness in a litigation case related to oseltamivir phosphate; Tamiflu [Roche] and in a labour case on influenza vaccines in healthcare workers in Canada. In 1997‐99 Dr Jefferson acted as consultant for Roche, in 2001‐2 for GSK and in 2003 for Sanofi‐Synthelabo for pleconaril (an anti‐rhinoviral which did not get approval from FDA). Dr Jefferson is a consultant for IMS Health.

Dr Doshi received EUR 1500 from the European Respiratory Society in support of his travel to the society's September 2012 annual congress in Vienna, where he gave an invited talk on oseltamivir.

Prof Del Mar was a Board member of two companies to commercialise research at Bond University, part of his responsibilities as Pro‐Vice Chancellor (Research) until 2010, receives fees for editorial and guideline developmental work and royalties from books, and is in receipt of institutional grants from NHMRC (Aus), NIHR (UK) and HTA (UK) and from a private donor (for support of the editorial base of the Cochrane ARI Group).

Dr Hama receives royalties from two books published in 2008 titled "Tamiflu: harmful as was afraid" and "In order to escape from drug‐induced encephalopathy". Dr Hama provided scientific opinions and expert testimony on 11 adverse reaction cases related to oseltamivir and gefitinib.

Dr Howick has received expenses and payments from Johns Hopkins and the American Society for Neurophysiological Monitoring as an EBM consultant. Dr Howick has received funding from the Wellcome Trust, the Medical Research Council of the UK, the Economics and Social Science Research Council of the UK and he is currently a National Institute for Health Research non‐clinical research fellow. He has received payment from the Canadian Medical Association Journal for writing a book review and receives royalties from the publication of his book from Blackwell/Wiley.

Dr Heneghan receives payment for running educational courses at the University of Oxford and University of Oxford ISIS consulting services for external teaching and training. He also receives royalties for books (Evidence Based Toolkit series by Blackwell BMJ Books).

Dr Onakpoya has no additional interests to disclose. Dr Thompson has no additional interests to disclose. Dr Jones has no additional interests to disclose. Dr Spencer has no additional interests to disclose. Dr Nunan has no additional interests to disclose. Dr Mahtani has no additional interests to disclose.

Figures

1
1
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
 'Other bias' includes potentially active placebos.
2
2
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
 'Other bias' includes potentially active placebos.
3
3
Flow diagram describing the number of studies identified, inclusion, exclusion and progression from identification to stage 1 to stage 2 of the review. NB Because of the absence of trial programmes for both drugs listing all sponsored trials completed or underway, we had to rely on a variety of sources for the reconstruction of the trial programmes and retrieval of relevant clinical study reports. This complexity is reflected in the flowchart, illustrating the study selection process for this review. The two main pathways were the spontaneous release of 77 clinical full clinical study reports by Roche and the requests to regulatory authorities and GSK for all the relevant reports. There was overlap in trial reports retrieved following the different pathways
4
4
Forest plot of comparison: 1 Oseltamivir versus placebo for treatment, outcome: 1.1 Time to first alleviation of symptoms in adult treatment (ITT population) [hours].
5
5
Forest plot of comparison: 3 Zanamivir versus placebo for treatment, outcome: 3.1 Time to first alleviation of symptoms in adult treatment (days).
6
6
Forest plot of comparison: 3 Zanamivir versus placebo for treatment, outcome: 3.68 Time to first alleviation of symptoms in adults with/without relief medication [days].
7
7
Forest plot of comparison: 1 Oseltamivir versus placebo for treatment, outcome: 1.17 Complications: pneumonia in adult treatment.
8
8
Example Diary card from case‐report form for Zanamivir trial
9
9
Example Diary card from case‐report form for Zanamivir trial (cont)
10
10
Forest plot of comparison: 2 Oseltamivir versus placebo for prophylaxis, outcome: 2.19 Adverse events: headache in adult prophylaxis (on‐treatment).
11
11
Forest plot of comparison: 2 Oseltamivir versus placebo for prophylaxis, outcome: 2.54 Adverse events: psychiatric body system in adult prophylaxis (on‐ and off‐treatment).
12
12
Sample "Adverse event or intercurrent illness" form (oseltamivir study M76001)
13
13
Sample "Secondary illness" form (oseltamivir study WV15670)
14
14
Sample "Diagnosis of secondary illness" form, page 1/2 (oseltamivir study WV15978)
15
15
Sample "Diagnosis of secondary illness" form, page 2/2 (oseltamivir study WV15978)
1.1
1.1. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 1 Time to first alleviation of symptoms in adult treatment (ITT population).
1.2
1.2. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 2 Hospital admission in adult treatment (safety population).
1.3
1.3. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 3 Defined as influenza‐infected at baseline in adult treatment.
1.4
1.4. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 4 Antibody rise four‐fold or greater in adult treatment.
1.5
1.5. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 5 Adverse events ‐ nausea in adult treatment (on‐treatment).
1.6
1.6. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 6 Adverse events ‐ vomiting in adult treatment (on‐treatment).
1.7
1.7. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 7 Adverse events ‐ diarrhoea in adult treatment (on‐treatment).
1.8
1.8. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 8 Withdrawal from adult treatment trial due to adverse events.
1.9
1.9. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 9 All withdrawals from adult treatment.
1.10
1.10. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 10 Adverse events ‐ cough in adult treatment (on‐treatment).
1.11
1.11. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 11 Adverse events ‐ abdominal pain in adult treatment (on‐treatment).
1.12
1.12. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 12 Adverse events: dizziness in adult treatment (on‐treatment).
1.13
1.13. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 13 Adverse events: headache in adult treatment (on‐treatment).
1.14
1.14. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 14 Serious adverse events: overall in adult treatment (on‐treatment).
1.15
1.15. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 15 Serious adverse events: overall in adult treatment (off‐treatment).
1.16
1.16. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 16 Complications: bronchitis in adult treatment.
1.17
1.17. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 17 Complications: pneumonia in adult treatment.
1.18
1.18. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 18 Complications: sinusitis in adult treatment.
1.19
1.19. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 19 Complications: otitis media in adult treatment.
1.20
1.20. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 20 Complications in adult trials classified as serious or leading to study withdrawal.
1.21
1.21. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 21 Culture‐positive at baseline in adult treatment.
1.22
1.22. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 22 Adverse events: general body system in adult treatment (on‐treatment).
1.23
1.23. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 23 Adverse events: neurological body system in adult treatment (on‐treatment).
1.24
1.24. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 24 Adverse events: respiratory body system in adult treatment (on‐treatment).
1.25
1.25. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 25 Adverse events: infection body system in adult treatment (on‐treatment).
1.26
1.26. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 26 Adverse events: gastrointestinal body system in adult treatment (on‐treatment).
1.27
1.27. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 27 Adverse events: cardiac body system in adult treatment (on‐treatment).
1.28
1.28. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 28 Adverse events: ear body system in adult treatment (on‐treatment).
1.29
1.29. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 29 Adverse events: eye body system in adult treatment (on‐treatment).
1.30
1.30. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 30 Adverse events: metabolism body system in adult treatment (on‐treatment).
1.31
1.31. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 31 Adverse events: musculoskeletal body system in adult treatment (on‐treatment).
1.32
1.32. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 32 Adverse events: psychiatric body system in adult treatment (on‐treatment).
1.33
1.33. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 33 Adverse events: skin body system in adult treatment (on‐treatment).
1.34
1.34. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 34 Adverse events: cardiac body system in adult treatment (off‐treatment).
1.35
1.35. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 35 Adverse events: ear body system in adult treatment (off‐treatment).
1.36
1.36. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 36 Adverse events: gastrointestinal body system in adult treatment (off‐treatment).
1.37
1.37. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 37 Adverse events: general body system in adult treatment (off‐treatment).
1.38
1.38. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 38 Adverse events: infection body system in adult treatment (off‐treatment).
1.39
1.39. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 39 Adverse events: musculoskeletal body system in adult treatment (off‐treatment).
1.40
1.40. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 40 Adverse events: neurological body system in adult treatment (off‐treatment).
1.41
1.41. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 41 Adverse events: respiratory body system in adult treatment (off‐treatment).
1.42
1.42. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 42 Adverse events: skin body system in adult treatment (off‐treatment).
1.43
1.43. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 43 Adverse events: cough in adult treatment (off‐treatment).
1.44
1.44. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 44 Adverse events: headache in adult treatment (off‐treatment).
1.45
1.45. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 45 Adverse events: nausea in adult treatment (off‐treatment).
1.46
1.46. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 46 Time to first alleviation of symptoms in child treatment [hours].
1.47
1.47. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 47 Hospital admission in child treatment (safety population).
1.48
1.48. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 48 Defined as influenza‐infected at baseline in child treatment.
1.49
1.49. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 49 Antibody rise four‐fold or greater in child treatment.
1.50
1.50. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 50 Complications: bronchitis in child treatment.
1.51
1.51. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 51 Complications: otitis media in child treatment.
1.52
1.52. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 52 Complications: pneumonia in child treatment.
1.53
1.53. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 53 Complications: sinusitis in child treatment.
1.54
1.54. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 54 Complications: pneumonia in child treatment by on‐ and off‐treatment.
1.55
1.55. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 55 Complications in trials of children classified as serious or leading to study withdrawal.
1.56
1.56. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 56 Withdrawal from child treatment trial due to adverse events.
1.57
1.57. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 57 All withdrawals from child treatment.
1.58
1.58. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 58 Serious adverse events: overall in child treatment (on‐treatment).
1.59
1.59. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 59 Serious adverse events: overall in child treatment (off‐treatment).
1.60
1.60. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 60 Adverse events: abdominal pain in child treatment (on‐treatment).
1.61
1.61. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 61 Adverse events: diarrhoea in child treatment (on‐treatment).
1.62
1.62. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 62 Adverse events: nausea in child treatment (on‐treatment).
1.63
1.63. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 63 Adverse events: vomiting in child treatment (on‐treatment).
1.64
1.64. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 64 Adverse events: abdominal pain in child treatment (off‐treatment).
1.65
1.65. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 65 Adverse events: cough in child treatment (off‐treatment).
1.66
1.66. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 66 Adverse events: diarrhoea in child treatment (off‐treatment).
1.67
1.67. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 67 Adverse events: headache in child treatment (off‐treatment).
1.68
1.68. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 68 Adverse events: vomiting in child treatment (off‐treatment).
1.69
1.69. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 69 Adverse events: ear body system in child treatment (on‐treatment).
1.70
1.70. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 70 Adverse events: gastrointestinal body system in child treatment (on‐treatment).
1.71
1.71. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 71 Adverse events: general body system in child treatment (on‐treatment).
1.72
1.72. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 72 Adverse events: infection body system in child treatment (on‐treatment).
1.73
1.73. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 73 Adverse events: neurological body system in child treatment (on‐treatment).
1.74
1.74. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 74 Adverse events: respiratory body system in child treatment (on‐treatment).
1.75
1.75. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 75 Adverse events: skin body system in child treatment (on‐treatment).
1.76
1.76. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 76 Adverse events: ear body system in child treatment (off‐treatment).
1.77
1.77. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 77 Adverse events: gastrointestinal body system in child treatment (off‐treatment).
1.78
1.78. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 78 Adverse events: general body system in child treatment (off‐treatment).
1.79
1.79. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 79 Adverse events: infection body system in child treatment (off‐treatment).
1.80
1.80. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 80 Adverse events: neurological body system in child treatment (off‐treatment).
1.81
1.81. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 81 Adverse events: respiratory body system in child treatment (off‐treatment).
1.82
1.82. Analysis
Comparison 1 Oseltamivir versus placebo for treatment, Outcome 82 Culture‐positive at baseline in child treatment.
2.1
2.1. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 1 Symptomatic influenza in adult prophylaxis of individuals.
2.2
2.2. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 2 Asymptomatic influenza in adult prophylaxis of individuals.
2.3
2.3. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 3 Symptomatic influenza in household prophylaxis.
2.4
2.4. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 4 Asymptomatic influenza in household prophylaxis.
2.5
2.5. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 5 Influenza‐like illness reported as adverse event (on‐treatment).
2.6
2.6. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 6 Influenza‐like illness reported as adverse event (off‐treatment).
2.7
2.7. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 7 Hospitalisation in adult prophylaxis (safety population).
2.8
2.8. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 8 Complications: bronchitis in adult prophylaxis.
2.9
2.9. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 9 Complications: sinusitis in adult prophylaxis.
2.10
2.10. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 10 Adverse events leading to study withdrawal in adult prophylaxis.
2.11
2.11. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 11 All withdrawals in adult prophylaxis.
2.12
2.12. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 12 Serious adverse events in adult prophylaxis (on‐treatment).
2.13
2.13. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 13 Serious adverse events in adult prophylaxis (off‐treatment).
2.14
2.14. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 14 Adverse events: abdominal pain in adult prophylaxis (on‐treatment).
2.15
2.15. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 15 Adverse events: cough in adult prophylaxis (on‐treatment).
2.16
2.16. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 16 Adverse events: diarrhoea in adult prophylaxis (on‐treatment).
2.17
2.17. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 17 Adverse events: dizziness in adult prophylaxis (on‐treatment).
2.18
2.18. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 18 Adverse events: fatigue in adult prophylaxis (on‐treatment).
2.19
2.19. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 19 Adverse events: headache in adult prophylaxis (on‐treatment).
2.20
2.20. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 20 Adverse events: nausea in adult prophylaxis (on‐treatment).
2.21
2.21. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 21 Adverse events: vomiting in adult prophylaxis (on‐treatment).
2.22
2.22. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 22 Adverse events: cough in adult prophylaxis (off‐treatment).
2.23
2.23. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 23 Adverse events: fatigue in adult prophylaxis (off‐treatment).
2.24
2.24. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 24 Adverse events: headache in adult prophylaxis (off‐treatment).
2.25
2.25. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 25 Adverse events: blood body system in adult prophylaxis (on‐treatment).
2.26
2.26. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 26 Adverse events: cardiac body system in adult prophylaxis (on‐treatment).
2.27
2.27. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 27 Adverse events: ear body system in adult prophylaxis (on treatment).
2.28
2.28. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 28 Adverse events: eye body system in adult prophylaxis (on‐treatment).
2.29
2.29. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 29 Adverse events: gastrointestinal body system in adult prophylaxis (on‐treatment).
2.30
2.30. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 30 Adverse events: general body system in adult prophylaxis (on‐treatment).
2.31
2.31. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 31 Adverse events: infection body system in adult prophylaxis (on‐treatment).
2.32
2.32. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 32 Adverse events: immune body system in adult prophylaxis (on‐treatment).
2.33
2.33. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 33 Adverse events: injury body system in adult prophylaxis (on‐treatment).
2.34
2.34. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 34 Adverse events: metabolism body system in adult prophylaxis (on‐treatment).
2.35
2.35. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 35 Adverse events: musculoskeletal body system in adult prophylaxis (on‐treatment).
2.36
2.36. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 36 Adverse events: neurological body system in adult prophylaxis (on‐treatment).
2.37
2.37. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 37 Adverse events: psychiatric body system in adult prophylaxis (on‐treatment).
2.38
2.38. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 38 Adverse events: renal body system in adult prophylaxis (on‐treatment).
2.39
2.39. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 39 Adverse events: reproductive body system in adult prophylaxis (on treatment).
2.40
2.40. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 40 Adverse events: respiratory body system in adult prophylaxis (on‐treatment).
2.41
2.41. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 41 Adverse events: skin body system in adult prophylaxis (on‐treatment).
2.42
2.42. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 42 Adverse events: surgical events in adult prophylaxis (on‐treatment).
2.43
2.43. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 43 Adverse events: vascular body system in adult prophylaxis (on‐treatment).
2.44
2.44. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 44 Adverse events: cardiac body system in adult prophylaxis (off‐treatment).
2.45
2.45. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 45 Adverse events: gastrointestinal body system in adult prophylaxis (off‐treatment).
2.46
2.46. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 46 Adverse events: general body system in adult prophylaxis (off‐treatment).
2.47
2.47. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 47 Adverse events: infection body system in adult prophylaxis (off‐treatment).
2.48
2.48. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 48 Adverse events: injury body system in adult prophylaxis (off‐treatment).
2.49
2.49. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 49 Adverse events: musculoskeletal body system in adult prophylaxis (off‐treatment).
2.50
2.50. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 50 Adverse events: neurological body system in adult prophylaxis (off‐treatment).
2.51
2.51. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 51 Adverse events: reproductive body system in adult prophylaxis (off‐treatment).
2.52
2.52. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 52 Adverse events: respiratory body system in adult prophylaxis (off‐treatment).
2.53
2.53. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 53 Adverse events: skin body system in adult prophylaxis (off‐treatment).
2.54
2.54. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 54 Adverse events: psychiatric body system in adult prophylaxis (on and off‐treatment).
2.55
2.55. Analysis
Comparison 2 Oseltamivir versus placebo for prophylaxis, Outcome 55 Adverse events: renal body system in adult prophylaxis (on and off‐treatment).
3.1
3.1. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 1 Time to first alleviation of symptoms in adult treatment (days).
3.2
3.2. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 2 Complications: pneumonia in adult treatment.
3.3
3.3. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 3 Complications: pneumonia confirmed with X‐ray in adult treatment.
3.4
3.4. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 4 Complications: bronchitis in adult treatment.
3.5
3.5. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 5 Complications: sinusitis in adult treatment.
3.6
3.6. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 6 Complications: otitis media in adult treatment.
3.7
3.7. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 7 Complications in adult trials classified as serious or leading to study withdrawal.
3.8
3.8. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 8 Proportion diagnosed as influenza‐infected in adult treatment.
3.9
3.9. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 9 Proportion with four‐fold rise in antibody titre in adult treatment.
3.10
3.10. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 10 Proportion with positive culture at baseline in adult treatment.
3.11
3.11. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 11 Serious adverse events in adult treatment.
3.12
3.12. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 12 Adverse events leading to study withdrawal in adult treatment.
3.13
3.13. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 13 All withdrawals in adult treatment.
3.14
3.14. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 14 Time to first alleviation of symptoms in children (days).
3.15
3.15. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 15 Complications: pneumonia in child treatment.
3.16
3.16. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 16 Complications: bronchitis in child treatment.
3.17
3.17. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 17 Complications: sinusitis in child treatment.
3.18
3.18. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 18 Complications: otitis media in child treatment.
3.19
3.19. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 19 Proportion diagnosed as influenza‐infected in child treatment.
3.20
3.20. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 20 Proportion with four‐fold increase in antibodies in child treatment.
3.21
3.21. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 21 Proportion with positive culture at baseline in child treatment.
3.22
3.22. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 22 All withdrawals in child treatment.
3.23
3.23. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 23 Adverse events: nausea and vomiting in child treatment (on‐treatment).
3.24
3.24. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 24 Adverse events: diarrhoea in child treatment (on‐treatment).
3.25
3.25. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 25 Adverse events: gastrointestinal body system in child treatment (on‐treatment).
3.26
3.26. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 26 Adverse events: respiratory body system in child treatment (on‐treatment).
3.27
3.27. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 27 Adverse events: neurological body system in child treatment (on‐treatment).
3.28
3.28. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 28 Adverse events: ear, nose and throat body system in child treatment (on‐treatment).
3.29
3.29. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 29 Adverse events: skin body system in child treatment (on‐treatment).
3.30
3.30. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 30 Adverse events: gastrointestinal body system in child treatment (off‐treatment).
3.31
3.31. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 31 Adverse events: ear nose and throat body system in child treatment (off‐treatment).
3.32
3.32. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 32 Adverse events: nausea/vomiting in adult treatment (on‐treatment).
3.33
3.33. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 33 Adverse events: diarrhoea in adult treatment (on‐treatment).
3.34
3.34. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 34 Adverse events: dizziness in adult treatment (on‐treatment).
3.35
3.35. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 35 Adverse events: headache in adult treatment (on‐treatment).
3.36
3.36. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 36 Adverse events: cough in adult treatment (on‐treatment).
3.37
3.37. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 37 Adverse events: gastrointestinal body system in adult treatment (on‐treatment).
3.38
3.38. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 38 Adverse events: respiratory body system in adult treatment (on‐treatment).
3.39
3.39. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 39 Adverse events: neurological body system in adult treatment (on‐treatment).
3.40
3.40. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 40 Adverse events: ear, nose and throat body system in adult treatment (on‐treatment).
3.41
3.41. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 41 Adverse events: skin body system in adult treatment (on‐treatment).
3.42
3.42. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 42 Adverse events: musculoskeletal body system in adult treatment (on‐treatment).
3.43
3.43. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 43 Adverse events: eye body system in adult treatment (on‐treatment).
3.44
3.44. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 44 Adverse events: hepato body system in adult treatment (on‐treatment).
3.45
3.45. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 45 Adverse events: renal body system in adult treatment (on‐treatment).
3.46
3.46. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 46 Adverse events: cardiovascular body system in adult treatment (on‐treatment).
3.47
3.47. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 47 Adverse events: blood body system in adult treatment (on‐treatment).
3.48
3.48. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 48 Adverse events: psychiatric body system in adult treatment (on‐treatment).
3.49
3.49. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 49 Adverse events: reproduction body system in adult treatment (on‐treatment).
3.50
3.50. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 50 Adverse events: endocrine and metabolic body system in adult treatment (on‐treatment).
3.51
3.51. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 51 Adverse events: injury body system in adult treatment (on‐treatment).
3.52
3.52. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 52 Adverse events: non‐site specific events in adult treatment (on‐treatment).
3.53
3.53. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 53 Adverse events: nausea/vomiting in adult treatment (off‐treatment).
3.54
3.54. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 54 Adverse events: cough in adult treatment (off‐treatment).
3.55
3.55. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 55 Adverse events: respiratory body system in adult treatment (off‐treatment).
3.56
3.56. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 56 Adverse events: headache in adult treatment (off‐treatment).
3.57
3.57. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 57 Adverse events: diarrhoea in adult treatment (off‐treatment).
3.58
3.58. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 58 Adverse events: fatigue in adult treatment (off‐treatment).
3.59
3.59. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 59 Adverse events: gastrointestinal body system in adult treatment (off‐treatment).
3.60
3.60. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 60 Adverse events: neurological body system in adult treatment (off‐treatment).
3.61
3.61. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 61 Adverse events: ear, nose and throat in adult treatment (off‐treatment).
3.62
3.62. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 62 Adverse events: skin body system in adult treatment (off‐treatment).
3.63
3.63. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 63 Adverse events: musculoskeletal body system in adult treatment (off‐treatment).
3.64
3.64. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 64 Adverse events: non‐site specific in adult treatment (off‐treatment).
3.65
3.65. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 65 Adverse events: injury body system in adult treatment (off‐treatment).
3.66
3.66. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 66 Adverse events: endocrine and metabolic body system in adult treatment (off‐treatment).
3.67
3.67. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 67 Adverse events: eye body system in adult treatment (off‐treatment).
3.68
3.68. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 68 Time to first alleviation of symptoms in adults with/without relief medication [days].
3.69
3.69. Analysis
Comparison 3 Zanamivir versus placebo for treatment, Outcome 69 Time to first alleviation of symptoms in adults by infection status [days].
4.1
4.1. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 1 Symptomatic influenza in prophylaxis of individuals.
4.2
4.2. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 2 Asymptomatic influenza in prophylaxis of individuals.
4.3
4.3. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 3 Symptomatic influenza in post‐exposure prophylaxis.
4.4
4.4. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 4 Asymptomatic influenza in post‐exposure prophylaxis.
4.5
4.5. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 5 Complications: pneumonia in adult prophylaxis.
4.6
4.6. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 6 Complications: bronchitis in adult prophylaxis.
4.7
4.7. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 7 Complications: sinusitis in adult prophylaxis.
4.8
4.8. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 8 Complications classified as serious or leading to study withdrawal.
4.9
4.9. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 9 Serious adverse events in adult prophylaxis.
4.10
4.10. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 10 Adverse events leading to study withdrawal in adult prophylaxis.
4.11
4.11. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 11 All withdrawals in adult prophylaxis.
4.12
4.12. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 12 Adverse events: abdominal pain in adult prophylaxis (on‐treatment).
4.13
4.13. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 13 Adverse events: cough in adult prophylaxis (on‐treatment).
4.14
4.14. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 14 Adverse events: diarrhoea in adult prophylaxis (on‐treatment).
4.15
4.15. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 15 Adverse events: dizziness in adult prophylaxis (on‐treatment).
4.16
4.16. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 16 Adverse events: fatigue in adult prophylaxis (on‐treatment).
4.17
4.17. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 17 Adverse events: headache in adult prophylaxis (on‐treatment).
4.18
4.18. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 18 Adverse events: blood body system in adult prophylaxis (on‐treatment).
4.19
4.19. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 19 Adverse events: nausea/vomiting in adult prophylaxis (on‐treatment).
4.20
4.20. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 20 Adverse events: cardiovascular body system in adult prophylaxis (on‐treatment).
4.21
4.21. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 21 Adverse events: ear, nose and throat body system in adult prophylaxis (on‐treatment).
4.22
4.22. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 22 Adverse events: endocrine and metabolic body system in adult prophylaxis (on‐treatment).
4.23
4.23. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 23 Adverse events: eye body system in adult prophylaxis (on‐treatment).
4.24
4.24. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 24 Adverse events: gastrointestinal body system in adult prophylaxis (on‐treatment).
4.25
4.25. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 25 Adverse events: injury body system in adult prophylaxis (on‐treatment).
4.26
4.26. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 26 Adverse events: musculoskeletal body system in adult prophylaxis (on‐treatment).
4.27
4.27. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 27 Adverse events: neurological body system in adult prophylaxis (on‐treatment).
4.28
4.28. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 28 Adverse events: non‐site specific in adult prophylaxis (on‐treatment).
4.29
4.29. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 29 Adverse events: psychiatric body system in adult prophylaxis (on‐treatment).
4.30
4.30. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 30 Adverse events: renal body system in adult prophylaxis (on‐treatment).
4.31
4.31. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 31 Adverse events: reproductive body system in adult prophylaxis (on‐treatment).
4.32
4.32. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 32 Adverse events: respiratory body system in adult prophylaxis (on‐treatment).
4.33
4.33. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 33 Adverse events: skin body system in adult prophylaxis (on‐treatment).
4.34
4.34. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 34 Adverse events: gastrointestinal body system in adult prophylaxis (off‐treatment).
4.35
4.35. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 35 Adverse events: respiratory body system in adult prophylaxis (off‐treatment).
4.36
4.36. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 36 Adverse events: nausea/vomiting in prophylaxis (off‐treatment).
4.37
4.37. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 37 Adverse events: diarrhoea in prophylaxis (off‐treatment).
4.38
4.38. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 38 Adverse events: headache in prophylaxis (off‐treatment).
4.39
4.39. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 39 Adverse events: cough in prophylaxis (off‐treatment).
4.40
4.40. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 40 Adverse events: fatigue in prophylaxis (off‐treatment).
4.41
4.41. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 41 Adverse events: neurological body system in prophylaxis (off‐treatment).
4.42
4.42. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 42 Adverse events: ear, nose and throat in prophylaxis (off‐treatment).
4.43
4.43. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 43 Adverse events: musculoskeletal body system in prophylaxis (off‐treatment).
4.44
4.44. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 44 Adverse events: non‐site specific in prophylaxis (off‐treatment).
4.45
4.45. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 45 Adverse events: injury in prophylaxis (off‐treatment).
4.46
4.46. Analysis
Comparison 4 Zanamivir versus placebo for prophylaxis, Outcome 46 Adverse events: endocrine and metabolic in prophylaxis (off‐treatment).
5.1
5.1. Analysis
Comparison 5 Neuraminidase inhibitor versus placebo for treatment or prophylaxis, Outcome 1 Complications: pneumonia.
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Update of

Comment in

References

References to studies included in this review

167‐101 {published data only}
    1. GSK. Investigation of the efficacy of GG167 (zanamivir) in the treatment of influenza viral infections (late Phase II study: dose comparison study). Data on file.
JNAI‐01 {published data only}
    1. GSK. Investigation of the efficacy of CG167 in the treatment of influenza viral infections (phase II study) (Protocol NoJNAI‐01). Double blind, double dummy, randomized, placebo controlled, parallel group, multicenter study to investigate safety and route of administration of CG167 when inhaled, CG167 10 mg, or the combination of inhaled CG167 10 mg plus intranasal CG167 6.4 mg, administered twice daily for 5 days in the treatment of influenza A and B viral infections. Data on file.
JNAI‐04 {published data only}
    1. GSK. A multicenter two way layout randomized placebo‐controlled double‐blind trial parallel group comparative trial on the efficacy and safety of GG167 (zanamivir) 10 mg twice a day and 20 mg twice a day in the treatment of influenza type A and type B infections (late Phase II study: dose comparison study) (Protocol No. JNAI‐04). Data on file.
JNAI‐07 {published data only}
    1. GSK. A multicenter two way layout randomized placebo‐controlled double‐blind trial parallel group comparative trial on the efficacy and safety of GG167 (zanamivir) 10 mg twice a day and 20 mg twice a day in the treatment of influenza type A and type B infections (late Phase II study: dose comparison study) (Protocol No.JNAI‐07). Data on file.
JV15823 {published data only}
    1. No authors listed. A randomized, placebo‐controlled, multicenter study of oseltamivir (Ro 64‐0796) in the treatment of influenza in Japanese subjects (Translation of summary Japanese report ‐ of 29 pages). Data on file.
JV15824 {published data only}
    1. No authors listed. Phase 3 study for prophylaxis of influenza with Ro64‐0796 (15 page summary from Japanese). Data on file.
M76001 {published data only}
    1. McGarty T. A randomized, double‐blind, placebo‐controlled, multicenter study of efficacy based on the time to treatment of influenza infection with the neuraminidase inhibitor Ro 64‐0796 (also known as GS 4104). Data on file.
ML16369 {published data only}
    1. No authors listed. A double‐blind, randomized, placebo‐controlled multicenter study of oseltamivir phosphate in the treatment of influenza infection in China. Data on file. - PubMed
NAI30008 {published data only}
    1. No authors listed. A double‐blind, randomized, placebo‐controlled, parallel group, multi‐center study to investigate the efficacy and safety of inhaled zanamivir 10 mg administered twice daily for five days in the treatment of influenza in patients 12 years or over diagnosed with asthma or chronic obstructive pulmonary disease. Data on file.
NAI30009 {published data only}
    1. Alfors S, Keene O, Grice R, Hammond J, Hendricks V, Martin N, et al. A double‐blind, randomized, placebo‐controlled, parallel‐group, multicenter study to investigate the efficacy and safety of zanamivir (GG167) 10 mg administered by inhalation twice daily for five days in the treatment of symptomatic influenza A and B viral infections in children ages 5‐12. Data on file.
NAI30010 {published data only}
    1. Hunter S, Reilly L, Sharp S, West M, Alfors S, Hammond J, et al. A double‐blind, randomized, placebo‐controlled, parallel‐group, multicenter study to investigate the efficacy and safety of inhaled zanamivir (GG167) 10 mg administered once a day for 10 days in the prevention of transmission of symptomatic influenza A and B viral infections within families. Data on file.
NAI30011 {published data only}
    1. No authors listed. A randomised, double‐blind, placebo‐controlled study to evaluate the impact of inhaled zanamivir treatment on workplace attendance due to influenza A and B infections. Data on file.
NAI30012 {published data only}
    1. No authors listed. A double‐blind, randomised, placebo‐controlled, parallel‐group, multicentre study to investigate the efficacy and safety of inhaled zanamivir 10 mg administered twice daily for five days in the treatment of symptomatic influenza A and B viral infections in subjects aged over 65 years. Data on file.
NAI30015 {published data only}
    1. No authors listed. A double‐blind, randomised, placebo‐controlled, parallel‐group, multicentre study to investigate the efficacy and safety of inhaled zanamivir 10 mg administered twice daily for five days in the treatment of symptomatic influenza A and B viral infections in armed services personnel. Data on file.
NAI30020 {unpublished data only}
    1. No authors listed. A double‐blind, randomised, placebo‐controlled, multicenter study in 2 parallel groups, to investigate the efficacy and safety of inhaled zanamivir (10 mg bd. via Diskhaler), for 5 days, in high risk patients with symptomatic influenza A and / or B infection. Data on file Synopsis only available.
NAI30028 {published data only}
    1. No authors listed. A double‐blind, randomised, placebo‐controlled, multicenter study in 2 parallel groups, to investigate the efficacy and safety of inhaled zanamivir (10 mg bd via Diskhaler), for 5 days, in children aged 5 to 12 years with symptomatic influenza A and / or B infection. Data on file.
NAI30031 {published data only}
    1. No authors listed. A double‐blind, randomised, placebo‐controlled, parallel‐group, multicentre study to investigate the efficacy and safety of inhaled zanamivir 10 mg administered once a day for 10 days in the prevention of transmission of symptomatic influenza A and B viral infections within households. Data on file.
NAI30034 {published data only}
    1. No authors listed. A double‐blind, randomized, placebo‐controlled, parallel‐group, multicentre study to investigate the efficacy and safety of inhaled zanamivir 10 mg administered once a day for 28 days in the prevention of symptomatic influenza A and B viral infections in community‐dwelling high‐risk populations. Data on file.
NAIA/B2008 {published data only}
    1. No authors listed. A double‐blind, randomized, placebo‐controlled, multicenter, parallel‐group study to investigate the efficacy and safety of zanamivir administered twice or four times a day for the treatment of influenza A and B viral infections. Data on file.
NAIA/B2009 {published data only}
    1. No authors listed. A double‐blind, randomised, placebo‐controlled, multicentre, parallel‐group study to demonstrate the efficacy and safety of zanamivir in the prevention and/or progression of influenza A and B viral infections. Data on file.
NAIA2005 {published data only}
    1. MacLeod A, Gummer M, Raniga K, Hirst H, Keene O, Ossi M, et al. A double‐blind, randomised, placebo‐controlled multi‐centre study to investigate the efficacy and safety of inhaled and intranasal zanamivir in the treatment of influenza A and B viral infections. Data on file.
NAIA2006 {published data only}
    1. No authors listed. A double‐blind, randomised, placebo‐controlled multicentre study to investigate the efficacy and safety of zanamivir therapy in the prevention of progression of influenza A and B viral infections. Data on file.
NAIA3002 {published data only}
    1. Elliott M, Flack N, Keene O, Szymborski P, Vega R (PharmaResearch, Inc). A double‐blind, randomized, placebo‐controlled, parallel‐group, multicenter study to investigate the efficacy and safety of inhaled zanamivir (GG167) 10 mg administered twice a day for five days in the treatment of symptomatic influenza A and B viral infections in adolescents and adults. Data on file.
NAIA3003 {published data only}
    1. No authors listed. A double‐blind, randomized, parallel‐group, multi‐center study to investigate the efficacy and safety of inhaled zanamivir 10 mg administered once a day compared to the standard of care in controlling nursing home influenza outbreaks. Data on file.
NAIA3004 {published data only}
    1. No authors listed. A double‐blind, randomized, placebo‐controlled, parallel‐group, multi‐center study to investigate the efficacy and safety of inhaled zanamivir 10 mg once a day in controlling nursing home influenza outbreaks. Data on file.
NAIA3005 {published data only}
    1. Elliott M, Hunter S, Flack N, Crisp A, Szymborski P, Vega R. A double‐blind, randomized, placebo‐controlled, parallel‐group, multicenter study to investigate the efficacy and safety of zanamivir (GG167) 10 mg administered once a day for 28 days in the prevention of symptomatic influenza A and B viral infections in community dwelling adults. Data on file.
NAIB2005 {published data only}
    1. Leong J, Brennan J, Gummer M, Keene O, Wightman K. A double‐blind, randomised, placebo‐controlled, parallel‐group, multi‐centre study to investigate the efficacy and safety of inhaled plus intranasal zanamivir in the treatment of influenza A and B viral infections. Data on file.
NAIB2006 {published data only}
    1. No authors listed. A double‐blind, randomised, placebo‐controlled, parallel‐group, multicentre study to investigate the efficacy and safety of inhaled zanamivir in preventing progression of influenza A and B viral infections. Data on file.
NAIB2007 {published data only}
    1. Perich R, Solterbeck A, Keene O, Leong J, Raniga K, MacLeod A. A double‐blind, randomised, placebo‐controlled, parallel‐group, multi‐centre study to investigate the efficacy and safety of inhaled and inhaled plus intranasal zanamivir in the treatment of influenza A and B viral infections. Data on file.
NAIB3001 {published data only}
    1. Campion K, Gummer M, Keene O. A double‐blind, randomized, placebo‐controlled, parallel‐group, multicenter study to investigate the efficacy and safety of zanamivir administered twice daily in the treatment of influenza A and B viral infections in adults. Data on file.
NAIB3002 {published data only}
    1. Man CY, Keene ON, Challoner T (Challoner Associates). A double‐blind, randomised, placebo‐controlled, parallel‐group, multicentre study to investigate the efficacy and safety of inhaled zanamivir (GG167) 10 mg administered twice a day for five days in the treatment of symptomatic influenza A and B viral infections in adolescents and adults. Data on file.
NV16871 {published data only}
    1. No authors listed. A double‐blind, randomized, stratified, placebo‐controlled study of oseltamivir in the treatment of influenza in children with asthma. Data on file.
PE‐01 {unpublished data only}
    1. No authors listed. A trial to investigate efficacy to reduce development of influenza symptoms in influenza infected patients treated with GG167 (protocol number PE‐01 phase II clinical trial). A double‐blind double‐dummy, randomized, placebo‐controlled, parallel group, multicenter study to investigate the efficacy reducing development of influenza symptoms and, safety and rout of administration of GG 157 when orally inhaled GG 167 10 mg, 6.4 mg nebulized intranasally or the combination of inhaled GG167 10 mg plus intranasal GG167 6.4 mg was administered twice day for 5 days in the treatment of influenza A and B viral infections. Data on file.
WV15670 {published data only}
    1. Dorkings J. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomized controlled trial. Data on file.
WV15671 {published data only}
    1. Dorkings J. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. Data on file. - PubMed
WV15673/WV15697 {published data only}
    1. No authors listed. Efficacy of Ro 64‐0796 when used as chemoprophylaxis against natural influenza infection. Data on file.
WV15707 {published data only}
    1. Grosse M. A multi‐center, randomized, double‐blind, placebo‐controlled, parallel group study of oseltamivir treatment in elderly patients with influenza. Data on file.
WV15708 {published data only}
    1. No authors listed. A double‐blind randomised placebo controlled study of Ro 64‐0796 (also known as GS4104) used in elderly subjects for the prevention of clinical influenza during influenza season. Data on file.
WV15730 {published data only}
    1. Dorkings J. A double‐blind, stratified, randomized, placebo controlled study of Ro 64‐0796 (GS4104) in the treatment of influenza infection in adults. Data on file.
WV15758 {published data only}
    1. No authors listed. A double‐blind, randomized, stratified, placebo‐controlled study of Ro 64‐0796 (also known as GS 4104) in the treatment of children with influenza. Data on file.
WV15759/WV15871 {published data only}
    1. Gerster T. A double‐blind, randomized, stratified, placebo‐controlled study of oseltamivir phosphate (Ro 64‐0796, also known as GS 4104) in the treatment of influenza in children with chronic asthma. Data on file.
WV15799 {published data only}
    1. No authors listed. A double‐blind randomised placebo controlled study of Ro 64‐0796 (also known as GS4104) for the prevention of clinical influenza post exposure in families. Data on file.
WV15812/WV15872 {published data only}
    1. McCarvil M. A double‐blind, stratified, randomised, placebo controlled study of Ro 64‐0796 (also known as GS4104) in the treatment of influenza in chronically ill adults. Data on file.
WV15819/WV15876/WV15978 {published data only}
    1. No authors listed. A double‐blind, randomized, stratified, placebo‐controlled study of Ro 64‐0796 (also known as GS4104) in the treatment of influenza infection in elderly patients. Data on file.
WV15825 {published data only}
    1. No authors listed. A double‐blind, randomised, placebo‐controlled study of Ro 64‐0796 (also known as GS4104) used in elderly subjects for the prevention of clinical influenza during the influenza season. Data on file.
WV16277 {published data only}
    1. No authors listed. A double‐blind, randomised, stratified, placebo‐controlled study of oseltamivir in the treatment of influenza infection in patients. Data on file.

References to studies excluded from this review

105934 {published data only}
    1. A post‐marketing surveillance to monitor the safety of RELENZA (zanamivir) administered in Korean subjects according to the prescribing information. Data on file.
107485 {published data only}
    1. An open label, single‐dose, five‐way crossover study examining relative oral bioavailability of zanamivir with bioenhancing excipients following direct release into mid‐small intestine using gamma scintigraphy and the InteliSite Companion Capsule in healthy subjects. Data on file.
108127 {published data only}
    1. An open‐label, non‐randomized, single‐dose study to evaluate serum zanamivir pharmacokinetics following intravenous administration to human subjects with renal impairment compared to subjects without renal impairment. Data on file.
112311 {published data only}
    1. Special drug use investigation for Relenza (resistant appearance). Data on file.
112312 {published data only}
    1. Special drug use investigation for Relenza (efficacy). Data on file.
113268 {published data only}
    1. Drug use investigation for Relenza. Data on file.
113502 {published data only}
    1. Prophylactic efficacy of Relenza against influenza A and B. Data on file.
113625 {published data only}
    1. A randomized, placebo controlled, 3‐way crossover study to investigate the safety, tolerability, and pharmacokinetics of repeat dose zanamivir/placebo 10 mg administered twice daily for 5 days by a rotahaler compared to the diskhaler in healthy subjects. Data on file.
113678 {published data only}
    1. An open‐label, multi‐center, single arm study to evaluate the safety and tolerability of intravenous zanamivir in the treatment of hospitalized adult, adolescent and pediatric subjects with confirmed influenza infection. Data on file.
114045 {published data only}
    1. Collection of patients' background information Relenza® sentinel site monitoring program in Japan. Data on file.
114373 {published data only}
    1. A phase III international, randomized, double‐blind, double‐dummy study to evaluate the efficacy and safety of 300 mg or 600 mg of intravenous zanamivir twice daily compared to 75 mg of oral oseltamivir twice daily in the treatment of hospitalized adults and adolescents with influenza. Data on file.
167‐02 {published data only}
    1. A study of GG167 single blind, single administration ‐ phase I. Data on file.
167‐03 {published data only}
    1. A study of GG167 single blind, single administration ‐ phase I. Data on file.
167‐04 {published data only}
    1. A study of GG167 single blind, single administration ‐ phase I. Data on file.
167‐05 {published data only}
    1. A study of GG167 single blind, single administration ‐ phase I. Data on file.
167T3‐11 {published data only}
    1. (Zanamivir trial. Title unknown). Data on file.
ADS‐TCAD‐PO206 {published data only}
    1. A randomized open label study comparing the efficacy, safety, and tolerability of oral administration of amantadine and ribavirin with oseltamivir versus oseltamivir to influenza A virus infected immunocompromised subjects. Data on file.
BP21288 {published data only}
    1. A single‐center, open‐label, single dose, exploratory study in Caucasian and Japanese healthy subjects to investigate the pharmacokinetics of oseltamivir and its metabolite in plasma and cerebrospinal fluid. Data on file.
C94‐009 {published data only}
    1. Cass LM, Efthymiopoulos C, Bye A. Pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers. Clinical Pharmacokinetics. 1999;36 Suppl 1:1‐11. Not posted to GSK CTR. - PubMed
C94‐085 {published data only}
    1. Cass LM, Gunawardena KA, Macmahon MM, Bye A: Pulmonary function and airway responsiveness in mild to moderate asthmatics given repeated inhaled doses of zanamivir. Respiratory Medicine 2000;94(2):166‐73. Posted to GSK CTR. - PubMed
GCP/95/045 {published data only}
    1. A study to investigate the pharmacokinetics of GG167 in subjects with impaired renal function. Data on file.
JNAI‐02 {published data only}
    1. (Zanamivir trial. Title unknown). Data on file.
JNAI‐03 {published data only}
    1. (Zanamivir trial. Title unknown). Data on file.
JP15734 {published data only}
    1. Single ascending oral dose study of tolerability, safety and pharmacokinetics (including effect of food) of the neuraminidase inhibitor Ro 64‐0796 in healthy male volunteers. Data on file.
JP15735 {published data only}
    1. Multiple oral dose study of the tolerability, safety and PK of the neuraminidase inhibitor Ro64‐0796: direct PK comparison between Japanese and Caucasian subjects. Data on file.
JV16284 {published data only}
    1. Phase II clinical study of oseltamivir phosphate (Ro64‐0796) for the treatment of influenza in children. Data on file.
JV21490 {unpublished data only}
    1. Post‐marketing clinical study of oseltamivir phosphate on nighttime ECG in healthy adult male subjects. Data on file 2008.
M76006 {published data only}
    1. Early administration of oral oseltamivir increases the benefits of influenza treatment. Data on file. - PubMed
ML17279 {unpublished data only}
    1. An observational study to assess the accuracy of diagnosis of influenza in community pharmacies. Data on file.
ML17713 {published data only}
    1. Phase IV study on Tamiflu® capsule 75 in the elderly aged 80 years or older (a single dose oral administration study for assessing pharmacokinetics in the elderly not infected with influenza virus). Data on file.
ML19340 {unpublished data only}
    1. Impact of oseltamivir (Tamiflu ®) in post‐exposure prophylaxis influenza on mortality and morbidity in institutionalised elderly people. [Impact de l'oseltamivir (Tamiflu®) en prophylaxie antigrippale post‐exposition, sur la mortalité et la morbidité des personnes âgées institutionnalisées.]. Data on file.
ML20542 {published data only}
    1. Evaluation of combination therapy with oseltamivir and zanamivir versus monotherapy in the treatment of virologically confirmed influenza in primary care a randomised double blind controlled trial study. Data on file.
ML21954 {published data only}
    1. Efficacy and safety of combination therapies with oseltamivir & zanamivir or oseltamivir & amantadine versus oseltamivir monotherapy in the treatment of seasonal influenza A infection. Data on file.
ML22789 {published data only}
    1. An unblinded, comparative, randomized study of influenza A/H1N1 2009 resistance in patients with standard and double dose oseltamivir treatment. Data on file.
ML22872 {published data only}
    1. Viral shedding/resistance with double duration oseltamivir in infected patients (New Zealand). Data on file.
ML22879 {published data only}
    1. Viral shedding/resistance with standard dose/duration oseltamivir in infected patients (UK). Data on file.
ML25018 {published data only}
    1. A study of the relative oral bioavailability of the antiflu medicine oseltamivir (Tamiflu®) in patients in the intensive care unit. Data on file.
ML25087 {published data only}
    1. Viral shedding/resistance with double dose oseltamivir in infected patients (Australia). Data on file.
ML25094 {published data only}
    1. Nasogastric administration of OP in infected patients with respiratory failure. Data on file.
ML25157 {published data only}
    1. Oseltamivir pharmacokinetics in morbid obesity. Data on file. - PubMed
ML25176 {published data only}
    1. Open‐label pharmacokinetic of oseltamivir in healthy obese Thai adult subjects. Data on file.
ML25179 {published data only}
    1. A randomized, double‐blinded controlled trial comparing high vs standard dose oseltamivir in severe, influenza infection in ICU. "ROSII Study". Data on file.
ML25265 {published data only}
    1. Probing the functional expression of carboxyl esterase in preterm neonates using oseltamivir: a pragmatic observational study. Data on file.
ML25266 {published data only}
    1. Plasma levels of oseltamivir in H1N1 infected patients supported by extracorporeal membrane oxygenation: a single‐centre cohort study. Data on file.
MP20691 {published data only}
    1. Effect of probenecid on the pharmacokinetics of oseltamivir. Data on file.
MV20043 {published data only}
    1. A prospective study to assess household transmission of influenza and emergence and transmissibility of drug resistance to oseltamivir following treatment of children with influenza A and B. Data on file.
MV20050 {published data only}
    1. High‐dose versus standard‐dose oseltamivir for the treatment of severe influenza and avian influenza: a phase II double‐blind, randomized clinical trial. Data on file.
MV22926 {published data only}
    1. A study on higher‐dose oseltamivir treatment's impact on viral clearance and clinical recovery in adults hospitalized with influenza. Data on file. - PubMed
MV22949 {published data only}
    1. A study of the pharmacology of oseltamivir (Tamiflu) in pregnancy. Data on file.
MV22951 {published data only}
    1. Pharmacokinetics of Tamiflu® (oseltamivir) in patients receiving extracorporeal membrane oxygenation (ECMO) and or continuous venovenous hemodialysis (CVVHD). Data on file.
MV22963 {published data only}
    1. Pharmacokinetics of oseltamivir in critically ill adult patients. Data on file.
MV22970 {published data only}
    1. Observational study on the pharmacokinetics of oseltamivir in the treatment of influenza during lactation. Data on file.
NAI106784 {published data only}
    1. Phase I, open‐label study to evaluate steady‐state serum and pulmonary pharmacokinetics following intravenous administration of zanamivir in healthy adult subjects. Data on file.
NAI108166 {published data only}
    1. Phase 1, open‐label study to evaluate potential pharmacokinetic interactions between orally‐administered oseltamivir and intravenous zanamivir in healthy Thai adult subjects. Data on file. - PMC - PubMed
NAI10901 {published data only}
    1. A double‐blind, randomised, placebo‐controlled study to evaluate the effect of inhaled zanamivir 10 mg od for 28 days on anti‐haemagglutinin antibody production (HAI titre) following co‐administration with Fluvirin™ trivalent influenza vaccine in healthy adult subjects. Data on file.
NAI10902 {published data only}
    1. An open label, randomized evaluation of the direct measurement of zanamivir concentrations in respiratory secretions following a single dose inhalation of 10 mg RELENZA™ via DISKHALER in health volunteers. Data on file.
NAI40012 {published data only}
    1. An open‐label, multi‐center study of the patient instructional leaflet for RELENZA DISKHALER. Data on file.
NAIA1009 {published data only}
    1. Pharmacokinetics of zanamivir (GG167) following inhaled administration in pediatric subjects with signs and symptoms of respiratory illness. Data on file.
NAIA2010 {published data only}
    1. Pilot, cluster randomised, open, single centre, parallel group study to evaluate the efficacy and safety of zanamivir in controlling influenza outbreaks and preventing the development of resistant influenza cases in a high risk nursing home population, compared with usual care. Data on file.
NAIB1001 {published data only}
    1. Cass LMR, Brown J, Pickford M, Fayinka S, Newman SP, Johansson CJ, et al. Pharmacoscintigraphic evaluation of lung deposition of inhaled zanamivir in healthy volunteers. Clinical Pharmacokinetics 1999 36:Suppl 1 (21‐31). Not posted to GSK CTR. - PubMed
NAIB1002 {published data only}
    1. A study to evaluate the effect of repeat doses of GG167 dry powder on pulmonary function and bronchial hyper‐responsiveness in asthmatic subjects. Data on file.
NAIB1007 {published data only}
    1. A GG167 Pharmacokinetic Study to Select a Regimen for Prophylaxis. Data on file.
NCT00297050 {published data only}
    1. A phase I double‐blind, placebo‐controlled, dose‐escalating study to evaluate the safety and tolerability of intravenous peramivir in healthy subjects. Data on file.
NCT00416962 {published data only}
    1. An open‐label, multiple dose, randomized, three‐period crossover study in healthy volunteers to evaluate the effect of co‐administration of amantadine 100 mg BID and oseltamivir 75 mg BID on the pharmacokinetic properties of amantadine and oseltamivir. Data on file.
NCT00867139 {published data only}
    1. TCAD vs. monotherapy for influenza A in immunocompromised patients. Data on file.
NCT00957996 {published data only}
    1. A phase 3, open‐label, randomized study of the antiviral activity, safety, and tolerability of intravenous peramivir in hospitalized subjects with confirmed or suspected influenza infection. Data on file.
NCT01063933 {published data only}
    1. A pharmacokinetic/pharmacodynamic and safety evaluation of investigational intravenous peramivir in children with influenza disease (CASG 117). Data on file.
Not applicable (registry) {published data only}
    1. (Oseltamivir trial. Title unknown). Data on file.
NP15525 {published data only}
    1. Multiple ascending oral dose study of the tolerability, safety and pharmacokinetics of the neuraminidase inhibitor Ro 64‐0796 in healthy volunteers. Data on file.
NP15717 {published data only}
    1. Study of the PD and PK of the neuraminidase inhibitor Ro 64‐0796 (GS4104) in the treatment of volunteers experimentally infected with human influenza B virus. Data on file.
NP15718 {published data only}
    1. An excretion balance and pharmacokinetic study of Ro 64‐0796 after a single oral dose of 14C‐labelled Ro 64‐0796 and an intravenous dose of 14C‐labelled Ro 64‐0802 in healthy male subjects. Data on file.
NP15719 {published data only}
    1. Study of the pharmacokinetics and absolute bioavailability of the neuraminidase inhibitor Ro 64‐0796. Data on file.
NP15728 {published data only}
    1. An open‐label study of the effect of cimetidine and probenecid on the pharmacokinetics of Ro 64‐0796/GS4104 in healthy subjects. Data on file.
NP15729 {published data only}
    1. An open‐label bioequivalence and food effect study of the clinical trial and market formulations of Ro 64‐0796 in healthy subjects. Data on file.
NP15743 {unpublished data only}
    1. No authors listed. A palatability study of the neuraminidase inhibitor (Ro 64‐0796), formulated as an oral formulation. Data on file.
NP15757 {published data only}
    1. No authors listed. Study of the pharmacokinetics and pharmacodynamics of the neuraminidase inhibitor Ro 64‐0796 (GS4104) in the prophylaxis of experimental infection of volunteers with the human influenza B virus. Data on file.
NP15810 {published data only}
    1. An open‐label bioequivalence and food effect study of the clinical trial and market formulations of Ro 64‐0796 in healthy subjects. Data on file.
NP15826 {published data only}
    1. An open‐label study of pharmacokinetics of Ro 64‐0796/GS4104 in children. Data on file.
NP15827 {published data only}
    1. Study of the pharmacodynamics of the neuraminidase inhibitor in the treatment of subjects experimentally infected with the human influenza B virus. Data on file.
NP15881 {published data only}
    1. Palatability testing of the neuraminidase inhibitor Ro 64‐0796 in children. Research Report No. W‐144154/27 October 1999. Data on file.
NP15901 {published data only}
    1. An open‐label, two‐way crossover pharmacokinetic drug interaction study of neuraminidase inhibitor Ro 64‐0796/GS4104 and amoxicillin in healthy volunteers. Data on file.
NP15912 {published data only}
    1. Palatability testing of the neuraminidase inhibitor Ro 64‐0796 in children. Data on file.
NP16472 {published data only}
    1. A single center, open label, multiple dose oral oseltamivir suspension study in end‐stage‐renal disease (ESRD) patients on hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD). Data on file.
NP22770 {published data only}
    1. An open‐label, multiple dose, randomized, three‐period crossover study in healthy subjects to evaluate the effect of co‐administration of oseltamivir (RO0640796) 75 mg twice daily and rimantadine 100 mg twice daily on the pharmacokinetic properties of oseltamivir and rimantadine. Data on file.
NP25138 {published data only}
    1. A study of intravenous oseltamivir [Tamiflu] in infants with influenza. Data on file.
NP25139 {published data only}
    1. A study of intravenous Tamiflu (oseltamivir) in children with influenza. Data on file.
NP25140 {published data only}
    1. PK and safety of multiple ascending doses of iv oseltamivir in healthy adults. Data on file.
NV20234 {published data only}
    1. A randomized, double‐blind trial evaluating conventional and high dose Tamiflu in the treatment of influenza in immunocompromised patients. Data on file.
NV20235 {published data only}
    1. A double‐blind, randomized, placebo controlled multicenter trial of oseltamivir for the seasonal prophylaxis of influenza in immunocompromised patients. Data on file.
NV20237 {published data only}
    1. An influenza resistance information study (IRIS). Data on file.
NV22155 {published data only}
    1. A randomized, multicenter trial of oseltamivir [Tamiflu] doses of 75 mg for 5 or 10 days versus 150 mg for 5 or 10 days to evaluate the effect on the duration of viral shedding in influenza patients with pandemic (H1N1) 2009. Data on file.
NV22158 {published data only}
    1. Avian/pandemic influenza registry final report, 30 August 2012. Data on file.
NV25118 {published data only}
    1. A randomized, multicenter, parallel study of the safety, pharmacokinetics and the effect on viral activity of intravenously administered Tamiflu [oseltamivir] in patients with influenza over 13 years of age. Data on file.
NV25182 {published data only}
    1. A prospective, observational safety study in children ≤ 24 months of age receiving oseltamivir for the treatment or prophylaxis of influenza infection. Data on file.
NV25655 {published data only}
    1. An open‐label, prospective, single oral dose study evaluating the pharmacokinetics, safety and tolerability of oseltamivir (Tamiflu) in adult subjects on peritoneal dialysis (PD) using a rapid cycle regimen to simulate automated peritoneal dialysis (APD) and in adult subjects with creatinine clearance from 10‐30 mL/min not on dialysis. Data on file.
PP15974 {published data only}
    1. A single oral dose, multi‐center, open label study of the pharmacokinetics, safety and tolerability of Ro 04‐0796/GS4104 in ESRD subjects on hemodialysis and peritoneal dialysis. Data on file.
PP16351 {published data only}
    1. An open label study of the pharmacokinetics of oseltamivir (Ro 64‐0796) in children aged 0 ‐ 5 years old after a single dose. Data on file.
PP16361 {published data only}
    1. Double‐blind, randomized, placebo controlled, single ascending i.v. dose study of the tolerability (with emphasis of nausea and vomiting), safety, pharmacokinetics of oseltamivir (Ro 64‐0796) and its active metabolite oseltamivir carboxylate (Ro 64‐0802) in healthy male volunteers. Data on file.
PV15615 {published data only}
    1. GS97802 ‐ challenge flu A treatment. Data on file.
PV15616 {published data only}
    1. GS‐97801 challenge flu A treatment. Data on file.
WP15517 {published data only}
    1. Single ascending oral dose study of the tolerability, safety and pharmacokinetics (including effect of food) of the neuraminidase inhibitor GS4104 in healthy volunteers. Data on file.
WP15525 {published data only}
    1. Multiple ascending oral dose study of the tolerability, safety and pharmacokinetics of the neuraminidase inhibitor, GS4104 in healthy volunteers. Data on file.
WP15647 {published data only}
    1. Multiple ascending oral dose study of the tolerability, safety and pharmacokinetics of the neuraminidase inhibitor Ro 64‐0796 in healthy elderly volunteers. Data on file.
WP15648 {published data only}
    1. Multiple oral dose study of the pharmacokinetics, tolerability and safety of the neuraminidase inhibitor Ro 64‐0796 in patients with renal impairment. Data on file.
WP15676 {published data only}
    1. Study of the safety and pharmacokinetics of the neuraminidase inhibitor Ro 64‐0796 in healthy volunteers when administered concomitantly with paracetamol (acetaminophen). Data on file.
WP15979 {published data only}
    1. An open‐label, relative bioavailability study of the phase III pediatric clinical trial and market formulations of Ro 64‐0796 in healthy volunteers. Data on file.
WP16094 {published data only}
    1. An open‐label, three‐way crossover, pharmacokinetic drug interaction study of neuraminidase inhibitor Ro 64‐0796 and aspirin in healthy subjects. Data on file.
WP16134 {published data only}
    1. An open label bioequivalence and food effect study of the enteric coated and immediate release formulations of oseltamivir in healthy subjects. Data on file.
WP16137 {published data only}
    1. An open‐label, bioequivalence study of the phase III pediatric clinical trial and market oral suspension formulations of Ro 64‐0796 in healthy volunteers. Data on file.
WP16225 {published data only}
    1. An open‐label, relative bioavailability study of the market suspension (with improved process), the clinical trial suspension and market capsule formulation of Ro 64‐0796 (Tamiflu, oseltamivir) in healthy subjects. Data on file.
WP16226 {published data only}
    1. A study of the pharmacokinetics of oseltamivir (Ro 64‐796) and its active metabolite Ro 64‐0802 following single oral dosing of Ro 64‐0796 to healthy volunteers and patients with moderate hepatic impairment. Data on file.
WP16254 {published data only}
    1. A pharmacokinetic drug interaction study of oseltamivir (Ro 64‐0796) and antacid in healthy volunteers. Data on file.
WP16263 {published data only}
    1. A randomized, double blind, parallel group, placebo controlled study of the effect of oseltamivir on ECG intervals in healthy subjects. Data on file.
WP16295 {unpublished data only}
    1. A randomized, open label study of the site of absorption of oseltamivir in healthy subjects using an Enterion capsule. Data on file.
WP17721 {published data only}
    1. Clinical pharmacokinetics of cyclosporine or mycophenolate with and without a concurrent single dose of oseltamivir phosphate in patients with a renal transplant. Data on file.
WP18308 {published data only}
    1. Comparison of the pharmacokinetics of Ro 64‐0802 following a single dose of oseltamivir phosphate either in a capsule or a drinking solution. Data on file.
WP20727 {published data only}
    1. A combined single ascending dose, multiple ascending dose and exploratory bioavailability study to investigate the safety, tolerability and pharmacokinetics of intravenous Ro 64‐0796 in healthy volunteers. Data on file.
WP20749 {published data only}
    1. Oseltamivir treatment for children less than 24 months of age with influenza. Data on file.
WP21272 {published data only}
    1. An open‐label, randomized 2‐period crossover study to investigate the pharmacodynamics, pharmacokinetics, safety and tolerability of warfarin, and the pharmacokinetics, safety and tolerability of oseltamivir, when given in combination. Data on file.
WP22849 {published data only}
    1. An open label, prospective, pharmacokinetic/pharmacodynamic and safety evaluation of oseltamivir (Tamiflu®) in the treatment of infants 0 to < 12 months of age with confirmed influenza infection. Data on file.
WV15731 {published data only}
    1. A double‐blind, randomized, stratified pilot study of Ro 64‐0796 (also known as GS4104) in children with influenza. Data on file.
WV16139 {published data only}
    1. (Oseltamivir trial. Title unknown). Data on file. [Mentioned in EMA EPAR dated 23 March 2006 pdf page 14 but possibly same trial as WV 16193]
WV16193 {published data only}
    1. A randomized, open‐label, parallel group study of oseltamivir used for management of influenza in households. Data on file.

References to studies awaiting assessment

JPRN‐JapicCTI‐111647 {published data only (unpublished sought but not used)}
    1. Kashiwagi S, Watanabe A, Ikematsu H, Awamura S, Okamoto T, Uemori M, et al. Laninamivir octanoate for post‐exposure prophylaxis of influenza in household contacts: a randomized double blind placebo controlled trial. Journal of Infection and Chemotherapy 2013;19:740‐9. - PMC - PubMed
ML20589 {published data only}
    1. Economic and social benefits of treating and preventing influenza in aged care facilities. Data on file.
ML20910 {published data only}
    1. A randomized, open label study to evaluate the effect of Tamiflu on viral shedding and on serum and cytoplasmic inflammatory cytokine concentrations in patients with laboratory‐confirmed influenza. Data on file.
ML21776 {published data only}
    1. Pilot study to develop a model to evaluate nosocomial transmission of influenza. Data on file.
MV21118 {published data only}
    1. A double‐blind, randomized, placebo‐controlled study of early oseltamivir treatment of influenza in children 1‐3 years of age. Data on file.
MV21737 {published data only}
    1. A phase 4, multi‐center, randomized, double blind, placebo controlled study, to evaluate the safety of inhaled zanamivir 10 mg versus placebo and oral oseltamivir 75 mg versus placebo for influenza prophylaxis in healthy volunteers for 16 weeks. Data on file.
MV21879 {published data only}
    1. Efficacy of oseltamivir in reducing the duration of clinical illness, viral shedding, and transmissibility reduction within households among participants in an influenza disease burden surveillance cohort in urban Dhaka, Bangladesh. Data on file.
MV22841 {published data only}
    1. Viral shedding/resistance with standard dose/duration oseltamivir in infected patients (South Africa). Data on file.
MV22940 {published data only}
    1. A randomised controlled trial on the effect of post‐exposure oseltamivir prophylaxis on influenza transmission in nursing homes (PEPpIE). Data on file.
NCT00419263 {published data only}
    1. A phase II, multicenter, randomized, double‐mask, placebo‐controlled study to evaluate the efficacy and safety of intramuscular peramivir in subjects with uncomplicated acute influenza. Data on file.
NCT00453999 {published data only}
    1. A phase II, multicenter, randomized, double‐mask, double‐dummy study comparing the efficacy and safety of peramivir administered intravenously once daily versus oseltamivir administered orally twice daily in adults with acute serious or potentially life‐threatening influenza. Data on file.
NCT00486980 {published data only}
    1. A phase 3 multicenter, randomized, double blind, placebo‐controlled study to evaluate the efficacy and safety of intramuscular peramivir in subjects with uncomplicated acute influenza. Data on file.
NCT00555893 {published data only}
    1. Monitoring influenza severity and transmission on Tamiflu (MISTT). Data on file.
NCT00610935 {published data only}
    1. A phase 3 multicenter, randomized, double‐blind, placebo‐controlled study to evaluate the efficacy and safety of intramuscular peramivir in subjects with uncomplicated acute influenza. Data on file.
NCT00705406 {published data only}
    1. A phase II, multicenter, randomized, placebo‐controlled, study to evaluate the efficacy and safety of intramuscular peramivir 600 mg in subjects with uncomplicated acute influenza. Data on file.
NCT00958776 {published data only}
    1. A phase 3, multicenter, randomized, double‐blind, controlled study to evaluate the efficacy and safety of peramivir administered intravenously in addition to standard of care compared to standard of care alone in adults and adolescents who are hospitalized due to serious influenza. Data on file.
NCT00980109 {published data only (unpublished sought but not used)}
    1. Anekthananon T, Pukritayakamee S, Ratanasuwan W, Jittamala P, Werarak P, Charunwatthana P, et al. Oseltamivir and inhaled zanamivir as influenza prophylaxis in Thai health workers: A randomized, double‐blind, placebo‐controlled safety trial over 16 weeks. Journal of Antimicrobial Chemotherapy 2013;68:697‐707. [NCT00980109 ] - PMC - PubMed
NCT01032837 {published data only (unpublished sought but not used)}
    1. Dharan NJ, Fry AM, Kieke BA, Coleman L, Meece J, Vandermause M, et al. Clinical and virologic outcomes in patients with oseltamivir‐resistant seasonal influenza A (H1N1) infections: results from a clinical trial. Influenza and Other Respiratory Viruses 2012;6:153‐8. - PMC - PubMed
NV20236 {published data only}
    1. An open label, multicenter trial of oseltamivir prophylaxis of seasonal influenza in children. Data on file.

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References to other published versions of this review

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