title: Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments.
abstract: OBJECTIVE
  To describe the potential benefits and harms of oseltamivir by reviewing all clinical study reports (or similar document when no clinical study report exists) of randomised placebo controlled trials and regulatory comments ("regulatory information").
  
  
  METHODS
  Systematic review of regulatory information.
  
  
  METHODS
  Clinical study reports, trial registries, electronic databases, regulatory archives, and correspondence with manufacturers.
  
  
  METHODS
  Randomised placebo controlled trials on adults and children who had confirmed or suspected exposure to natural influenza.
  
  
  METHODS
  Time to first alleviation of symptoms, influenza outcomes, complications, admissions to hospital, and adverse events in the intention to treat population.
  
  
  RESULTS
  From the European Medicines Agency and Roche, we obtained clinical study reports for 83 trials. We included 23 trials in stage 1 (reliability and completeness screen) and 20 in stage 2 (formal analysis). In treatment trials on adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval 8.4 to 25.1 hours, P<0.001). There was no effect in children with asthma, but there was an effect in otherwise healthy children (mean difference 29 hours, 95% confidence interval 12 to 47 hours, P=0.001). In treatment trials there was no difference in admissions to hospital in adults (risk difference 0.15%, 95% confidence interval -0.91% to 0.78%, P=0.84) and sparse data in children and for prophylaxis. In adult treatment trials, oseltamivir reduced investigator mediated unverified pneumonia (risk difference 1.00%, 0.22% to 1.49%; number needed to treat to benefit (NNTB) 100, 95% confidence interval 67 to 451). The effect was not statistically significant in the five trials that used a more detailed diagnostic form for "pneumonia," and no clinical study reports reported laboratory or diagnostic confirmation of "pneumonia." The effect on unverified pneumonia in children and for prophylaxis was not significant. There was no significant reduction in risk of unverified bronchitis, otitis media, sinusitis, or any complication classified as serious or that led to study withdrawal. 14 of 20 trials prompted participants to self report all secondary illnesses to an investigator. Oseltamivir in the treatment of adults increased the risk of nausea (risk difference 3.66%, 0.90% to 7.39%; number needed to treat to harm (NNTH) 28, 95% confidence interval 14 to 112) and vomiting (4.56%, 2.39% to 7.58%; 22, 14 to 42). In treatment of children, oseltamivir induced vomiting (5.34%, 1.75% to 10.29%; 19, 10 to 57). In prophylaxis trials, oseltamivir reduced symptomatic influenza in participants by 55% (3.05%, 1.83% to 3.88%; NNTB 33, 26 to 55) and households (13.6%, 9.52% to 15.47%; NNTB 7, 6 to 11) based on one study, but there was no significant effect on asymptomatic influenza and no evidence of a reduction in transmission. In prophylaxis studies, oseltamivir increased the risk of psychiatric adverse events during the combined "on-treatment" and "off-treatment" periods (risk difference 1.06%, 0.07% to 2.76%; NNTH 94, 36 to 1538) and there was a dose-response effect on psychiatric events in two "pivotal" treatment trials of oseltamivir, at 75 mg (standard dose) and 150 mg (high dose) twice daily (P=0.038). In prophylaxis studies, oseltamivir increased the risk of headaches on-treatment (risk difference 3.15%, 0.88% to 5.78%; NNTH 32, 18 to 115), renal events with treatment (0.67%, -0.01% to 2.93%), and nausea while receiving treatment (4.15%, 0.86% to 9.51%; NNTH 25, 11 to 116).
  
  
  CONCLUSIONS
  In prophylactic studies oseltamivir reduces the proportion of symptomatic influenza. In treatment studies it also modestly reduces the time to first alleviation of symptoms, but it causes nausea and vomiting and increases the risk of headaches and renal and psychiatric syndromes. The evidence of clinically significant effects on complications and viral transmission is limited because of rarity of such events and problems with study design. The trade-off between benefits and harms should be borne in mind when making decisions to use oseltamivir for treatment, prophylaxis, or stockpiling.
authors.affiliation: Cochrane Acute Respiratory Infections Group, Via Puglie 23, 00187 Rome, Italy.
authors.forename: Tom
authors.initials: T
authors.lastname: Jefferson
authors.forename: Mark
authors.initials: M
authors.lastname: Jones
authors.forename: Peter
authors.initials: P
authors.lastname: Doshi
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Spencer
authors.forename: Igho
authors.initials: I
authors.lastname: Onakpoya
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Heneghan
mesh_terms: D000328:Adult; D000367:Age Factors; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D006261:Headache / Q000139:chemically induced; D006801:Humans; D007251:Influenza, Human / Q000188:drug therapy* / Q000401:mortality; D007674:Kidney Diseases / Q000139:chemically induced; D009325:Nausea / Q000139:chemically induced; D053139:Oseltamivir / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000998:Antiviral Agents; D053139:Oseltamivir