Oseltamivir and zanamivir have been stockpiled in many countries to treat and prevent seasonal and pandemic influenza, before an influenza vaccine matched to the circulating virus becomes available. Oseltamivir is classified by the World Health Organization as an essential medicine.
How this review has been approached
We have updated and combined our reviews on the antiviral drugs zanamivir and oseltamivir for influenza in adults and children on the basis of the manufacturers' reports to regulators (clinical study reports) and the regulators' comments. We have called these comments and reports 'regulatory information'. Clinical study reports are unpublished, extensive documents with great detail on the trials that formed the basis for market approval. They include the protocols, methods and results. Clinical study reports have until now been confidential, seen only by the manufacturers and regulators.
Why we have taken this approach
In previous versions of this review we identified unresolved discrepancies in the data presented in published trial reports and substantial publication bias. As a consequence, we elected not to use data from journal articles but included the documents generated during licensing processes. We have accessed such data from the UK, USA, European Medicines Agency (EMA), Japanese regulators and clinical study reports from the manufacturers (after a protracted media campaign). This has enabled us to verify information from the randomised, placebo-controlled trials on adults and children with confirmed or suspected exposure to naturally occurring influenza.
Based on our assessments of the regulatory documents (in excess of 160,000 pages), we came to the conclusion that there were substantial problems with the design, conduct, reporting and availability of information from many of the trials.
What we have found
We have used data from 46 trials (20 oseltamivir and 26 zanamivir studies) in this review. We identified problems in the design of many of the studies that we included, which affects our confidence in their results. We found that both drugs shorten the duration of symptoms of influenza-like illness (unconfirmed influenza or 'the flu') by less than a day. Oseltamivir did not affect the number of hospitalisations, based on the data from all the people enrolled in treatment trials of oseltamivir. Zanamivir trials did not record this outcome. The effects on pneumonia and other complications of influenza, such as bronchitis, middle ear infection (otitis media) and sinusitis, were unreliably reported, as shown by the case report form in the trial documents. Some forms showed limitations in the diagnostic criteria for pneumonia. Regulatory comments noted problems with missing follow-up diary cards from participants. In children with asthma there was no clear effect on the time to first alleviation of symptoms.
Prophylaxis trials showed that oseltamivir and zanamivir reduced the risk of symptomatic influenza in individuals and households. There was no evidence of an effect on asymptomatic influenza or on non-influenza, influenza-like illness, but trial conduct problems prevent any definitive conclusion.
Oseltamivir use was associated with nausea, vomiting, headaches, renal and psychiatric events; these last three were when it was used to prevent influenza (prophylaxis). Its effect on the heart is unclear: it may reduce cardiac symptoms, but may induce serious heart rhythm problems. In adult treatment trials of zanamivir there was no increased risk of reported adverse events. The evidence on the possible harms associated with the treatment of children with zanamivir was sparse.
Agreement with other findings
The lack of good evidence demonstrating an effect on complications agrees with the conservative conclusions on both drugs drawn by the US Food and Drug Administration (FDA). The FDA only allowed claims of effectiveness of both drugs for the prevention and treatment of symptoms of influenza and not for other effects (including the interruption of person-to-person spread of the influenza virus or prevention of pneumonia). The FDA described the overall performance of both drugs as 'modest'.
Mechanism of action for beneficial effects
These findings all suggest that the low immune response with low levels of pro-inflammatory cytokines, which is induced by the action of oseltamivir carboxylate, may reduce the symptoms of influenza unrelated to an inhibition of influenza virus replication. The potential hypothermic or antipyretic effect of oseltamivir as a central nervous system depressant may also contribute to the apparent reduction of host symptoms. Statements made on the capacity of oseltamivir to interrupt viral transmission and reduce complications are not supported by any data we have been able to access.
The mechanism of action proposed by the producers (influenza virus-specific) does not fit the clinical evidence which suggests a multi-system and central action.