Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children

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. OBJECTIVE: 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benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports of published and unpublished randomised, placebo-controlled trials and regulatory comments. METHODS 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 fol- 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. Oseltamivi...

The mechanisms of sudden-onset type adverse reactions to oseltamivir

“…These findings are consistent with clinically-observed psychiatric symptoms in post-marketing spontaneous reports [6] (in particular, many cases in which sleep was followed by sudden death or abnormal behaviours with fatal outcome), some prospective cohort studies [16-20], and a systematic review of the cohort studies [21] and a systematic review of RCTs [22]. …”

“…If oseltamivir has affinity to NMDA receptors, as suggested by the data reported in Lindeman et al [66], and if oseltamivir is used for a long period of time, it could induce psychiatric reactions including psychosis, confusion, and depression in humans, as reported in the RCTs for prophylaxis of influenza [22]. …”

“…Nausea and vomiting were demonstrated as adverse reactions to oseltamivir in treatment trials involving both adults and children [22] and are the established adverse reactions to oseltamivir. Dose-dependent increase of headache was demonstrated only in prophylaxis trials, because common symptoms of influenza including headache were not considered adverse event in the treatment trials [22].…”

“…Dose-dependent increase of headache was demonstrated only in prophylaxis trials, because common symptoms of influenza including headache were not considered adverse event in the treatment trials [22]. One of the definitions of adverse events of the trials was “any adverse change from the subject's baseline (pre-treatment) condition, which occurred during the course of the study after treatment had started, whether considered related to treatment or not” [22]. Nausea and vomiting may be symptoms of gastrointestinal system dysfunction but could also be induced by central nervous system disturbance, such as increased intra-cranial pressure.…”

“…A recent systematic review and meta-analysis of both treatment and prophylaxis randomized controlled trials including adults and children shows that oseltamivir increased risk of nausea; vomiting; headaches; psychiatric, renal, diabetic/hyperglycaemic events; and pain in the limbs. However, zanamivir did not [22]. According to the prospective cohort studies [16-21], NNTH (number needed to treat to harm) of oseltamivir for abnormal behaviours is estimated about 25 (95%CI: 19-35).…”