Review of anti-flu drugs find little benefit, side effects, flaws in approval processes

Two Cochrane systematic reviews on flu relief drugs, which for the first time considered clinical study reports in addition to published studies, concluded that the medicines didn't have much impact on the course of symptoms.

The studies and accompanying editorials appeared online April 10 at BMJ.

In the first study, oseltamivir (Tamiflu) reduced the time to first alleviation of symptoms in adults by 16.8 hours (95% CI, 8.4 to 25.1 hours; P<0.001). While there was no effect in children with asthma, there was an effect in otherwise-healthy children (mean difference, 29 hours; 95% CI, 12 to 47 hours; P=0.001). There was no difference in hospital admissions in adults (risk difference, 0.15%; 95% CI, −0.91% to 0.78%, P=0.84).

Oseltamivir in adults increased the risk of nausea (risk difference, 3.66%; 95% CI, 0.90% to 7.39%; number needed to treat to harm [NNTH], 28; 95% CI, 14 to 112) and vomiting (risk difference, 4.56%; 95% CI, 2.39% to 7.58%; NNTH, 22; 95% CI, 14 to 42). In children, oseltamivir increased vomiting (risk difference, 5.34%; 95% CI, 1.75% to 10.29%; NNTH, 19; 95% CI, 10 to 57).

In prophylaxis studies, oseltamivir increased the risk of psychiatric adverse events during the combined “on-treatment” and “off-treatment” periods (risk difference, 1.06%; 95% CI, 0.07% to 2.76%; NNTH, 94; 95% CI, 36 to 1,538). Also, there was a dose-response effect on psychiatric events in 2 treatment trials, at doses of 75 mg and 150 mg twice daily (P=0.038). In prophylaxis studies, oseltamivir increased the on-treatment risks of headaches (risk difference, 3.15%; 95% CI, 0.88% to 5.78%; NNTH, 32; 95% CI, 18 to 115), renal events with treatment (risk difference, 0.67%; 95% CI, −0.01% to 2.93%), and nausea during treatment (risk difference, 4.15%; 95% CI, 0.86% to 9.51%; NNTH, 25; 95% CI, 11 to 116).

The authors wrote, “Given that oseltamivir is now recommended as an essential medicine for the treatment of seriously ill patients or those in higher risk groups with pandemic influenza, the issues of mode of action, lack of sizeable benefits, and toxicity are of concern. This is made worse by the record and stated intentions of governments to distribute oseltamivir to healthy people to prevent complications and interrupt transmission on the basis of a published evidence base that has been affected by reporting bias, ghost authorship, and poor methods. We believe these findings provide reason to question the stockpiling of oseltamivir, its inclusion on the [World Health Organization] list of essential drugs, and its use in clinical practice as an anti-influenza drug.”

The second study found that zanamivir (Relenza) reduced the time to symptomatic improvement in adults, but not in children, and the difference might have stemmed from symptom relief medication. For adults, zanamivir reduced the time to first alleviation of symptoms of influenza-like illness by 0.60 day (95% CI, 0.39 to 0.81 day; P<0.001), or a 10% reduction in mean duration of symptoms from 6.6 days to 6.0 days. Time to first alleviation of symptoms was shorter in all participants when any relief drugs were allowed compared with no use.

In prophylaxis studies, symptomatic influenza in individuals was significantly reduced, with event rates lowered from 3.26% to 1.27%, (number needed to treat, 51; 95% CI, 40 to 103). The prophylactic effect on asymptomatic influenza cases was not significant in individuals or in households. Prophylaxis in adults reduced unverified pneumonia (0.32%, 95% CI, 0.09% to 0.41%; number needed to treat, 311, 95% CI, 244 to 1,086) but had no effect on pneumonia in children or on bronchitis or sinusitis in adults or children.

The authors concluded that “zanamivir is no more effective in relieving symptoms than commonly used over the counter symptomatic drugs (such as paracetamol or NSAIDs).” No further clinical trials of zanamivir are warranted, they added.

An editorialist criticized the drug approval process and government decisions to stockpile oseltamivir despite the lack of evidence. “The review's conclusion should lead to serious soul searching among policy makers,” the editorial stated. A second editorialist wrote, “For now, health professionals can communicate the available evidence to anyone contemplating taking oseltamivir and zanamivir for prophylaxis or treatment, with confidence that nothing is hidden from view. Many patients may consider the risk of adverse effects to more than offset the prospect of shortening symptoms by half a day. For those who pay out of pocket, the additional costs may also be a deterrent.”