NPC Archive Item: FDA examines safety of salmeterol in children

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In an internal memorandum, drug safety staff at the FDA in the USA have commented that salmeterol “may have an unfavorable risk benefit ratio in the treatment of pediatric asthma” and recommend a “more thoroughgoing, formal risk-benefit analysis of salmeterol” in this indication.

The authors of the memorandum state that “adult trial data show an increase in asthma mortality and severe asthma events with salmeterol; available data do not provide any reason to believe that the paediatric population does not share the same risk; and definitive evidence of a protective effect of inhaled corticosteroids is lacking for long-acting beta agonists (LABAs), and in fact there is evidence that inhaled corticosteroids are not protective in paediatric patients receiving formoterol (another LABA)”

It has been reported that these concerns will be discussed at an FDA meeting this week.

What is the background to this?

The Medicines and Healthcare Products Regulatory Agency (MHRA) is currently reviewing the risks and benefits of LABAs.

Concerns were first raised about the safety of LABAs in adults. The SMART study was a large, multicentre randomised controlled trial (RCT) in which patients with asthma aged over than 12 years, who had not previously used a LABA were randomised to receive either salmeterol or placebo. Patients in the salmeterol group had a greater risk of respiratory-related deaths, asthma-related deaths, and combined asthma-related deaths or life-threatening experiences. This finding was most prominent among African-American patients, although the reasons for this occurrence are not known. There was a fairly low usage of inhaled steroids alongside salmeterol and patients who were not using inhaled steroids from the outset of treatment had poorer outcomes than those who were using inhaled steroids.

More recently, a meta-analysis of 19 RCTs (both in children and adults) reported that, compared with placebo, salmeterol and formoterol were associated with more frequent worsening of asthma that required admission to hospital or that was life-threatening. This meta-analysis also found a two-fold increased risk of admission to hospital even in trials where more than 75% (mean 90%) of patients were also using an inhaled corticosteroid.  Similar risks were found with both LABAs, and in children and adults

How does this fit with current guidance?

The current advice from the Commission on Human Medicines (CHM) appears to apply to patients of all ages.  The CHM advise that salmeterol and formoterol should:

  • be added to therapy only if regular use of standard-dose inhaled steroids has failed to control asthma adequately

  • not be initiated in patients with rapidly deteriorating asthma

  • be introduced at a low dose and the effect properly monitored before an increase in dose is considered

  • be discontinued in the absence of benefit

  • be reviewed as clinically appropriate: stepping down therapy should be considered when good long term asthma control has been achieved

Patients should be asked to report any deterioration in symptoms following initiation of a LABA.

This is entirely consistent with national guidance on management of asthma in children and adults, published jointly by SIGN and the BTS. This was last updated in November 2007. There is a strong emphasis in the guidance on achieving control of asthma symptoms by using appropriate treatment, but also on stepping down to the minimum level of treatment required for control and a good quality of life.


Healthcare professionals should follow current CHM advice and national guidance on management of asthma. LABAs should be initiated (at step 3) only if inhaled corticosteroids at moderate doses are failing to control asthma symptoms adequately. Before initiating a new drug therapy practitioners should recheck compliance, inhaler technique and eliminate trigger factors. If LABAs are introduced this should be in context of a therapeutic trial.

Professionals should take particular note that LABAs should not be initiated in patients with rapidly deteriorating asthma: they are for “stable but poorly controlled” asthma. Practitioners should consider stepping down LABA use when good long term asthma control has been achieved.


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