Asthma: Long-acting ß₂ agonists

Asthma is characterised by a reversible narrowing of the airways in the lungs, which leads to a cough, wheezing, and difficulty in breathing, and can change in its severity over short periods. Asthma may occur as a result of: an allergic reaction; taking other drugs (such as aspirin or non-steroidal anti-inflammatories); physical exertion; emotional stress; an infection; or air pollution. Onset of asthma can occur in childhood or adulthood. Avoidance of factors known to cause allergies—such as the house dust mite, those carried by pets, and those in food additives—as well as avoidance of smoking help reduce the frequency of asthma attacks.

According to Asthma UK, about 5.2 million people in the UK are receiving treatment for asthma—about one person in every five households. About 2.6 million people have severe symptoms, about 0.5 million of whom have asthma that is difficult to control.

Asthma can be categorised as acute or chronic. Acute asthma is a worsening of underlying asthma (characterised by a persistent shortness of breath, high pulse rate, and a low rate of breathing air out of the lungs) and requires urgent treatment. Chronic asthma requires continual treatment to keep symptoms under control; people with mild chronic asthma have a good prognosis and rarely progress to having severe disease.

Treatment
Doctors treat asthma to: minimise or eliminate symptoms; improve lung function; and to enable patients to control their asthma, with the eventual aim of minimal treatment and side-effects of treatment.
 
Several different types of drugs are used to treat asthma, including those that: expand the airways of the lungs (“bronchodilators”—β2 agonists, antimuscarinic bronchodilators, and theophylline); reduce inflammation in the airways (corticosteroids and drugs that block the action of inflammatory molecules called leukotrienes); and those that may alleviate asthma as a result of an allergic reaction (cromoglicate and nedocromil). Treatment can be given in various ways—as an inhaler, orally, or as an injection—and all are available only on prescription.

Patients with chronic asthma should be treated in a stepwise manner, in which treatment can be added if symptoms are not being controlled and may subsequently be reduced on control of symptoms. The British Thoracic Society (external link) and the British National Formulary (external link) has details on the stepwise treatment of chronic asthma.

To relieve symptoms, patients with asthma are often prescribed short-acting β2 agonists such as salbutamol (Ventmax, Ventolin, Volmax, Airomir, Asmasal, Ventodisks) or terbutaline (Bricanyl) that act quickly when inhaled.

Patients who use short-acting β2 agonists may also benefit from regular preventer therapy in the form of corticosteroids to control inflammation of the airways. Corticosteroids that help control asthma are: budesonide (Novolizer, Pulmicort); fluticasone (Flixotide); mometasone (Asmanex); ciclesonide (Alvesco); and beclometasone (Beclazone, AeroBec, Asmabec, Becodisks. Becotide, Qvar—for more information about Qvar please see the following press release:
› Press release: Medicines regulator informs healthcare professionals about prescribing UK beclometasone dipropionate CFC-free inhalers for asthma).

Long-acting β2 agonists such as formoterol (Atimos, Foradil, Oxis) and salmeterol (Serevent) play a part in long-term control of chronic asthma when used as add-on therapy to regular treatment with corticosteroids. Long-acting β2 agonists are also used to control nocturnal asthma (that which occurs at night or in the early hours of the morning), and formoterol can help prevent asthma symptoms associated with exercise. Oxis may also be used for relief of short-term symptoms of airway obstruction. Some inhalers deliver a corticosteroid and a long-acting β2 agonist together in a fixed-dose combination. These combination products include Symbicort (budenoside and formoterol) and Seretide (fluticasone and salmeterol).

Long-acting β2 agonists should not be used without also taking regular corticosteroids—when used alone, long-acting β2 agonists have been associated with a worsening of asthma in some patients, sometimes severely so. Low doses of long-acting β2 agonist work for most patients, and thus patients should receive the lowest dose that works for them.

Safety
The MHRA monitors the safety of all medicines and devices licensed in the UK, and if necessary takes action to safeguard the public. No medicine is risk-free; however, such risks must not outweigh the benefits of treatment. The MHRA seeks expert advice from the independent Commission on Human Medicines (CHM, previously called Commission on Safety of Medicines CSM) and the Pharmacovigilance Expert Advisory Group (PEAG).

In 2003, an article in the publication Current Problems in Pharmacovigilance reminded healthcare professionals to prescribe long-acting β2 agonists for chronic asthma only alongside inhaled corticosteroids—an analysis of prescribing information for salmeterol and formoterol showed that some patients prescribed these drugs may not be taking corticosteroids at the same time.
› Current Problems in Pharmacovigilance - Vol 29, Sept 2003

In November 2005, the MHRA posted updated prescribing advice, along with a series of questions and answers, on the website:
› Updated prescribing advice for salmeterol and formoterol, with questions and answers on the safety of long-acting β2 agonists

In 2006, researchers published the final results of a large US study called SMART (Salmeterol Multi-Center Asthma Research Trial), in which 26 355 patients with asthma who had not previously used a long-acting β2 agonist were enrolled onto the study and randomly assigned either inhaled salmeterol or inhaled placebo (dummy treatment) in addition to their normal asthma treatment.
› The Salmeterol Multicenter Asthma Research Trial (external link)

SMART found that there were more respiratory-related deaths, asthma-related deaths, and combined asthma-related deaths or life-threatening experiences in the salmeterol group than in the placebo group. This finding was most prominent in those of African-American origin, although the reasons for this occurrence are not known. However, there was a fairly low usage of inhaled steroid alongside salmeterol, and outcomes were poorer among those who did not use steroids from the outset of treatment. In October 2005, CSM discussed these findings, and advised that patients given long-acting β2 agonists should be monitored closely at the start of treatment, and that the findings from SMART should be reported in Current Problems in Pharmacovigilance.

In May 2006, an article in Current Problems in Pharmacovigilance reminded healthcare professionals that: patients given a long-acting β2 agonist should also be prescribed a corticosteroid; patients with deteriorating asthma should not start salmeterol and formoterol; and that patients should be monitored closely during early treatment.
› Current Problems in Pharmacovigilance - Vol 31, May 2006

In June 2006, Shelley Salpeter and colleagues in the USA reported the results of an analysis of 19 randomised placebo-controlled trials that in total studied 33 826 patients who had been randomly allocated a long-acting β2 agonist or a placebo. This meta-analysis reported that compared with placebo, the long-acting β2 agonists salmeterol and formoterol were associated with more-frequent worsening of asthma that required admission to hospital (for adults and children) or that was life-threatening.
› Meta-Analysis: Effect of Long-Acting ß-Agonists on Severe Asthma Exacerbations and Asthma-Related Deaths (external link).

In July, 2006, this analysis was discussed by CHM and PEAG, who concluded that further communications, research, and analysis in relation to the safety and most appropriate use of long-acting β2 agonists are needed. The precise timescale of the research and analysis has yet to be confirmed, although further communications are included in the September 2006 edition of the British National Formulary. The safety of long-acting β2 agonists have also been considered in Europe, whose expert committees generally agreed with the advice from the UK. The product information for long-acting β2 agonists are being updated in the European Union in line with UK advice.

Current advice
The MHRA will continue to monitor the safety of asthma medicines closely. Any adverse reactions that are thought to occur as a result of treatment for asthma can be reported to the MHRA through the Yellow Card Scheme. An assessment of the risks and benefits associated with the use of long-acting β2 agonists is in progress:
› MHRA review of formoterol and salmeterol in asthma and chronic obstructive pulmonary disease

At present, however, the benefits of long-acting β2 agonists outweigh the risks, and it is important that patients take their asthma medicine as prescribed to them. Patients should discuss any concerns regarding their asthma treatment with their doctor.

To ensure safe use, CHM has advised that for the management of chronic asthma, long-acting β2 agonists (formoterol and salmeterol) should:

• be added only if regular use of standard-dose inhaled corticosteroids 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 considering dose increase;
• 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 report any deterioration in symptoms following initiation of treatment with a long-acting β2 agonist.