Salmeterol

Key points

• Salmeterol reaches only low plasma concentrations after inhaled dosing, approximately 200 picogram/mL or less at therapeutic doses, and the product information notes that only limited pharmacokinetic data on salmeterol are available because of the technical difficulty of assaying it in plasma.
• An in vitro study using human liver microsomes showed that salmeterol is extensively metabolised to the metabolite α-hydroxysalmeterol by the enzyme CYP3A4.
• Salmeterol carries a boxed warning: long-acting beta2-adrenergic agonists such as salmeterol increase the risk of asthma-related death.

How it works

Salmeterol is a selective long-acting (12 hour) beta2 adrenoceptor agonist with a long side chain that binds to a specific exo-site on the receptor, according to the Seretide 50 Evohaler product information. It produces bronchodilation lasting for at least 12 hours.

Safety specific to Salmeterol

Salmeterol carries an FDA boxed warning. Long-acting beta2-adrenergic agonists (LABAs), such as salmeterol, one of the active ingredients in ADVAIR DISKUS, increase the risk of asthma-related death. In a large placebo-controlled US study that added salmeterol (SEREVENT Inhalation Aerosol) or placebo to usual asthma therapy, asthma-related deaths were more frequent in patients receiving salmeterol: 13 deaths out of 13,176 patients treated for 28 weeks on salmeterol, against 3 out of 13,179 patients on placebo. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates this increased risk of asthma-related death from LABAs, and available data from controlled clinical trials suggest that LABAs also increase the risk of asthma-related hospitalisation in paediatric and adolescent patients.

Because of this risk, prescribing guidance restricts combination inhalers such as ADVAIR DISKUS to patients whose asthma is not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, alone, or whose disease severity clearly warrants starting both an inhaled corticosteroid and a LABA together. Once asthma control is achieved and maintained, the guidance calls for reassessing the patient at regular intervals and stepping down therapy, discontinuing the LABA component if possible, while maintaining the patient on a long-term asthma control medication such as an inhaled corticosteroid alone. ADVAIR DISKUS should not be used for patients whose asthma is already adequately controlled on low or medium doses of an inhaled corticosteroid.

Beyond the boxed warning, salmeterol has its own systemic effects as a beta-agonist. Salmeterol, a component of ADVAIR DISKUS, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and symptoms, and excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats per minute, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise and insomnia. Beta-adrenergic agonist medications may also produce significant hypokalaemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects, though the decrease in serum potassium is usually transient and does not usually require supplementation. Patients using ADVAIR DISKUS should not use an additional LABA, such as salmeterol, formoterol fumarate or arformoterol tartrate, for any reason, including prevention of exercise-induced bronchospasm or the treatment of asthma or COPD.

When to seek urgent care

Sudden and progressive deterioration in control of asthma is potentially life-threatening and should prompt urgent medical assessment. Increased need for a reliever inhaler, or a reliever that works less well than usual, are both signs that asthma control is worsening and should be reviewed by a physician. Seretide should not be used to treat acute asthma symptoms for which a fast and short-acting bronchodilator is required, so patients should have their reliever inhaler for an acute asthma attack available at all times.

As with other inhaled medications, a salmeterol-containing inhaler can produce paradoxical bronchospasm, which may be life threatening. If this occurs following dosing, it should be treated immediately with an inhaled, short-acting bronchodilator, the salmeterol-containing inhaler should be discontinued immediately, and alternative therapy should be instituted. Upper airway symptoms such as stridor, choking, or laryngeal irritation and swelling have also been reported in patients receiving fluticasone propionate and salmeterol.

Further reading

• ADVAIR DISKUS- fluticasone propionate and salmeterol powder
• Seretide 50 Evohaler