Pharmacology Update
Advair—A New Combination Inhaler for Maintenance Therapy of Asthma
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Glaxo wellcome has received fda approval to market a combination inhaler comprised of fluticasone propionate and salmeterol xinafoate for the long-term maintenance treatment of asthma. Fluticasone is a synthetic, trifluorinated corticosteroid that is currently available under the tradename Flovent, while salmeterol, a long-acting beta adrenergic agonist, is available as Serevent. The dry powder, fixed combination inhaler, will be marketed in three strengths under the tradename Advair.
Indications
Fluticasone/salmeterol is dosed twice daily and is indicated for the long-term maintenance treatment of asthma in patients 12 years of age and older. This combination should not be used for transferring patients from systemic steroids, initiated in patient with deteriorating or potentially life-threatening episodes of asthma, or used to treat acute symptoms.1
Dosage
The recommended dose is one inhalation twice daily about 12 hours apart, morning and evening. The starting dose should be based on the patient’s current asthma regimen. For corticosteroid-naive patients whose disease status dictates maintenance therapy with two drugs, the starting dose is 100 mcg fluticasone and 50 mcg of salmeterol. For patients currently on corticosteroid therapy the recommended starting dose is based on current daily dose. If the patient’s daily dose of beclomethasone is 420 mcg or less, budesonide 400 mcg or less, flunisolide or triamcinolone 1000 mcg or less, fluticasone inhalation aerosol 176 mcg or less, or fluticasone inhalation powder 200 mcg or less, the starting dose of Advair is 100/50 twice daily. If the patient’s daily dose of beclomethasone is 462-840 mcg, budesonide 800 mcg-1200 mcg, flunisolide 1250 mcg-2000 mcg, or triamincolone 1100 mcg-1600 mcg, fluticasone inhalation 440 mcg, or fluticasone inhalation powder 500 mcg, the starting dose of Advair is 250/50 twice daily. If the patient’s daily dose of budesonide is 1600 mcg, fluticasone inhaler 660-880 mcg, or fluticasone inhalation powder 1000 mcg, the recommended dose is Advair 500/50 twice daily.
Advair is supplied as an inhalation powder containing salmeterol 50 mcg with 100 mcg, 250 mcg, or 500 mcg of fluticasone propionate. The powder is administered with a Diskus inhalation device.
Potential Advantages
Fluticasone and salmeterol have high lipid solubility and long duration of pharmacologic effect and may provide complementary effects when used in combination.6 In patients who remain symptomatic on inhaled corticosteroids, the addition of salmeterol appears to provide greater benefit than increasing the dose of the corticosteroid.2-4,6,8,9 Advair provides a more convenient inhaled delivery system for the two drugs and may improve compliance.
Potential Disadvantages
The fixed combination reduces flexibility in dose titration, mainly the corticosteroid component. It is not clear if the three doses of fluticasone provided, 100 mcg, 250 mcg, and 500 mcg, offer adequate flexibility. The fixed doses of Advair may result in physicians being less vigilant in titrating patients to the lowest effective dose of corticosteroids and minimizing potential side effects.
Comments
Clinical trials have shown that patients with moderate to severe asthma, who remain symptomatic despite treatment with high-dose budesonide (800-1200 mcg), achieve better control with the addition of a fixed combination of medium-dose fluticasone and salmeterol than increasing the dose of budesonide to 1600 mcg daily.4,6 Significant improvement has been seen in mean morning and evening peak expiratory flow, and control of daytime symptoms with the combination of the two drugs. This effect may be in part due to the greater potency of fluticasone over budesonide. However, similar effect was reported in mild-to-moderate asthma when the addition of salmeterol to fluticasone was found to be more effective than doubling the dose of fluticasone.3 Large 24-week trials suggest that symptom control and exacerbation rates between salmeterol plus a corticosteroid or increasing the dose of the corticosteroid are comparable.4,8,9 The effects of the fixed combination appear to be comparable to administering the components separately.6 The combination may have a complementary interaction involving various proposed mechanisms. Recent data suggest that salmeterol in combination with a corticosteroid may produce additional reductions in pro-inflammatory cells, cytokines, and cell adhesions molecules compared to corticosteroid alone.2
Clinical Implications
Salmeterol in combination with a low-medium dose of inhaled corticosteroid is recommended as an alternative to medium dose inhaled corticosteroids in the long-term management of moderate persistent asthma.5 Data suggest that there is improved lung function and symptom control with two drugs compared to increasing the dose of the corticosteroid. Salmeterol is also an important part of the regimen along with inhaled corticosteroids in severe, persistent asthma. Advair potentially can improve compliance by simplifying dosing. On the other hand, there is potentially less flexibility and there may be a tendency to prescribe the fixed combination without carefully titrating the patient to the lowest dose of inhaled corticosterod. In the United Kingdom, the cost of the fixed combination was less than that of the two drugs dispensed separately.7 The cost in the United States has not been announced as the product is expected to be available early in 2001. v
References
1. Advair Product Information. August 2000. Glaxo Wellcome.
2. Walters EH, et al. Respir Med 2000;94(Suppl F): S26-31.
3. Van Noor JA, et al. Thorax 1999;54(3):207-212.
4. Jenkins C, et al. Respir Med 2000;94(7):715-723.
5. National Institute of Health. Guidelines for the Diagnosis and Management of Asthma. Expert Panel Report 2. July 1997.
6. Caroline M, Jarvis B. Drugs 1999;57(6):933-940.
7. Barnes P. Drugs 1999;57(6):942-943.
8. Greening AP, et al. Lancet 1994;344(8917):219-214.
9. Woolcock A, et al. Am Respir Crit Care Med 1996; 153(5):1481-1488.
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