The salmeterol/fluticasone propionate dry powder inhaler (DPI) [Advair Diskus(R), Seretide(TM) Accuhaler(R)] contains the long-acting beta(2)-adrenoceptor agonist salmeterol and the inhaled corticosteroid fluticasone propionate. In the US, twice-daily salmeterol/fluticasone propionate 50/250mug is approved for use in adults with chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis, and in the EU, the twice-daily 50/500mug dosage is approved for use in patients with severe COPD, repeat exacerbations and significant symptoms despite bronchodilator therapy. In patients with moderate-to-severe COPD, twice-daily inhaled salmeterol/fluticasone propionate 50/250 or 50/500mug for 24-52 weeks improves predose forced expiratory volume in 1 second (FEV1) significantly more than salmeterol monotherapy, improves postdose or postbronchodilator FEV1 significantly more than fluticasone propionate monotherapy and results in clinically significant improvements in health-related quality of life. Salmeterol/fluticasone propionate 50/500mug significantly reduced annual COPD exacerbations, especially in severe COPD. Some corticosteroid-related adverse events were increased in recipients of fluticasone propionate with or without salmeterol versus salmeterol monotherapy or placebo; withdrawal from fluticasone propionate, including combination therapy, needs careful management to minimise COPD exacerbations. The DPI combining a corticosteroid and long-acting beta(2)-agonist provides benefits over monotherapy and may encourage patient compliance in COPD. Pharmacological Properties Salmeterol, a long-acting beta(2)-adrenoceptor agonist, and fluticasone propionate, an inhaled corticosteroid with anti-inflammatory properties, demonstrated individual and synergistic pharmacodynamic benefits in COPD. Salmeterol increases cyclic adenosine monophosphate (cAMP) concentrations when it catalyses the conversion of adenosine triphosphate to cAMP in bronchial smooth muscle, causing it to relax. Salmeterol and fluticasone, alone or together, significantly improved ciliary function in vitro and in healthy volunteers, reduced fibroblast proliferation in vitro, reduced thrombin-stimulated fibroblast mitosis, and displayed anti-inflammatory activity in vitro (salmeterol) and in patients with COPD (fluticasone propionate). At some concentrations, salmeterol and fluticasone propionate were synergistic. FEV1 improved significantly from baseline in patients with moderate-to-severe COPD after a single dose of salmeterol/fluticasone propionate 50/250mug or formoterol/budesonide 12/400mug, both via DPI. The systemic response to salbutamol (albuterol) with twice-daily salmeterol 100mug was similar with salmeterol monotherapy or salmeterol/fluticasone propionate in healthy volunteers treated for 11 days via the Diskus(R) DPI, and significantly different than with placebo. In this study, mean 24-hour urinary cortisol excretion decreased with twice-daily fluticasone propionate 500mug with or without salmeterol Mug. In patients with severe COPD, fluticasone propionate 1000mug twice daily via a metered dose inhaler (supratherapeutic dosage) for 2 weeks decreased serum osteocalcin and overnight urinary cortisol excretion. Inhaled salmeterol and fluticasone propionate both act locally and, thus, plasma concentrations are low. No systemic pharmacokinetic interactions between salmeterol and fluticasone propionate after administration of the combination via DPI were apparent in a study in healthy volunteers. At steady state, twice-daily fluticasone propionate 500mug reached a mean maximum plasma concentration (C-max) of approximate to112 pg/mL, time to C-max (t(max)) of approximate to1 hour, plasma exposure of approximate to720 pg (.) h/mL, and median elimination half-life (t1/2beta) of approximate to8 hours. Values for twice-daily salmeterol 100mug were a C-max of approximate to0.202 ng/mL (vs 0.155 ng/mL after a single dose) and a t(max) of 5 minutes; plasma exposure and t1/2beta could not be determined. Bioavailability of fluticasone propionate via the Diskus(R) averaged approximate to13% in patients with COPD versus 21% in healthy volunteers. Plasma binding is 91%. Fluticasone propionate metabolism occurs mostly in the liver, via the cytochrome P450 (CYP) 3A4 enzyme. Accumulation may occur in patients with hepatic impairment and significant increases in fluticasone propionate concentrations have been demonstrated after coadministration of other CYP 3A4 inhibitors. Therapeutic Efficacy Twice-daily salmeterol/fluticasone propionate 50/500mug and 50/250mug significantly improved pre- and postdose/post-bronchodilator FEV1 versus placebo in three large, randomised, 24- to 52-week trials in patients with moderate-to-severe COPD. After 24 weeks, predose FEV1 improved significantly more with combined therapy than with salmeterol 50mug and 2-hour postdose or post-bronchodilator FEV1 significantly more than with fluticasone propionate 250 or 500mug (all twice daily via Diskus(R)); over 52 weeks, combined therapy was significantly better than both monotherapies. Improvements in FEV1 in combined-therapy recipients occurred within 2 weeks and significant increases in peak expiratory flow (PEF) within 1 day. Clinically significant improvements versus placebo in health status and, in some trials dyspnoea, were seen with twice-daily salmeterol/fluticasone propionate; the improvements in dyspnoea also occurred within I week. Use of supplementary salbutamol also decreased significantly. Over 1 year, significantly fewer exacerbations (mean approximate to1 vs 1.3 per patient-year) occurred with any active treatment versus placebo, particularly exacerbations requiring oral corticosteroids in patients with an FEV1 <50% predicted. In combined therapy recipients with FEV1 <50% predicted, annual exacerbations decreased by 30% versus placebo and those requiring oral corticosteroids by 42%. Recipients of twice-daily inhaled salmeterol/fluticasone propionate 50/250mug for 8 weeks achieved significantly greater improvements in predose FEV1, PEF and most symptomatic endpoints than recipients of four-times-daily salbutamol/ipratropium bromide 206/36mug. Over 4 months, salmeterol/fluticasone propionate 50/500mug and fluticasone propionate plus oral titrated theophylline both improved FEV1, but dyspnoea and rescue salbutamol use improved significantly more with salmeterol/fluticasone propionate. Although absolute differences were small, FEV1, FEV1/forced vital capacity and dyspnoea deteriorated significantly more in patients who changed treatment from inhaled salmeterol/fluticasone propionate to salmeterol, than in patients who did not. Similarly, fluticasone propionate withdrawal resulted in an increase in first and second exacerbations in COPD patients after a 4-month run-in with four-times-daily ipratropium bromide plus twice-daily fluticasone propionate, particularly in those with FEV1 <50% predicted. Tolerability Drug-related adverse events in recipients of salmeterol/fluticasone propionate in placebo-controlled trials reflected those that occur with the respective monotherapies. The incidence was 16% and 20% with saimeterol/fluticasone 50/500 or 50/250mug, 19% and 15% with fluticasone propionate 500 or 250mug, 12% and 11% with salmeterol 50mug and 14% and 9% with placebo (all twice daily via Diskus(R)). Oropharyngeal candidiasis, throat infection or hoarseness, COPD exacerbation, oral inflammation, nausea or vomiting, headaches, tremor and vertigo affected less than or equal to6% of salmeterol/fluticasone propionate recipients. After 24 weeks in a 1-year trial, recipients of twice-daily fluticasone propionate 500mug with or without salmeterol 50mug, had significantly lower mean serum cortisol levels than placebo recipients. At 52 weeks, only the fluticasone propionate monotherapy group was significantly different to the placebo group. In a nested case-control study, the odds ratio for fracture incidence in patients receiving inhaled corticosteroids within the last 30 days was 1.42 (vs non-recipients). However, the incidence of fractures in a pooled analysis was 15 per 1000 patient-years with twice-daily fluticasone propionate 500mug (with or without salmeterol) for up to 3 years, versus 23 with placebo.
