Inhaled Fluticasone Propionate

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Abstract
Fluticasone propionate is a corticosteroid with comparatively high receptor affinity and topical activity. Inhaled fluticasone propionate ≤500 µg/day provided effective corticosteroid maintenance treatment in patients with mild to moderate asthma in randomised, controlled clinical studies of 4 to 24 weeks in duration. Dosages of 50 to 250µg twice daily produced consistent improvement in spirometric measures of lung function, reduced the frequency of as-needed β2-agonist bronchodilator use, asthma symptom scores and night-time wakenings, and prevented asthma exacerbations compared with placebo. Fluticasone propionate ≤250µg twice daily provided significantly greater improvements in lung function than nedocromil 4mg 4 times daily, theophylline (5 to 15 mg/L) or zafirlukast 20mg twice daily. Health-related quality of life improved significantly with fluticasone propionate 88µg twice daily, but not zafirlukast 20mg twice daily or placebo. In comparative trials in which fluticasone propionate was given at half the dosage of beclomethasone dipropionate, budesonide or flunisolide, fluticasone propionate ≤250µg twice daily produced equivalent or greater improvement in spirometric parameters and equivalent reductions in the use of as-needed β2-agonists than beclomethasone dipropionate, budesonide or flunisolide. Fluticasone propionate 250µg twice daily was generally more effective than triamcinolone acetonide 200µg 4 times daily in two 24-week trials. The combination of inhaled fluticasone propionate ≤250 plus salmeterol ≤50µg twice daily allowed for the use of lower dosages of the inhaled corticosteroid. The incidence of adverse events in patients receiving inhaled fluticasone propionate 50 to 250µg twice daily was similar to that in beclomethasone dipropionate 168 to 500µg twice daily and budesonide 100 to 600µg twice daily recipients and greater than that in recipients of triamcinolone acetonide 200µg 4 times daily in comparative trials. The incidence of oral candidiasis was ≤8% in patients treated with fluticasone propionate ≤250µg twice daily or other agents. There was no evidence of clinically significant hypothalamo-pituitary-adrenal (HPA) axis suppression with fluticasone propionate ≤250µg twice daily in comparative trials. Conclusions. Inhaled fluticasone propionate ≤500 µg/day is an effective anti-inflammatory therapy for mild to moderate asthma in adolescents and adults. The drug is more effective than nedocromil, theophylline or zafirlukast and is at least as effective as other inhaled corticosteroids administered at twice the fluticasone propionate dosage. The addition of inhaled salmeterol allows the use of lower maintenance dosages of fluticasone propionate. The drug is well tolerated and there is no evidence of a clinically significant effect of this dosage on HPA axis function. Hence, fluticasone propionate ≤500 µg/day is a particularly suitable agent for patients with mild to moderate asthma. Fluticasone propionate ≤250µg twice daily attenuates antigen processing, suppresses recruitment and activation of inflammatory cells and reduces the thickness of the basement membrane in the airways of patients with mild asthma. At dosages ranging from 100 to 250 µg/day the drug generally reduced bronchial hyperresponsiveness, as measured by the dose of inhaled histamine, methacholine or adenosine 5′-monophosphate required to provoke a 20% decline (PD20) in forced expiratory volume in 1 second (FEV1) in patients with mild to moderate asthma. The PD20 for histamine was significantly greater after 2 weeks’ treatment with fluticasone propionate 100µg twice daily than zafirlukast 20mg twice daily in a crossover study. Fluticasone propionate 250µg and salmeterol 50µg, each given alone or in combination, reduced bronchial hyperresponsiveness in patients with significant diurnal variation in the PD20 of methacholine. In general, fluticasone propionate ≤250µg twice daily had minimal effects on hypothalamo-pituitary-adrenal (HPA) axis function in adult patients with mild to moderate asthma enrolled in placebo-controlled studies and there was no difference in HPA axis function when fluticasone propionate dosages ≤500 µg/day were compared with other inhaled corticosteroids in clinical trials. Plasma concentrations of fluticasone propionate were below the limit of detection (1 in patients treated with fluticasone propionate 25 to 250µg twice daily were generally significantly greater than in those treated with placebo, inhaled nedocromil 4mg 4 times daily, oral theophylline (titrated to plasma concentrations of 5 to 15 mg/L) or oral zafirlukast 20mg twice daily. In comparative trials with inhaled beclomethasone 168 to 500µg twice daily, budesonide 200 to 600µg twice daily or flunisolide 500µg twice daily, in which fluticasone propionate was given at half or less than half the microgram dosage of the other inhaled corticosteroid (i.e. fluticasone propionate 50 to 250µg twice daily), improvements in morning and/or evening PEF in fluticasone propionate recipients were generally similar to, or significantly greater than, those in patients treated with the comparator. In two 24-week trials, improvements in morning PEF and FEV1 after 24 weeks were significantly greater in fluticasone propionate 250µg twice daily recipients than in triamcinolone acetonide 200µg 4 times daily or placebo recipients. In concert with improvements in lung function, requirements for as-needed β2-agonists and nocturnal awakenings generally decreased and asthma symptoms improved in patients treated with fluticasone propionate 25 to 250µg twice daily in comparative trials. The frequency of as-needed β2-agonist use decreased significantly in fluticasone propionate 25 to 250µg twice daily recipients compared with those receiving placebo, nedocromil 4mg 4 times daily or zafirlukast 20mg twice daily. Recipients of fluticasone propionate 100 but not 50µg twice daily used significantly less supplementary salbutamol compared with theophylline-treated patients. The frequency of as-needed β2-agonist use decreased from baseline in comparative trials in which fluticasone propionate was administered at half or less than half the microgram dose of beclomethasone dipropionate 200 to 336µg twice daily or budesonide 200 or 400µg twice daily. Furthermore, requirements for supplementary salbutamol decreased significantly in patients treated with fluticasone propionate 250µg twice daily compared with those receiving triamcinolone acetonide 200µg 4 times daily or placebo. The frequency of withdrawal from comparative trials because of loss of efficacy generally declined in patients treated with fluticasone propionate 25 to 250µg twice daily. More than half (52 to 71%) of the placebo-treated patients withdrew from 5 of 7 placebo controlled trials because of asthma exacerbations; however, the frequency of withdrawal was significantly lower in fluticasone propionate 25 to 250µg twice daily recipients (6 to 37%) with no statistical differences between fluticasone propionate dosage groups. Loss of efficacy was significantly less frequent in fluticasone propionate 250µg twice daily (15%) than nedocromil 4mg 4 times daily recipients (27%) in 1 trial, but not in a second. Significantly fewer fluticasone propionate 50 or 100µg twice daily recipients experienced asthma exacerbations (≤19%) compared with those receiving theophylline (38%) or placebo (52%) during a 12-week trial. Withdrawal because of loss of efficacy occurred infrequently in comparative trials involving fluticasone propionate 50 to 250µg twice daily and beclomethasone dipropionate 200 to 500µg twice daily (≤20.8%) or budesonide 100 to 600µg twice daily (≤7.8%) with no significant differences between treatment groups. Loss of efficacy was significantly less frequent in fluticasone propionate 250µg twice daily (17%) or triamcinolone acetonide 200µg 4 times daily recipients (≤33%) than placebo (≤65%) in two 24 week trials, in 1 of which there was a significant difference in the frequency of loss of efficacy between fluticasone propionate and triamcinolone acetonide groups. Fluticasone propionate ≤250µg twice daily had a beneficial effect on health-related quality of life (QOL) in patients with mild to moderate asthma. Health status, as measured by a disease-specific instrument (Living with Asthma), sleep patterns, and scores on the physical functioning and role-physical dimensions of the Medical Outcomes Study Short Form-36 (SF-36) improved significantly in fluticasone 50, 100 and 250µg twice daily recipients compared with placebo. Those in the 2 higher dosage groups also had significantly higher SF-36 scores in health perceptions, vitality and mental health compared with placebo. In other studies, QOL was measured with the Asthma Quality of Life Questionnaire (AQLQ). Global AQLQ scores and scores on each of the 4 domains (Activity Limitation, Asthma Symptoms, Emotional Function and Environmental Exposure) were significantly higher after 12 weeks treatment with fluticasone propionate 88µg twice daily than either zafirlukast 20mg twice daily or placebo and more patients treated with fluticasone propionate than zafirlukast or placebo experienced moderate or large improvements in Global AQLQ scores. In another study Global AQLQ scores and scores on 3 of the 4 domains on the scale (all except Environmental Exposure) were significantly higher after 24 weeks of treatment with fluticasone propionate 250µg twice daily than with either triamcinolone acetonide 200µg 4 times daily or placebo. Moreover, the difference in global AQLQ scores between fluticasone propionate and placebo recipients was considered to be clinically significant. Combining inhaled salmeterol with fluticasone propionate may improve asthma control and allow for the use of a lower fluticasone propionate dosage. The combination of salmeterol 42µg plus fluticasone propionate 220µg twice daily produced significantly greater improvements in FEV1 compared with either drug given separately. Loss of efficacy was significantly less frequent in those treated with salmeterol 50µg plus fluticasone propionate 100µg twice daily (5%) compared with either drug given alone (≤24%) or placebo (44%). Equivalent daily dosages of fluticasone propionate ≤500 µg/day administered once or twice daily improved or maintained lung function in patients with mild to moderate asthma. However, twice daily, compared with once daily administration generally provided numerically greater improvement in morning and evening PEF. The incidence of adverse effects was generally not significantly different in patients treated with inhaled fluticasone propionate ≤250µg twice daily or placebo in comparative studies. Withdrawal because of adverse events occurred in ≤4% and ≤2% of fluticasone propionate and placebo recipients, respectively. Oral candidiasis and dysphonia (hoarseness) or pharyngitis were reported by ≤6% and ≤3% of fluticasone propionate and placebo recipients, respectively. In trials comparing fluticasone propionate ≤250µg twice daily with either beclomethasone dipropionate or budesonide, the frequency of adverse events was similar between groups. Oral candidiasis was reported by ≤6.5% of patients receiving fluticasone propionate or the other inhaled corticosteroid in these studies. The frequency of treatment-related adverse events was significantly greater in patients treated with fluticasone propionate 250µg twice daily (20%) than either triamcinolone acetonide 200µg 4 times daily (5%) or placebo (5%) in 1 trial. In a second, similar trial, the incidence of oral candidiasis was significantly greater in fluticasone propionate 250µg twice daily recipients (8%) than either triamcinolone acetonide 200µg 4 times daily (3%) or placebo recipients (1%). In trials comparing fluticasone propionate ≤250µg twice daily with other inhaled corticosteroids or nedocromil <10% of patients were withdrawn from any treatment group because of adverse events. In the UK the recommended dosage of inhaled fluticasone propionate for patients aged ≥16 years with mild asthma is 100 to 250µg twice daily and for those with moderate asthma, 250 to 500µg twice daily. In the US, the recommended dosage in patients ≥12 years of age is 88 to 440µg twice daily by metered dose inhaler or 100 to 500µg twice daily by dry powder inhaler.

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