AirFluSal

Pharmacotherapeutic group: Drugs for obstructive airway diseases; adrenergics in combination with corticosteroids or other drugs, excl.‍​‍‍‍​‍‍‍‍‍‍‍‍​‍ anticholinergics ATC code: R03AK06 Mechanism of action: AirFluSal Forspiro contains salmeterol and fluticasone propionate which have differing modes of action. The respective mechanisms of action of both active substances are discussed below: Salmeterol: Salmeterol is a selective long-acting (12 hour) β 2 -adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor. Salmeterol produces a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting β 2 agonists (SABA). Fluticasone propionate: Fluticasone propionate given by inhalation at recommended doses has a glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, with less adverse effects than when corticosteroids are administered systemically. Clinical efficacy and safety: The studies described below (GOAL, TORCH and SMART) were carried out with this same fixed-dose combination, salmeterol xinafoate and fluticasone propionate, but studied a previously authorised product; the studies described were not carried out with AirFluSal Forspiro. Salmeterol/Fluticasone propionate – Asthma clinical trials A twelve month study (Gaining Optimal Asthma ControL, GOAL), in 3416 adult and adolescent patients with persistent asthma, compared the safety and efficacy of salmeterol/fluticasone propionate versus inhaled corticosteroid (fluticasone propionate) alone to determine whether the goals of asthma management were achievable. Treatment was stepped up every 12 weeks until ** total control was achieved or the highest dose of study drug was reached. GOAL showed more patients treated with salmeterol/fluticasone propionate achieved asthma control than patients treated with inhaled corticosteroid (ICS) alone and this control was attained at a lower corticosteroid dose. * Well Controlled asthma was achieved more rapidly with salmeterol/fluticasone propionate than with ICS alone. The time on treatment for 50% of subjects to achieve a first individual Well Controlled week was 16 days for salmeterol/fluticasone propionate compared with 37 days for the ICS group. In the subset of steroid naive asthmatics the time to an individual Well Controlled week was 16 days in the salmeterol/fluticasone propionate treatment compared with 23 days following treatment with ICS. The overall study results showed: Percentage of Patients Attaining *Well Controlled (WC) and **Totally Controlled (TC) Asthma over 12 months Pre-Study Treatment salmeterol/ fluticasone propionate fluticasone propionate WC TC WC TC No ICS (SABA alone) 78% 50% 70% 40% Low dose ICS (≤500 micrograms BDP or equivalent/day) 75% 44% 60% 28% Medium dose ICS (>500-1000 micrograms BDP or equivalent/day) 62% 29% 47% 16% Pooled results across the 3 treatment levels 71% 41% 59% 28% *Well controlled asthma; less than or equal to 2 days with symptom score greater than 1 (symptom score 1 defined as 'symptoms for one short period during the day'), SABA use on less than or equal to 2 days and less than or equal to 4 occasions/week, greater than or equal to 80% predicted morning peak expiratory flow, no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy **Total control of asthma; no symptoms, no SABA use, greater than or equal to 80% predicted morning peak expiratory flow, no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy The results of this study suggest that salmeterol/fluticasone 50/100 microgram twice daily may be considered as initial maintenance therapy in patients with moderate persistent asthma for whom rapid control of asthma is deemed essential. A double-blind, randomised, parallel group study in 318 patients with persistent asthma aged ≥18 years evaluated the safety and tolerability of administering two inhalations twice daily (double dose) of salmeterol/fluticasone propionate for two weeks. The study showed that doubling the inhalations of each strength of salmeterol/fluticasone propionate for up to 14 days resulted in a small increase in β agonist-related adverse events (tremor - 1 patient [1%] vs 0, palpitations - 6 [3%] vs 1 [<1%], muscle cramps - 6[3%] vs 1 [<1%]) and a similar incidence of inhaled corticosteroid related adverse events (e.g. oral candidiasis - 6 [6%] vs 16 [8%], hoarseness - 2 [2%] vs 4 [2%]) compared with one inhalation twice daily. The small increase in β agonist-related adverse events should be taken into account if doubling the dose of salmeterol/fluticasone propionate is considered by the physician in adult patients requiring additional short-term (up to 14 days) inhaled corticosteroid therapy. Salmeterol/fluticasone propionate – Chronic obstructive pulmonary disease (COPD) clinical trials TORCH was a 3-year study to assess the effect of treatment with salmeterol/fluticasone propionate 50/500 microgram twice daily, salmeterol 50 micrograms twice daily, fluticasone propionate 500 micrograms twice daily or placebo on all-cause mortality in patients with COPD. COPD patients with a baseline (pre-bronchodilator) FEV 1 <60% of predicted normal were randomised to double-blind medication. During the study, patients were permitted usual COPD therapy with the exception of other inhaled corticosteroids, long-acting bronchodilators and long-term systemic corticosteroids. Survival status at 3 years was determined for all patients regardless of withdrawal from study medication. The primary endpoint was reduction in all-cause mortality at 3 years for salmeterol/fluticasone propionate vs placebo. Placebo N = 1524 salmeterol 50 N = 1521 fluticasone propionate 500 N = 1534 salmeterol/ fluticasone propionate 50/500 N = 1533 All-cause mortality at 3 years Number of deaths (%) 231 (15.2%) 205 (13.5%) 246 (16.0%) 193 (12.6%) Hazard Ratio vs Placebo (CIs) p value N/A 0.879 (0.73, 1.06) 0.180 1.060 (0.89, 1.27) 0.525 0.825 (0.68, 1.00 ) 0.052 1 Hazard Ratio salmeterol/ fluticasone propionate 50/500 vs components (CIs) p value N/A 0.932 (0.77, 1.13) 0.481 0.774 (0.64, 0.93) 0.007 N/A 1 Non significant p value after adjustment for 2 interim analyses on the primary efficacy comparison from a log-rank analysis stratified by smoking status There was a trend towards improved survival in subjects treated with salmeterol/fluticasone propionate compared with placebo over 3 years however this did not achieve the statistical significance level p≤0.05. The percentage of patients who died within 3 years due to COPD-related causes was 6.0% for placebo, 6.1% for salmeterol, 6.9% for fluticasone propionate and 4.7% for salmeterol/fluticasone propionate. The mean number of moderate to severe exacerbations per year was significantly reduced with salmeterol/fluticasone propionate as compared with treatment with salmeterol, fluticasone propionate and placebo (mean rate in the salmeterol/fluticasone propionate group 0.85 compared with 0.97 in the salmeterol group, 0.93 in the fluticasone propionate group and 1.13 in the placebo group). This translates to a reduction in the rate of moderate to severe exacerbations of 25% (95% CI: 19% to 31%; p<0.001) compared with placebo, 12% compared with salmeterol (95% CI: 5% to 19%, p=0.002) and 9% compared with fluticasone propionate (95% CI: 1% to 16%, p=0.024). Salmeterol and fluticasone propionate significantly reduced exacerbation rates compared with placebo by 15% (95% CI: 7% to 22%; p<0.001) and 18% (95% CI: 11% to 24%; p<0.001) respectively. Health Related Quality of Life, as measured by the St George's Respiratory Questionnaire (SGRQ) was improved by all active treatments in comparison with placebo. The average improvement over three years for salmeterol/fluticasone compared with placebo was -3.1 units (95% CI: -4.1 to -2.1; p<0.001), compared with salmeterol was -2.2 units (p<0.001) and compared with fluticasone propionate was -1.2 units (p=0.017). A 4-unit decrease is considered clinically relevant. The estimated 3-year probability of having pneumonia reported as an adverse event was 12.3% for placebo, 13.3% for salmeterol, 18.3% for fluticasone propionate and 19.6% for salmeterol/fluticasone propionate (hazard ratio for salmeterol/fluticasone propionate vs placebo: 1.64, 95% CI: 1.33 to 2.01, p<0.001). There was no increase in pneumonia related deaths; deaths while on treatment that were adjudicated as primarily due to pneumonia were 7 for placebo, 9 for salmeterol, 13 for fluticasone propionate and 8 for salmeterol/fluticasone propionate. There was no significant difference in probability of bone fracture (5.1% placebo, 5.1% salmeterol, 5.4% fluticasone propionate and 6.3% salmeterol/fluticasone propionate; hazard ratio for salmeterol/fluticasone propionate vs placebo: 1.22, 95% CI: 0.87 to 1.72, p=0.248. Placebo-controlled clinical trials, over 6 and 12 months, have shown that regular use of salmeterol/fluticasone propionate 50/500 micrograms improves lung function and reduces breathlessness and the use of relief medication. Studies SCO40043 and SCO100250 were randomised, double-blind, parallel-group, replicate studies comparing the effect of salmeterol/fluticasone propionate 50/250 micrograms twice daily (a dose not licensed for COPD treatment in the European Union) with salmeterol 50 micrograms twice daily on the annual rate of moderate/severe exacerbations in subjects with COPD with FEV1 less than 50% predicted and a history of exacerbations. Moderate/ severe exacerbations were defined as worsening symptoms that required treatment with oral corticosteroids and/or antibiotics or in-patient hospitalisation. The trials had a 4-week run-in period during which all subjects received open-label salmeterol/ fluticasone propionate 50/250 to standardize COPD pharmacotherapy and stabilise disease prior to randomisation to blinded study medication for 52 weeks. Subjects were randomised 1:1 to salmeterol/ fluticasone propionate 50/250 (total ITT n=776) or salmeterol (total ITT n=778). Prior to run-in, subjects discontinued use of previous COPD medications except short-acting bronchodilators. The use of concurrent inhaled long-acting bronchodilators (β 2 agonist and anticholinergic drugs), salbutamol/ipratropium bromide combination products, oral β 2 agonists, and theophylline preparations were not allowed during the treatment period. Oral corticosteroids and antibiotics were allowed for the acute treatment of COPD exacerbations with specific guidelines for use. Subjects used salbutamol on an as-needed basis throughout the studies. The results of both studies showed that treatment with salmeterol/fluticasone propionate 50/250 resulted in a significantly lower annual rate of moderate/severe COPD exacerbations compared with salmeterol (SCO40043: 1.06 and 1.53 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001; SCO100250: 1.10 and 1.59 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001). Findings for the secondary efficacy measures (time to first moderate/severe exacerbation, the annual rate of exacerbations requiring oral corticosteroids, and pre-dose morning (AM) FEV1) significantly favoured salmeterol/fluticasone propionate 50/250 micrograms twice daily over salmeterol. Adverse event profiles were similar with the exception of a higher incidence of pneumonias and known local side effects (candidiasis and dysphonia) in the salmeterol/fluticasone propionate 50/250 micrograms twice daily group compared with salmeterol. Pneumonia-related events were reported for 55 (7%) subjects in the salmeterol/fluticasone propionate 50/250 micrograms twice daily group and 25 (3%) in the salmeterol group. The increased incidence of reported pneumonia with salmeterol/fluticasone propionate 50/250 micrograms twice daily appears to be of similar magnitude to the incidence reported following treatment with salmeterol/fluticasone propionate 50/500 micrograms twice daily in TORCH. The Salmeterol Multi-center Asthma Research Trial (SMART) SMART was a multi-centre, randomised, double blind, placebo-controlled, parallel group 28-week study in the US which randomised 13,176 patients to salmeterol (50 micrograms twice daily) and 13,179 patients to placebo in addition to the patients' usual asthma therapy. Patients were enrolled if ≥12 years of age, with asthma and if currently using asthma medication (but not a LABA). Baseline ICS use at study entry was recorded, but not required in the study. The primary endpoint in SMART was the combined number of respiratory-related deaths and respiratory-related life-threatening experiences. Key findings from SMART: primary endpoint Patient group Number of primary endpoint events /number of patients Relative Risk (95% confidence intervals) salmeterol placebo All patients 50/13,176 36/13,179 1.40 (0.91, 2.14) Patients using inhaled steroids 23/6,127 19/6,138 1.21 (0.66, 2.23) Patients not using inhaled steroids 27/7,049 17/7,041 1.60 (0.87, 2.93) African-American patients 20/2,366 5/2,319 4.10 (1.54, 10.90) (Risk in bold is statistically significant at the 95% level.) Key findings from SMART by inhaled steroid use at baseline: secondary endpoints Number of secondary endpoint events /number of patients Relative Risk (95% confidence intervals) salmeterol placebo Respiratory-related death Patients using inhaled steroids 10/6127 5/6138 2.01 (0.69, 5.86) Patients not using inhaled steroids 14/7049 6/7041 2.28 (0.88, 5.94) Combined asthma-related death or life-threatening experience Patients using inhaled steroids 16/6127 13/6138 1.24 (0.60, 2.58) Patients not using inhaled steroids 21/7049 9/7041 2.39 (1.10, 5.22) Asthma-related death Patients using inhaled steroids 4/6127 3/6138 1.35 (0.30, 6.04) Patients not using inhaled steroids 9/7049 0/7041 * (*=could not be calculated because of no events in placebo group. Risk in bold figures is statistically significant at the 95% level. The secondary endpoints in the table above reached statistical significance in the whole population.) The secondary endpoints of combined all cause death or life-threatening experience, all cause death, or all cause hospitalisation did not reach statistical significance in the whole population. Paediatric population AirFluSal Forspiro is not recommended for use in children and adolescents aged less than 18 years. The safety and efficacy of AirFluSal Forspiro in this young population have not been established. The data presented below refer to a lower dose of the fixed-dose combination containing these two actives, a dose and strength which is not available for AirFluSal Forspiro. The studies described were carried out with a previously authorised product available in three different strengths; the studies were not carried out with AirFluSal Forspiro. In a study in 158 children aged 6 to 16 years with symptomatic asthma, the combination of fluticasone propionate/salmeterol is as efficacious as doubling the dose of fluticasone propionate in respect of symptom control and lung function. This study was not designed to investigate the effect on exacerbations. In a 12-week trial of children aged 4 to 11 years [n=257] treated with either salmeterol/fluticasone propionate 50/100 or salmeterol 50 micrograms + fluticasone propionate 100 micrograms both twice daily, both treatment arms experienced a 14% increase in peak expiratory flow rate as well as improvements in symptom score and rescue salbutamol use. There were no differences between the two treatment arms. There were no differences in safety parameters between the two treatment arms. In a 12-week trial of children 4 to 11 years of age [n=203] randomized in a parallel-group study with persistent asthma and who were symptomatic on inhaled corticosteroid, safety was the primary objective. Children received either salmeterol/fluticasone propionate (50/100 micrograms) or fluticasone propionate (100 micrograms) alone twice daily. Two children on fluticasone propionate/salmeterol and 5 children on fluticasone propionate withdrew because of worsening asthma. After 12 weeks no children in either treatment arm had abnormally low 24-hour urinary cortisol excretion. There were no other differences in safety profile between the treatment arms.