Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Cipla (EU) limited, Dixcart House, Addlestone Road, Bourne Business Park, Addlestone, Surrey, KT15 2LE, United Kingdom
Pharmacotherapeutic group: Adrenergics in combination with corticosteroids or other drugs, excl. Anticholinergics
ATC Code: R03AK06
Sereflo contains salmeterol and fluticasone propionate which have differing modes of action.
The respective mechanisms of action of both medicinal products are discussed below.
Salmeterol is a selective long-acting (12 hour) β2 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 β2 agonists.
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.
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 and fluticasone propionate as a fixed-dose combination 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 and fluticasone propionate as a fixed-dose combination 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 the salmeterol and fluticasone propionate fixed-dose combination than with ICS alone. The time on treatment for 50% of subjects to achieve a first individual well-controlled week was 16 days for the salmeterol and fluticasone propionate fixed-dose combination compared to 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 and fluticasone propionate fixed-dose combination treatment group compared to 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/FP | FP | ||
|---|---|---|---|---|
| WC | TC | WC | TC | |
| No ICS (Short Acting β Agonist (SABA) alone) | 78% | 50% | 70% | 40% |
| Low dose ICS ( ≤500 microgram BDP or equivalent/day) | 75% | 44% | 60% | 28% |
| Medium dose ICS (>500 to 1000 microgram 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 and fluticasone propionate 50/100 microgram bd 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 and fluticasone propionate as a fixed-dose combination for two weeks. The study showed that doubling the inhalations of each strength of the salmeterol and fluticasone propionate fixed-dose combination 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 to one inhalation twice daily. The small increase in β agonist-related adverse events should be taken into account if doubling the dose of the salmeterol and fluticasone propionate fixed-dose combination is considered by the physician in adult patients requiring additional short-term (up to 14 days) inhaled corticosteroid therapy.
The Salmeterol Multi-center Asthma Research Trial (SMART) was a 28-week US study that evaluated the safety of salmeterol compared to placebo added to usual therapy in adult and adolescent subjects. Although there were no significant differences in the primary endpoint of the combined number of respiratory-related deaths and respiratory-related life-threatening experiences, the study showed a significant increase in asthma-related deaths in patients receiving salmeterol (13 deaths out of 13,176 patients treated with salmeterol versus 3 deaths out of 13,179 patients on placebo). The study was not designed to assess the impact of concurrent inhaled corticosteroid use, and only 47% of subjects reported ICS use at baseline.
Two multi-centre 26-week studies were conducted to compare the safety and efficacy of salmeterol-FP versus FP alone, one in adult and adolescent subjects (AUSTRI trial), and the other in paediatric subjects 4-11 years of age (VESTRI trial). For both studies, enrolled subjects had moderate to severe persistent asthma with history of asthma-related hospitalisation or asthma exacerbation in the previous year. The primary objective of each study was to determine whether the addition of LABA to ICS therapy (salmeterol-FP) was non-inferior to ICS (FP) alone in terms of the risk of serious asthma related events (asthma-related hospitalisation, endotracheal intubation, and death). A secondary efficacy objective of these studies was to evaluate whether ICS/LABA (salmeterol-FP) was superior to ICS therapy alone (FP) in terms of severe asthma exacerbation (defined as deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or an in-patient hospitalisation or emergency department visit due to asthma that required systemic corticosteroids).
A total of 11,679 and 6,208 subjects were randomized and received treatment in the AUSTRI and VESTRI trials, respectively. For the primary safety endpoint, non-inferiority was achieved for both trials (see Table below).
Serious Asthma-Related Events in the 26-Week AUSTRI and VESTRI Trials:
| AUSTRI | VESTRI | |||
|---|---|---|---|---|
| Salmeterol-FP (n=5,834) | FP Alone (n=5,845) | Salmeterol-FP (n=3,107) | FP Alone (n=3,101) | |
| Composite endpoint (Asthma-related hospitalisation, endotracheal intubation, or death) | 34 (0.6%) | 33 (0.6%) | 27 (0.9%) | 27 (0.7%) |
| Salmeterol-FP/FP Hazard ratio (95% CI) | 1.029 (0.638-1.662)a | 1.285 (0.726-2.272)b | ||
| Death | 0 | 0 | 0 | 0 |
| Asthma-related hospitalisation | 34 | 33 | 27 | 21 |
| Endotracheal intubation | 0 | 2 | 0 | 0 |
a If the resulting upper 95% CI estimate for the relative risk was less than 2.0, then non-inferiority was concluded.
b If the resulting upper 95% CI estimate for the relative risk was less than 2.675, then non-inferiority was concluded.
For the secondary efficacy endpoint, reduction in time to first asthma exacerbation for salmeterol-FP relative to FP was seen in both studies, however only AUSTRI met statistical significance
| AUSTRI | VESTRI | |||
|---|---|---|---|---|
| Salmeterol-FP (n=5,834) | FP Alone (n=5,845) | Salmeterol-FP (n=3,107) | FP Alone (n=3,101) | |
| Number of subjects with an asthma exacerbation | 480 (8%) | 597 (10%) | 265 (9%) | 309 (10%) |
| Salmeterol-FP/FP Hazard ratio (95% CI) | 0.787 (0.698, 0.888) | 0.859 (0.729, 1.012) | ||
In trial SAM101667, in 158 children aged 6 to 16 years with symptomatic asthma, the combination of salmeterol/fluticasone propionate is equally efficacious to doubling the dose of fluticasone propionate regarding symptom control and lung function. This study was not designed to investigate the effect on exacerbations.
In a trial which randomized children aged 4 to 11 years [n=428], salmeterol/fluticasone propionate Diskus (50/100 microgram, one inhalation twice daily) was compared with salmeterol/fluticasone propionate MDI (25/50 microgram, two inhalations twice daily) over a 12-week treatment period. The adjusted mean change from baseline in mean morning peak expiratory flow over Weeks 1-12 was 37.7L/min in the Diskus group and 38.6L/min in the MDI group. Improvements were also seen in both treatment groups on rescue and symptom free days and nights.
An observational retrospective epidemiological cohort study utilising electronic health records from the United Kingdom was conducted to evaluate the risk of MCMs following first trimester exposure to inhaled FP alone and salmeterol-FP relative to non-FP containing ICS. No placebo comparator was included in this study.
Within the asthma cohort of 5362 first trimester ICS-exposed pregnancies, 131 diagnosed MCMs were identified; 1612 (30%) were exposed to FP or salmeterol-FP of which 42 diagnosed MCMs were identified. The adjusted odds ratio for MCMs diagnosed by 1 year was 1.1 (95%CI: 0.5-2.3) for FP exposed vs non-FP ICS exposed women with moderate asthma and 1.2 (95%CI: 0.7-2.0) for women with considerable to severe asthma. No difference in the risk of MCMs was identified following first trimester exposure to FP alone versus salmeterol-FP. Absolute risks of MCM across the asthma severity strata ranged from 2.0 to 2.9 per 100 FP-exposed pregnancies which is comparable to results from a study of 15,840 pregnancies unexposed to asthma therapies in the General Practice Research Database (2.8 MCM events per 100 pregnancies).
When salmeterol and fluticasone propionate were administered in combination by the inhaled route, the pharmacokinetics of each component were similar to those observed when the medicinal products were administered separately. For pharmacokinetic purposes therefore each component can be considered separately.
Salmeterol
Salmeterol acts locally in the lung therefore plasma levels are not an indication of therapeutic effects. In addition there are only limited data available on the pharmacokinetics of salmeterol because of the technical difficulty of assaying the drug in plasma due to the low plasma concentrations at therapeutic doses (approximately 200 picogram/mL or less) achieved after inhaled dosing.
Fluticasone propionate
The absolute bioavailability of a single dose of inhaled fluticasone propionate in healthy subjects varies between approximately 5 to 11% of the nominal dose depending on the inhalation device used. In patients with asthma a lesser degree of systemic exposure to inhaled fluticasone propionate has been observed.
Systemic absorption occurs mainly through the lungs and is initially rapid then prolonged. The remainder of the inhaled dose may be swallowed but contributes minimally to systemic exposure due to the low aqueous solubility and pre-systemic metabolism, resulting in oral availability of less than 1%. There is a linear increase in systemic exposure with increasing inhaled dose.
The disposition of fluticasone propionate is characterised by high plasma clearance (1150 mL/min), a large volume of distribution at steady-state (approximately 300 L) and a terminal half-life of approximately 8 hours.
Plasma protein binding is 91%.
Fluticasone propionate is cleared very rapidly from the systemic circulation. The main pathway is metabolism to an inactive carboxylic acid metabolite, by the cytochrome P450 enzyme CYP3A4. Other unidentified metabolites are also found in the faeces.
The renal clearance of fluticasone propionate is negligible. Less than 5% of the dose is excreted in urine, mainly as metabolites. The main part of the dose is excreted in faeces as metabolites and unchanged drug.
Paediatric population
The effect of 21 days of treatment with the fixed-dose combination of salmeterol and fluticasone propionate 25/50 microgram administered via a pressurised metered dose inhaler (pMDI) (2 inhalations twice daily with or without a spacer) or the fixed-dose combination of salmeterol and fluticasone propionate administered as an inhalation powder via the Diskus 50/100 microgram (1 inhalation twice daily) was evaluated in 31 children aged 4 to 11 years with mild asthma.
Systemic exposure to fluticasone propionate was similar when administered via the pMDI with spacer (107 pg hr/mL [95% CI: 45.7, 252.2]) and when administered as an inhalation powder via the Diskus (138 pg hr/mL [95% CI: 69.3, 273.2]), but lower when administered via the pMDI without spacer (24 pg hr/mL [95% CI: 9.6, 60.2]). Systemic exposure to salmeterol was similar when administered via the pMDI without spacer, via the pMDI with spacer and as an inhalation powder via the Diskus (126 pg hr/mL [95% CI: 70, 225], 103 pg hr/mL [95% CI: 54, 200], and 110 pg hr/mL [95% CI: 55, 219], respectively).
The only safety concerns for human use derived from animal studies of salmeterol and fluticasone propionate given separately were effects associated with exaggerated pharmacological actions.
In animal reproduction studies, glucocorticosteroids have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not seem to be relevant for man given recommended doses. Animal studies with salmeterol have shown embryofetal toxicity only at high exposure levels. Following co-administration, increased incidences of transposed umbilical artery and incomplete ossification of occipital bone were found in rats at doses associated with known glucocorticoid-induced abnormalities. Neither salmeterol xinafoate or fluticasone propionate have shown any potential for genetic toxicity.
The non-CFC propellant, norflurane, has been shown to have no toxic effect at very high vapour concentrations, far in excess of those likely to be experienced by patients, in a wide range of animal species exposed daily for periods of two years.
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