Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2021 Publisher: GlaxoSmithKline NZ Limited, Private Bag 106600, Downtown, Auckland, New Zealand
Pharmacotherapeutic group: Adrenergics in combination with corticosteroids or other drugs, excl. Anticholinergics.
ATC code: R03AK06
SERETIDE contains salmeterol and fluticasone propionate which have differing modes of action. Salmeterol provides symptomatic relief while fluticasone propionate improves lung function and prevents exacerbations of the condition. SERETIDE can offer a more convenient regime for patients on concurrent long-acting beta-agonist and inhaled corticosteroid therapy. The respective mechanisms of action of both agents are discussed below:
Salmeterol is a selective long-acting (12 hour) beta-2-adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor.
These pharmacological properties of salmeterol offer a slower onset of action, but more effective protection against histamine-induced bronchoconstriction and produce a longer duration of bronchodilation, lasting for approximately 12 hours, than recommended doses of conventional short-acting beta-2-agonists.
In vitro tests have shown salmeterol is a potent and long-lasting inhibitor of the release, from human lung, of mast cell mediators such as histamine, leukotrienes and prostaglandin D2.
In man, salmeterol inhibits the early and late phase response to inhaled allergen; the latter persisting for over 30 hours after a single dose when the bronchodilator effect is no longer evident. Single dosing with salmeterol attenuates bronchial hyperresponsiveness. These properties indicate that salmeterol has additional nonbronchodilator activity but the full clinical significance is not yet clear. This mechanism is different from the anti-inflammatory effect of corticosteroids.
Fluticasone propionate given by inhalation at recommended doses has a potent glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.
Daily output of adrenocortical hormones usually remain within the normal range during chronic treatment with inhaled fluticasone propionate, even at the highest recommended doses in children and adults. After transfer from other inhaled steroids, the daily output gradually improves despite past and present intermittent use of oral steroids, thus demonstrating return of normal adrenal function on inhaled fluticasone propionate. The adrenal reserve also remains normal during chronic treatment, as measured by a normal increment on a stimulation test. However, any residual impairment of adrenal reserve from previous treatment may persist for a considerable time and should be borne in mind (see Section 4.4 Special warnings and precautions for use).
Safety and efficacy of salmeterol-fluticasone propionate versus fluticasone propionate alone in asthma:
Two multi-centre 26-week studies were conducted to compare the safety and efficacy of salmeterol-fluticasone propionate versus fluticasone propionate 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-fluticasone propionate) was non-inferior to ICS (fluticasone propionate) 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-fluticasone propionate) was superior to ICS therapy alone (fluticasone propionate) 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 randomised and received treatment in the AUSTRI and VESTRI trials, respectively. For the primary safety endpoint, noninferiority was achieved for both trials (see Table below).
Serious Asthma-Related Events in the 26-Week AUSTRI and VESTRI Trials:
| AUSTRI | VESTRI | |||
|---|---|---|---|---|
| Salmeterolfluticasone propionate (n = 5,834) | Fluticasone propionate alone (n = 5,845) | Salmeterolfluticasone propionate (n = 3,107) | Fluticasone propionate alone (n = 3,101) | |
| Composite endpoint (Asthma-related hospitalisation, endotracheal intubation, or death) | 34 (0.6%) | 33 (0.6%) | 27 (0.9%) | 21 (0.7%) |
| Salmeterolfluticasone propionate/fluticasone propionate 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-fluticasone propionate relative to fluticasone propionate was seen in both studies, however only AUSTRI met statistical significance:
| AUSTRI | VESTRI | |||
|---|---|---|---|---|
| Salmeterolfluticasone propionate (n = 5,834) | Fluticasone propionate alone (n = 5,845) | Salmeterolfluticasone propionate (n = 3,107) | Fluticasone propionate alone (n = 3,101) | |
| Number of subjects with an asthma exacerbation | 480 (8%) | 597 (10%) | 265 (9%) | 309 (10%) |
| Salmeterolfluticasone propionate/fluticasone propionate Hazard ratio (95% CI) | 0.787 (0.698, 0.888) | 0.859 (0.729, 1.012) | ||
A large twelve-month study (Gaining Optimal Asthma ControL, GOAL) in 3416 asthma patients compared the efficacy and safety of salmeterol-fluticasone propionate versus inhaled corticosteroid alone in achieving pre-defined levels of asthma control. Treatment was stepped-up every 12 weeks until ##‘Total control’ was achieved or the highest dose of study drug was reached. Control needed to be sustained for at least 7 out of the last 8 weeks of treatment. The study showed that:
These effects were observed earlier with salmeterol-fluticasone propionate compared with inhaled corticosteroid alone and at a lower inhaled corticosteroid dose.
The GOAL study also showed that:
# 6Well 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.
Two further studies have shown improvements in lung function, percentage of symptom free days and reduction in rescue medication use, at 60% lower inhaled corticosteroid dose with salmeterol-fluticasone propionate compared to treatment with inhaled corticosteroid alone, whilst the control of the underlying airway inflammation, measured by bronchial biopsy and bronchoalveolar lavage, was maintained.
Additional studies have shown that treatment with salmeterol-fluticasone propionate significantly improves asthma symptoms, lung function and reduces the use of rescue medication compared to treatment with the individual components alone and placebo. Results from GOAL show that the improvements seen with salmeterolfluticasone propionate, in these endpoints, are maintained over at least 12 months.
Symptomatic COPD patients who demonstrated less than 10% reversibility to a short acting beta-2-agonist:
Placebo-controlled clinical trials, over 6 and 12 months, have shown that regular use of SERETIDE 50/500 micrograms rapidly and significantly improves lung function, significantly reduced breathlessness and the use of relief medication. Over a 12- month period the risk of COPD exacerbations and the need for additional courses of oral corticosteroids was significantly reduced. There were also significant improvements in health status.
SERETIDE 50/500 micrograms was effective in improving lung function, health status and reducing the risk of COPD exacerbations, in both current and ex-smokers.
Symptomatic COPD patients without restriction to 10% reversibility to a short acting beta-2-agonist:
Placebo-controlled clinical trials, over 6 months, have shown that regular use of both SERETIDE 50/250 and 50/500 micrograms rapidly and significantly improves lung function, significantly reduced breathlessness and the use of relief medication. There were also significant improvements in health status.
TORCH study (Towards a Revolution in COPD Health):
TORCH was a 3 year study to assess the effect of treatment with SERETIDE 50/500 mcg twice daily, fluticasone propionate 500 mcg twice daily, salmeterol 50 mcg twice daily, or placebo on all-cause mortality in patients with COPD. Patients with moderate to severe COPD with a baseline (pre-bronchodilator) FEV1 <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 SERETIDE vs placebo.
| Placebo N=1524 | Salmeterol 50 N=1521 | Fluticasone propionate 500 N=1534 | Seretide 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) 0.0521 |
| Hazard ratio Seretide 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 P value adjusted 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 SERETIDE 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 SERETIDE.
SERETIDE reduced the rate of moderate to severe COPD exacerbations by 25% (p <0.001) compared with placebo. SERETIDE reduced the exacerbation rate by 12% compared with salmeterol (p=0.002) and 9% compared with fluticasone propionate (p=0.024).
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 3 years for SERETIDE compared with placebo was -3.1 units (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). The odds of SERETIDE subjects achieving a clinically significant improvement in health status (ie. ≥4 point reduction in SGRQ) was 86% greater compared to placebo (p<0.001), 40% greater compared to salmeterol (p <0.001) and 24% greater compared to fluticasone propionate (p=0.006).
Over the 3 year treatment period, FEV1 values were higher in subjects treated with SERETIDE than those treated with placebo (average difference over 3 years 92 mL, p<0.001). SERETIDE was also more effective than salmeterol or fluticasone propionate in improving FEV1 (average difference 50 mL, p <0.001 for salmeterol and 44 mL, p <0.001 for fluticasone propionate).
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 SERETIDE (Hazard ratio for SERETIDE vs placebo: 1.64, 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 SERETIDE. There was no significant difference in probability of bone fracture between treatments. The incidence of adverse events of eye disorders, bone disorders, and HPA axis disorders was low and there was no difference observed between treatments. There was no evidence of an increase in cardiac adverse events in the treatment groups receiving salmeterol.
The all-cause mortality findings from TORCH were further supported by data from another study, INSPIRE, which was a 2 year randomised (n=1323), double blind study comparing the effects of SERETIDE 50/500 mcg twice daily with tiotropium 18 mcg once daily in COPD patients with post bronchodilator FEV1 <50% predicted normal. All-cause mortality was a safety end point in this study. The results showed that for time to death on-treatment, there was a 52% reduction in the risk of dying at anytime on therapy over the 2 year study period for SERETIDE compared to tiotropium (p=0.012).
There is no evidence in animal or human subjects that the administration of salmeterol and fluticasone propionate together by the inhaled route affects the pharmacokinetics of either component.
For pharmacokinetic purposes therefore each component can be considered separately.
Even though plasma levels of SERETIDE are very low, potential interactions with other substrates and inhibitors of CYP 3A4 cannot be excluded.
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 agent in plasma due to the low plasma concentrations at therapeutic doses (approximately 200pg/mL or less) achieved after inhaled dosing. After regular dosing with salmeterol xinafoate, hydroxynaphthoic acid can be detected in the systemic circulation, reaching steady state concentrations of approximately 100 ng/mL. These concentrations are up to 1000 fold lower than steady state levels observed in toxicity studies. No detrimental effects have been seen following long-term regular dosing (more than 12 months) in patients with airway obstruction.
In a placebo-controlled, crossover drug interaction study in 15 healthy subjects, coadministration of salmeterol (50 mcg twice daily inhaled) and the CYP3A4 inhibitor ketoconazole (400 mg once daily orally) for 7 days resulted in a significant increase in plasma salmeterol exposure (1.4-fold Cmax and 15-fold AUC). There was no increase in salmeterol accumulation with repeat dosing. Three subjects were withdrawn from salmeterol and ketoconazole co-administration due to QTc prolongation or palpitations with sinus tachycardia. In the remaining 12 subjects, coadministration of salmeterol and ketoconazole did not result in a clinically significant effect on heart rate, blood potassium or QTc duration (see Section 4.4 Special warnings and precautions for use, and Section 4.5 Interaction with other medicines and other forms of interaction).
The absolute bioavailability of fluticasone propionate for each of the available inhaler devices has been estimated from within and between study comparisons of inhaled and intravenous pharmacokinetic data. In healthy adult subjects the absolute bioavailability has been estimated for fluticasone propionate Accuhaler (7.8%), fluticasone propionate Inhaler (10.9%), SERETIDE Inhaler (5.3%) and SERETIDE Accuhaler (5.5%) respectively. In patients with ROAD or COPD 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 300L) and a terminal half-life of approximately 8 hours. Plasma protein binding is moderately high (91%). Fluticasone propionate is cleared very rapidly from the systemic circulation, principally by metabolism to an inactive carboxylic acid metabolite, by the cytochrome P450 enzyme CYP3A4.
The renal clearance of fluticasone propionate is negligible (<0.2%) and less than 5% as the metabolite. Care should be taken when co-administering known CYP3A4 inhibitors, as there is potential for increased systemic exposure to fluticasone propionate.
Salmeterol xinafoate and fluticasone propionate have been extensively evaluated in animal toxicity tests. Significant toxicities occurred only at doses in excess of those recommended for human use and were those expected for a potent beta-2-adrenoreceptor agonist and glucocorticosteroid. Neither salmeterol xinafoate nor fluticasone propionate has shown any potential for genetic toxicity.
In long term studies, salmeterol xinafoate induced benign tumours of smooth muscle in the mesovarium of rats and the uterus of mice. Rodents are sensitive to the formation of these pharmacologically-induced tumours. Salmeterol is not considered to represent a significant oncogenic hazard to man.
Co-administration of salmeterol and fluticasone propionate resulted in some cardiovascular interactions at high doses. In rats, mild atrial myocarditis and focal coronary arteritis were transient effects that resolved with regular dosing. In dogs, heart rate increases were greater after co-administration than after salmeterol alone. No clinically relevant serious adverse cardiac effects have been observed in studies in man.
Co-administration did not modify other class-related toxicities in animals.
The non-CFC propellant, HFA134a, 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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