Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic Group:        Adrenergics in combination with corticosteroids or other drugs, excl.
anticholinergics.

ATC Code:                         R03AK06

Mechanism of action and pharmacodynamic effects:
Seretide contains salmeterol and fluticasone propionate which have differing modes of action.

The respective mechanisms of action of both drugs are discussed below.

Salmeterol:
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:

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

Seretide 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 Seretide 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 Seretide achieved asthma control than patients treated with ICS alone and this control was attained at a lower corticosteroid dose.

*Well controlled asthma was achieved more rapidly with Seretide than with ICS alone. The time on treatment for 50% of subjects to achieve a first individual well controlled week was 16 days for Seretide 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 Seretide treatment 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
Salmeterol/FP                   FP
Pre-Study Treatment                    WC            TC          WC           TC No ICS (SABA alone)                              78%          50%         70%          40% Low dose ICS ( ≤500 micrograms BDP               75%          44%         60%          28% or equivalent/day)
Medium dose ICS (>500 to 1000                    62%          29%         47%          16% micrograms BDP or equivalent/day)
Pooled results across the 3 treatment            71%          41%         59%          28% levels
*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 Seretide 50/100 micrograms bd may be considered as initial maintenance therapy in patients with moderate persistent asthma for whom rapid control of asthma is deemed essential (see section 4.2).

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 Seretide for two weeks. The study showed that doubling the inhalations of each strength of Seretide 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 Seretide is considered by the physician in adult patients requiring additional short-term (up to 14 days) inhaled corticosteroid therapy.

Seretide COPD clinical trials

TORCH was a 3-year study to assess the effect of treatment with Seretide Diskus 50/500 micrograms bd, salmeterol Diskus 50 micrograms bd, fluticasone propionate (FP) Diskus 500 micrograms bd or placebo on all-cause mortality in patients with COPD. COPD patients 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.

Seretide
Placebo        Salmeterol 50     FP 500
50/500
N = 1524       N = 1521          N = 1534
N = 1533
All cause mortality at 3 years
Number of deaths        231            205                246               193 (%)                     (15.2%)        (13.5%)            (16.0%)           (12.6%) Hazard Ratio vs                        0.879              1.060             0.825 Placebo (CIs)           N/A            (0.73, 1.06)       (0.89, 1.27)      (0.68, 1.00 ) p value                                0.180              0.525             0.0521 Hazard Ratio
0.932              0.774
Seretide 50/500 vs
N/A            (0.77, 1.13)       (0.64, 0.93)      N/A components (CIs)
0.481              0.007 p value
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 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 FP and 4.7% for Seretide.

The mean number of moderate to severe exacerbations per year was significantly reduced with Seretide as compared with treatment with salmeterol, FP and placebo (mean rate in the Seretide group 0.85 compared with 0.97 in the salmeterol group, 0.93 in the FP group and 1.13 in the placebo). 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 FP (95% CI: 1% to 16%, p=0.024). Salmeterol and FP 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 Seretide 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
FP 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 FP and 19.6% for Seretide (Hazard ratio for Seretide 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 FP and 8 for Seretide. There was no significant difference in probability of bone fracture (5.1% placebo, 5.1% salmeterol, 5.4% FP and 6.3% Seretide; Hazard ratio for Seretide 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 Seretide 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 Seretide 50/250 micrograms bd (a dose not licensed for COPD treatment in the European Union) with salmeterol 50 micrograms bd 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/ FP 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/ FP 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 (β2 agonist and anticholinergic), ipratropium/salbutamol combination products, oral β2 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 Seretide 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 Seretide 50/250 micrograms bd 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 Seretide 50/250 micrograms bd group compared with salmeterol.
Pneumonia-related events were reported for 55 (7%) subjects in the Seretide 50/250 micrograms bd group and 25 (3%) in the salmeterol group. The increased incidence of reported pneumonia with Seretide 50/250 micrograms bd appears to be of similar magnitude to the incidence reported following treatment with Seretide 50/500 micrograms bd in TORCH.

Asthma
The Salmeterol Multi-center Asthma Research Trial (SMART)

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.

Safety and efficacy of salmeterol-FP versus FP alone in asthma

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        FP Alone       Salmeterol-FP      FP Alone
(n = 5,834)        (n = 5,845)      (n = 3,107)      (n = 3,101)
Composite endpoint                34 (0.6%)          33 (0.6%)        27 (0.9%)        21 (0.7%) (Asthma-related hospitalisation, endotracheal intubation, or death)
Salmeterol-FP/FP Hazard             1.029                               1.285 ratio (95% CI)                  (0.638-1.662)a                      (0.726-2.272)b Death                                 0                   0               0                  0 
Asthma-related                      34                 33                27              21 hospitalisation
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       FP Alone       Salmeterol-FP       FP Alone
(n = 5,834)       (n = 5,845)      (n = 3,107)       (n = 3,101)
Number of subjects with an         480 (8%)         597 (10%)         265 (9%)         309 (10%) asthma exacerbation
Salmeterol-FP/FP Hazard                      0.787                              0.859 ratio (95% CI)                           (0.698, 0.888)                     (0.729, 1.012) 

Paediatric population:
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 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 2 treatment arms. There were no differences in safety parameters between the 2 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 salmeterol/fluticasone propionate 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.

Fluticasone propionate containing medications in asthma during pregnancy 
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).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
For pharmacokinetic purposes 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 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 presystemic 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

In a population pharmacokinetic analysis utilizing data from 9 controlled clinical trials with different devices (Diskus, metered dose inhaler) that included 350 patients with asthma aged 4 to 77 years (174 patients 4 to 11 years of age) higher fluticasone propionate systemic exposure following treatment with Seretide Diskus 50/100 compared to fluticasone propionate Diskus 100 were seen.

Geometric Mean Ratio [90% CI] for the Salmeterol/fluticasone propionate vs. fluticasone propionate Diskus Comparison in Children and Adolescent/Adult Populations 
Treatment (test vs. ref)           Population             AUC                   Cmax Salmeterol/ fluticasone            Children               1.20 [1.06 – 1.37]    1.25 [1.11 – 1.41] propionate Diskus 50/100           (4–11yr) fluticasone propionate Diskus
100
Salmeterol/fluticasone             Adolescent/Adult       1.52 [1.08 – 2.13]    1.52 [1.08 – 2.16] propionate Diskus 50/100           ( ≥12yr) fluticasone propionate Diskus
100


The effect of 21 days of treatment with Seretide Inhaler 25/50 micrograms (2 inhalations twice daily with or without a spacer) or Seretide Diskus 50/100 micrograms (1 inhalation twice daily) was evaluated in 31 children aged 4 to 11 years with mild asthma. Systemic exposure to salmeterol was similar for Seretide Inhaler, Seretide Inhaler with spacer, and Seretide 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). Systemic exposure to fluticasone propionate was similar for Seretide Inhaler with spacer (107 pg hr/mL [95% CI: 45.7, 252.2]) and Seretide Diskus (138 pg hr/mL [95% CI: 69.3, 273.2]), but lower for Seretide Inhaler (24 pg hr/mL [95% CI: 9.6, 60.2]).”