Source: Health Products Regulatory Authority (IE) Revision Year: 2023 Publisher: Cipla Europe NV, De Keyserlei 58-60, Box-19, 2018 Antwerp, Belgium
Pharmacotherapeutic group: other drugs for obstructive airway diseases, inhalants, glucocorticoids
ATC code: R03BA05
Fluticasone propionate given by inhalation at recommended doses has a glucocorticoidanti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.
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 combination 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-FPICS exposed women with moderate asthma and 1.2 (95% CI: 0.7–2.0) for women with considerable to severe asthma. No differencein the risk of MCMs was identified following first trimester exposure to FP alone versus salmeterol-FP combination. 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).
TORCH wasa 3-year study to assess the effect of treatment with Seretide Diskus 50/500 mcgbd, salmeterol Diskus 50mcgbd, fluticasone propionate (FP) Diskus 500mcgbd 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.
| Placebo N=1524 | Salmeterol50 N=1521 | FP500 N=1534 | Seretide50/500 | |
|---|---|---|---|---|
| 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) | N/A | 0.879 (0.73, 1.06) | 1.060 (0.89, 1.27) | 0.825 (0.68, 1.00) |
| p value | 0.180 | 0.525 | 0.05211 | |
| Hazard Ratio Seretide 50/500 vs components | 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
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 pā¤0.05.
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% to31%; p<0.001) compared with placebo, 12% compared with salmeterol (95% CI: 5% to19%, 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<0.00l) 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). A4-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 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).
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 of fluticasone propionate inhaler is (10.9%). 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 pres systemic metabolism, resulting in oral availability of less than 1%. There is a linear increase in systemic exposure with increasing inhaled dose.
Fluticasone propionate has a large volume of distribution at steady-state (approximately 300l).Plasma proteinbinding ismoderately high(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 disposition of fluticasone propionate is characterised by high plasma clearance (1150 ml/min) and a terminal half-life of approximately 8 hours.
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.
Toxicology has shown only those class effects typical of potent corticosteroids, and these only at doses in excess of that proposed for therapeutic use. No novel effects were identified in repeat dose toxicity tests, reproductive studies or teratology studies. Fluticasone propionate is devoid of mutagenic activity in-vitro and in-vivo and showed no tumorigenic potential in rodents. It is both non-irritant and nonsensitizing in animal models.
Subcutaneous embryofetal development studies in mouse and rat at 45 and 100 mcg/kg, respectively (approximately equivalent to 4 and 6 times the maximum recommended daily inhaled dose of 500 mcg twice daily in adults based on mouse and rat plasma levels of 486 and 710 pg/mL, respectively) resulted in fetal developmental toxicity characteristic of a potent corticosteroid, including cleft palate and embryonic fetal growth retardation, at doses that caused maternal toxicity. The no effect level for these finding in rat were associated with systemic exposures approximately 3 times the highest clinical exposure based on rat plasma level of 310 pg/mL. In the rabbit, fetal weight reduction and cleft palate occurred at a maternally toxic subcutaneous dose of 4 mcg/kg (less than 1.4 times the maximum recommended inhaled dose of 500 mcg twice daily based on rabbit plasma level of 149 pg/mL). However, fluticasone propionate administered via inhalation to rats did not induce teratogenicity at maternal toxic doses associated with exposures 13 times the human exposure achieved with the maximum recommended daily inhaled dose based on rat plasma level of 1430 pg/mL.
The non-CFC propellant, HFA134a, has been shown to have no toxic effect at very high vapor 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
The use of HFA 134a as a propellant has not altered the toxicity profile of fluticasone propionate compared to that using the conventional CFC propellant.
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