Flixotide Mechanism of Action

Pharmacology: Pharmacodynamics: FLIXOTIDE given by inhalation at recommended doses has a potent glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma.
Clinical Studies: COPD: There is a significant reduction of symptoms of COPD and an improvement in lung function regardless of patient age, gender, lung base line function, smoking status or atopy status. This can result in a significant improvement in the quality of life.
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 fluticasone propionate (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-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 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).
Pharmacokinetics: Absorption: 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/Diskus (7.8%), fluticasone propionate Diskhaler (9.0%) and fluticasone propionate Evohaler (10.9%) respectively. 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 pre-systemic metabolism, resulting in oral availability of less than 1%. There is a linear increase in systemic exposure with increasing inhaled dose.
Distribution: Fluticasone propionate has a large volume of distribution at steady-state (approximately 300 l). Plasma protein binding is moderately high (91%).
Metabolism: 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. Care should be taken when co-administering known CYP3A4 inhibitors, as there is potential for increased systemic exposure to fluticasone propionate.
Elimination: 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 0.2%) and less than 5% as the metabolite.
Toxicology: Non-Clinical Information: Toxicology has shown only those class effects typical of potent corticosteroids, and these only at doses in excess of those 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 non-sensitising in animal models.
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.