Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Glaxo Wellcome UK Ltd, trading as GlaxoSmithKline UK, Stockley Park West, Uxbridge, Middlesex, UB11 1BT
Fluticasone propionate given by inhalation at recommended doses has a potent glucocorticoid anti-inflammatory action within the lungs, resulting in a reduction of both symptoms and exacerbations of asthma, with a lower incidence and severity of adverse effects than those 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 major congenital malformations following first trimester exposure to inhaled fluticasone propionate alone and salmeterol-fluticasone propionate combination relative to non- fluticasone propionate containing inhaled corticosteroids. No placebo comparator was included in this study.
Within the asthma cohort of 5362 first trimester inhaled corticosteroids -exposed pregnancies, 131 diagnosed major congenital malformations were identified; 1612 (30%) were exposed to fluticasone propionate or salmeterol-fluticasone propionate of which 42 diagnosed major congenital malformations were identified. The adjusted odds ratio for major congenital malformations diagnosed by 1 year was 1.1 (95%CI: 0.5–2.3) for fluticasone propionate exposed vs non-fluticasone propionate inhaled corticosteroids 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 major congenital malformations was identified following first trimester exposure to fluticasone propionate alone versus salmeterol-fluticasone propionate combination. Absolute risks of major congenital malformations across the asthma severity strata ranged from 2.0 to 2.9 per 100 fluticasone propionate -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 major congenital malformations events per 100 pregnancies).
In healthy subjects the mean systemic bioavailability of Flixotide Evohaler is 28.6%. In patients with asthma (FEV1 <75% predicted) the mean systemic absolute bioavailability was reduced by 62%. Systemic absorption occurs mainly through the lungs and has been shown to be linearly related to dose over the dose range 500 to 2000 micrograms. Absorption is initially rapid then prolonged and the remainder of the dose may be swallowed.
Absolute oral bioavailability is negligible (<1%) due to a combination of incomplete absorption from the GI tract and extensive first-pass metabolism.
87-100% of an oral dose is excreted in the faeces, up to 75% as parent compound. There is also a non-active major metabolite.
After an intravenous dose, fluticasone propionate is extensively distributed in the body. The very high clearance rate indicates extensive hepatic clearance.
Toxicology has shown only those class effects typical of potent corticosteroids, and these only at doses greatly 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 non-sensitising 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, HFA 134a, 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.
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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