Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Chiesi Limited, 333 Styal Road, Manchester, M22 5LG, United Kingdom
Pharmacotherapeutic Group: Corticosteroids for local use
ATC Code: A07EA07
Clipper tablets contain beclometasone dipropionate (BDP), a pro-drug with weak glucocorticoid receptor binding affinity. BDP is hydrolysed via esterase enzymes to the active metabolite, beclometasone-17-monopropionate (B-17-MP), which has high topical anti-inflammatory activity (approximately thirty times the potency of BDP).
Scintigraphic study in healthy volunteers with Clipper demonstrated that tablets' integrity was maintained whilst the preparation resided within the stomach. Once in the small intestine, the tablets remained intact for a considerable period of time (57 to 118 minutes), before showing initial signs of disintegration. The prolonged release tablets core gradually eroded and a complete disintegration was achieved within 4 to 5 hours in the proximal colon and small intestine.
Effects on the pituitary-adrenal axis were evaluated in four clinical studies as well as in clinical pharmacology study conducted in ulcerative colitis patients. Even if serum morning cortisol level was influenced by the administration of Clipper Tablets, which lead to a suppression of the endogenous cortisol level at the end of treatment in a maximum of 25% of patients, no corticosteroid-related adverse drug reaction was reported during the limited treatment period of the clinical trials.
As treatment with Clipper Tablets lasts for no more than four weeks, the effect on HPA–axis could be considered as transient and a recovery of HPA function is expected to occur after withdrawal of the drug.
Beclometasone dipropionate (BDP) is very rapidly hydrolysed to its active metabolite (B-17-MP), via esterase enzymes found mostly in liver and lung tissues. In human serum and intestinal juices, B-17-MP is probably formed by pancreatine. Minor inactive metabolites, beclometasone-21-monopropionate (B-21-MP), and beclometasone (BOH), are also formed. The hydrolysis of BDP in the intestinal fluids was confirmed during a study aimed to quantitate BDP and its metabolites in ileostomy effluents of patients who had a terminal ileostom. Following intravenous dosing, the disposition of BDP and B-17-MP are characterised by high plasma clearance (150 L per hour and 120 L per hour, respectively), with a small volume of distribution at steady state for BDP (20 L) and larger tissue distribution for B-17-MP (424 L). The terminal elimination half-lives are 0.5 hour and 2.7 hours for BDP and B-17-MP, respectively. Plasma protein binding is moderately high. The renal excretion of BDP and its metabolites is negligible. Faecal excretion is the major route of BDP elimination mainly as polar metabolites.
The pharmacokinetics of BDP and its active metabolite, B-17-MP after single and repeated oral administrations of Clipper was evaluated in ulcerative colitis disease patients. BDP levels were always under the limit of quantitation (<20 µg per ml). The maximum plasma concentration of B-17-MP obtained after two weeks treatment with Clipper 5 mg, once daily, appeared to be similar, ie. approximately 1 ng per ml, to the Cmax observed with a 1 mg dose of BDP administered by inhalation. The systemic availability of B-17-MP evaluated in comparison with an intravenous dose was about 20%.
Chronic toxicity studies with beclometasone dipropionate resulted in dose dependent effects typical of glucocorticoids.
Beclometasone dipropionate is non-genotoxic and no evidence of carcinogenicity was observed in rats.
Reproduction toxicity studies in animals have revealed teratogenic and embryo-foetal effects in mice and rabbits and an increased abortion rate and retarded uterine growth in monkeys.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
