AUROBEVERINE Modified-release capsule, hard Ref.[7479] Active ingredients: Mebeverine

Source: Medicines & Healthcare Products Regulatory Agency (GB)  Revision Year: 2019  Publisher: Milpharm Limited, Ares Block, Odyssey Business Park, West End Road, Ruislip HA4 6QD, United Kingdom

Pharmacodynamic properties

Pharmacotherapeutic group: Synthetic anticholinergics, esters with tertiary amino group
ATC code: A03AA04

Mechanism of action and pharmacodynamics effects

Mebeverine is a musculotropic antispasmodic with a direct action on the smooth muscle of the gastrointestinal tract, relieving spasm without affecting normal gut motility. Since the autonomic nervous system is not involved in this mechanism of action, typical systemic anticholinergic side-effects are absent.

Clinical efficacy and safety

All formulations of mebeverine were generally safe and well tolerated in the recommended dose regimen.

Pharmacokinetic properties

Absorption

Mebeverine is rapidly and completely absorbed after oral administration of tablets. The modified release formulation permits a twice daily dosing scheme.

Distribution

No significant accumulation occurs after multiple doses.

Biotransformation

Mebeverine hydrochloride is mainly metabolised by esterases, initially splitting the ester bonds into veratric acid and mebeverine alcohol. The main metabolite in plasma is DMAC (Demethylated carboxylic acid). The steady state elimination half-life of DMAC is 5.77h. During multiple dosing (200 mg b.i.d.) the Cmax of DMAC is 804 ng/ml and tmax is about 3 hrs. The relative bioavailability of the modified release capsule appears to be optimal with a mean ratio of 97%.

Elimination

Mebeverine is not excreted as such, but metabolised completely; the metabolites are excreted nearly completely. Veratric acid is excreted into the urine; mebeverine alcohol is also excreted into the urine, partly as the corresponding carboxylic acid (MAC) and partly as the demethylated carboxylic acid (DMAC).

Paediatric population

No pharmacokinetic studies have been performed in children under 10 years old.

Preclinical safety data

Effects in repeat-dose toxicity studies, after oral and parenteral doses, were indicative of central nervous involvement with behavioural excitation, mainly tremor and convulsions. In the dog, the most sensitive species, these effects were seen at oral doses equivalent to 3 times the maximum recommended clinical dose of 400 mg/day based on body surface area (mg/m²) comparisons.

The reproductive toxicity of mebeverine was not sufficiently investigated in animal studies.

There was no indication of teratogenic potential in rats and rabbits. However, embryotoxic effects (reduction in litter size, increased incidence of resorption) were noticed in rats at doses equivalent to twice the maximum daily clinical dose. This effect was not observed in rabbits. No effects on male or female fertility were noted in rats at doses equivalent to the maximum clinical dose.

In conventional in vitro and in vivo genotoxicity tests mebeverine was devoid of genotoxic effects. No carcinogenicity studies have been performed.

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