COLOFAC Modified release capsule Ref.[27745] Active ingredients: Mebeverine

Source: Medicines & Healthcare Products Regulatory Agency (GB)  Revision Year: 2016  Publisher: Mylan Products Ltd., 20 Station Close, Potters Bar, Herts, EN6 1TL, United Kingdom

5.1. Pharmacodynamic properties

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

Mebeverine is a musculotropic antispasmodic with a direct action on the smooth muscle of the gastrointestinal tract, without affecting normal gut motility. The exact mechanism of action is not known, but multiple mechanisms, such as a decrease in ion channel permeabilities, blockade of noradrenaline reuptake, a local anesthetic effect, changes in water absorption as well as weak anti-muscarinergic and phosphodiesterase inhibitory effect might contribute to the local effect of mebeverine on the gastrointestinal tract. Systemic side-effects as seen with typical anti-cholinergics are absent."

Clinical efficacy and safety

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

Paediatric population

The efficacy and safety of the product has only been evaluated in adults.

5.2. 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 metabolized 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

The safety and efficacy of the product has only been evaluated in adults.

5.3. 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 400mg/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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