Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2016 Publisher: Mylan Products Ltd., 20 Station Close, Potters Bar, Herts, EN6 1TL, United Kingdom
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.
All formulations of mebeverine were generally safe and well tolerated in the recommended dose regimen.
The safety and efficacy of the product has only been evaluated in adults.
Mebeverine is rapidly and completely absorbed after oral administration of tablets.
No significant accumulation occurs after multiple doses.
Mebeverine hydrochloride is mainly metabolized by esterases, which split the ester bonds into veratric acid and mebeverine alcohol firstly.
The main metabolite in plasma is DMAC (demethylated carboxylic acid).
The steady state elimination half-life of DMAC is 2.45 h. During multiple dosing Cmax of DMAC for the coated tablets with 135 mg is 1670 ng/ml and tmax is 1 h.
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).
The safety and efficacy of the product has only been evaluated in adults.
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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