Colofac

Colofac^® MR. Modified release capsule.

Mebeverine hydrochloride 200 mg.

For excipients, see section 6.1

Modified release capsule.

White, opaque, modified release capsule imprinted with “245”

For the symptomatic relief of irritable bowel syndrome.

Adults (including the elderly):

The capsules should be swallowed with a sufficient amount of water (at least 100 ml water). They should not be chewed because the coating is intended to ensure a prolonged release mechanism (see 5.2).

One capsule of 200 mg twice daily, to be given one in the morning and one in the evening.

Paediatric Population

Mebeverine 200 mg modified release capsules are not recommended for use in children and adolescents below 18, due to insufficient data on safety and efficacy.

Duration of use is not limited.

If one or more doses are missed, the patient should continue with the next dose as prescribed; the missed dose(s) should not be taken in addition to the regular dose.

Special Population

No posology studies in elderly, renal and/or hepatic impaired patients have been performed. No specific risk for elderly, renal and/or hepatic impaired patients could be identified from available post-marketing data. No dosage adjustment is deemed necessary in elderly, renal and/or hepatic impaired patients.

Hypersensitivity to the active substance or to any of the excipients.

None

No interaction studies have been performed, except with alcohol. In vitro and in vivo studies in animals have demonstrated the absence of any interaction between mebeverine hydrochloride and ethanol.

Pregnancy

There are no or limited amounts of data from the use of mebeverine in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). mebeverine is not recommended during pregnancy.

Lactation

It is unknown whether mebeverine or its metabolites are excreted in human milk. The excretion of mebeverine in milk has not been studied in animals. Mebeverine should not be used during breast-feeding.

Fertility

There are no clinical data on male or female fertility; however, animal studies do not indicate harmful effects of mebeverine (see section 5.3).

No studies on the effects on the ability to drive and use machines have been performed. The pharmacodynamic and pharmacokinetic profile as well as postmarketing experience do not indicate any harmful effect of mebeverine on the ability to drive or to use machines

The following adverse reactions have been reported spontaneously during postmarketing use. A precise frequency cannot be estimated from available data.

Allergic reactions mainly but not exclusively limited to the skin have been observed.

Immune system disorders:

Hypersensitivity (anaphylactic reactions)

Skin and subcutaneous tissue disorders:

Urticaria, angioedema, face oedema, exanthema.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Theoretically CNS excitability may occur in cases of overdose. In cases where mebeverine was taken in overdose, symptoms were either absent or mild and usually rapidly reversible. Observed symptoms of overdose were of a neurological and cardiovascular nature.

No specific antidote is known and symptomatic treatment is recommended.

Gastric lavage should only be considered in case of multiple intoxication or if discovered within about one hour. Absorption reducing measures are not necessary.

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.

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.

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.

Capsule content Modified release granules:

Magnesium stearate, polyacrylate dispersion 30%, talc, hypromellose, methacrylic-acid ethyl acrylate copolymer 1:1 dispersion 30%, glycerol triacetate

Capsule shell:

Gelatine, titanium dioxide (E171), printing inks: shellac (E904), black iron oxide (E172), propylene glycol, concentrated ammonia solution, potassium hydroxide.

Not applicable.

3 years when stored in the original container.

Do not store above 30°C.

Do not refrigerate or freeze.

Store in the original package.

Boxes containing 10 or 60 capsules in PVC-Al press through strips.

None.

Mylan Products Ltd.

20 Station Close

Potters Bar

Herts

EN6 1TL

United Kingdom

PL 46302/0023

14/08/1998 / 04/07/2003

26 August 2016