Symptomatic treatment of irritable bowel syndrome (IBS) and painful, spastic states of distal parts of the intestinal tract (colon and rectum), for relief of abdominal pain, distension and motility disorders in patients older than 18 years old, caused by smooth muscle spasm of distal parts of the intestinal tract.

Pharmacological treatment of irritable bowel syndrome should be started with previously introduced non-pharmacological measures (change of life style, diet, emotional support, psychotherapy) if they did not bring the wanted therapeutic effect on their own.

Posology

Recommended single dose is one 40 mg tablet, recommended daily dose is 80-120 mg (1 tablet 2 to 3 times daily) Dosage is prescribed depending on the clinical picture and response to treatment, and in accordance with therapeutic guidelines for the treatment of irritable bowel syndrome.

Duration of treatment: there is no limitation, it depends on the disease course. Physicians should periodically assess the need for continued treatment.

Special populations

Patients with hepatic or renal impairment Dose adjustment is not necessary (see section 5.2).

Older people

Dose adjustment is not necessary.

Paediatric population

Clinical data on the use of otilonium bromide in paediatric patients below 18 years is limited, therefore this medicinal product is not recommended for use in this population.

Method of administration

Tablets should be swallowed whole, with a glass of water, preferably 20 minutes before meal.

Caution is needed when used in patients with glaucoma, prostatic hypertrophy and pyloric stenosis.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the lactase deficiency or glucose-galactose malabsorption should not take this medicine.

No interaction studies of otilonium bromide with other products were performed.

It seems that the effect of otilonium bromide on total time of gastrointestinal transit, at the recommended dose of 40 mg 2 or 3 times daily, is not relevant for the absorption of other, orally taken concomitant medicinal products .

There are no clinical data about the use of otilonium bromide in pregnant and lactating women. Animal studies did not show embryotoxic, teratogenic or mutagenic effects or reproductive or developmental toxicity- Like all drugs, DEBROMU should only be recommended to pregnant women and nursing mothers only if absolutely necessary and under close medical supervision.

DEBROMU has no or negligible influence on the ability to drive and use machines.

In the clinial trial conducted with otilonium bromide the drug was well tollerated, the reported adverse event are very few in number and superimposable to those reported in placebo/reference drug groups (see table below)

Tabulated list of adverse reactions collected during clinical trials

The frequency of adverse reactions occurring in patients treated with otilonium bromide is classified as follows: Common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100) and rare (>1/10,000 to <1/1,000)

During postmarketing surveillance, isolated reports on skin hypersensitivity reactions (urticaria, angioedema) have been received. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which, therefore is not known.

-      To report any side effect (s)

·    Saudi Arabia:

Otilonium bromide was proven practically devoid of toxicity in animals, used in doses that exceeded many times the usual pharmacological dose (please see section 5.3) . Therefore, also in man, no symptoms of overdose are expected. In case of overdose an appropriate symptomatic and supporting therapy is recommended.

Pharmacotherapeutic group: Synthetic anticholinergic agents, quaternary ammonium compounds, ATC code: A03AB06

Otilonium bromide is the prototype of a class of 2-aminoethyl-N-benzoylamino benzoate quaternary salts.

Pharmacodynamic effects

Otilonium bromide possesses an antispastic action on the smooth muscle of the distal part of the intestine (colon and rectum). It has this effect at doses that do not affect gastric secretion or produce typical atropine-like adverse effects.

Mechanism of action

Otilonium bromide acts predominantly by modifying Ca(2+) ion fluxes from cellular and extracellular sites and therefore reduces the trigger of contractile activity. It inhibits opening of L-type Ca-channels and Ca(2+) ions entry into intestinal smooth muscle cells. The additional pharmacodynamic effect is achieved by inhibition of tachykinin and muscarinic receptors

Clinical efficacy and safety

An extended analysis of a double-blind, placebo-controlled, 15-week study with otilonium bromide, conducted in 378 IBS patients (SpC1M study) showed that the rate of response to treatment within 2-4 months was significantly higher in the otilonium bromide group (36.9%) than in the placebo group (22.5%; P=0.007). In each month of treatment, the rate of monthly response was higher in the otilonium bromide group as compared to the placebo group (P < 0.05). The total monthly and weekly shares of population that responded to the treatment regarding single endpoints (intensity and frequency of pain and discomfort, meteorism/abdominal distension, severity of diarrhoea or constipation and mucus in the stool) were significantly bigger in the group treated with otilonium bromide than in the placebo- treated group, with differences of shares ranging from 10% to 20%. The subgroup analysis of the outcome of frequency of defecation and stool consistency indicates that patients with diarrhoea have an additional benefit. Safety findings about use of otilonium bromide were superimposable to those of placebo.

Otilonium bromide has been confirmed effective in a recent double-blind, placebo controlled large (n=356 IBS patients) clinical trial (OBIS study ) confirming its superiority to placebo in reducing the frequency of abdominal pain, severity of abdominal bloating and prevention from symptom relapse.

Otilonium bromide comes to the site of pharmacological effect probably directly through the intestinal wall, because the systemic absorption of the drug after oral administration is very low (3%). Therefore, its plasma concentration is low.

After oral use, high distribution of the drug in the smooth muscles of the colon and rectum has been described. Drug use shortly before the meal ensures pharmacologically effective local bioavailability of the product, on the site of therapeutic action and in time of the expected most prominent symptoms of the disease.

Otilonium bromide is not studied in patients with impaired renal and hepatic function. Since orally used otilonium bromide is very scarcely absorbed in systemic circulation, the effect of reduced hepatic and renal function on its local exposition is not expected.

Acute toxicity: no fatal cases were reported at oral doses of up to 1000 mg/kg in dogs, DL50 of orally used otilonium bromide in rats is 1500 mg/kg.

Chronic toxicity: animal studies showed no haematological or histological abnormalities at otilonium bromide doses of 80 mg/kg for 180 days.

Embriotoxicity: no embryotoxic and teratogenic effects were observed in rats and rabbits at doses of up to 60 mg/kg.

Genotoxicity: standard in vitro and in vivo non clinical tests have not shown any mutagenic potential of otilonium bromide.

Lactose hydrate

rice starch

sodium starch glycolate

magnesium stearate

hypromellose

titanium dioxide

macrogol 4000 and 6000 talc

Not known.

Do not store above 30°C

DEBROMU 40 mg tablets are packaged in blister pack as primary packaging and carton as secondary packaging.

Type of material

1)     Aluminium sheets spread with heat-sealing coating material for PVC/PVDC,

2)     Polyvinyl chloride sheets coated with polyvinylidene chloride (PVC/PVDC).

No special precautions.