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 daily dose is one tablet of 40 mg two to three times per day (80-120 mg 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).

Elderly

Dose adjustment is not necessary.

Paediatric population

The safety and efficacy of otilonium bromide in patients below 18 years have not been established, therefore this medicinal product is not recommended for use in this population.

Method of administration

Tablet should be swallowed whole, with a glass of water, preferably 20 minutes before meal (see section 4.4).

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

Tablet should be swallowed whole, with a glass of water. If the tablet is kept in the mouth or taken without water or with a limited amount of water, local reactions like irritation and pain in the throat, difficulty in swallowing and damage of mucosa in mouth and/or throat may occur.

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

This medicine contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially ‘sodium-free’.

No interaction studies of otilonium bromide with other products have been 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.

Pregnancy

There are no clinical data about the use of otilonium bromide in pregnant women.

Animal studies did not show embryotoxic, teratogenic or mutagenic effects or reproductive or developmental toxicity (see section 5.3).

Breast-feeding

There are no clinical data on the use of otilonium bromide in lactating women.

As a precautionary measure, it is preferable to avoid the use of DEBROMU during pregnancy and breast-feeding. DEBROMU should only be given to pregnant women and nursing mothers only if absolutely necessary and under close medical supervision.

Fertility

There are no data on the effect of otilonium bromide on human fertility. No effects on fertility have been observed in animal studies with female and male rats.

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

Tabulated list of adverse reactions collected during clinical trials and post marketing monitoring

The frequency of adverse reactions occurring in patients treated with otilonium bromide is classified as follows:

Very common (≥1/10)

Common (≥1/100 to <1/10)

Uncommon (≥1/1,000 to <1/100)

Rare (≥1/10,000 to <1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

*Reports from post-marketing surveillance

Description of selected adverse reaction

During post-marketing surveillance, one serious case of anticholinergic effects was reported after use of this medicine. In the concerned case urinary retention, constipation and hypohidrosis symptoms that required hospitalization were reported.

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.

To report any side effect(s):

• Saudi Arabia:

• Other GCC States:

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.

Mechanism of action

Otilonium bromide acts predominantly by modifying Ca(2+) ion fluxes from cellular and extracellular sites and reduces  activation of contraction and visceral pain,  through the inhibition of L-type and T-type Ca-channels on intestinal smooth muscle cells, and enteric sensory neurons, respectively.

Additional pharmacological effect is exerted through the interaction with tachykinin and muscarinic receptors in the colon.

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.

Clinical efficacy and safety

An extended analysis of a double-blind, placebo-controlled, 15-week study with otilonium bromide used 3 times daily in a 40 mg dose, conducted in 325 IBS patients (SpC1M study) showed that the rate of response to treatment within 2 to 4 months was significantly higher in the otilonium bromide group  than in the placebo group (36.9 % vs. 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, even when the first month of treatment is included in the analysis (P < 0.05). The total monthly and weekly shares of population that responded to the treatment regarding single endpoints (intensity and frequency of pain, meteorism/abdominal distension, severity of diarrhoea or constipation, number of evacuations and mucus in the stool) were significantly bigger in the group treated with otilonium bromide in regards to 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 double-blind, placebo-controlled clinical trial (OBIS study ) conducted in 356 IBS patients confirming its superiority to placebo in reducing the frequency of abdominal pain, severity of abdominal bloating and prevention from symptom relapse.

Absorption

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.

Distribution

After oral use, high distribution of the drug in the smooth muscles of the colon and rectum has been described. Drug used 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.

Renal and hepatic impairment

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.

Non-clinical data reveal no special hazard for humans based on conventional studies of acute toxicity, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and development.

Otilonium bromide does not produce significant reproductive or developmental toxicity; the mild effect observed on the progeny in the rabbit study at 60 mg/kg / day (slight decreased body weight of female newborns) does not likely represent a direct toxicity of otilonium bromide on fetuses, as this effect was associated with a reduction of maternal food intake and an increase in the number of newborns.  A marginal delayed delivery was also observed in a study on peri- and postnatal developmental toxicity at 60 mg/kg/day, but this had no effects on newborns.

Environmental Risk Assessment

Environmental risk assessment studies have shown that otilonium bromide may pose a risk for soils (see section 6.6 for a correct disposal).

Tablet core:

rice starch

lactose hydrate

sodium starch glycolate

magnesium stearate

Film coat:

hypromellose

titanium dioxide (E 171)

macrogol 4000

macrogol 6000

talc

Not applicable

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).

This medicinal product may pose a risk to the environment (see section 5.3). Any unused medicinal product or waste material should be disposed of in accordance with local requirements.