Source: Medicines Authority (MT) Revision Year: 2021 Publisher: A. Menarini Industrie Farmaceutiche Riunite Srl, Via Sette Santi 3, 50131 Florence, Italy
Pharmacotherapeutic group: synthetic anticholinergics, quaternary ammonium compounds
ATC code: A03AB06
Otilonium bromide is the prototype of a class of 2-aminoethyl-N-benzoylamino-benzoate quaternary salts.
Otilonium bromide is endowed with a marked spasmolytic action on the smooth muscle of the digestive tract.
Otilonium Bromide acts predominantly by modifying Ca2+ ion fluxes from cellular and extracellular sites and therefore reduces the trigger of contractile activity and visceral pain, most likely through the inhibition of L- and T-type Ca-channels into intestinal smooth muscle cells and peripheral sensory neurons, respectively. Additionally pharmacological effects could be exerted through the interaction with NK1 and NK2 tachykinin receptors.
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.
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 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 muscle 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.
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.
Otilonium bromide displayed low oral toxicity, as the lowest lethal oral doses were 900 and 1250 mg/kg in rats and mice, respectively, whereas no mortalities were observed in dogs up to 1000 mg/kg.
No signs of toxicity, including alterations of hematochemical and histological exams, were observed in dogs orally dosed up to 80 mg/kg/day for 26 weeks.
No mutagenic or clastogenic effects have been observed in standard in vitro or in vivo tests performed.
No effects have been observed in long-term studies carried out in mice (87 weeks) and rats (104 weeks) up to doses of 300 mg/kg/day.
No effects on fertility, and no embryotoxic, fetotoxic, teratogenic or developmental effects have been observed in rats up to 60 mg/kg/day. Likewise, no teratogenic, embryotoxic or fetotoxic effects have been detected at this dose in rabbits (see Section 4.6).
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