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Pharmacology: BUSCOPAN exerts a spasmolytic action on the smooth muscle of the gastro-intestinal, biliary and genito-urinary tracts. As a quaternary ammonium derivative, hyoscine butylbromide does not enter the central nervous system. Therefore, anticholinergic side effects at the central nervous system do not occur. Peripheral anticholinergic action results from a ganglion-blocking action within the visceral wall as well as from an anti-muscarinic activity.
Pharmacokinetics: Absorption: As a quaternary ammonium compound, hyoscine butylbromide is highly polar and hence only partially absorbed following oral (8%) or rectal (3%) administration. After oral administration of single doses of hyoscine butylbromide in the range of 20 to 400 mg, mean peak plasma concentrations between 0.11 ng/mL and 2.04 ng/mL were found at approximately 2 hours. In the same dose range, the observed mean AUCO-tz-values varied from 0.37 to 10.7 ng h/mL.The median absolute bioavailabilities of different dosage forms, i.e. coated tablets, suppositories and oral solution, containing 100 mg of hyoscine butylbromide each were found to be less than 1%.
Distribution: Because of its high affinity for muscarinic receptors and nicotinic receptors, hyoscine butylbromide is mainly distributed on muscle cells of the abdominal and pelvic area as well as in the intramural ganglia of the abdominal organs. Plasma protein binding (albumin) of hyoscine butylbromide is approximately 4.4% Animal studies demonstrate that hyoscine butylbromide does not pass the blood-brain barrier, but no clinical data
to this effect is available. Hyoscine butylbromide (1 mM) has been observed to interact with the choline transport (1.4 nM) in epithelial cells of human placenta in vitro.
Metabolism and Elimination: Following oral administration of single doses in the range of 100 to 400 mg, the terminal elimination half-lives ranged from 6.2 to 10.6 hours. The main metabolic pathway is the hydrolytic cleavage of the ester bond. Orally administered hyoscine butylbromide is excreted in the faeces and in the urine. Studies in man show that 2 to 5% of radioactive doses is eliminated renally after oral, and 0.7 to 1.6% after rectal administration. Approximately 90% of recovered radioactivity can be found in the faeces after oral administration. The urinary excretion of hyoscine butylbromide is less than 0.1% of the dose. The mean apparent oral clearances after oral doses of 100 to 400 mg range from 881 to 1420 L/min, whereas the corresponding volumes of distribution for the same range vary from 6.13 to 11.3 x 105 L, probably due to very low systemic availability.
The metabolites excreted via the renal route bind poorly to the muscarinic receptors and are therefore not considered to contribute to the effect of the hyoscine butylbromide.
Toxicology:Acutely, hyoscine butylbromide has a low index of toxicity: oral LD50 values were 1000 - 3000 mg/kg in mice, 1040 - 3300 mg/kg in rats, and 600 mg/kg in dogs. Toxic signs were ataxia and decreased muscle tone, additionally, in mice tremor and convulsions, in dogs mydriasis, dry mucous membranes and tachycardia. Deaths from respiratory arrest occurred within 24 h. The intravenous LD50 values of hyoscine butylbromide were 10 - 23 mg/kg in mice and 18 mg/kg in rats.
In repeated oral dose toxicity studies over 4 weeks, rats tolerated 500 mg/kg = "no observed adverse effect level (NOAEL). At 2000 mg/kg, by the action on parasympathetic ganglia of visceral area, hyoscine butylbromide paralysed the gastrointestinal function resulting in obstipation. Eleven out of 50 rats died. Haematology and clinical chemistry results did not show dose related variations.
Over 26 weeks, rats tolerated 200 mg/kg, while at 250 and 1000 mg/kg, the gastrointestinal function was depressed and deaths occurred. The NOAEL for a 39-week oral (capsule) dog study was 30 mg/kg. The majority of clinical findings were attributable to acute effects of hyoscine butylbromide at high dosages (200 mg/kg). No adverse histopathological findings were observed.
A repeated intravenous dose of 1 mg/kg was well tolerated by rats in a 4-week study. At 3 mg/kg, convulsions occurred immediately after injection. Rats dosed with 9 mg/kg died from respiratory paralysis. Dogs treated intravenously over 5 weeks at 2 x 1, 2 x 3 and 2 x 9 mg/kg, showed a dose-dependent mydriasis in all treated animals, in addition at 2 x 9 mg/kg, ataxia, salivation and decreased body weight and food intake were observed. The solutions were locally well tolerated.
After repeated i.m. injection, the dose of 10 mg/kg was systemically well tolerated, but lesions of muscles at the site of injection were distinctly increased if compared to control rats. At 60 and 120 mg/kg, mortality was high and local damages were dose-dependently-increased.
Hyoscine butylbromide was neither embryotoxic nor teratogenic at oral doses of up to 200 mg/kg in the diet (rat) or 200 mg/kg by gavage or 50 mg/kg s.c. (rabbit). Fertility was not impaired at doses of up to 200 mg/kg p.o.
Like other cationic drugs, hyoscine butylbromide interacts with the choline transport system of human placental epithelial cells in vitro. Transfer of hyoscine butylbromide to the foetal compartment has not been proved.
Hyoscine butylbromide-suppositories were locally well tolerated.
In special studies concerning local tolerability, a repeated i.m. injection of 15 mg/kg BUSCOPAN over 28 days was studied in dogs and monkeys. Small focal necroses at the site of injection were seen only in dogs. BUSCOPAN was well tolerated in arteries and veins of the rabbit's ear. In vitro, 2 % BUSCOPAN injectable solution showed no haemolytic action when mixed with 0.1 ml human blood.
Hyoscine butylbromide revealed no mutagenic or clastogenic potential in the Ames test, in the in vitro gene mutation assay in mammalian V79 cells (HPRT test) and in an in vitro chromosome aberration test in human peripheral lymphocytes. In vivo, hyoscine butylbromide was negative in the rat bone marrow micronucleus assay.
There are no in vivo carcinogenicity studies. Nevertheless, hyoscine butylbromide did not show a tumorigenic potential in two oral 26-week-studies in rats given up to 1000 mg/kg.
