Source: Health Products and Food Branch (CA) Revision Year: 2023
Benzodiazepines, such as chlordiazepoxide hydrochloride, act as depressants of the central nervous system, producing all levels of CNS depression from mild sedation to hypnosis to coma depending on the dose taken.
Anticholinergics, such as clidiniumbromide, inhibit the muscarinic actions of acetylcholine on structures innervated by postganglionic cholinergic nerves as well as on smooth muscles that respond to acetylcholine but lack cholinergic innervation. These postganglionic receptor sites are present in the autonomic effector cells of the smooth muscle, cardiac muscle, sinoatrial and atrioventricular nodes, and exocrine glands. Depending on the dose, anticholinergics may reduce the motility and secretory activity of the gastrointestinal system (see 7 WARNINGS AND PRECAUTIONS, Gastrointestinal).
Pharmacologic experiments have shown that chlordiazepoxide hydrochloride is a potent central nervous system depressant and muscle relaxant.
The dose which induces definite neurologic symptoms in various animal species is in the range of 10-40 mg/kg p.o.; effects on behaviour and aggression can be seen with administration of 1-3 mg/kg, p.o., in more sensitive tests. Hostile monkeys were made tame by oral doses which did not cause sedation but eliminated fear and aggression. The taming effect was further demonstrated in rats made vicious by lesions in the septal area in the brain.
Clidinium bromide is a quaternary ammonium compound with anticholinergic and antispasmodic activity. Clidinium bromide inhibits gastrointestinal motility and gastric secretions. As an anticholinergic agent, its activity approximates that of atropine sulfate against acetylcholine-induced spasms in isolated intestinal strips. In mice, oral administration proved it to be an effective antisialagogue in preventing pilocarpineinduced salivation. Spontaneous intestinal motility in both rats and dogs is reduced following oral dosing with 0.1 to 0.25 mg/kg.
Potent cholinergic ganglionic blocking effects (vagal) are produced with intravenous usage in anaesthetized dogs. Oral doses of 2.5 mg/kg to dogs produced signs of nasal dryness and slight pupillary dilation. In monkeys and rabbits, doses of 5 mg/kg p.o., given 3 times daily for 5 days did not produce apparent secretory or visual changes.
Chlordiazepoxide hydrochloride is well absorbed from the gastrointestinal tract within 1 to 2 hours. Metabolic studies in animals and man have indicated that oral chlordiazepoxide hydrochloride is rapidly absorbed from the gastro-intestinal tract.
Clidiniumbromide is poorly and very irregularly absorbed from the gastrointestinal tract. The action of clidinium bromide starts at about 1 hour after ingestion and lasts for approximately 3 hours.
Chlordiazepoxide hydrochloride is highly protein bound (96%).
Chlordiazepoxide hydrochloride and clidiniumbromideare both metabolized in the liver. Chlordiazepoxide hydrochloride is demethylated to a metabolite identified as Ro 5-0883, deaminated to the “lactam” Ro 5-2092 and finally converted to the “open lactam” which is pharmacologically inert and is excreted in the urine as such or in the form of alkali-labile conjugates. Repeated administration of 20 mg of chlordiazepoxide b.i.d. for 14 days to adult subjects produced serum levels of about 2 µg/mL of chlordiazepoxide, 1 µg/mL of the demethylated metabolite Ro 5-0883, and 1 µg/mL of the “lactam” Ro 5-2092.
The biological half-life for chlordiazepoxide hydrochloride is between 5 and 30 hours. In man, the half-life of chlordiazepoxide hydrochloride in plasma is 22-24 hours; in dogs 10-14 hours. Chlordiazepoxide hydrochlorideis eliminated by the kidneys and clidinium bromide by the kidneys and in the feces.
No microbiological information is required for this drug product.
The oral LD50 of single doses of chlordiazepoxide hydrochloride is 720±51 mg/kg, as determined in mice observed for a period of five days following dosage.
Chronic toxicity studies in rats, dogs, monkeys and chicken have shown that chlordiazepoxide hydrochloride did not exhibit specific organotoxic properties.
The oral LD50 of single doses of clidinium bromide is 860±57 mg/kg as determined in mice observed for a period of 5 days following dosage.
In rats, reproduction studies in which chlordiazepoxide hydrochloride was administered orally at doses of 10, 20, and 80 mg/kg/day showedno congenital anomalies, no effect on lactation or growth of the offspring.
However, at an oral dose of 100 mg/kg/day, there was observed a significant decrease in the fertilization rate and a marked decrease in the viability and body weight of the offspring which may be attributed to sedation of dams.
Studies in rats employing dosages of 2.5 and 10 mg/kg/day of clidinium bromide showed no significant effects on fertility, gestation, viability of off-spring, lactation, or fetal abnormalities.
In a rat reproductive study, oral daily doses were administered through two successive matings, in two concentrations of 2.5 mg/kg chlordiazepoxide hydrochloride with 1.25 mg/kg clidinium bromide, or 25 mg/kg chlordiazepoxide hydrochloride with 12.5 mg/kg clidinium bromide. No significant differences were noted between the control and treated groups, except a slight decrease in the number of animals surviving through lactation at the highest dosage in the first mating, and a slight decrease in the number of pregnant females and in the percentage of off-spring surviving until weaning in the second mating.
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