Source: Health Products Regulatory Authority (ZA) Revision Year: 2024 Publisher: Umsebe Healthcare, 506 Sunclare Building, 21 Dreyer Street, Claremont, Cape Town, 7708, South Africa Name of Manufacturer: Sintetica SA
Pharmacological classification: 5.11 Others
Pharmacotherapeutic group: Parasympathomimetics, Anticholinesterases
ATC code: N07AA51
Glycopyrronium bromide is a quaternary ammonium anticholinergic agent. The quaternary ammonium moiety renders glycopyrronium bromide highly ionised at physiological pH and it thus penetrates the blood brain and placental barriers poorly. Glycopyrronium bromide, like other anticholinergic (antimuscarinic) agents, inhibits the action of acetylcholine on structures innervated by postganglionic, cholinergic nerves and on smooth muscles that respond to acetylcholine, but lack cholinergic innervation. These peripheral cholinergic receptors are present in the autonomic effector cells of smooth muscle, cardiac muscle, the sinoatrial node, the atrioventricular node, exocrine glands, and, to a limited degree, in the autonomic ganglia. Thus, it diminishes the volume and free acidity of gastric secretion and controls excessive pharyngeal, tracheal, and bronchial secretions.
Glycopyrronium bromide antagonises muscarinic symptoms (e.g. bronchorrhoea, bronchospasm, bradycardia, and intestinal hypermotility) induced by cholinergic medicines such as the anticholinesterases. Glycopyrronium bromide has a more gradual onset and longer duration of action than atropine.
Neostigmine metilsulphate is a quaternary ammonium anticholinesterase.
The combination of glycopyrronium bromide 0,5 mg/ml and neostigmine metilsulfate 2,5 mg/ml solution for injection is associated with less initial tachycardia and better protection against the subsequent cholinergic effects of neostigmine metilsulfate than a mixture of atropine and neostigmine metilsulfate.
In addition, residual central anticholinergic effects are minimised due to the limited penetration of glycopyrronium bromide into the central nervous system. Administration of glycopyrronium bromide with neostigmine metilsulfate is associated with greater cardiostability than administration of glycopyrronium bromide and neostigmine metilsulfate separately.
Glycopyrronium bromide and neostigmine metilsulfate are routinely administered simultaneously to reverse residual non-depolarising (competitive) neuromuscular block. Numerous clinical studies, which demonstrate this to be a safe and effective combination, have been published.
With intravenous injection, the onset of action is generally evident within one minute. Over 90% of the glycopyrronium bromide disappears from serum within 5 minutes following intravenous administration.
The pharmacokinetics of neostigmine metilsulfate are described in literature. In one study, following intravenous administration, the plasma concentration declined to about 8% of its initial value after 5 minutes with a distribution half-life of less than one minute.
The medicine is rapidly excreted into bile with the highest concentrations being found 30 to 60 minutes after dosing with some product being detected up to 48 hours after administration. Glycopyrronium bromide is also rapidly excreted into urine with the highest concentrations being found within 3 hours of administration. Over 85% of product is excreted within 48 hours. It has subsequently been confirmed in a single dose pharmacokinetic study using radioimmunological assay procedures that glycopyrronium bromide was rapidly distributed and/or excreted after intravenous administration. The terminal elimination phase was relatively slow with quantifiable plasma levels remaining up to 8 hours after administration. The elimination half-life was 1,7 hours.
The elimination half-life of neostigmine ranged from about 15 to 30 minutes. Trace amounts of neostigmine metilsulfate could be detected in the plasma after one hour. In a study in non-myasthenic patients, the plasma half-life was 0,89 hours.
Non-clinical data on glycopyrronium bromide or neostigmine metilsulfate reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
Effects attributable to the muscarinic receptor antagonist properties of glycopyrronium bromide included mild to moderate increases in heart rate in dogs, lens opacities in rats and, reversible changes associated with reduced glandular secretions in rats and dogs. Mild irritancy or adaptive changes in the respiratory tract were seen in rats. All these findings occurred at exposures sufficiently in excess of those anticipated in humans. Glycopyrronium was not teratogenic in rats or rabbits following inhalation administration.
Fertility and pre- and post-natal development were not affected in rats. Glycopyrronium bromide and its metabolites did not significantly cross the placental barrier of pregnant mice, rabbits and dogs. Glycopyrronium bromide (including its metabolites) was excreted into the milk of lactating rats and reached up to 10-fold higher concentrations in the milk than in the blood of the dam.
Genotoxicity studies did not reveal any mutagenic or clastogenic potential for glycopyrronium bromide. Carcinogenicity studies in transgenic mice using oral administration and in rats using inhalation administration revealed no evidence of carcinogenicity at systemic exposures (AUC) of approximately 53-fold higher in mice and 75-fold higher in rats than the maximum recommended dose of 44 micrograms once daily for humans.
In embryofoetal development studies, rats and rabbits were administered neostigmine metilsulfate at human equivalent doses (HED, on a mg/m basis) of 1,6, 4 and 8,1 mcg/kg/day 3,2, 8,1, and 13 mcg/kg/day, respectively, during the period of organogenesis (Gestation Days 6 through 17 for rats and Gestation Days 6 through 18 for rabbits). There was no evidence for a teratogenic effect in rats and rabbits up to HED 8,1 and 13 mcg/kg/day, in the presence of minimal maternal toxicity (tremors, ataxia, and prostration). The studies resulted in exposures in the animals well below predicted exposures in humans.
In a pre- and postnatal development study in rats, neostigmine metilsulfate was administered to pregnant female rats at human equivalent doses (HED) of 1,6, 4 and 8,1 mcg/kg/day from Day 6 of gestation through Day 20 of lactation, with weaning on Day 21. There were no adverse effects on physical development, behaviour, learning ability, or fertility in the offspring occurred at HED doses up 8,1 mcg/kg/day in the presence of minimal maternal toxicity (tremors, ataxia, and prostration). The studies resulted in exposures in the animals well below predicted exposures in humans.
In a fertility and early embryonic development study in rats, male rats were treated for 28 days prior to mating and female rats were treated for 14 days prior to mating with intravenous neostigmine metilsulfate (human equivalent doses of 1,6, 4, and 8,1 mcg/kg/day, based on body surface area). No adverse effects were reported at any dose.
Long-term animal studies have not been performed to evaluate the carcinogenic potential of neostigmine metilsulfate. Neostigmine metilsulfate was not genotoxic in the in vitro bacterial reverse mutation assay (Ames test), in the in vitro chromosome aberration assay, or the in vivo rat micronucleus assay.
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