Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2022 Publisher: AbbVie Ltd., Maidenhead, SL6 4UB, UK
Pharmacotherapeutic group: Sympathomimetics in glaucoma therapy
ATC code: S01EA05
Brimonidine is an alpha2-adrenergic receptor agonist that is 1000-fold more selective for the alpha2-adrenoceptor than the alpha1-adrenoreceptor.
This selectivity results in no mydriasis and the absence of vasoconstriction in microvessels associated with human retinal xenografts.
Topical administration of brimonidine tartrate decreases intraocular pressure (IOP) in humans with minimal effect on cardiovascular or pulmonary parameters.
Limited data are available for patients with bronchial asthma showing no adverse effects.
Alphagan has a rapid onset of action, with peak ocular hypotensive effect seen at two hours post-dosing. In two 1 year studies, Alphagan lowered IOP by mean values of approximately 4-6 mmHg.
Fluorophotometric studies in animals and humans suggest that brimonidine tartrate has a dual mechanism of action. It is thought that Alphagan may lower IOP by reducing aqueous humour formation and enhancing uveoscleral outflow.
Clinical trials show that Alphagan is effective in combination with topical beta-blockers. Shorter term studies also suggest that Alphagan has a clinically relevant additive effect in combination with travoprost (6 weeks) and latanoprost (3 months).
After ocular administration of a 0.2% solution twice daily for 10 days, plasma concentrations were low (mean Cmax was 0.06 ng/ml). There was a slight accumulation in the blood after multiple (2 times daily for 10 days) instillations. The area under the plasma concentration-time curve over 12 hours at steady state (AUC0- 12h) was 0.31 ng·hr/ml, as compared to 0.23 ng·hr/ml after the first dose. The mean apparent half-life in the systemic circulation was approximately 3 hours in humans after topical dosing.
The plasma protein binding of brimonidine after topical dosing in humans is approximately 29%.
Brimonidine binds reversibly to melanin in ocular tissues, in vitro and in vivo. Following 2 weeks of ocular instillation, the concentrations of brimonidine in iris, ciliary body and choroid-retina were 3- to 17-fold higher than those after a single dose. Accumulation does not occur in the absence of melanin.
The significance of melanin binding in humans is unclear. However, no significant ocular adverse reaction was found during biomicroscopic examination of eyes in patients treated with Alphagan for up to one year, nor was significant ocular toxicity found during a one year ocular safety study in monkeys given approximately four times the recommended dose of brimonidine tartrate.
Following oral administration to man, brimonidine is well absorbed and rapidly eliminated. The major part of the dose (around 75% of the dose) was excreted as metabolites in urine within five days; no unchanged drug was detected in urine. In vitro studies, using animal and human liver, indicate that the metabolism is mediated largely by aldehyde oxidase and cytochrome P450. Hence, the systemic elimination seems to be primarily hepatic metabolism.
No great deviation from dose proportionality for plasma Cmax and AUC was observed following a single topical dose of 0.08%, 0.2% and 0.5%.
The Cmax, AUC, and apparent half-life of brimonidine are similar in the elderly (subjects 65 years or older) after a single dose compared with young adults, indicating that its systemic absorption and elimination are not affected by age.
Based on data from a 3 month clinical study, which included elderly patients, systemic exposure to brimonidine was very low.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.
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