Mechanism of Action

Brimonidine tartrate is an alpha adrenergic receptor agonist. It has a peak ocular hypotensive effect occurring at two hours post-dosing. Fluorophotometric studies in animals and humans suggest that brimonidine tartrate has a dual mechanism of action by reducing aqueous humor production and increasing uveoscleral outflow.

Pharmacokinetics

After ocular administration of a 0.2% solution, plasma concentrations peaked within 1 to 4 hours and declined with a systemic half-life of approximately 3 hours. In humans, systemic metabolism of brimonidine is extensive. It is metabolized primarily by the liver. Urinary excretion is the major route of elimination of the drug and its metabolites. Approximately 87% of an orally- administered radioactive dose was eliminated within 120 hours, with 74% found in the urine.

Clinical Studies

Elevated IOP presents a major risk factor in glaucomatous field loss. The higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss. Brimonidine tartrate has the action of lowering intraocular pressure with minimal effect on cardiovascular and pulmonary parameters.

In comparative clinical studies with timolol 0.5%, lasting up to one year, the IOP lowering effect of brimonidine was approximately 4-6 mm Hg compared with approximately 6 mm Hg for timolol. In these studies, both patient groups were dosed BID, however, due to the duration of action of brimonidine, it is recommended that brimonidine be dosed TID. Eight percent of the subjects were discontinued from studies due to inadequately controlled intraocular pressure, which in 30% of these patients occurred during the first month of therapy. Approximately 20% were discontinued due to adverse experiences.

General

Although brimonidine had minimal effect on blood pressure of patients in clinical studies, caution should be exercised in treating patients with severe cardiovascular disease.

Brimonidine has not been studied in patients with hepatic or renal impairment; caution should be used in treating such patients.

Brimonidine should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension or thromboangiitis obliterans. During the studies there was a loss of effect in some patients. The IOP-lowering efficacy observed with brimonidine tartrate ophthalmic solution during the first month of therapy may not always reflect the long-term level of IOP reduction. Patients prescribed IOP-lowering medication should be routinely monitored for IOP.

Information for Patients

The preservative in brimonidine, benzalkonium chloride, may be absorbed by soft contact lenses. Patients wearing soft contact lenses should be instructed to wait at least 15 minutes after instilling brimonidine to insert soft contact lenses.

As with other drugs in this class, brimonidine may cause fatigue and/or drowsiness in some patients. Patients who engage in hazardous activities should be cautioned of the potential for a decrease in mental alertness.

Drug Interactions

Although specific drug interaction studies have not been conducted with brimonidine, the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anesthetics) should be considered. Alpha-agonists, as a class, may reduce pulse and blood pressure. Caution in using concomitant drugs such as beta-blockers (ophthalmic and systemic), antihypertensives and/or cardiac glycosides is advised.

Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic clonidine. It is not known whether the concurrent use of these agents with brimonidine in humans can lead to resulting interference with the IOP lowering effect. No data on the level of circulating catecholamines after brimonidine are available. Caution, however, is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No compound-related carcinogenic effects were observed in either mice or rats following a 21-month and 24-month study, respectively. In these studies, dietary administration of brimonidine tartrate at doses up to 2.5 mg/kg/day in mice and 1.0 mg/kg/day in rats achieved ~77 and 118 times, respectively, the plasma drug concentration estimated in humans treated with one drop brimonidine into both eyes 3 times per day.

Brimonidine tartrate was not mutagenic or cytogenic in a series of in vitro and in vivo studies including the Ames test, chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells, a host-mediated assay and cytogenic studies in mice, and dominant lethal assay.

Reproductive studies performed in rats with oral doses of 0.66 mg base/kg revealed no evidence of harm to the fetus due to brimonidine.

Pregnancy

Nursing Mothers

It is not known whether this drug is excreted in human milk; in animal studies brimonidine tartrate was excreted in breast milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

In a well-controlled clinical study conducted in pediatric glaucoma patients (ages 2 to 7 years) the most commonly observed adverse events with brimonidine tartrate ophthalmic solution 0.2% dosed three times daily were somnolence (50% - 83% in patients ages 2 to 6 years) and decreased alertness. In pediatric patients 7 years of age or older (>20 kg), somnolence appears to occur less frequently (25%). The most commonly observed adverse event was somnolence. Approximately 16% of patients on brimonidine tartrate ophthalmic solution discontinued from the study due to somnolence.

The safety and effectiveness of brimonidine have not been studied in pediatric patients below the age of 2 years. Brimonidine is not recommended for use in pediatric patients under the age of 2 years (see ADVERSE REACTIONS).

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and other adult patients.