Alphagan (Brimonidine Tartrate)



Brimonidine Tartrate

Elevated Intraocular Pressure Therapy

Action And Clinical Pharmacology: Mechanism of Action: Brimonidine is a relatively selective alpha adrenergic receptor agonist that in radioligand binding assays and in functional assays, is approximately 1 000 times more selective for the alpha-2 adrenoceptor than the alpha-1 adrenoceptor. This selectivity results in the absence of vasoconstriction in microvessels associated with human retinal xenografts.

Topical administration of brimonidine decreases intraocular pressure (IOP) in humans. When used as directed, brimonidine ophthalmic solution reduces elevated IOP with minimal effect on cardiovascular parameters.

Brimonidine has a rapid onset of action, with the peak ocular hypotensive effect occurring at approximately 2 hours post-dosing. The duration of effect is 12 hours or greater.

Fluorophotometric studies in animals and humans suggest that brimonidine has a dual mechanism of action. Brimonidine lowers IOP by reducing aqueous humor production and increasing uveoscleral outflow.

Pharmacodynamics: Brimonidine has no effect on pulmonary function or exercise-induced tachycardia. The cardiovascular effects of brimonidine during exercise in normal volunteers were found to be limited to a slight suppression of systolic blood pressure, which was clinically insignificant, during the recovery period following a treadmill test.

Pharmacokinetics: After ocular administration of brimonidine 0.2% twice daily (both eyes) in humans for 10 days, plasma concentrations were low (mean Cmax=0.06 ng/mL). Plasma brimonidine levels peaked within 1 to 4 hours and declined with a systemic half-life of approximately 3 hours.

In humans, brimonidine is eliminated rapidly via extensive systemic metabolism; there is no marked systemic accumulation after multiple dosing. 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 in the first 96 hours.

Clinical Studies: Brimonidine lowers intraocular pressure with minimal effect on cardiovascular parameters (heart rate, systolic and diastolic blood pressure) and no apparent effect on pulmonary parameters (spirometry, respiratory rate).

The long-term efficacy of brimonidine 0.2% dosed b.i.d. was demonstrated in two 1-year multicenter studies in subjects with open angle glaucoma or ocular hypertension. In these trials brimonidine 0.2% lowered IOP by mean values of 4.3 mm Hg at trough and 6.7 mm Hg at peak. IOP decreases were maintained for the duration of the studies in the majority of patients; no tachyphylaxis was observed. Nine percent of subjects were discontinued from the studies due to inadequately controlled intraocular pressure.

Indications And Clinical Uses: For the control of intraocular pressure in patients with chronic open-angle glaucoma or ocular hypertension.

Contra-Indications: Patients with hypersensitivity to brimonidine or any component of this medication. It is also contraindicated in patients receiving monoamine oxidase (MAO) inhibitor therapy.

Manufacturers’ Warnings In Clinical States: For topical ophthalmic use only.

Children: The use of brimonidine in pediatric patients is currently not recommended. Several serious adverse reactions have been reported in association with the administration of brimonidine to infants in the age range of 28 days to 3 months (see Adverse Effects).

Precautions: General: Brimonidine ophthalmic solution 0.2% should be used with caution in patients with known hypersensitivity to other alpha-adrenoceptor agonists.

Although brimonidine had minimal effect on blood pressure and heart rate 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 exercised 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.

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.

Brimonidine did not have clinically significant effects on pulse and blood pressure in chronic clinical studies. However, since alpha-agonists, as a class, may reduce pulse and blood pressure, caution in the concomitant use of drugs such as beta-blockers (ophthalmic and/or 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 can lead to an interference in IOP lowering effect. No data are available on the level of circulating catecholamines after brimonidine is instilled. 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 21-month and 2-year studies in mice and rats given oral doses of 2.5 mg base/kg/day and 1.0 mg base/kg/day, respectively. These oral doses are approximately 830 and 330 times greater, respectively, than the maximum recommended human daily ophthalmic dosage for brimonidine (0.003 mg base/kg/day) based on a 60 kg human.

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

Pregnancy: Teratogenicity studies showed no adverse effects in rats and rabbits when oral doses (1.65 mg base/kg/day and 3.33 mg base/kg/day) were administered at approximately 550 and 1 110 times, respectively, the maximum recommended human daily ophthalmic dosage for brimonidine (based on a 60 kg human).

There are no studies of brimonidine in pregnant women; however, in animal studies, brimonidine crossed the placenta and entered into the fetal circulation to a limited extent (ratio of drug-related material in fetal:maternal blood = 0.1 to 0.3). Drug-derived material was eliminated from fetal tissues by 24 hours postdose. Brimonidine should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Lactation : It is not known whether brimonidine is excreted in human milk; although in animal studies, brimonidine has been shown to be excreted in breast milk. During treatment with brimonidine, 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.

Children: The use of brimonidine in pediatric patients is currently not recommended. Several serious adverse reactions have been reported in association with the administration of brimonidine ophthalmic solution to infants in the age range of 28 days to 3 months (see Adverse Effects).

Information to be Provided to the Patient: Occupational Hazards: Brimonidine, as with other similar medications, can potentially 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.

The preservative in Alphagan, 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 the product to insert soft contact lenses.

Adverse Reactions: In clinical studies including 717 patients on brimonidine, the most frequently reported adverse events were oral dryness [25.8%], ocular hyperemia [24.8%], burning and stinging [22.5%], blurring [17.3%], headache [16.3%], foreign body sensation [15.5%], fatigue/drowsiness [15.2%], corneal staining/erosion [10.0%], ocular allergic reactions [9.9%], and ocular pruritus [9.8%], and conjunctival follicles [9.6%].

Events occurring less frequently included photophobia [7.4%], ocular dryness [7.0%], eyelid erythema [6.1%], ocular ache/pain [6.0%], upper respiratory symptoms [6.0%], tearing [5.6%], conjunctival edema [5.3%], eyelid edema [4.9%], dizziness [4.2%], conjunctival blanching [3.8%], blepharitis [3.6%], ocular irritation [3.1%], gastrointestinal symptoms [3.1%], asthenia [2.8%], abnormal vision [2.6%], abnormal taste [1.4%], conjunctival discharge [1.4%] conjunctival papillae [1.0%], and nasal dryness [1.0%].

Serious Reports of Adverse Reactions in Pediatric Patients: Several serious adverse reactions have been reported in association with the administration of brimonidine ophthalmic solution to infants in the age range of 28 days to 3 months. These reactions included: bradycardia, hypotension, hypothermia, hypotonia, apnea, dyspnea, hypoventilation, cyanosis and lethargy resulting in hospitalization. Upon discontinuation of brimonidine the infants recovered without sequelae.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: No data are available on overdosage of brimonidine ophthalmic solution in humans. Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway should be maintained. Evacuation of the stomach should be considered during the first few hours after an overdosage.

Dosage And Administration: The recommended dose is 1 drop of ophthalmic solution in the affected eye(s) twice daily (doses taken approximately 12 hours apart).

Availability And Storage: Each mL of sterile ophthalmic solution contains: brimonidine tartrate 2 mg (0.2%). Nonmedicinal ingredients: benzalkonium chloride (as preservative), citric acid, hydrochloric acid and/or sodium hydroxide (to adjust pH), polyvinyl alcohol, purified water, sodium chloride and sodium citrate. White, opaque plastic dropper bottles of 5 and 10 mL with C Cap Compliance Cap b.i.d. (twice daily). Store at 15 to 25°C.

ALPHAGAN™ Allergan Brimonidine Tartrate Elevated Intraocular Pressure Therapy

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