THERAPEUTIC INDICATION

It is indicated for the lowering of intraocular pressure (lOP) in patient with open-angle glaucoma or ocular hypertension.

DOSAGE AND ADMINISTRATION

Posology

The recommended dose is one drop of Brimonidine Tartrate Eye Drops IP in the affected eye(s) three times daily, approximately 8 hours a part or as directed by the Physician.

Method of administration: For ocular use only.

Brimonidine Tartrate Eye Drops IP may be used concomitanty with other topical Ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic product is being used, the products should be administered at least 5 to 15 minutes apart.

To reduce possible systemic absorption, it is recommended that the lachrymal sac be compressed at the medial canthus (punctul occlusion) for one minute immediately after the instillation of each drop.

If a dose is missed, treatment should be continued with the next dose as planned. The dose should not exceed one drop in the affected eye(s) three times daily.

To prevent contamination of the dropper tip and solution, care must be taken no to touch the eyelids, surrounding areas or other surfaces with the dropper tip of the bottle. Instruct patients to keep the bottle tightly closed when not in use. Instruct the patient to shake the bottle well before use.

CONTRAINDICATION

Brimonidine Tartrate Eye Drops IP is contraindicated in patients with hypersensitivity to brimonidine tartrate or any component of this medication. If is also contraindicated in the following:

Patients receiving monoamine oxidase (MAO) inhibitor therapy.

Neonates and infants (under the age of 2 years)

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Potentiation of vascular insufficiency

Brimonidine may potentiate syndromes associated with vascular insufficiency. Brimonidine should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, or thromboangiitis obliterans.

Severe cardiovascular disease

Although Brimonidine Tartrate Eye Drops had minimal effect on the blood pressure of patients in clinical studies, caution should be exercised in treating patients with severe cardiovascular disease.

Contamination or topical ophthalmic products after use

There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface. 

General

Although brimonidine tartrate ophthalmic solution had minimal effect on the 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. Patients prescribed lOP-lowering medication should be routinely monitored for IOP.

DRUG INTERATIONS

Antihypertensives/Cardiac Glycosides

Because brimonidine may reduce blood pressure, caution in using drugs such as antihypertensives and/or cardiac glycosides with brimonidine, is advised.

CNS Depressants

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.

Tricyclic Antidepressants

Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic clonidine. Itis not known whether the concurrent use of these agents with Brimonidine in humans can lead to resulting interference with the lOP lowering effect. Caution is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines.

Monoamine Oxidase Inhibitors

Monoamine oxidase (MAO) inhibitors may theoretically interfere with the metabolism of brimonidine and potentially result in an increased systemic side-effect such as hypotension. Caution is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B: Teratogenicity studies have been performed in animals.

Brimonidine tartrate was not teratogenic when given orally during gestation days 6 through 15 in rats and days 6 through 18 in rabbits. The highest doses of brimonidine tartrate in rats (2.5 mg/kg/day) and rabbits (5.0 mg/kg/day) achieved AUC exposure values 360- and 20-fold higher, or 260- and 15-fold higher, respectively, than similar values estimated in humans treated with Brimonidine Tartrate Eye Drops IP 0.1% or 0.15%, 1 drop in both eyes three times daily.

There are no adequate and well controlled studies in pregnant women:however, in animal studies, brimonidine crossed the placenta and entered into the fetal circulation to a limited extent. Because animal reproduction studies are not always predictive of human response, Brimonidine Tartrate Eyee Drops IP should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether brimonidine tartrate is excreted in human milk, although in animal studies, brimonidine tartrate has been shown to be excreted in breast milk. Because of the potential for serious adverse reactions from Brimonidine Tartrate Eye Drops IP in nursing infants, 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

Brimonidine Tartrate Eye Drops IP is contraindicated in children under the age of 2 years. During postmarketing surveillance, apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in infants receiving brimonidine. The safety and effectiveness of brimonidine tartrate have not been studied in children below the age of 2 years. In a well-controlled clinical study conducted in pediatric glaucoma patients (ages 2 to 7 years) the most commonly observed adverse reactions 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 (>20 kg), somnolence appears to occur less frequently (25%). Approximately 16% of patients on Brimonidine Tartrate Eye Drops discontinued from the study due to somnolence.

Geriatric Use

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

In patients with hepatic impairment

Brimonidine Tartrate Eye Drops IP has not been studied in patients with hepatic impairment.

In patients with renal impairment

Brimonidine Tartrate Eye Drops IP has not been studied in patients with renal impairment. The effect of dialysis on brimonidine pharmacokinetics in patients with renal failure is not Known.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Brimonidine eye drops may cause fatigue and/or drowsiness which may impair the ability to drive or to use machinery. They may also cause blurred and/or abnormal vision, which may impair the ability to drive or to use machinery, especially at night or in reduced lighting. The patient should wait until these symptoms have cleared before driving or operating machinery.

UNDESIRABLE EFFECTS

Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of another drug cannot be compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Adverse reactions occurring in approximately 10-20% of the subjects receiving Brimonidine Tartrate Eye Drops IP (0.1-0.2%) included: allergic conjunctivitis, conjunctival hyperemia, and eye pruritus. Adverse reactions occurring in approximately 5-9% included: burning sensation, conjunctival folliculosis, hypertension, ocular allergic reaction, oral dryness, and visual disturbance.

Adverse reactions occurring in approximately 1-4% of the subjects receiving Brimonidine Tartrate Eye Drops IP (0.1-0.2%) included: abnormal taste, allergic reaction, asthenia, blepharitis, blepharoconjunctivitis, blurred vision, bronchitis, cataract, conjunctival edema, conjunctival hemorrhage, conjunctivitis, cough, dizziness, dsypepsiam dsypnea, epiphora, eye discharge, eye dryness, eye irritation, eye pain, eyelid edema, eyelid erythema, fatigue, flu syndrome, follicular conjunctivitis, foreign body sensation, gastrointestinal disorder, headache, hypercholesterolemia, hypotension, infection (primarily colds and respiratory infections), insomnia,keratitis, lid disorder, pharyngitis, photophobia, rash, rhinitis, sinus infection, sinusitis, somnolence, stinging, superficial punctate keratopathy, tearing, visual field defect, vitreous detachment, vitreous disorder, vitreous floaters, and worsened visual acuity.

The following reactions were reported in less than 1% of subjects: coneal erosion, hordeolum, nasal dryness, and taste perversion.

Postmarketing Experience

The following reactions have been identified during postmarketing use of brimonidine tartrate ophthalmic solutions in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to brimonidine tartrate ophthalmic solutions, or a combination of these factors, include: bradycardia, depression, hypersensitivity, iritis, keratoconjunctivitis sicca, miosis, nausea, skin reactions (including erythema, eyelid pruritus, rash, and vasodilation), syncope, and tachycardia. Apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in infants receiving brimonidine tartrate ophthalmic solutions.

OVERDOSE

Very limited information exists on accidental ingestion of brimonidine in adults; the only adverse reaction reported to date has been hypotension. Symptoms of brimonidine overdose have been reported in neonates, infants, and children receiving Brimonidine Tartrate Eye Drops IP as part of medical treatment of congenital glaucoma or by accidental oral ingestion.

Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway should be maintained.

PHARMACOLOGICAL PROPERTIES

Pharmacoovnamic properties

Pharmacotherapeutic Group: Sympathomimetics in glaucoma therapy.

Brimonidine is an alpha-2 adrenergic receptor agonist that is 1000-fold more selective for the alpha-2 adrenoceptor than the alpha-1 adrenoceptor. 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 in humans with minimal effect on cardiovascular or pulmonary parameters.

Limited data are available for patients with bronchial asthma showing no adverse effects. Brimonidine has a rapid onset of action, with peak ocular hypotensive effect seen at 2 hours a post-dosing. In two 1 year studies, brimonidine has been shown to lower intraocular pressure by mean values of approximately 4-6 mmHg.

Mechanism of Action

Brimonidine Tartrate Eye Drops IP is a relatively selective alpha-2 adrenergic receptor agonist with a peak ocular hypotensive effect occurring at two hours post-dosing.

Flourophotometric studies in animals and humans suggest that brimonidine tartrate has a dual mechanism of action. It is thought that it may lower intraocular pressure by reducing aqueous humour formation and enhancing uveoscleral outflow.

Pharmacokinetic properties

Absorption

After ocular administration of either a 0.1% or 0.2% solution, plasma concentrations peaked within 0.5 to 2.5 hours and declined with a systemic half-life of approximately 2 hours.

Distribution

The protein binding of brimonidine has not been studied.

Metabolism

In humans, brimonidine is extensively metabolized by the liver.

Excretion

Urinary excretion is the major route of elimination of brimonidine and its metabolites. Approximately 87% of an orally-administered radioactive dose of brimonidine was eliminated within 120 hours, with 74% found in the urine.

STORAGE AND HANDLING INSTRUCTIONS

Store below 25°C. Protect from light & moisture. Do not freeze.

Keep out of reach of children.

PATIENT COUNSELING INFORMATION

Patients should be instructed that ocular solutions, if handled improperly or if the tip of the dispensing container the eye or surrounding structures, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions. Always replace the cap after using. If solution changes color or becomes cloudy, do not use. Do not use the product after the expiration date marked on the bottle.

Patients also should be advised that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma or infection), they should immediately seek their physician’s advice concerning the continued use of the present multidose container.

If more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart. As with other similar medications, Brimonidine Tartrate Eye Drops IP 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.

PRESENTATION

BRIMOSOFT Eye Drops is available in 5ml pack.