4.1 Neonates and Infants (under the age of 2 years)

ALPHAGAN® P is contraindicated in neonates and infants (under the age of 2 years).

4.2 Hypersensitivity Reactions

ALPHAGAN® P is contraindicated in patients who have exhibited a hypersensitivity reaction to any component of this medication in the past.

5.1 Potentiation of Vascular Insufficiency

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

5.2 Severe Cardiovascular Disease

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.

5.3 Contamination of 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 (see PATIENT COUNSELING INFORMATION, 17).

6.1 Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly 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 ophthalmic solution (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 ophthalmic solution (0.1-0.2%) included: abnormal taste, allergic reaction, asthenia, blepharitis, blepharoconjunctivitis, blurred vision, bronchitis, cataract, conjunctival edema, conjunctival hemorrhage, conjunctivitis, cough, dizziness, dyspepsia, dyspnea, 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: corneal erosion, hordeolum, nasal dryness, and taste perversion.

6.2 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.

7.1 Antihypertensives/Cardiac Glycosides

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

7.2 CNS Depressants

Although specific drug interaction studies have not been conducted with ALPHAGAN® P, the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anesthetics) should be considered.

7.3 Tricyclic Antidepressants

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 ALPHAGAN® P in humans can lead to resulting interference with the IOP lowering effect. Caution is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines.

7.4 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.

8.1 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 ALPHAGAN® P 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, ALPHAGAN® P should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

8.3 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 ALPHAGAN® P 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.

8.4 Pediatric Use

ALPHAGAN® P is contraindicated in children under the age of 2 years (see CONTRAINDICATIONS, 4.1). 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 ophthalmic solution discontinued from the study due to somnolence.

8.5 Geriatric Use

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

8.6 Special Populations

ALPHAGAN® P has not been studied in patients with hepatic impairment.

ALPHAGAN® P has not been studied in patients with renal impairment. The effect of dialysis on brimonidine pharmacokinetics in patients with renal failure is not known.

12.1 Mechanism of Action

ALPHAGAN® P is a relatively selective alpha-2 adrenergic receptor agonist with 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.

12.3 Pharmacokinetics

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.

13.1 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 mg/kg/day in rats achieved 150 and 120 times or 90 and 80 times, respectively, the plasma Cmax drug concentration in humans treated with one drop of ALPHAGAN® P 0.1% or 0.15% into both eyes 3 times per day, the recommended daily human dose.

Brimonidine tartrate was not mutagenic or clastogenic in a series of in vitro and in vivo studies including the Ames bacterial reversion test, chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells, and three in vivo studies in CD-1 mice: a host-mediated assay, cytogenetic study, and dominant lethal assay.

Reproduction and fertility studies in rats with brimonidine tartrate demonstrated no adverse effect on male or female fertility at doses which achieve up to approximately 125 and 90 times the systemic exposure following the maximum recommended human ophthalmic dose of ALPHAGAN® P 0.1% or 0.15%, respectively.