4.1       Neonates and Infants (Pediatric Patients Younger than 2 Years Old)

Brimonidine tartrate ophthalmic solution 0.1% and 0.15% is contraindicated in neonates and infants (pediatric patients younger than 2 years old) [see Use in Specific Populations (8.4)].

4.2       Hypersensitivity Reactions

Brimonidine tartrate ophthalmic solution 0.1% and 0.15% 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

Brimonidine tartrate ophthalmic solution 0.1% and 0.15% may potentiate syndromes associated with vascular insufficiency. Brimonidine tartrate ophthalmic solution 0.1% and 0.15% 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. Do not touch the tip of the dispensing container to the eye or surrounding structures. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions [see Patient Counseling Information (17)].

6.1       Clinical Trials Experience

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

Adverse reactions occurring in approximately 10% to 20% of the subjects receiving brimonidine ophthalmic solution (0.1% to 0.2%) included: allergic conjunctivitis, conjunctival hyperemia, and eye pruritus. Adverse reactions occurring in approximately 5% to 9% included: burning sensation, conjunctival folliculosis, hypertension, ocular allergic reaction, oral dryness, and visual disturbance.

Adverse reactions occurring in approximately 1% to 4% of the subjects receiving brimonidine ophthalmic solution (0.1% to 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 postapproval use of brimonidine tartrate ophthalmic solutions. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Bradycardia, depression, hypersensitivity, iritis, keratoconjunctivitis sicca, miosis, nausea, skin reactions (including erythema, eyelid pruritus, rash, and vasodilation), syncope, and tachycardia.
  
• Apnea, 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 brimonidine tartrate ophthalmic solution 0.1% and 0.15% may reduce blood pressure, caution in using drugs such as antihypertensives and/or cardiac glycosides with brimonidine tartrate ophthalmic solution 0.1% and 0.15% is advised.

7.2       CNS Depressants

Although specific drug interaction studies have not been conducted with brimonidine tartrate ophthalmic solution 0.1% and 0.15%, 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 brimonidine tartrate ophthalmic solution 0.1% and 0.15% 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

Risk Summary

There are no adequate and well-controlled studies with brimonidine tartrate ophthalmic solution 0.1% and 0.15% in pregnant women. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

In animal studies, brimonidine crossed the placenta and entered into the fetal circulation to a limited extent (see Data). Because animal reproduction studies are not always predictive of human response, brimonidine tartrate ophthalmic solution 0.1% and 0.15% should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Data

Human Data

Limited available data from postmarketing safety reports and published literature with topical use of brimonidine ophthalmic solution in pregnant women are insufficient to inform a drug-associated risk of pregnancy-related adverse outcomes including miscarriage, stillbirth, congenital anomaly, and events experienced by offspring while breastfeeding.

Animal Data

Embryofetal studies were conducted in pregnant rabbits administered brimonidine tartrate by daily oral gavage on gestation days 6 to 18, to target the period of organogenesis. Brimonidine caused miscarriage at 5 mg/kg/day (approximately 70- or 50-times the recommended human ophthalmic dose [RHOD] based on AUC, respectively for brimonidine tartrate 0.1% and 0.15%). The no observed adverse effect level (NOAEL) for developmental toxicity in rabbits was 1 mg/kg/day (approximately 9- and 6-fold the RHOD based on AUC, respectively for brimonidine tartrate 0.1% and 0.15%). No treatment-related malformations were observed in rabbits. Signs of maternal sedation and fatigue were observed at all dose levels; the lowest observed adverse effect level (LOAEL) for maternal toxicity was 5 mg/kg/day, based on the dose response for these signs.

Embryofetal studies were conducted in pregnant rats administered brimonidine tartrate by daily oral gavage on gestation days 6 to 15, to target the period of organogenesis. The NOAEL for developmental toxicity was 2.5 mg/kg/day (approximately 1100- and 750-fold the RHOD based on AUC, respectively for brimonidine tartrate 0.1% and 0.15%). No treatment-related malformations were observed in rats. The LOAEL for maternal toxicity was 2.5 mg/kg/day, based on signs of sedation and fatigue. The maternal NOAEL was 1.0 mg/kg/day (250- and 180-fold the RHOD based on AUC, respectively for brimonidine tartrate 0.1% and 0.15%).

After pregnant rats received a single oral dose of 14C-brimonidine tartrate, brimonidine and metabolites crossed the placenta and were detectable in fetal blood and organs.

8.2       Lactation

Risk Summary

It is not known whether brimonidine tartrate is excreted in human milk. In animal studies, brimonidine tartrate has been shown to cross the blood-brain barrier and is excreted into breast milk after oral administration to lactating rats (see Data). Because of the potential for serious adverse reactions, including central nervous system depression and apnea, from brimonidine tartrate ophthalmic solution 0.1% and 0.15% in nursing infants, brimonidine tartrate ophthalmic solution 0.1% and 0.15% is not recommended for use during lactation.

Data

Animal Data

After a single oral dose of 14C-labeled brimonidine tartrate to lactating rats, brimonidine and metabolites were detected in milk. After male and female rats received a single oral dose of 14C-brimonidine tartrate, brimonidine crossed the blood-brain barrier. Radiolabel was detected in the cerebellum, cerebrum, and spinal cord.

8.4       Pediatric Use

Brimonidine tartrate ophthalmic solution 0.1% and 0.15% is contraindicated in pediatric patients younger than 2 years old [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.

In a well-controlled clinical study conducted in pediatric glaucoma patients aged 2 to 7 years old) the most commonly observed adverse reactions with brimonidine tartrate ophthalmic solution 0.2% dosed three times daily were somnolence (50% to 83% in patients aged 2 to 6 years old) and decreased alertness. In pediatric patients aged 7 years and older (greater than 20 kg), somnolence appears to occur less frequently (25%). Approximately 16% of pediatric patients on brimonidine tartrate ophthalmic solution 0.2% 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.

12.1       Mechanism of Action

Brimonidine tartrate ophthalmic solution 0.1% and 0.15% 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

Brimonidine was approximately 29% bound to plasma proteins in healthy subjects.

Elimination

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

Carcinogenesis

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 approximately 150 and 120 times or 93 and 76 times the recommended human ophthalmic dose (RHOD) based on Cmax respectively for brimonidine tartrate 0.1% or 0.15%.  

Mutagenesis

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.

Impairment of Fertility

A reproduction and fertility study in rats with brimonidine tartrate demonstrated no adverse effect on male or female fertility at oral doses up to 1mg/kg (approximately 250 or 180 times the recommended human ophthalmic dose [RHOD] based on estimated AUC) respectively for brimonidine tartrate 0.1% and 0.15%.