Brimonidine (ophthalmic)

7 DRUG INTERACTIONS • Concomitant use with systemic beta-blockers may potentiate systemic beta-blockade ( 7.1 ). • Use with CNS depressants may result in an additive or potentiating effect ( 7.2 ). • Tricyclic antidepressants may potentially blunt the hypotensive effect of systemic clonidine ( 7.3 ). • Monoamine oxidase inhibitors may result in increased hypotension ( 7.4 ).

7.1 Anti-hypertensives / Cardiac Glycosides Alpha-2 agonists, as a class, may reduce blood pressure. Caution in using drugs such as beta-blockers (ophthalmic and systemic), anti-hypertensives and/or cardiac glycosides is advised.

7.2 CNS Depressants Although specific drug interaction studies have not been conducted with brimonidine tartrate ophthalmic solution, 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, 0.15% in humans can lead to resulting interference with its IOP-lowering effect. Caution, however, 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, 0.15% 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, 0.15% 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 tartrate 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 experiences 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 50-times the recommended human ophthalmic dose (RHOD) based on AUC).

The no observed adverse effect level (NOAEL) for developmental toxicity in rabbits was 1 mg/kg/day (approximately 6-fold the RHOD based on AUC). 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 750-fold the RHOD based on AUC).

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 mg/kg/day (180-fold the RHOD based on AUC). After pregnant rats received a single oral dose of 14 C-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 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, 0.15% in nursing infants, brimonidine tartrate ophthalmic solution, 0.15% is not recommended for use during lactation. Data Animal Data After a single oral dose of 14 C-labeled brimonidine tartrate to lactating rats, brimonidine and metabolites were detected in milk.

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