Brinzolamide and brimonidine

Oral Carbonic Anhydrase Inhibitors (7.1) High-dose Salicylate Therapy (7.2) Central Nervous System Depressants (7.3) Antihypertensives/Cardiac Glycosides (7.4) Tricyclic Antidepressants (7.5) Monoamine Oxidase (MAO) Inhibitors (7.6)

7.1 Oral Carbonic Anhydrase Inhibitors There is a potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and brinzolamide ophthalmic suspension 1%, a component of SIMBRINZA ophthalmic suspension. The concomitant administration of SIMBRINZA and oral carbonic anhydrase inhibitors is not recommended.

7.2 High-Dose Salicylate Therapy Carbonic anhydrase inhibitors may produce acid-base and electrolyte alterations. These alterations were not reported in the clinical trials with brinzolamide ophthalmic suspension 1%. However, in patients treated with oral carbonic anhydrase inhibitors, rare instances of acid-base alterations have occurred with high-dose salicylate therapy. Therefore, the potential for such drug interactions should be considered in patients receiving SIMBRINZA.

7.3 Central Nervous System Depressants Although specific drug interaction studies have not been conducted with SIMBRINZA, the possibility of an additive or potentiating effect with Central Nervous System (CNS) depressants (alcohol, opiates, barbiturates, sedatives, or anesthetics) should be considered.

7.4 Antihypertensives/Cardiac Glycosides Because brimonidine tartrate, a component of SIMBRINZA, may reduce blood pressure, caution in using drugs such as antihypertensives and/or cardiac glycosides with SIMBRINZA is advised.

7.5 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 SIMBRINZA 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.

7.6 Monoamine Oxidase Inhibitors Monoamine oxidase (MAO) inhibitors may theoretically interfere with the metabolism of brimonidine tartrate 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 Developmental toxicity studies with brinzolamide in rabbits at oral doses of 1, 3, and 6 mg/kg/day (20, 60, and 120 times the recommended human ophthalmic dose) produced maternal toxicity at 6 mg/kg/day and a significant increase in the number of fetal variations, such as accessory skull bones, which was only slightly higher than the historic value at 1 and 6 mg/kg. In rats, statistically decreased body weights of fetuses from dams receiving oral doses of 18 mg/kg/day (180 times the recommended human ophthalmic dose) during gestation were proportional to the reduced maternal weight gain, with no statistically significant effects on organ or tissue development.

Increases in unossified sternebrae, reduced ossification of the skull, and unossified hyoid that occurred at 6 and 18 mg/kg were not statistically significant. No treatment-related malformations were seen. Following oral administration of 14 C-brinzolamide to pregnant rats, radioactivity was found to cross the placenta and was present in the fetal tissues and blood. Developmental toxicity studies performed in rats with oral doses of 0.66 mg brimonidine base/kg revealed no evidence of harm to the fetus. Dosing at this level resulted in a plasma drug concentration approximately 100 times higher than that seen in humans at the recommended human ophthalmic dose.

In animal studies, brimonidine crossed the placenta and entered into the fetal circulation to a limited extent. There are no adequate and well-controlled studies in pregnant women. SIMBRINZA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.