Included as part of the "PRECAUTIONS" Section
Sulfonamide Hypersensitivity Reactions
SIMBRINZA contains brinzolamide, a sulfonamide and although administered topically is absorbed
systemically. Therefore, the same types of adverse reactions that are attributable to sulfonamides may
occur with topical administration of SIMBRINZA. Fatalities have occurred due to severe reactions to
sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic
necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Sensitization may recur when a
sulfonamide is re-administered irrespective of the route of administration. If signs of serious reactions
or hypersensitivity occur, discontinue the use of this preparation. [see PATIENT INFORMATION].
Carbonic anhydrase activity has been observed in both the cytoplasm and around the plasma membranes
of the corneal endothelium. There is an increased potential for developing corneal edema in patients
with low endothelial cell counts. Caution should be used when prescribing SIMBRINZA to this group
Severe Renal Impairment
SIMBRINZA has not been specifically studied in patients with severe renal impairment (CrCl < 30
mL/min). Since brinzolamide and its metabolite are excreted predominantly by the kidney, SIMBRINZA
is not recommended in such patients.
Acute Angle-Closure Glaucoma
The management of patients with acute angle-closure glaucoma requires therapeutic interventions in
addition to ocular hypotensive agents. SIMBRINZA has not been studied in patients with acute angleclosure
Contact Lens Wear
The preservative in SIMBRINZA, benzalkonium chloride, may be absorbed by soft contact lenses.
Contact lenses should be removed during instillation of SIMBRINZA but may be reinserted 15 minutes
after instillation [see PATIENT INFORMATION].
Severe Cardiovascular Disease
Brimonidine tartrate, a component of SIMBRINZA, has a less than 5% mean decrease in blood pressure
2 hours after dosing in clinical studies; caution should be exercised in treating patients with severe
Severe Hepatic Impairment
Because brimonidine tartrate, a component of SIMBRINZA, has not been studied in patients with hepatic
impairment, caution should be exercised in such patients.
Potentiation Of Vascular Insufficiency
Brimonidine tartrate, a component of SIMBRINZA, may potentiate syndromes associated with vascular
insufficiency. SIMBRINZA should be used with caution in patients with depression, cerebral or
coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, or thromboangiitis obliterans.
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 have been inadvertently contaminated by patients who, in
most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface [see PATIENT INFORMATION].
Carcinogenesis , Mutagenesis , Impairment Of Fertility
Brinzolamide caused urinary bladder tumors in female mice at oral doses of 10 mg/kg/day and in male
rats at oral doses of 8 mg/kg/day in 2 year studies. Brinzolamide was not carcinogenic in male mice or
female rats dosed orally for up to 2 years. The carcinogenicity appears secondary to kidney and urinary
bladder toxicity. These levels of exposure cannot be achieved with topical ophthalmic dosing in
The following tests for mutagenic potential of brinzolamide were negative: (1) in vivo mouse
micronucleus assay; (2) in vivo sister chromatid exchange assay; and (3) Ames E. coli test. The in vitro
mouse lymphoma forward mutation assay was negative in the absence of activation, but positive in the
presence of microsomal activation. In this assay, there was no consistent dose-response relationship to
the increased mutation frequency and cytotoxicity likely contributed to the high mutation frequency.
Carbonic anhydrase inhibitors, as a class, are not mutagenic and the weight of evidence supports that
brinzolamide is consistent with the class. In reproduction studies of brinzolamide in rats, there were no
adverse effects on the fertility or reproductive capacity of males or females at doses up to 18
mg/kg/day (180 times the recommended human ophthalmic dose).
Brimonidine tartrate was not carcinogenic in either a 21-month mouse or 24-month rat study. 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 resulted in plasma drug concentrations 80 and 120 times higher than the human plasma
drug level at the recommended clinical dose, respectively. Brimonidine tartrate was not mutagenic or
cytogenic in a series of in vitro and in vivo studies including the Ames test, chromosomal aberration
assay in Chinese Hamster Ovary (CHO) cells, a host-mediated assay and cytogenic studies in mice, and
a dominant lethal assay. In reproductive studies performed in rats with oral doses of 0.66 mg
brimonidine base/kg (approximately 100 times the plasma drug concentration level seen in humans
following multiple ophthalmic doses), fertility was not impaired.
Use In Specific Populations
Pregnancy Category C
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 14C-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.
In a study of brinzolamide in lactating rats, decreases in body weight gain in offspring at an oral dose of
15 mg/kg/day (150 times the recommended human ophthalmic dose) were observed during lactation. No
other effects were observed. However, following oral administration of 14C-brinzolamide to lactating
rats, radioactivity was found in milk at concentrations below those in the blood and plasma. In animal
studies, brimonidine was excreted in breast milk.
It is not known whether brinzolamide and brimonidine tartrate are excreted in human milk following
topical ocular administration. Because many drugs are excreted in human milk and because of the
potential for serious adverse reactions in nursing infants from SIMBRINZA (brinzolamide/brimonidine
tartrate ophthalmic suspension) 1%/0.2%, 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.
The individual component, brinzolamide, has been studied in pediatric glaucoma patients 4 weeks to 5
years of age. The individual component, brimonidine tartrate, has been studied in pediatric patients 2 to 7
years old. Somnolence (50-83%) and decreased alertness was seen in patients 2 to 6 years old.
SIMBRINZA ophthalmic suspension is contraindicated in children under the age of 2 years [see CONTRAINDICATIONS].
No overall differences in safety or effectiveness have been observed between elderly and adult