The following Structured Product Label (SPL) was submitted to the FDA by Micro Labs Limited for the product Brimonidine Tartrate (NDC 42571-419). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding 1 indications and usage, 2 dosage and administration, 3 dosage forms and strengths, 4.1 neonates and infants (under the age of 2 years), 4.2 hypersensitivity reactions, 5.1 potentiation of vascular insufficiency, 5.2 severe cardiovascular disease, 5.3 contamination of topical ophthalmic products after use, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
Brimonidine tartrate ophthalmic solution 0.2% is indicated for lowering intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.
The IOP lowering efficacy of brimonidine tartrate ophthalmic solution diminishes over time in some patients. This loss of effect appears with a variable time of onset in each patient and should be closely monitored.
The recommended dose is one drop of brimonidine tartrate ophthalmic solution 0.2% in the affected eye(s) three times daily, approximately 8 hours apart.
Brimonidine tartrate ophthalmic solution may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic product is to be used, the different products should be instilled at least 5 minutes apart.
Solution containing 2 mg/mL brimonidine tartrate.
Brimonidine tartrate ophthalmic solution is contraindicated in neonates and infants (under the age of 2 years) [ see Use in Specific Populations ( 8.4) ].
Brimonidine tartrate ophthalmic solution may potentiate syndromes associated with vascular insufficiency.
Brimonidine tartrate ophthalmic solution should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, or thromboangiitis obliterans.
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.
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)] .
The preservative in brimonidine tartrate ophthalmic solution, benzalkonium chloride, may be absorbed by soft contact lenses. Patients wearing soft contact lenses should be instructed to wait at least 15 minutes after instilling brimonidine tartrate ophthalmic solution to insert soft contact lenses.
The following serious adverse reactions are described elsewhere in the labeling:
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.
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:
Because brimonidine tartrate ophthalmic solution may reduce blood pressure, caution in using drugs such as antihypertensives and/or cardiac glycosides with brimonidine tartrate ophthalmic solution is advised.
Although specific drug interaction studies have not been conducted with brimonidine tartrate ophthalmic solution, the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anesthetics) should be considered.
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 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.
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.
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 mg/kg/day) achieved AUC exposure values 375-fold higher or 19-fold higher, respectively, than similar values estimated in humans treated with brimonidine tartrate ophthalmic solution 0.2%, one drop in one eye, twice 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, brimonidine tartrate ophthalmic solution should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
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 brimonidine tartrate ophthalmic solution 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.
Brimonidine tartrate ophthalmic solution 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 to 83% in patients ages 2 to 6 years) and decreased alertness. In pediatric patients 7 years of age (greater than 20 kg), somnolence appears to occur less frequently (25%). Approximately 16% of patients on brimonidine tartrate ophthalmic solution 0.2% discontinued from the study due to somnolence.
No overall differences in safety or effectiveness have been observed between elderly and other adult patients.
Brimonidine tartrate ophthalmic solution has not been studied in patients with hepatic impairment.
Brimonidine tartrate ophthalmic solution has not been studied in patients with renal impairment. The effect of dialysis on brimonidine pharmacokinetics in patients with renal failure is not known.
Very limited information exists on accidental ingestion of brimonidine in adults; the only adverse reaction reported to date has been hypotension. Symptoms of brimonidine overdose have been reported in neonates, infants, and children receiving brimonidine tartrate as part of medical treatment of congenital glaucoma or by accidental oral ingestion [ see Use In Specific Populations ( 8.4) ]. Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway should be maintained.
Brimonidine tartrate ophthalmic solution 0.2%, sterile, is a relatively selective alpha-2 adrenergic receptor agonist (topical intraocular pressure lowering agent).
The structural formula of brimonidine tartrate is:
Brimonidine-str.jpg (Brimonidine Str)
Chemical name: 5-Bromo-6-(2-imidazoline-2-ylamino)quinoxaline L-tartrate (1:1)
Molecular formula: C 15H 16BrN 5O 6
Molecular weight: 442.22 g/mol.
In solution, brimonidine tartrate ophthalmic solution 0.2% has a clear, greenish-yellow color. It has an osmolality of 280 to 330 mOsml/kg and a pH of 5.9 to 6.5.
Each mL of brimonidine tartrate ophthalmic solution contains the active ingredient brimonidine tartrate 0.2% (2 mg/mL) with the inactive ingredients benzalkonium chloride 0.005% (0.05 mg/mL) as a preservative; citric acid monohydrate; polyvinyl alcohol; sodium chloride; tri sodium citrate dihydrate; and purified water. Hydrochloric acid and/or sodium hydroxide may be added to adjust pH.
Brimonidine tartrate ophthalmic solution 0.2% 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.
Absorption
After ocular administration of a 0.2% solution, plasma concentrations peaked within 1 to 4 hours and declined with a systemic half-life of approximately 3 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.
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 1.0 mg/kg/day in rats achieved ~77 and 118 times, respectively, the plasma C maxdrug concentration estimated in humans treated with one drop brimonidine tartrate ophthalmic solution 0.2% into both eyes 2 times per day.
Brimonidine tartrate was not mutagenic or clastogenic in a series of in vitroand in vivostudies including the Ames bacterial reversion test, chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells, and three in vivostudies in CD-1 mice: a host-mediated assay, cytogenetic study, and dominant lethal assay.
A reproduction and fertility study in rats with brimonidine tartrate demonstrated no adverse effect on male or female fertility at oral doses up to 1 mg/kg, estimated as approximately 200 times the systemic exposure (AUC) following the maximum recommended human ophthalmic dose of brimonidine tartrate ophthalmic solution 0.5%.
Elevated IOP presents a major risk factor in glaucomatous field loss. The higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss. Brimonidine tartrate has the action of lowering intraocular pressure with minimal effect on cardiovascular and pulmonary parameters.
In comparative clinical studies with timolol 0.5%, lasting up to one year, the IOP lowering effect of brimonidine tartrate ophthalmic solution was approximately 4 to 6 mm Hg compared with approximately 6 mm Hg for timolol. In these studies, both patient groups were dosed BID; however, due to the duration of action of brimonidine tartrate ophthalmic solution, it is recommended that brimonidine tartrate ophthalmic solution be dosed TID. Eight percent of subjects were discontinued from studies due to inadequately controlled intraocular pressure, which in 30% of these patients occurred during the first month of therapy. Approximately 20% were discontinued due to adverse experiences.
Brimonidine tartrate ophthalmic solution 0.2% is supplied sterile, in white opaque LDPE plastic bottles and tips with purple high density polyethylene (HDPE) caps as follows:
5 mL in 10 mL bottle: NDC 42571-419-92
10 mL in 10 mL bottle: NDC 42571-419-56
15 mL in 15 mL bottle: NDC 42571-419-57
Storage: Store at 15° to 25°C (59° to 77°F).
Handling the Container
Instruct patients that ocular solutions, if handled improperly or if the tip of the dispensing container contacts the eye or surrounding structures, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions [ see Warnings and Precautions ( 5.3) ]. Always replace the cap after using. If solution changes color or becomes cloudy, do not use. Do not use the product after the expiration date marked on the bottle.
When to Seek Physician Advice
Advise patients that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma or infection), they should immediately seek their physician's advice concerning the continued use of the present multidose container.
Use with Contact Lenses
Advise patients that contact lenses should be removed prior to instillation of brimonidine tartrate ophthalmic solution and may be reinserted 15 minutes following its administration.
Use with Other Ophthalmic Drugs
Advise patients that if more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart.
Potential for Decreased Mental Alertness
As with other similar medications, brimonidine tartrate ophthalmic solution may cause fatigue and/or drowsiness in some patients. Caution patients who engage in hazardous activities of the potential for a decrease in mental alertness.
Manufactured by:
Micro Labs Limited
Bangalore - 560099, INDIA.
Manufactured for:
Micro Labs USA, Inc.
Somerset, NJ 08873
Rev. 04/2023
NDC 42571-419-92
Rx only
Brimonidine Tartrate Ophthalmic Solution
0.2%
For Topical Ophthalmic Use
Sterile
5 mL
Micro Labs Limited
Brimonidine-lbla.jpg (Brimonidine Lbla)
NDC 42571-419-92
Brimonidine Tartrate Ophthalmic Solution
0.2%
For Topical Ophthalmic Use
Sterile
Rx only
5 mL
Micro Labs Limited
Brimonidine-carta.jpg (Brimonidine Carta)
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