BRIMONIDINE TARTRATE - brimonidine tartrate solution/ drops 
Indoco Remedies Limited

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use BRIMONIDINE TARTRATE OPHTHALMIC SOLUTION, 0.2% safely and effectively. See full prescribing information for Brimonidine tartrate ophthalmic solution, 0.2% Brimonidine tartrate ophthalmic solution, 0.2%
For Topical Ophthalmic Use
Initial U.S. Approval: 1996

INDICATIONS AND USAGE

Brimonidine Tartrate Ophthalmic Solution, 0.2% is an alpha adrenergic agonist indicated for lowering intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. (1)

DOSAGE AND ADMINISTRATION

One drop in the affected eye(s), three times daily, approximately 8 hours apart. (2)

DOSAGE FORMS AND STRENGTHS

Solution containing 2 mg/mL brimonidine tartrate. (3)

CONTRAINDICATIONS

Neonates and infants (under the age of 2 years). (4.1)

WARNINGS AND PRECAUTIONS

Potentiation of vascular insufficiency. (5.1)

ADVERSE REACTIONS

Most common adverse reactions occurring in approximately 10 to 30% of patients receiving brimonidine tartrate ophthalmic solution 0.2% included oral dryness, ocular hyperemia, burning and stinging, headache, blurring, foreign body sensation, fatigue/drowsiness, conjunctival follicles, ocular allergic reactions, and ocular pruritus. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Indoco Remedies Limited at +1-855-642-2594 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

• Antihypertensives/cardiac glycosides may lower blood pressure. (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)

USE IN SPECIFIC POPULATIONS

Use with caution in children > 2 years of age. (8.4)

See 17 for PATIENT COUNSELING INFORMATION

Revised: 09/2018

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 12/2018

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS & USAGE

2 DOSAGE & ADMINISTRATION

3 DOSAGE FORMS & STRENGTHS

4 CONTRAINDICATIONS

4.1 Neonates and Infants (under the age of 2 years)

4.2 Hypersensitivity Reactions

5 WARNINGS AND PRECAUTIONS

5.1 Potentiation of Vascular Insufficiency

5.2 Severe Cardiovascular Disease

5.3 Contamination of Topical Ophthalmic Products After Use

5.4 Use with Contact Lenses

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Antihypertensive/Cardiac Glycosides

7.2 CNS Depressants

7.3 Tricyclic Antidepressants

7.4 Monoamine Oxidase Inhibitors

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Special Population

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*
Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

1 INDICATIONS & USAGE

Brimonidine tartrate ophthalmic solution, 0.2% is indicated for lowering intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

The IOP lowering efficacy of Brimonidine tartrate ophthalmic solution, 0.2% 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.

2 DOSAGE & ADMINISTRATION

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, 0.2% may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic product is being used, the products should be administered at least 5 minutes apart.

3 DOSAGE FORMS & STRENGTHS

Solution containing 2 mg/mL brimonidine tartrate.

4 CONTRAINDICATIONS

Brimonidine Tartrate Ophthalmic Solution, 0.2% is contraindicated in patients with hypersensitivity to brimonidine tartrate or any component of this medication. It is also contraindicated in patients receiving monoamine oxidase (MAO) inhibitor therapy.

4.1 Neonates and Infants (under the age of 2 years)

Brimonidine tartrate ophthalmic solution, 0.2% is contraindicated in neonates and infants (under the age of 2 years) [see Use in Specific Populations (8.4)].

4.2 Hypersensitivity Reactions

Brimonidine tartrate ophthalmic solution, 0.2% is contraindicated in patients who have exhibited a hypersensitivity reaction to any component of this medication in the past [see Adverse Reactions (6.1) and (6.2)].

5 WARNINGS AND PRECAUTIONS

5.1 Potentiation of Vascular Insufficiency

Brimonidine tartrate ophthalmic solution, 0.2% may potentiate syndromes associated with vascular insufficiency.

Brimonidine tartrate ophthalmic solution, 0.2% 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 [see Patient Counseling Information (17)].

5.4 Use with Contact Lenses

The preservative in Brimonidine tartrate ophthalmic solution, 0.2%, 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, 0.2% to insert soft contact lenses.

6 ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling:


6.1 Clinical Studies Experience

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.

  • Adverse reactions occurring in approximately 10 to 30% of the subjects (in descending order): oral dryness, ocular hyperemia, burning and stinging, headache, blurring, foreign body sensation, fatigue/drowsiness, conjunctival follicles, ocular allergic reactions, and ocular pruritus.
  • Adverse reactions occurring in approximately 3 to 9% of the subjects (in descending order): corneal staining/erosion, photophobia, eyelid erythema, ocular ache/pain, ocular dryness, tearing, upper respiratory symptoms, eyelid edema, conjunctival edema, dizziness, blepharitis, ocular irritation, gastrointestinal symptoms, asthenia, conjunctival blanching, abnormal vision and muscular pain.
  • Adverse reactions reported < 3% of the patients: lid crusting, conjunctival hemorrhage, abnormal taste, insomnia, conjunctival discharge, depression, hypertension, anxiety, palpitations/arrhythmias, nasal dryness and syncope.

6.2 Postmarketing Experience

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:
• Bradycardia; conjunctivitis; hypersensitivity; hypotension; iritis; keratoconjunctivitis sicca; lacrimation increased; miosis; nausea; skin reactions (including erythema, eyelid pruritus, rash, and vasodilation); and tachycardia.
• Apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence in infants receiving brimonidine tartrate ophthalmic solutions.


7 DRUG INTERACTIONS

7.1 Antihypertensive/Cardiac Glycosides

Because brimonidine tartrate ophthalmic solution, 0.2% may reduce blood pressure, caution in using drugs such as antihypertensives and/or cardiac glycosides with brimonidine tartrate ophthalmic solution, 0.2% is advised.

7.2 CNS Depressants

Although specific drug interaction studies have not been conducted with brimonidine tartrate ophthalmic solution, 0.2%, 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, 0.2% 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 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B: 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, 0.2% should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

8.3 Nursing Mothers

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, 0.2% 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.

8.4 Pediatric Use

Brimonidine tartrate ophthalmic solution, 0.2% 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.

8.5 Geriatric Use


No overall differences in safety or effectiveness have been observed between elderly and other adult patients.

8.6 Special Population

Brimonidine tartrate ophthalmic solution, 0.2% has not been studied in patients with hepatic impairment.

Brimonidine tartrate ophthalmic solution, 0.2% has not been studied in patients with renal impairment. The effect of dialysis on brimonidine pharmacokinetics in patients with renal failure is not known

10 OVERDOSAGE

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.

11 DESCRIPTION


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:


str

5-Bromo-6-(2-imidazolidinylideneamino) quinoxaline L-tartrate; MW= 442.24

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 5.6 to 6.6.

Each mL of brimonidine tartrate ophthalmic solution 0.2% 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; polyvinyl alcohol; sodium chloride; sodium citrate; and water for injection. Hydrochloric acid and/or sodium hydroxide may be added to adjust pH.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

12.3 Pharmacokinetics

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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

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 Cmax drug 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 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.

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%.

 

14 CLINICAL STUDIES

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, 0.2% 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, 0.2%, it is recommended that Brimonidine tartrate ophthalmic solution, 0.2% 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.

16 HOW SUPPLIED/STORAGE AND HANDLING

Brimonidine tartrate ophthalmic solution, 0.2% is supplied sterile, in white opaque LDPE plastic bottles and natural nozzle with purple tear-off HDPE caps as follows:


5 mL in 5mL bottle        NDC 14445-400-05
10 mL in 10 mL bottle   NDC 14445-400-10
15 mL in 15 mL bottle   NDC 14445-400-15.

STORAGE:
Store between 20°-  25°C (68°-  77°F) [See USP Controlled Room Temperature].

KEEP OUT OF THE REACH OF CHILDREN.

TEAR AND DISCARD RING BEFORE USE

Do not use if tear-off ring is broken or missing.

17 PATIENT COUNSELING INFORMATION

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 0.2%  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 0.2% 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.


logo

Manufactured by:
Indoco Remedies Limited,
L-32, 33, 34, Verna Industrial Area,
Verna, Goa – 403722. India.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL


NDC 14445-400-05.

Indoco Remedies Limited.
 
Brimonidine Tartrate Ophthalmic Solution, 0.2%.
 
5ml in 5ml bottle Carton Label


cart5ml



BRIMONIDINE TARTRATE 
brimonidine tartrate solution/ drops
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:14445-400
Route of Administration OPHTHALMIC
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
BRIMONIDINE TARTRATE (UNII: 4S9CL2DY2H) (BRIMONIDINE - UNII:E6GNX3HHTE) BRIMONIDINE TARTRATE 2 mg  in 1 mg
Inactive Ingredients
Ingredient Name Strength
Citric Acid Monohydrate (UNII: 2968PHW8QP)  
Polyvinyl Alcohol (UNII: 532B59J990)  
Sodium Chloride (UNII: 451W47IQ8X)  
Sodium Citrate (UNII: 1Q73Q2JULR)  
Water (UNII: 059QF0KO0R)  
Hydrochloric acid (UNII: QTT17582CB)  
Sodium hydroxide (UNII: 55X04QC32I)  
Benzalkonium Chloride (UNII: F5UM2KM3W7)  
Packaging
# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:14445-400-05 05 mg in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 01/01/2015
2 NDC:14445-400-10 10 mg in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 01/01/2015
3 NDC:14445-400-15 15 mg in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 01/01/2015
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA091691 01/01/2015
Labeler - Indoco Remedies Limited (650445950)
Establishment
Name Address ID/FEI Business Operations
INDOCO REMEDIES LIMITED 915851870 ANALYSIS(14445-400) , MANUFACTURE(14445-400)

Revised: 12/2018
Document Id: 383421a5-5d33-4f15-88f4-8b66fcbfac71
Set id: 383421a5-5d33-4f15-88f4-8b66fcbfac71
Version: 1
Effective Time: 20181227
 
Indoco Remedies Limited