BRIMONIDINE TARTRATE AND TIMOLOL MALEATE - brimonidine tartrate and

timolol maleate solution/ drops

Alembic Pharmaceuticals Limited
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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use BRIMONIDINE TARTRATE
and TIMOLOL MALEATE OPHTHALMIC SOLUTION safely and effectively. See full prescribing
information for BRIMONIDINE TARTRATE and TIMOLOL MALEATE ophthalmic solution.
Brimonidine Tartrate and Timolol Maleate ophthalmic solution 0.2%/0.5%
For Topical Administration
Initial U.S. Approval: 2007.
INDICATIONS AND USAGE

Brimonidine tartrate and timolol maleate ophthalmic solution is an alpha-adrenergic receptor agonist with
a beta-adrenergic receptor inhibitor indicated for the reduction of elevated intraocular pressure (IOP) in
patients with glaucoma or ocular hypertension who require adjunctive or replacement therapy due to
inadequately controlled IOP; the IOP-lowering of brimonidine tartrate and timolol maleate ophthalmic
solution dosed twice a day was slightly less than that seen with the concomitant administration of timolol
maleate ophthalmic solution, 0.5% dosed twice a day and brimonidine tartrate ophthalmic solution, 0.2%
dosed three times per day. (1)
DOSAGE AND ADMINISTRATION
One drop in the affected eye(s), twice daily approximately 12 hours apart. (2)
DOSAGE FORMS AND STRENGTHS
Solution containing 2 mg/mL brimonidine tartrate and 5 mg/mL timolol. (3)
CONTRAINDICATIONS
Bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease. (4.1,
5.1, 5.3)
Sinus bradycardia, atrioventricular block, overt cardiac failure, cardiogenic shock. (4.2, 5.2)
Neonates and infants (under the age of 2 years). (4.3)
Hypersensitivity to any component of this product. (4.4)

WARNINGS AND PRECAUTIONS

Potential for Severe Respiratory or Cardiac Reactions (5.1)
Cardiac Failure (5.2)
Obstructive Pulmonary Disease (5.3)
Potentiation of Vascular Insufficiency (5.4)
Increased Reactivity to Allergens (5.5)
Potentiation of Muscle Weakness (5.6)
Masking of Hypoglycemic Symptoms in Patients with Diabetes Mellitus (5.7)
Masking of Thyrotoxicosis (5.8)
Ocular Hypersensitivity (5.9)

ADVERSE REACTIONS
Most common adverse reactions occurring in approximately 5 to 15% of patients included allergic
conjunctivitis, conjunctival folliculosis, conjunctival hyperemia, eye pruritus, ocular burning, and stinging.
(6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceutical, Inc. at 1-866-

210-9797 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
Antihypertensives/cardiac glycosides may lower blood pressure. (7.1)
Concomitant use with systemic beta-blockers may potentiate systemic beta-blockade. (7.2)
Oral or intravenous calcium antagonists may cause atrioventricular conduction disturbances, left
ventricular failure, and hypotension. (7.3)
Catecholamine-depleting drugs may have additive effects and produce hypotension and/or marked
bradycardia. (7.4)
 Use with CNS depressants may result in an additive or potentiating effect.(7.5)
Digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction
time. (7.6)
CYP2D6 inhibitors may potentiate systemic beta-blockade. (7.7)
Tricyclic antidepressants may potentially blunt the hypotensive effect of systemic clonidine. (7.8)
Monoamine oxidase inhibitors may result in increased hypotension. (7.9)

USE IN SPECIFIC POPULATIONS

Not for use in children below the age of 2 years. Use with caution in children ≥ 2 years of age. (8.4)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 8/2023

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS & USAGE
2 DOSAGE & ADMINISTRATION
3 DOSAGE FORMS & STRENGTHS
4 CONTRAINDICATIONS
4.1 Reactive Airway Disease Including Asthma, COPD
4.2 Sinus Bradycardia, AV Block, Cardiac Failure, Cardiogenic Shock
4.3 Neonates and Infants (Under the Age of 2 Years)
4.4 Hypersensitivity Reactions
5 WARNINGS AND PRECAUTIONS
5.1 Potential for Severe Respiratory or Cardiac Reactions
5.2 Cardiac Failure
5.3 Obstructive Pulmonary
5.4 Potentiation of Vascular Insufficiency
5.5 Increased Reactivity to Allergens
5.6 Potentiation of Muscle Weakness
5.7 Masking of Hypoglycemic Symptoms in Patients with Diabetes Mellitus
5.8 Masking of Thyrotoxicosis
5.9 Ocular Hypersensitivity
5.10 Contamination of Topical Ophthalmic Products After Use
5.11 Impairment of Beta-adrenergically Mediated Reflexes During Surgery
6 ADVERSE REACTIONS
6.1 Clinical Studies Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Antihypertensives/Cardiac Glycosides
7.2 Beta-adrenergic Blocking Agents
7.3 Calcium Antagonists
7.4 Catecholamine-depleting Drugs
7.5 CNS Depressants
7.6 Digitalis and Calcium Antagonists
7.7 CYP2D6 Inhibitors
7.8 Tricyclic Antidepressants
7.9 Monoamine Oxidase Inhibitors
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
 8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
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 and timolol maleate ophthalmic solution 0.2% /0.5% is an alpha-
adrenergic receptor agonist with a beta-adrenergic receptor inhibitor indicated for the
reduction of elevated intraocular pressure (IOP) in patients with glaucoma or ocular
hypertension who require adjunctive or replacement therapy due to inadequately
controlled IOP; the IOP-lowering of brimonidine tartrate and timolol maleate ophthalmic
solution dosed twice a day was slightly less than that seen with the concomitant
administration of 0.5% timolol maleate ophthalmic solution dosed twice a day and 0.2%
brimonidine tartrate ophthalmic solution dosed three times per day.

2 DOSAGE & ADMINISTRATION

The recommended dose is one drop of brimonidine tartrate and timolol maleate
ophthalmic solution in the affected eye(s) twice daily approximately 12 hours apart. If
more than one topical ophthalmic product is to be used, the different products should
be instilled at least 5 minutes apart.

3 DOSAGE FORMS & STRENGTHS

Solution containing 2 mg/mL brimonidine tartrate and 5 mg/mL timolol (6.8 mg/mL
timolol maleate).

4 CONTRAINDICATIONS

4.1 Reactive Airway Disease Including Asthma, COPD

Brimonidine tartrate and timolol maleate ophthalmic solution is contraindicated in
patients with reactive airway disease including bronchial asthma; a history of bronchial
asthma; severe chronic obstructive pulmonary disease [see Warnings and Precautions
(5.1, 5.3)].

4.2 Sinus Bradycardia, AV Block, Cardiac Failure, Cardiogenic Shock

Brimonidine tartrate and timolol maleate ophthalmic solution is contraindicated in
patients with sinus bradycardia; second or third degree atrioventricular block; overt
cardiac failure [see Warnings and Precautions (5.2)]; cardiogenic shock.

4.3 Neonates and Infants (Under the Age of 2 Years)

Brimonidine tartrate and timolol maleate ophthalmic solution is contraindicated in
neonates and infants (under the age of 2 years).

4.4 Hypersensitivity Reactions

Local hypersensitivity reactions have occurred following the use of different

components of brimonidine tartrate and timolol maleate ophthalmic solution. Brimonidine
tartrate and timolol maleate ophthalmic solution is contraindicated in patients who have
exhibited a hypersensitivity reaction to any component of this medication in the past.

5 WARNINGS AND PRECAUTIONS

5.1 Potential for Severe Respiratory or Cardiac Reactions

Brimonidine tartrate and timolol maleate ophthalmic solution contains timolol maleate;
and although administered topically can be absorbed systemically. Therefore, the same
types of adverse reactions found with systemic administration of beta-adrenergic
blocking agents may occur with topical administration. For example, severe respiratory
reactions and cardiac reactions including death due to bronchospasm in patients with
asthma, and rarely death in association with cardiac failure have been reported following
systemic or ophthalmic administration of timolol maleate [see Contraindications (4.1)].
Additionally, ophthalmic beta-blockers may impair compensatory tachycardia and
increase risk of hypotension.

5.2 Cardiac Failure

Sympathetic stimulation may be essential for support of the circulation in individuals with
diminished myocardial contractility, and its inhibition by beta-adrenergic receptor
blockade may precipitate more severe failure.

In patients without a history of cardiac failure, continued depression of the myocardium

with beta-blocking agents over a period of time can, in some cases, lead to cardiac
failure. At the first sign or symptom of cardiac failure, brimonidine tartrate and timolol
maleate ophthalmic solution should be discontinued [see Contraindications (4.2)].

5.3 Obstructive Pulmonary

Patients with chronic obstructive pulmonary disease (e.g., chronic bronchitis,
emphysema) of mild or moderate severity, bronchospastic disease, or a history of
bronchospastic disease (other than bronchial asthma or a history of bronchial asthma,
in which brimonidine tartrate and timolol maleate ophthalmic solution is contraindicated
[see Contraindications (4.1)]) should, in general, not receive beta-blocking agents,
including brimonidine tartrate and timolol maleate ophthalmic solution.

5.4 Potentiation of Vascular Insufficiency

Brimonidine tartrate and timolol maleate ophthalmic solution may potentiate syndromes
associated with vascular insufficiency. Brimonidine tartrate and timolol maleate
ophthalmic solution should be used with caution in patients with depression, cerebral or
coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, or
thromboangiitis obliterans.

5.5 Increased Reactivity to Allergens

While taking beta-blockers, patients with a history of atopy or a history of severe
anaphylactic reactions to a variety of allergens may be more reactive to repeated
accidental, diagnostic, or therapeutic challenge with such allergens. Such patients may
be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.

5.6 Potentiation of Muscle Weakness

Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent
with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness).
Timolol has been reported rarely to increase muscle weakness in some patients with
myasthenia gravis or myasthenic symptoms.

5.7 Masking of Hypoglycemic Symptoms in Patients with Diabetes Mellitus

Beta-adrenergic blocking agents should be administered with caution in patients subject

to spontaneous hypoglycemia or to diabetic patients (especially those with labile
diabetes) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic
receptor blocking agents may mask the signs and symptoms of acute hypoglycemia.

5.8 Masking of Thyrotoxicosis

Beta-adrenergic blocking agents may mask certain clinical signs (e.g., tachycardia) of
hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed
carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents that might
precipitate a thyroid storm.

5.9 Ocular Hypersensitivity

Ocular hypersensitivity reactions have been reported with brimonidine tartrate
ophthalmic solutions 0.2%, with some reported to be associated with an increase in
intraocular pressure [see Contraindications (4.4)].

5.10 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)].

5.11 Impairment of Beta-adrenergically Mediated Reflexes During Surgery

The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to
major surgery is controversial. Beta-adrenergic receptor blockade impairs the ability of
the heart to respond to beta-adrenergically mediated reflex stimuli. This may augment
the risk of general anesthesia in surgical procedures. Some patients receiving beta-
adrenergic receptor blocking agents have experienced protracted severe hypotension
during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been
reported. For these reasons, in patients undergoing elective surgery, some authorities
recommend gradual withdrawal of betaadrenergic receptor blocking agents.
If necessary during surgery, the effects of beta-adrenergic blocking agents may be
reversed by sufficient doses of adrenergic agonists.

6 ADVERSE REACTIONS

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.

Brimonidine tartrate and timolol maleate ophthalmic solution

In clinical trials of 12 months duration with brimonidine tartrate and timolol maleate
ophthalmic solution, the most frequent reactions associated with its use occurring in
approximately 5% to 15% of the patients included: allergic conjunctivitis, conjunctival
folliculosis, conjunctival hyperemia, eye pruritus, ocular burning, and stinging.

The following adverse reactions were reported in 1% to 5% of patients: asthenia,

blepharitis, corneal erosion, depression, epiphora, eye discharge, eye dryness, eye
irritation, eye pain, eyelid edema, eyelid erythema, eyelid pruritus, foreign body
sensation, headache, hypertension, oral dryness, somnolence, superficial punctate
keratitis, and visual disturbance.

Other adverse reactions that have been reported with the individual components are
listed below.

Brimonidine Tartrate (0.1% - 0.2%)

Abnormal taste, allergic reaction, blepharoconjunctivitis, blurred vision, bronchitis,

cataract, conjunctival blanching, conjunctival edema, conjunctival hemorrhage,
conjunctivitis, cough, dizziness, dyspepsia, dyspnea, fatigue, flu syndrome, follicular
conjunctivitis, gastrointestinal disorder, hypercholesterolemia, hypotension, infection
(primarily colds and respiratory infections), hordeolum, insomnia, keratitis, lid crusting,
lid disorder, muscular pain, nasal dryness, ocular allergic reaction, pharyngitis,
photophobia, rash, rhinitis, sinus infection, sinusitis, superficial punctate keratopathy,
tearing, upper respiratory symptoms, visual field defect, vitreous detachment, vitreous
disorder, vitreous floaters, and worsened visual acuity.

Timolol (Ocular Administration)

Body as a whole: chest pain; Cardiovascular: Arrhythmia, bradycardia, cardiac arrest,
cardiac failure, cerebral ischemia, cerebral vascular accident, claudication, cold hands
and feet, edema, heart block, palpitation, pulmonary edema, Raynaud’s phenomenon,
syncope, and worsening of angina pectoris; Digestive: anorexia, diarrhea, nausea;
Immunologic: Systemic lupus erythematosus; Nervous System/Psychiatric: Increase in
signs and symptoms of myasthenia gravis, insomnia, nightmares, paresthesia,
behavioral changes and psychic disturbances including confusion, hallucinations,
anxiety, disorientation, nervousness, and memory loss; Skin: Alopecia, psoriasiform rash
or exacerbation of psoriasis; Hypersensitivity: Signs and symptoms of systemic allergic
reactions, including anaphylaxis, angioedema, urticaria, and generalized and localized
rash; Respiratory: Bronchospasm (predominantly in patients with pre-existing
bronchospastic disease) [see Contraindications (4.1)], dyspnea, nasal congestion,
respiratory failure, upper respiratory infections; Endocrine: Masked symptoms of
hypoglycemia in diabetes patients [see Warnings and Precautions (5.7)]; Special Senses:
diplopia, choroidal detachment following filtration surgery, cystoid macular edema,
decreased corneal sensitivity, pseudopemphigoid, ptosis, refractive changes, tinnitus;
Urogenital: Decreased libido, impotence, Peyronie’s disease, retroperitoneal fibrosis.

6.2 Postmarketing Experience

The following reactions have been identified during post-marketing use of brimonidine
tartrate ophthalmic solutions, timolol ophthalmic solutions, or both in combination, 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, timolol ophthalmic solutions, or
a combination of these factors, include: eyelid erythema extending to the cheek or
forehead, hypersensitivity, iritis, keratoconjunctivitis sicca, miosis, nausea, skin reactions
(including erythema, rash, and vasodilation), and tachycardia. In infants, apnea,
bradycardia, coma, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and
somnolence have been reported [see Contraindications (4.3) and Use in Specific
Populations (8.4)].

Oral Timolol/Oral Beta-blockers

The following additional adverse reactions have been reported in clinical experience with
ORAL timolol maleate or other ORAL beta-blocking agents and may be considered
potential effects of ophthalmic timolol maleate: Allergic: Erythematous rash, fever
combined with aching and sore throat, laryngospasm with respiratory distress; Body as
a whole: Decreased exercise tolerance, extremity pain, weight loss; Cardiovascular:
Vasodilatation, worsening of arterial insufficiency; Digestive: Gastrointestinal pain,
hepatomegaly, ischemic colitis, mesenteric arterial thrombosis, vomiting; Hematologic:
Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura; Endocrine:
Hyperglycemia, hypoglycemia; Skin: Increased pigmentation, pruritus, skin irritation,
sweating; Musculoskeletal: Arthralgia; Nervous System/Psychiatric: An acute reversible
syndrome characterized by disorientation for time and place, decreased performance on
neuropsychometrics, diminished concentration, emotional lability, local weakness,
reversible mental depression progressing to catatonia, slightly clouded sensorium,
vertigo; Respiratory: Bronchial obstruction, rales; Urogenital: Urination difficulties.

7 DRUG INTERACTIONS

7.1 Antihypertensives/Cardiac Glycosides

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

7.2 Beta-adrenergic Blocking Agents

Patients who are receiving a beta-adrenergic blocking agent either orally or intravenously
and brimonidine tartrate and timolol maleate ophthalmic solution should be observed for
potential additive effects of beta-blockade, both systemic and on intraocular pressure.
The concomitant use of two topical beta-adrenergic blocking agents is not
recommended.

7.3 Calcium Antagonists

Caution should be used in the co-administration of beta-adrenergic blocking agents,
such as brimonidine tartrate and timolol maleate ophthalmic solution, and oral or
intravenous calcium antagonists because of possible atrioventricular conduction
disturbances, left ventricular failure, and hypotension. In patients with impaired cardiac
function, co-administration should be avoided.

7.4 Catecholamine-depleting Drugs

Close observation of the patient is recommended when a beta blocker is administered to

patients receiving catecholamine-depleting drugs such as reserpine, because of possible
additive effects and the production of hypotension and/or marked bradycardia, which
may result in vertigo, syncope, or postural hypotension.

7.5 CNS Depressants

Although specific drug interaction studies have not been conducted with brimonidine
tartrate and timolol maleate ophthalmic solution, the possibility of an additive or
potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or
anesthetics) should be considered.

7.6 Digitalis and Calcium Antagonists

The concomitant use of beta-adrenergic blocking agents with digitalis and calcium
antagonists may have additive effects in prolonging atrioventricular conduction time.
7.7 CYP2D6 Inhibitors
Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been
reported during combined treatment with CYP2D6 inhibitors (e.g., quinidine, SSRIs) and
timolol.

7.8 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 and timolol maleate ophthalmic solution in humans can lead to resulting
interference with the IOP-lowering effect. Caution, however, is advised in patients taking
tricyclic antidepressants which can affect the metabolism and uptake of circulating
amines.

7.9 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, however, 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
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 580 and 37-fold higher,
respectively, than similar values estimated in humans treated with brimonidine tartrate
and timolol maleate ophthalmic solution, 1 drop in both eyes twice daily.

Teratogenicity studies with timolol in mice, rats, and rabbits at oral doses up to 50
mg/kg/day [4,200 times the maximum recommended human ocular dose of 0.012
mg/kg/day on a mg/kg basis (MRHOD)] demonstrated no evidence of fetal
malformations. Although delayed fetal ossification was observed at this dose in rats,
there were no adverse effects on postnatal development of offspring. Doses of 1,000
mg/kg/day (83,000 times the MRHOD) were maternotoxic in mice and resulted in an
increased number of fetal resorptions. Increased fetal resorptions were also seen in
rabbits at doses 8,300 times the MRHOD without apparent maternotoxicity.

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 and timolol maleate ophthalmic solution should be
used during pregnancy only if the potential benefit to the mother justifies the potential
risk to the fetus.
8.3 Nursing Mothers
Timolol has been detected in human milk following oral and ophthalmic drug
administration. 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
and timolol maleate 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.

8.4 Pediatric Use

Brimonidine tartrate and timolol maleate ophthalmic solution is contraindicated in children

under the age of 2 years [see Contraindications (4.3)]. During post-marketing
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 and timolol maleate
have not been studied in children below the age of 2 years.

The safety and effectiveness of brimonidine tartrate and timolol maleate ophthalmic
solution have been established in the age groups 2 to 16 years of age. Use of
brimonidine tartrate and timolol maleate ophthalmic solution in these age groups is
supported by evidence from adequate and well-controlled studies of brimonidine tartrate
and timolol maleate ophthalmic solution in adults with additional data from a study of the
concomitant use of brimonidine tartrate ophthalmic solution 0.2% and timolol maleate
ophthalmic solution in pediatric glaucoma patients (ages 2 to 7 years). In this study,
brimonidine tartrate ophthalmic solution 0.2% was dosed three times a day as adjunctive
therapy to beta-blockers. The most commonly observed adverse reactions were
somnolence (50% to 83% in patients 2 to 6 years) and decreased alertness. In pediatric
patients 7 years of age or older (>20 kg), somnolence appears to occur less frequently
(25%). Approximately 16% of patients on brimonidine tartrate ophthalmic solution
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.

10 OVERDOSAGE
There have been reports of inadvertent overdosage with timolol ophthalmic solution
resulting in systemic effects similar to those seen with systemic beta-adrenergic
blocking agents such as dizziness, headache, shortness of breath, bradycardia,
bronchospasm, and cardiac arrest. With the exception of hypotension, very limited
information exists on accidental ingestion of brimonidine in adults. Symptoms of
brimonidine overdose have been reported in neonates, infants, and children receiving
brimonidine ophthalmic solutions 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 and timolol maleate ophthalmic solution 0.2%/0.5%, sterile, is a

relatively selective alpha-2 adrenergic receptor agonist with a non-selective beta-
adrenergic receptor inhibitor (topical intraocular pressure lowering agent).

The structural formulae are:

Brimonidine tartrate:

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

Timolol maleate:

(-)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)-oxy]-2-propanol maleate
(1:1) (salt); MW= 432.50 as the maleate salt
In solution, brimonidine tartrate and timolol maleate ophthalmic solution 0.2% /0.5% has
a clear, greenish-yellow color. It has an osmolality of 260 to 330 mOsmol/kg and a pH
during its shelf life of 6.5 to 7.3.

Brimonidine tartrate appears as an off-white, or white to pale-yellow powder and is

soluble in both water (1.5 mg/mL) and in the product vehicle (3 mg/mL) at pH 7.2.
Timolol maleate appears as a white, odorless, crystalline powder and is soluble in water,
methanol, and alcohol.

Each mL of brimonidine tartrate and timolol maleate ophthalmic solution contains the
active ingredients brimonidine tartrate 0.2% and timolol 0.5% with the inactive
ingredients benzalkonium chloride 0.005%; sodium phosphate, monobasic; sodium
phosphate, dibasic; purified water; and hydrochloric acid and/or sodium hydroxide to
adjust pH.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Brimonidine tartrate and timolol maleate ophthalmic solution is comprised of two
components: brimonidine tartrate and timolol. Each of these two components decreases
elevated intraocular pressure, whether or not associated with glaucoma. Elevated
intraocular pressure is a major risk factor in the pathogenesis of optic nerve damage
and glaucomatous visual field loss. The higher the level of intraocular pressure, the
greater the likelihood of glaucomatous field loss and optic nerve damage.

Brimonidine tartrate and timolol maleate ophthalmic solution is a relatively selective

alpha-2 adrenergic receptor agonist with a non-selective beta-adrenergic receptor
inhibitor. Both brimonidine and timolol have a rapid onset of action, with peak ocular
hypotensive effect seen at two hours post-dosing for brimonidine and one to two hours
for timolol.

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.

Timolol maleate is a beta1 and beta2 adrenergic receptor inhibitor that does not have
significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic
(membrane-stabilizing) activity.

12.3 Pharmacokinetics

Absorption
Systemic absorption of brimonidine and timolol was assessed in healthy volunteers and
patients following topical dosing with brimonidine tartrate and timolol maleate ophthalmic
solution. Normal volunteers dosed with one drop of brimonidine tartrate and timolol
maleate ophthalmic solution twice daily in both eyes for seven days showed peak plasma
brimonidine and timolol concentrations of 30 pg/mL and 400 pg/mL, respectively. Plasma
brimonidine and timolol concentrations of 30 pg/mL and 400 pg/mL, respectively. Plasma
concentrations of brimonidine peaked at 1 to 4 hours after ocular dosing. Peak plasma
concentrations of timolol occurred approximately 1 to 3 hours post-dose.

In a crossover study of brimonidine tartrate and timolol maleate ophthalmic solution,

brimonidine tartrate 0.2%, and timolol 0.5% administered twice daily for 7 days in healthy
volunteers, the mean brimonidine area-under-the-plasma-concentration-time curve
(AUC) for brimonidine tartrate and timolol maleate ophthalmic solution was 128 ± 61
pg•hr/mL versus 141 ± 106 pg•hr/mL for the respective monotherapy treatments;
mean Cmax values of brimonidine were comparable following bimonidine tartrate and
timolol maleate ophthalmic solution treatment versus monotherapy (32.7 ± 15 pg/mL
versus 34.7 ± 22.6 pg/mL, respectively). Mean timolol AUC for brimonidine tartrate and
timolol maleate ophthalmic solution was similar to that of the respective monotherapy
treatment (2919 ± 1679 pg•hr/mL versus 2909 ± 1231 pg•hr/mL, respectively); mean
Cmax of timolol was approximately 20% lower following brimonidine tartrate and timolol
maleate ophthalmic solution treatment versus monotherapy.

In a parallel study in patients dosed twice daily with brimonidine tartrate and timolol
maleate ophthalmic solution, twice daily with timolol 0.5%, or three times daily with
brimonidine tartrate 0.2%, one-hour post dose plasma concentrations of timolol and
brimonidine were approximately 30-40% lower with brimonidine tartrate and timolol
maleate ophthalmic solution than their respective monotherapy values. The lower plasma
brimonidine concentrations with brimonidine tartrate and timolol maleate ophthalmic
solution appears to be due to twice-daily dosing for brimonidine tartrate and timolol
maleate ophthalmic solution versus three-times dosing with brimonidine tartrate 0.2%.

Distribution
The protein binding of timolol is approximately 60%. The protein binding of brimonidine
has not been studied.

Metabolism
In humans, brimonidine is extensively metabolized-by the liver. Timolol is partially
metabolized by the liver.

Excretion
In the crossover study in healthy volunteers, the plasma concentration of brimonidine
declined with a systemic half-life of approximately 3 hours. The apparent systemic half-
life of timolol was about 7 hours after ocular administration.
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. Unchanged timolol and its
metabolites are excreted by the kidney.

Special Populations
Brimonidine tartrate and timolol maleate ophthalmic solution has not been studied in
patients with hepatic impairment.

Brimonidine tartrate and timolol maleate ophthalmic solution has not been studied in
patients with renal impairment.

A study of patients with renal failure showed that timolol was not readily removed by
dialysis. The effect of dialysis on brimonidine pharmacokinetics in patients with renal
failure is not known.

Following oral administration of timolol maleate, the plasma half-life of timolol is

essentially unchanged in patients with moderate renal insufficiency.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

With brimonidine tartrate, 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 mg/kg/day in rats achieved 150 and 210 times, respectively, the plasma Cmax
drug concentration in humans treated with one drop of brimonidine tartrate and timolol
maleate ophthalmic solution into both eyes twice daily, the recommended daily human
dose.

In a two-year study of timolol maleate administered orally to rats, there was a

statistically significant increase in the incidence of adrenal pheochromocytomas in male
rats administered 300 mg/kg/day [approximately 25,000 times the maximum
recommended human ocular dose of 0.012 mg/kg/day on a mg/kg basis (MRHOD)].

Similar differences were not observed in rats administered oral doses equivalent to
approximately 8,300 times the daily dose of brimonidine tartrate and timolol maleate
ophthalmic solution in humans.

In a lifetime oral study of timolol maleate in mice, there were statistically significant
increases in the incidence of benign and malignant pulmonary tumors, benign uterine
polyps and mammary adenocarcinomas in female mice at 500 mg/kg/day,
(approximately 42,000 times the MRHOD), but not at 5 or 50 mg/kg/day (approximately
420 to 4,200 times higher, respectively, than the MRHOD). In a subsequent study in
female mice, in which post-mortem examinations were limited to the uterus and the
lungs, a statistically significant increase in the incidence of pulmonary tumors was again
observed at 500 mg/kg/day.

The increased occurrence of mammary adenocarcinomas was associated with

elevations in serum prolactin which occurred in female mice administered oral timolol at
500 mg/kg/day, but not at doses of 5 or 50 mg/kg/day. An increased incidence of
mammary adenocarcinomas in rodents has been associated with administration of
several other therapeutic agents that elevate serum prolactin, but no correlation
between serum prolactin levels and mammary tumors has been established in humans.
Furthermore, in adult human female subjects who received oral dosages of up to 60 mg
of timolol maleate (the maximum recommended human oral dosage), there were no
clinically meaningful changes in serum prolactin.
clinically meaningful changes in serum prolactin.

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.

Timolol maleate was devoid of mutagenic potential when tested in vivo (mouse) in the
micronucleus test and cytogenetic assay (doses up to 800 mg/kg) and in vitro in a
neoplastic cell transformation assay (up to 100 mcg/mL). In Ames tests the highest
concentrations of timolol employed, 5,000 or 10,000 mcg/plate, were associated with
statistically significant elevations of revertants observed with tester strain TA100 (in
seven replicate assays), but not in the remaining three strains. In the assays with tester
strain TA100, no consistent dose response relationship was observed, and the ratio of
test to control revertants did not reach 2. A ratio of 2 is usually considered the criterion
for a positive Ames test.

Reproduction and fertility studies in rats with timolol maleate and in rats with
brimonidine tartrate demonstrated no adverse effect on male or female fertility at doses
up to approximately 100 times the systemic exposure following the maximum
recommended human ophthalmic dose of brimonidine tartrate and timolol maleate
ophthalmic solution.

14 CLINICAL STUDIES
Clinical studies were conducted to compare the IOP-lowering effect over the course of
the day of brimonidine tartrate and timolol maleate ophthalmic solution administered
twice a day (BID) to individually-administered brimonidine tartrate ophthalmic solution,
0.2% administered three times per day (TID) and timolol maleate ophthalmic solution,
0.5% BID in patients with glaucoma or ocular hypertension. Brimonidine tartrate and
timolol maleate ophthalmic solution BID provided an additional 1 to 3 mm Hg decrease in
IOP over brimonidine treatment TID and an additional 1 to 2 mm Hg decrease over
timolol treatment BID during the first 7 hours post dosing. However, the IOP-lowering of
brimonidine tartrate and timolol maleate ophthalmic solution BID was less (approximately
1-2 mm Hg) than that seen with the concomitant administration of 0.5% timolol BID and
0.2% brimonidine tartrate TID. Brimonidine tartrate and timolol maleate ophthalmic
solution administered BID had a favorable safety profile versus concurrently
administered brimonidine TID and timolol BID in the self-reported level of severity of
sleepiness for patients over age 40.

16 HOW SUPPLIED/STORAGE AND HANDLING

Brimonidine tartrate and timolol maleate ophthalmic solution is supplied sterile, in white
opaque plastic LDPE bottles and nozzles, with blue high density polyethylene (HDPE)
caps as follows:
5 mL in 10 mL bottle NDC 46708-706-05
10 mL in 10 mL bottle NDC 46708-706-10
15 mL in 15 mL bottle NDC 46708-706-15

Storage: Store at 15° to 25°C (59° to 77°F). Protect from light.

17 PATIENT COUNSELING INFORMATION

Patients with bronchial asthma, a history of bronchial asthma, severe chronic
obstructive pulmonary disease, sinus bradycardia, second or third degree
atrioventricular block, or cardiac failure should be advised not to take this product [see
Contraindications (4.1, 4.2)].

Patients should be instructed 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 or
by inadvertent contact with the dropper tip [see Warnings and Precautions (5.10)].
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.

Patients also should be advised 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.

If more than one topical ophthalmic drug is being used, the drugs should be
administered at least five minutes apart.

Patients should be advised that brimonidine tartrate and timolol maleate ophthalmic
solution contains benzalkonium chloride which may be absorbed by soft contact lenses.
Contact lenses should be removed prior to administration of the solution. Lenses may
be reinserted 15 minutes following administration of brimonidine tartrate and timolol
maleate ophthalmic solution.

As with other similar medications, brimonidine tartrate and timolol maleate ophthalmic
solution may cause fatigue and/or drowsiness in some patients. Patients who engage in
hazardous activities should be cautioned of the potential for a decrease in mental
alertness.

Made in India.

Manufactured by:
Alembic Pharmaceuticals Limited
Karkhadi 391450, Gujarat, India

Revised: June 2023

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

5 mL Container Label

10 mL Container Label

15 mL Container Label

5 mL Carton Label
10 mL Carton Label
15 mL Carton Label
BRIMONIDINE TARTRATE AND TIMOLOL MALEATE
brimonidine tartrate and timolol maleate solution/ drops

Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:46708-706

Route of Administration OPHTHALMIC

 Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
BRIMONIDINE TARTRATE (UNII: 4S9CL2DY2H) (BRIMONIDINE - BRIMONIDINE 2 mg
UNII:E6GNX3HHTE) TARTRATE in 1 mL
TIMOLOL MALEATE (UNII: P8Y54F701R) (TIMOLOL ANHYDROUS - 5 mg
TIMOLOL ANHYDROUS
UNII:5JKY92S7BR) in 1 mL

Inactive Ingredients
Ingredient Name Strength
BENZALKONIUM CHLORIDE (UNII: F5UM2KM3W7)
SODIUM PHOSPHATE, MONOBASIC, MONOHYDRATE (UNII: 593YOG76RN)
SODIUM PHOSPHATE, DIBASIC, HEPTAHYDRATE (UNII: 70WT22SF4B)
WATER (UNII: 059QF0KO0R)
HYDROCHLORIC ACID (UNII: QTT17582CB)
SODIUM HYDROXIDE (UNII: 55X04QC32I)

Packaging
Marketing Start Marketing End
# Item Code Package Description
Date Date
NDC:46708-
1 1 in 1 CARTON 08/25/2023
706-05
5 mL in 1 BOTTLE, DROPPER; Type 0: Not a
1
Combination Product
NDC:46708-
2 1 in 1 CARTON 08/25/2023
706-10
10 mL in 1 BOTTLE, DROPPER; Type 0: Not a
2
Combination Product
NDC:46708-
3 1 in 1 CARTON 08/25/2023
706-15
15 mL in 1 BOTTLE, DROPPER; Type 0: Not a
3
Combination Product

Marketing Information
Marketing Application Number or Monograph Marketing Start Marketing End
Category Citation Date Date
ANDA ANDA215230 08/25/2023

Labeler - Alembic Pharmaceuticals Limited (650574663)

Establishment
Name Address ID/FEI Business Operations
Alembic Pharmaceuticals Limited (F3) 675480734 MANUFACTURE(46708-706)

Revised: 8/2023 Alembic Pharmaceuticals Limited