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Brimonidine (EENT)

Class: alpha-Adrenergic Agonists
ATC Class: S01EA05
VA Class: OP109
Chemical Name: [S-(R*,R*,)]-2,3-Dihydroxybutanedioate-5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine
Molecular Formula: C11H10BrN5 • C4H6O6
CAS Number: 79570-19-7
Brands: Alphagan P, Lumify

Medically reviewed by Drugs.com. Last updated on Dec 21, 2020.

Introduction

Relatively selective α2-adrenergic agonist.1 3 11 19

Uses for Brimonidine (EENT)

Ocular Hypertension and Glaucoma

Brimonidine tartrate 0.1, 0.15, and 0.2%: Reduction of elevated IOP in patients with open-angle glaucoma or ocular hypertension.1 3 13 19 Ocular hypotensive effect of the 0.1 or 0.15% solution is equivalent to that of the 0.2% solution; reduction in IOP was approximately 2–6 mm Hg in clinical studies.1 15 16

Fixed-combination brinzolamide 1% and brimonidine tartrate 0.2%: Reduction of elevated IOP in patients with open-angle glaucoma or ocular hypertension.20 When administered 3 times daily, IOP-lowering effect was 1–3 mm Hg greater than that of either drug administered at the same dosage as monotherapy.20

Fixed-combination brimonidine tartrate 0.2% and timolol 0.5%: Used topically in patients with glaucoma or ocular hypertension who require adjunctive or replacement therapy because of inadequately controlled IOP.21 When administered twice daily, IOP-lowering effect was 1–3 mm Hg greater than that of brimonidine tartrate 0.2% administered 3 times daily, 1–2 mm Hg greater than that of timolol 0.5% administered twice daily, and approximately 1–2 mm Hg less than that achieved with concurrent use of brimonidine tartrate 0.2% administered 3 times daily and timolol 0.5% administered twice daily.21

When selecting an initial ocular hypotensive agent, consider extent of the required IOP reduction, coexisting medical conditions, and drug characteristics (e.g., dosing frequency, adverse effects, cost).130 132 With single-agent regimens, the reduction in IOP is approximately 25–33% with topical prostaglandin analogs; 20–25% with topical β-adrenergic blocking agents, α-adrenergic agonists, or miotic (parasympathomimetic) agents; 20–30% with oral carbonic anhydrase inhibitors; 18% with topical rho kinase inhibitors; and 15–20% with topical carbonic anhydrase inhibitors.130 131

A prostaglandin analog frequently is considered for initial therapy in the absence of other considerations (e.g., contraindications, cost considerations, intolerance, adverse effects, patient refusal) because of relatively greater activity, once-daily administration, and low frequency of systemic adverse effects; however, ocular adverse effects can occur.130 131 132 134

Goal is to maintain an IOP at which visual field loss is unlikely to substantially reduce quality of life during the patient's lifetime.130 132

Reduction of pretreatment IOP by ≥25% shown to slow progression of primary open-angle glaucoma.130 131 Set an initial target IOP (based on extent of optic nerve damage and/or visual field loss, baseline IOP at which damage occurred, rate of progression, life expectancy, and other considerations) and reduce IOP toward this goal.130 131 132 Adjust target IOP up or down as needed over course of disease.130 131 132

Combination therapy with drugs from different therapeutic classes often required to control IOP.131 133

Conjunctival Congestion

Brimonidine tartrate 0.025%: Self-medication for temporary relief of ocular redness due to minor irritation.22

No evidence of tachyphylaxis in clinical studies, and minimal rebound ocular congestion observed following drug discontinuance.23 24 25 26

Brimonidine (EENT) Dosage and Administration

General

  • When used for ocular hypertension or glaucoma, determine IOP after about 4 weeks of therapy with the drug; thereafter, determine IOP as necessary.17

Administration

Ophthalmic Administration

Apply topically to the affected eye(s) as an ophthalmic solution (brimonidine alone or in fixed combination with timolol) or suspension (fixed-combination brinzolamide and brimonidine).1 19 20 21 22

Shake the ophthalmic suspension well prior to administration of each dose.20

Avoid contamination of the dispensing container.1 19 20 21 (See Bacterial Keratitis under Cautions.)

Some preparations contain benzalkonium chloride.19 20 21 22 Remove contact lenses before administering each dose of these preparations; may reinsert lenses 15 minutes after the dose.19 20 21 Manufacturer of brimonidine tartrate 0.025% ophthalmic solution states contact lenses may be reinserted 10 minutes after the dose.22 (See Use with Contact Lenses under Cautions.)

If more than one topical ophthalmic preparation is used, administer the preparations at least 5 minutes apart.1 11 19 20 21

Dosage

Pediatric Patients

Ocular Hypertension and Glaucoma
Ophthalmic

Brimonidine tartrate 0.1, 0.15, or 0.2% ophthalmic solution in pediatric patients ≥2 years of age: Manufacturer makes no specific dosage recommendations.17 (See Pediatric Use under Cautions.)

Brimonidine tartrate 0.2% and timolol 0.5% ophthalmic solution in pediatric patients ≥2 years of age: One drop in the affected eye(s) twice daily (approximately every 12 hours).21

Conjunctival Congestion
Ophthalmic

Brimonidine tartrate 0.025% ophthalmic solution in pediatric patients ≥5 years of age: One drop in the affected eye(s) every 6–8 hours.22

Adults

Ocular Hypertension and Glaucoma
Ophthalmic

Brimonidine tartrate 0.1, 0.15, or 0.2% ophthalmic solution: One drop in the affected eye(s) 3 times daily (approximately every 8 hours).1 11 19

Brinzolamide 1% and brimonidine tartrate 0.2% ophthalmic suspension: One drop in the affected eye(s) 3 times daily.20

Brimonidine tartrate 0.2% and timolol 0.5% ophthalmic solution: One drop in the affected eye(s) twice daily (approximately every 12 hours).21

If target IOP not achieved, may initiate additional or alternative ocular hypotensive agents.130 131 133 (See Ocular Hypertension and Glaucoma under Uses.)

Conjunctival Congestion
Ophthalmic

Brimonidine tartrate 0.025% ophthalmic solution: One drop in the affected eye(s) every 6–8 hours.22

Prescribing Limits

Pediatric Patients

Conjunctival Congestion
Ophthalmic

Brimonidine tartrate 0.025% ophthalmic solution: Maximum of 4 times daily.22

Adults

Conjunctival Congestion
Ophthalmic

Brimonidine tartrate 0.025% ophthalmic solution: Maximum of 4 times daily.22

Cautions for Brimonidine (EENT)

Contraindications

  • Neonates and infants <2 years of age.1 (See Pediatric Use under Cautions.)

  • Known hypersensitivity to brimonidine or any ingredient in the formulation.1 19

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Ocular hypersensitivity reactions (e.g., allergic conjunctivitis, conjunctival hyperemia, ocular pruritus) reported.1 If sensitivity reaction occurs, discontinue brimonidine.17

Possible partial cross-sensitivity between brimonidine and apraclonidine;18 use with caution in patients with a history of hypersensitivity to apraclonidine.17

Use of Fixed Combinations

When used in fixed combination with timolol or brinzolamide, consider the cautions, precautions, contraindications, and drug interactions associated with each agent in the fixed combination.20 21

Cardiovascular Disease

Minimal effects on BP in clinical studies; however, use with caution in patients with severe cardiovascular conditions.1 19

Vascular Insufficiency

May potentiate syndromes associated with vascular insufficiency; use with caution in patients with mental depression, orthostatic hypotension, cerebral or coronary insufficiency, Raynaud phenomenon, or thromboangiitis obliterans.1 19

IOP Monitoring

IOP-lowering effect of brimonidine may diminish over time; routinely monitor IOP.19

Bacterial Keratitis

Bacterial keratitis reported with use of multiple-dose containers of topical ophthalmic preparations.1 Containers were inadvertently contaminated by patients, most of whom had concurrent corneal disease or disruption of the ocular epithelial surface.1

Improper handling of ophthalmic preparations can result in contamination of the preparation by common bacteria known to cause ocular infections.1 Serious damage to the eye and subsequent loss of vision may result from using contaminated ophthalmic preparations.1 (See Advice to Patients.)

Use with Contact Lenses

Some brimonidine ophthalmic preparations contain benzalkonium chloride, which may be absorbed by soft contact lenses.19 20 21 22 Remove contact lenses before administering each dose of these preparations; may reinsert lenses 15 minutes after the dose.19 20 21 Manufacturer of brimonidine tartrate 0.025% ophthalmic solution states contact lenses may be reinserted 10 minutes after the dose.22

Specific Populations

Pregnancy

Category B.1 19

In studies in animals, brimonidine crossed the placenta and entered the fetal circulation to a limited extent; no evidence of teratogenicity was observed.1

No adequate and well-controlled studies in pregnant women.1 Use brimonidine only if potential benefits justify possible risk to the fetus.1

Lactation

Distributed into milk in rats;1 17 not known whether distributed into human milk following topical application to the eye.1 19 Discontinue nursing or the drug.1 19

Pediatric Use

Potentially serious adverse effects, including apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence, reported in infants;1 8 19 contraindicated in infants <2 years of age.1 6 19

Safety and efficacy of topical brimonidine for treatment of open-angle glaucoma or ocular hypertension not established in pediatric patients <2 years of age.1 19 In children 2–7 years of age with glaucoma, the most common adverse effects of brimonidine (0.2% solution administered 3 times daily) were somnolence and decreased mental alertness; approximately 16% of children discontinued therapy because of somnolence.1 19 Incidence of somnolence appeared to be age and weight related,1 6 occurring in 50–83% of children 2–6 years of age and 25% of those 7 years of age who weighed >20 kg.1 19

The individual components of brinzolamide and brimonidine ophthalmic suspension have been studied in pediatric patients 4 weeks to 5 years of age (brinzolamide) and 2–7 years of age (brimonidine).20

Safety and efficacy of brimonidine and timolol ophthalmic solution established in pediatric patients 2–16 years of age based on evidence from adequate and well-controlled studies of the fixed combination in adults and additional data from a study evaluating the individually administered drugs (brimonidine tartrate 0.2% administered 3 times daily as an adjunct to timolol therapy) in children 2–7 years of age with glaucoma.21

Safety and efficacy of topical brimonidine for self-medication for relief of ocular redness due to minor irritation not established in children <5 years of age.22 23 Safety and efficacy in pediatric patients ≥5 years of age are supported by evidence from controlled clinical trials in adults and additional data from a safety study in adults and pediatric patients ≥5 years of age.23

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.1 19

Hepatic Impairment

Not been studied in patients with hepatic impairment; use with caution.1 19 20

Renal Impairment

Not studied in patients with renal impairment.1 19

Common Adverse Effects

Brimonidine tartrate 0.1–0.2% ophthalmic solution: Oral dryness, ocular or conjunctival hyperemia, burning and stinging, allergic conjunctivitis, headache, blurring, foreign body sensation, fatigue/drowsiness, conjunctival follicles, ocular allergic reactions, ocular pruritus.1 19

Brimonidine tartrate 0.2% ophthalmic solution in children 2–7 years of age with glaucoma: Age- and weight-related somnolence and decreased mental alertness reported.1 6 19 (See Pediatric Use under Cautions.)

Brimonidine tartrate 0.025% ophthalmic solution in adults and pediatric patients: Decreased visual acuity, conjunctival or ocular hyperemia, dry eye, instillation site pain, headache.26

Interactions for Brimonidine (EENT)

No formal drug interaction studies have been performed.1 19

Specific Drugs

Drug

Interaction

Comment

β-Adrenergic blocking agents (topical or systemic)

Possible additive IOP-lowering and cardiovascular effects3 4 11

Use with caution1 19

Increased IOP-lowering effect used to therapeutic advantage21

Antidepressants, tricyclic (TCAs)

TCAs that affect the metabolism and uptake of circulating amines may interfere with IOP-lowering effect of brimonidine1 19

Use with caution1 19

Cardiac glycosides

Possible additive cardiovascular effects11

Use with caution1 19

CNS depressants (e.g., alcohol, barbiturates, general anesthetics, opiates, sedatives)

Possible additive CNS depressant effects1 19

Hypotensive agents

Possible additive IOP-lowering and cardiovascular effects3 4 11

Use with caution1 19

MAO inhibitors

Theoretical potential for interference with brimonidine metabolism, possibly resulting in increased systemic adverse effects (e.g., hypotension)1

Use with caution1

Brimonidine (EENT) Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations occurred within 0.5–4 hours after ocular administration of brimonidine tartrate 0.1 or 0.2% ophthalmic solution.1 19

Onset

Peak ocular hypotensive effects occur 2–3 hours following topical administration of brimonidine.1 3 19

Distribution

Extent

Distributed into milk in animals; not known whether the drug distributes into milk in humans.1 19

Elimination

Metabolism

Extensively metabolized in the liver.1 19

Elimination Route

Brimonidine and its metabolites are excreted principally in urine.1 19

Half-life

2–3 hours.1 19

Special Populations

Renal failure: Effect of dialysis on brimonidine pharmacokinetics not established.1

Stability

Storage

Ophthalmic

Solution

Brimonidine tartrate: 15–25°C.1 19 22

Brimonidine tartrate and timolol: 15–25°C.21

Brinzolamide and brimonidine tartrate: 2–25°C.20

Actions

  • Reduces IOP by decreasing aqueous humor production and increasing uveoscleral outflow.1 3 4 11 19

  • Selectivity for α2- versus α1-adrenergic receptors at least 10 or 28 times greater than that of clonidine or apraclonidine, respectively;3 9 11 may result in reduction in adverse pulmonary and cardiovascular effects.1 11

  • At low dosages (i.e., brimonidine tartrate 0.025%) in individuals with normal IOP, vasoconstrictive effects of the drug relieve ocular redness without altering IOP.23 26

Advice to Patients

  • Importance of advising patients that brimonidine may cause fatigue and/or drowsiness and to exercise caution when engaged in hazardous activities requiring mental alertness.1 19

  • Importance of learning and adhering to proper administration techniques to avoid contamination of the ophthalmic preparation with common bacteria that can cause ocular infections (e.g., bacterial keratitis).1 Instruct patients that the tip of the dispensing container should not touch the eye, surrounding structures, or any other surface.1 22 Serious damage to the eye and subsequent loss of vision may result from using contaminated ophthalmic preparations.1 Importance of always replacing the container cap immediately after use and of not using preparations that are cloudy or discolored or are past the labeled expiration date.1

  • Advise patients to immediately contact their clinician for advice regarding continued use of the current multidose container if they experience an intercurrent ocular condition (e.g., trauma, infection) or require ocular surgery.1

  • If using more than one topical ophthalmic preparation, importance of administering the preparations at least 5 minutes apart.1 19 20 21

  • For patients receiving brimonidine preparations that contain benzalkonium chloride as a preservative, importance of removing contact lenses before administering each dose and delaying reinsertion of the lenses for at least 15 minutes after the dose, since benzalkonium chloride in the preparation may be absorbed by soft contact lenses.19 20 21 May reinsert contact lenses 10 minutes after a dose of brimonidine tartrate 0.025% ophthalmic solution.22

  • Importance of discontinuing self-medication with brimonidine and contacting a clinician if ocular pain develops, changes in vision occur, ocular redness or irritation persists for >3 days, or the ocular condition worsens.22

  • For patients receiving brinzolamide and brimonidine fixed-combination ophthalmic suspension, potential for temporary blurring of vision following administration; importance of exercising caution when driving or operating machinery.20

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 19

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1 19

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Brimonidine Tartrate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Ophthalmic

Solution

0.025%

Lumify

Bausch & Lomb

0.1%

Alphagan P

Allergan

0.15%*

Alphagan P

Allergan

Brimonidine Tartrate Ophthalmic Solution

0.2%*

Brimonidine Tartrate Ophthalmic Solution

Brimonidine Tartrate Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Ophthalmic

Solution

0.2% with Timolol Maleate 0.5% (of timolol)

Combigan

Allergan

Suspension

0.2% with Brinzolamide 1%

Simbrinza

Alcon

AHFS DI Essentials™. © Copyright 2021, Selected Revisions December 21, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Allergan, Inc. Alphagan P (brimonidine tartrate ophthalmic solution) prescribing information. Irvine, CA; 2013 Sep.

2. Allergan, Inc. Alphagan (brimonidine tartrate ophthalmic solution) prescribing information. Irvine, CA; 2001 Dec.

3. Cantor LB. The evolving pharmacotherapeutic profile of brimonidine, an α2-adrenergic agonist, after four years of continuous use. Expert Opin Pharmacother. 2000; 1:815-34. http://www.ncbi.nlm.nih.gov/pubmed/11249518?dopt=AbstractPlus

4. Larsson LI. Aqueous humor flow in normal human eyes treated with brimonidine and timolol, alone and in combination. Arch Ophthalmol. 2001; 119:492-5. http://www.ncbi.nlm.nih.gov/pubmed/11296014?dopt=AbstractPlus

5. Schuman JS, Horwitz B, Choplin NT et al for the Chronic Brimonidine Study Group. A 1-year study of brimonidine twice daily in glaucoma and ocular hypertension. A controlled, randomized, multicenter clinical trial. Arch Ophthalmol. 1997; 115:847-52. http://www.ncbi.nlm.nih.gov/pubmed/9230823?dopt=AbstractPlus

6. Enyedi LB, Freedman SF. Safety and efficacy of brimonidine in children with glaucoma. J AAPOS. 2001; 5:281-4. http://www.ncbi.nlm.nih.gov/pubmed/11641636?dopt=AbstractPlus

7. Serle JB for the Brimonidine Study Group III. A comparison of the safety and efficacy of twice daily brimonidine 0.2% versus betaxolol 0.25% in subjects with elevated intraocular pressure. Surv Ophthalmol. 1996; 41(Suppl 1):S39-47.

8. Carlsen JO, Zabriskie NA, Kwon YH et al. Apparent central nervous system depression in infants after the use of topical brimonidine. Am J Ophthalmol. 1999; 128:255-6. http://www.ncbi.nlm.nih.gov/pubmed/10458196?dopt=AbstractPlus

9. Walters TR. Development and use of brimonidine in treating acute and chronic elevations of intraocular pressure: a review of safety, efficacy, dose response, and dosing studies. Surv Ophthalmol. 1996; 41(Suppl 1):S19-26. http://www.ncbi.nlm.nih.gov/pubmed/8970246?dopt=AbstractPlus

10. Melamed S, David R for the Brimonidine Study Group II. Ongoing clinical assessment of the safety profile and efficacy of brimonidine compared with timolol: year-three results. Clin Ther. 2000; 22:103-11. http://www.ncbi.nlm.nih.gov/pubmed/10688394?dopt=AbstractPlus

11. Maus TL, Nau C, Brubaker RF. Comparison of the early effects of brimonidine and apraclonidine as topical ocular hypotensive agents. Arch Ophthalmol. 1999; 117:586-91. http://www.ncbi.nlm.nih.gov/pubmed/10326954?dopt=AbstractPlus

12. Williams GC, Orengo-Nania S, Gross RL. Incidence of brimonidine allergy in patients previously allergic to apraclonidine. J Glaucoma. 2000; 9:235-8. http://www.ncbi.nlm.nih.gov/pubmed/10877374?dopt=AbstractPlus

13. Lewis PR, Phillips TG, Sassani JW. Topical therapies for glaucoma: what family physicians need to know. Am Fam Physician. 1999; 59:1871-9. http://www.ncbi.nlm.nih.gov/pubmed/10208706?dopt=AbstractPlus

14. Derick RJ, Robin AL, Walters TR et al. Brimonidine tartrate: a one-month dose response study. Ophthalmology. 1997; 104:131-6. http://www.ncbi.nlm.nih.gov/pubmed/9022117?dopt=AbstractPlus

15. Food and Drug Administration summary basis of approval on brimonidine tartrate 0.15% ophthalmic solution. NDA No. 21-262. Rockville, MD: undated. From the FDA website. Accessed March 25, 2002. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

16. Katz LJ. Twelve-month evaluation of brimonidine-Purite versus brimonidine in patients with glaucoma or ocular hypertension. J Glaucoma. 2002; 11:119-26. http://www.ncbi.nlm.nih.gov/pubmed/11912359?dopt=AbstractPlus

17. Allergan, Inc, Irvine, CA; Personal communication.

18. Williams GC, Orengo-Nania S, Gross RL. Incidence of brimonidine allergy in patients previously allergic to apraclonidine. J Glaucoma. 2000; 9:235-8. http://www.ncbi.nlm.nih.gov/pubmed/10877374?dopt=AbstractPlus

19. Bausch & Lomb Pharmaceuticals, Inc. Brimonidine tartrate ophthalmic solution 0.2% prescribing information. Bridgewater, NJ; 2018 Nov.

20. Alcon. Simbrinza (brinzolamide and brimonidine tartrate) ophthalmic suspension prescribing information. Fort Worth, TX; 2015 Nov.

21. Allergan. Combigan (brimonidine tartrate and timolol maleate) ophthalmic solution prescribing information. Irvine, CA; 2019 Jun.

22. Bausch & Lomb. Lumify (brimonidine tartrate) ophthalmic solution drug facts. Bridgewater, NJ; Undated.

23. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 208144Orig1s000: Summary review. From FDA website. Accessed 2019 Sep 30. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208144Orig1s000SumR.pdf

24. Torkildsen GL, Sanfilippo CM, DeCory HH et al. Evaluation of Efficacy and Safety of Brimonidine Tartrate Ophthalmic Solution, 0.025% for Treatment of Ocular Redness. Curr Eye Res. 2018; 43:43-51. http://www.ncbi.nlm.nih.gov/pubmed/29120262?dopt=AbstractPlus

25. McLaurin E, Cavet ME, Gomes PJ et al. Brimonidine Ophthalmic Solution 0.025% for Reduction of Ocular Redness: A Randomized Clinical Trial. Optom Vis Sci. 2018; 95:264-271. http://www.ncbi.nlm.nih.gov/pubmed/29461408?dopt=AbstractPlus

26. Ackerman SL, Torkildsen GL, McLaurin E et al. Low-dose brimonidine for relief of ocular redness: integrated analysis of four clinical trials. Clin Exp Optom. 2019; 102:131-139. http://www.ncbi.nlm.nih.gov/pubmed/30525235?dopt=AbstractPlus

130. Prum BE Jr, Rosenberg LF, Gedde SJ et al. Primary open-angle glaucoma preferred practice pattern guideline [published corrigendum appears in Ophthalmology. 2018; 125: 949]. San Francisco, CA: American Academy of Ophthalmology; 2015. From the American Academy of Ophthalmology website. https://www.aao.org/preferred-practice-pattern/primary-open-angle-glaucoma-ppp-2015

131. Liebmann JM, Lee JK. Current therapeutic options and treatments in development for the management of primary open-angle glaucoma. Am J Manag Care. 2017; 23(15 Suppl):S279-S292. http://www.ncbi.nlm.nih.gov/pubmed/29164845?dopt=AbstractPlus

132. Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA. 2014; 311:1901-11. http://www.ncbi.nlm.nih.gov/pubmed/24825645?dopt=AbstractPlus

133. Gupta D, Chen PP. Glaucoma. Am Fam Physician. 2016; 93:668-74. http://www.ncbi.nlm.nih.gov/pubmed/27175839?dopt=AbstractPlus

134. Inoue K. Managing adverse effects of glaucoma medications. Clin Ophthalmol. 2014; 8:903-13. http://www.ncbi.nlm.nih.gov/pubmed/24872675?dopt=AbstractPlus