Ophthalmic Beta-Adrenergic Antagonists Drug Class … · review focuses on the ophthalmic...

Drug Class Review

Ophthalmic Beta-Adrenergic Antagonists 52:40.08 Beta-Adrenergic Blocking Agents

Betaxolol (Betoptic®) Carteolol (Ocupress®)

Levobunolol (Betagan®) Metipranolol (Optipranolol®)

Timolol (Betimol®, Timoptic®, others) Timolol/Brimonidine (Combigan®)

Timolol/Dorzolamide (Cosopt®; Cosopt PF®)

Final Report November 2015

Review prepared by: Melissa Archer, PharmD, Clinical Pharmacist Carin Steinvoort, PharmD, Clinical Pharmacist Gary Oderda, PharmD, MPH, Professor University of Utah College of Pharmacy Copyright © 2015 by University of Utah College of Pharmacy Salt Lake City, Utah. All rights reserved.

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Table of Contents

Executive Summary ......................................................................................................................... 3 Introduction .................................................................................................................................... 5 Table 1. Glaucoma Therapies ................................................................................................. 6 Table 2. Summary of Agents .................................................................................................. 7 Disease Overview ...................................................................................................................... 10 Table 3. Summary of Current Clinical Practice Guidelines .................................................. 11 Pharmacology ............................................................................................................................... 12 Methods ........................................................................................................................................ 12 Clinical Efficacy .............................................................................................................................. 12 Adverse Drug Reactions ................................................................................................................ 16 Table 4. Rate of Adverse Events Reported with Ophthalmic Beta‐Adrenergic Antagonists 17 References .................................................................................................................................... 21 Appendix: Evidence Tables ........................................................................................................... 26 Evidence Table 1. Clinical Trials Evaluating the Ophthalmic Beta‐Adrenergic Antagonists ......... 26 Evidence Table 2. Clinical Trials Evaluating the Ophthalmic Beta‐Adrenergic Antagonists in

Special Populations ................................................................................................................. 31

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Executive Summary

Introduction: Five ophthalmic beta-blocking agents are currently available for this use in the United States: betaxolol (Betoptic®), carteolol (Ocupress®), levobunolol (Betagan®), metipranolol (Optipranolol®) and timolol (Timoptic®). Two combination agents are also available for use: one beta-adrenergic antagonist in combination with an alpha2 agonist (timolol/brimonidine, Combigan®) and one beta-adrenergic antagonist in combination with a carbonic anhydrase inhibitor (timolol/dorzolamide, Cosopt®). All of the agents are indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma and are dosed one drop in the affected eye(s) once to twice daily. Glaucoma is a leading cause of blindness worldwide. Reducing intraocular pressure (IOP) is directly associated with slowing glaucoma progression and protecting the optic nerve, and is the main measurable goal of open-angle glaucoma (OAG) treatment. Options for lowering IOP include medications, surgery and laser procedures. Current treatment guidelines from the American Academy of Ophthalmology do not specify a preferred procedure or medication for treating glaucoma. Topical prostaglandins and beta-adrenergic blockers are the most commonly used medications for open-angle glaucoma. The beta-adrenergic antagonists may be considered a first-line agent because they are effective, well tolerated and generically available.

Clinical Efficacy: The efficacy of the ophthalmic beta-adrenergic antagonist agents is evaluated in a number of comparative clinical trials. A total of 11 clinical trials were identified for inclusion in this analysis. Each of the 11 trials evaluated the efficacy of timolol versus at least one other ophthalmic beta-adrenergic antagonist. The majority of published data suggest similar IOP reduction with timolol compared to the four other available agents. Some evidence suggests higher rates of IOP lowering with the non-selective ophthalmic beta-adrenergic antagonist, timolol, compared to the cardioselective ophthalmic beta-adrenergic antagonist, betaxolol, and higher rates of improved visual field changes with betaxolol compared to timolol. This evidence suggests more research is required to determine whether the differences in reported outcomes between nonselective and cardioselective beta-blocker glaucoma therapies result in differences in overall efficacy and disease progression in the treatment of OAG.

Adverse Drug Reactions: The ophthalmic beta-adrenergic antagonist agents are generally well-tolerated and the most common ocular adverse events reported with agents include blurriness and burning/stinging upon administration, dry eyes and keratitis. Benzalkonium chloride is a preservative used in a number of the ophthalmic beta-adrenergic antagonist agents and may be associated with allergic reactions and corneal opacity. All preparations, especially the non-selective agents, are rarely associated with systemic effects including bronchoconstriction, bradycardia, depression, confusion and fatigue. The ophthalmic beta-adrenergic antagonists should be avoided in patients with cardiac conduction defects and in patient with obstructive airways disease (of note, cardioselective betaxolol may be a safer option in these patients).

Summary: The ophthalmic beta-adrenergic antagonist agents are commonly used in the treatment of OAG because they are effective in reducing IOP, are well tolerated and are available in generic formulations. Clinical guidelines do not recommend a specific beta-antagonist agent

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or even a specific class of medications for patients with glaucoma. The ophthalmic beta-blocking agents demonstrate similar rates of IOP reductions. Differences in adverse effects have been reported between the agents but overall, the adverse events reported in clinical trials tend to be mild in nature. To reduce the risk of systemic adverse events, patients should receive the lowest effective concentration of medication and receive instruction on proper method of topical administration.

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Introduction

Several classes of topical ophthalmic medications are available for treating glaucoma in

the United States: beta-adrenergic blockers, carbonic anhydrase inhibitors, miotics, prostaglandins and sympathomimetics.1,2 Table 1 compares these medication classes. This review focuses on the ophthalmic beta-adrenergic antagonists. Five ophthalmic beta-blocking agents are currently available for this use in the United States: betaxolol (Betoptic®), carteolol (Ocupress®), levobunolol (Betagan®), metipranolol (Optipranolol®) and timolol (Timoptic®). In addition, two combination agents are available for use one beta-adrenergic antagonist in combination with an alpha-2 agonist (timolol/brimonidine, Combigan®) and one beta-adrenergic antagonist in combination with a carbonic anhydrase inhibitor (timolol/dorzolamide, Cosopt®).3 Table 2 provides a summary of the available ophthalmic beta-adrenergic antagonists agents.

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Table 1. Glaucoma Therapies1,4 Characteristic Prostaglandins Beta‐Adrenergic Blockers Carbonic Anhydrase Inhibitors Sympathomimetics Miotic Agents

Agents in Class Bimatoprost Latanoprost Tafluprost Travoprost

Betaxolol Carteolol Levobetaxolol [DSC] Levobunolol Metipranolol Timolol

Brinzolamide Dorzolamide

Apraclonidine Brimonidine Dipivefrin

Acetylcholine Carbachol Echothiophate Iodide Pilocarpine

Generics Available in Class Yes Yes None Yes Yes

Combination Products Latanoprost/Timolol [NA] Travoprost/Timolol [NA]

Brimonidine/Timolol Brinzolamide/Timolol [NA] Dorzolamide/Timolol Latanoprost/Timolol [NA] Travoprost/Timolol [NA]

Brinzolamide/Brimonidine Brinzolamide/Timolol [NA] Dorzolamide/Timolol

Brinzolamide/Brimonidine Brimonidine/Timolol

None

Duration of Action 24 hrs 12 – 24 hrs 8 – 12 hrs 7 – 12 hrs Eyedrops: 4 – 8 hrs Echothiophate: 1–4 weeks Pilocarpine gel: 18–24 hrs Pilocarpine insert: 1 week

Pharmacologic Effects

Decrease aqueous production

Not reported Significant effect Significant effect Apraclonidine, Brimonidine: Moderate to significant effect Dipivefrin, Epinephrine: Some effect

Not reported

Increase aqueous outflow Significant effect No effect to Some effect Not reported Moderate effect Significant effect

Effect on pupil Not reported Not reported Not reported Mydriasis Miosis

Effect on ciliary muscle Not reported Not reported Not reported Not reported Accommodation

Magnitude of IOP Lowering 25 – 35% 20 – 30% 15 – 26% 2 – 5 hrs: 18 – 27% 8 – 12 hrs: 10%

20 – 30%

Key adverse effects

Ocular Redness, increased iris pigmentation, eyelash changes

Stinging, burning Allergic sensitivity, burning, stinging

Hyperemia, lid edema, itching, foreign‐object sensation

Stinging, irritation, miosis

Systemic Upper respiratory tract infections

Bradycardia, bronchial constriction, blood pressure reduction

Altered taste Dizziness, dry mouth, fatigue

Headache

Key: DSC ‐ discontinued, NA ‐ not available in the US

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Table 2. Summary of Agents*1,4-6 Characteristic Betaxolol

(Betoptic®) Carteolol (Ocupress®) Levobunolol

(Betagan®) Metipranolol (Optipranolol®)

Timolol (Betimol®)

Timolol/Brimonidine (Combigan®)

Timolol/Dorzolamide (Cosopt®)

Concentrations Suspension: 0.25% Solution: 0.5%

Solution: 1% Solution: 0.25%, 0.5% Solution: 0.3% Gel Forming Solution: 0.25%, 0.5% Solution, as hemihydrate: 0.25%, 0.5% Solution, as maleate: 0.25%, 0.5% Solution, as maleate, preservative‐free: 0.25%, 0.5%

Solution: Brimonidine tartrate 0.2% and timolol 0.5%

Solution: Dorzolamide 2% and timolol 0.5% Solution, preservative‐free: Dorzolamide 2% and timolol 0.5%

Package Sizes Available

0.25%: 10mL, 15mL 0.5%: 5mL, 10mL, 15mL

5mL, 10mL, 15mL 0.25%: 5mL, 10mL 0.5%: 5mL, 10mL, 15mL

5mL, 10mL 0.25%: 5mL, 10mL, 15mL 0.5%: 2.5mL, 5mL, 10 mL, 15mL preservative free: 0.25% (60 doses); 0.5% (60 doses)

5mL, 10mL 10 mL preservative‐free: 60 doses

Generic Available? 0.25%: No 0.5%: Yes

Yes Yes Yes Timoptic Ocudose (preservative‐free): No Betimol (hemihydrate base): No Others: Yes

No Yes Preservative‐free: No

Labeled Use Chronic open‐angle glaucoma Ocular hypertension

Open‐angle glaucoma Intraocular hypertension

Chronic open‐angle glaucoma Ocular hypertension

Chronic open‐angle glaucoma Ocular hypertension

Ocular hypertension or open‐angle glaucoma

Elevated intraocular pressure

Elevated intraocular pressure

pH 7.4‐7.6 6.2‐7.2 5.5‐7.5 5.0‐5.8 ~7.0 6.5‐7.3 5.65

Osmolality 290 mOsmol/kg 263‐306 mOsmol/kg 250‐360 mOsm/kg 265‐330 mOsmol/kg 274‐328 mOsm/kg

260‐330 mOsmol/kg 242‐323 mOsM/kg

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Characteristic Betaxolol (Betoptic®)

Carteolol (Ocupress®) Levobunolol (Betagan®)

Metipranolol (Optipranolol®)

Timolol (Betimol®)



Plasma Concentration after Ophthalmic Use

Up to 9.43 ng/ml Up to 8.00 ng/ml 1.60 ng/ml 6.5 ng/ml Up to 9.89 ng/ml Brimonidine: 0.0327 ng/ml Timolol: 0.406 ng/ml

0.46 ng/mL

Time to Peak Concentration

2 hours 2 hours 2‐6 hours 2 hours 1‐2 hours ~1 hour 2 hours

Volume of Distribution

4.9 L/kg ‐ 8.8 L/kg 4.05 L/kg 5.5 L/kg 3.5 L/kg 1.3‐1.7 L/kg See individual products See individual products

Elimination Route Urine Urine Urine and Feces Urine Urine Urine Urine

Plasma Half‐life 14‐22 hours Carteolol: ~6 hours 8‐hydroxycarteolol (active metabolite): ~8‐12 hours

~20 hours ~3 hours 2.5‐5 hours Brimonidine: 3 hours Timolol: 7 hours

Up to 4 months

Labeled Dosage Range, Adults

1‐2 drops into affected eye(s) twice daily Pediatric: Elevated intraocular pressure: 1 drop into affected eye(s) twice daily

1 drop in affected eye(s) twice daily Not indicated in the pediatric population

1‐2 drops into affected eye(s) once to twice daily Not indicated in the pediatric population

1 drop in the affected eye(s) twice daily Not indicated in the pediatric population

1 drop into affected eye(s) once to twice daily Pediatric (may be off‐label): Elevated intraocular pressure: Use lowest effective dose, gel formulation may be preferable due to decreased systemic absorption7; Gel‐forming solution: Instill 1 drop once daily into affected eye(s)7; Solution: 0.25% solution, 1 drop twice daily into affected eye(s); increase to 0.5% solution if response not adequate8

1 drop into affected eye(s) twice daily Pediatric: Glaucoma, ocular hypertension: Children ≥2 years: 1 drop into affected eye(s) twice daily *Note: In the Canadian labeling, use in children (at any age) is not recommended

1 drop in affected eye(s) twice daily Pediatric: Elevated intraocular pressure: Children ≥2 years and Adolescents: Refer to adult dosing

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Characteristic Betaxolol (Betoptic®)

Carteolol (Ocupress®) Levobunolol (Betagan®)

Metipranolol (Optipranolol®)

Timolol (Betimol®)



Preservative in Product

Benzalkonium chloride 0.01%

Benzalkonium Chloride 0.005%

benzalkonium chloride 0.004%

Benzalkonium Chloride 0.004%

Benzalkonium Chloride; preservative‐free agent available

Benzalkonium chloride 0.005%

Benzalkonium chloride 0.0075%; preservative‐free agent available

Contraindications Hypersensitivity; sinus bradycardia; heart block greater than first‐degree; cardiogenic shock; uncompensated cardiac failure

Hypersensitivity; sinus bradycardia; heart block greater than first‐degree; cardiogenic shock; bronchial asthma, bronchospasm, or COPD; uncompensated cardiac failure; pulmonary edema

Hypersensitivity; bronchial asthma; severe COPD; sinus bradycardia; second‐ or third‐degree AV block; overt cardiac failure; cardiogenic shock

Hypersensitivity; bronchial asthma; severe COPD; sinus bradycardia; second‐ and third‐degree AV block; cardiac failure; cardiogenic shock

Hypersensitivity; sinus bradycardia; sinus node dysfunction; heart block greater than first degree; cardiogenic shock; uncompensated cardiac failure; bronchospastic disease

Hypersensitivity; current or history of bronchial asthma; severe chronic obstructive pulmonary disease (COPD); sinus bradycardia; second‐ or third‐degree atrioventricular block; overt cardiac failure; cardiogenic shock; children <2 years of age; also see individual agents

Hypersensitivity; bronchial asthma or a history of bronchial asthma; severe chronic obstructive pulmonary disease; sinus bradycardia; second‐ or third‐degree atrioventricular block; overt cardiac failure; cardiogenic shock

Storage Refrigerator or room temperature (36°F to 77°F)

Room temperature away from light and moisture

Room temperature (59°‐86°F, away from light

Room temperature (59°‐86°), away from heat, moisture & light

Room temperature (59°‐77°F); protect from light

Room temperature (59°F to 86°F); protect from light

Room temperature (59°F to 86°F); protect from light

Latest Patent/ Exclusivity Expiration Date

expired December 2010, no generic product available for 0.25% product

expired, generic available



Betimol ‐ 7/2010 Timoptic Ocudose ‐ expired

Apr 19, 2022 Feb 1, 2015

*Data summarized based on package labeling. Please see Full Prescribing Information for most up‐to‐date and complete dosing information.

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Disease Overview

Glaucoma is one of the leading causes of blindness in the United States and abroad. All forms of glaucoma are characterized by optic neuropathy resulting in a loss of visual sensitivity and visual field.9,10 The two major forms are open-angle glaucoma and angle-closure glaucoma. Optic neuropathy associated with angle-closure glaucoma results from reduced access of aqueous fluid to the drainage system. Open-angle glaucoma is characterized by a chronic, persistent worsening of optic neuropathy, with associated optic disk and visual field decline as a result of abnormalities within the drainage system.11 Open-angle glaucoma is usually a bilateral disease but disease severity is generally greater in one eye than the other. Primary OAG accounts for the majority of glaucoma cases. Less common forms of OAG include congenital glaucomas and secondary glaucomas caused by medication, disease or injury. 9,12

In OAG, the trabecular meshwork of the eye is compromised, impairing outflow

of aqueous humor from the anterior chamber of the eye. Build-up of aqueous humor results in elevated intraocular pressure (IOP, > 21 mm Hg).10,11 Although elevated IOP is the primary known contributor to glaucoma-associated optic neuropathy, 16-50% of patients with OAG do not have consistently elevated IOP and glaucoma can progress even when IOP is normal. Other factors associated with disease progression are unclear.11 The loss of vision associated with OAG is thought to result from loss of retinal ganglion cells resulting in defects in field of vision. The reasons for ganglion cell loss are unclear but may be tied to a combination of hypoxia linked to reduction of retinal circulation in addition to chronic increased IOP.13 Regardless of whether IOP is elevated or normal, IOP reduction is directly related to slowing glaucoma progression and protecting the optic nerve. The primary measurable short-term goal in OAG treatment is IOP reduction.9,12 Because patients with OAG present with IOP measurements ranging from normal to extremely elevated, there is no commonly established target IOP goal. Target IOPs are specific to each patient depending on the presence of other risk factors and disease severity. In general, an initial IOP reduction of at least 25% is sought, even in patients with normal baseline IOP. Patients with disease progression at the established target IOP reduction require adjustment to a lower target.9 Intraocular hypertension (IOH) is defined as IOP > 21 mm Hg with no visual field or optic disk involvement in patients with open angles.11 Only a small percentage of patients with IOH develop OAG but patients with IOH are 16 times more likely to develop OAG than those with IOP < 16 mm Hg. The 5-year risk of visual field impairment is 6.7% for patients with IOP > 21 mm Hg, compared to 1.5% in those with IOP < 20 mm Hg.

The US guidelines for diagnosing and treating primary OAG developed by the

American Academy of Ophthalmology (2005, 2010) are considered the standard of care.9 Guidelines do not specify a preferred ophthalmic medication for treating of OAG. Treatment selection is tailored to the needs of the individual. Prostaglandins and beta-adrenergic blockers are the most commonly used medications for OAG. Prostaglandins are often preferred because they can be dosed once daily and are well tolerated. Beta-adrenergic blockers are also commonly used because they are well tolerated and generic formulations are available.9,11 Patients with an inadequate IOP response to a single

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medication are either treated with combination therapy or switched to a different medication class. Concurrent use of multiple ophthalmic medications should be avoided, as increased regimen complexity is associated with decreased compliance, and noncompliance is a major source of treatment failure in OAG. Surgical or laser treatment for OAG can also be considered initially or after inadequate response to ophthalmic medications. However, many patients still require treatment with an ophthalmic medication for additive IOP lowering effects after these procedures. Five to ten year failure rates after common OAG surgeries or laser treatments range from 20-50%, and failure rates increase dramatically after subsequent procedures.9

Table 3. Summary of Current Clinical Practice Guidelines14

Guideline Recommendations

American Academy of Ophthalmology (AAO, 2010)9

Definition of OAG: Evidence of either or both: (a) optic disc or RNFL defects; (b) VF defect; Adult‐onset; Open angles; Absence of other causes Goals of Treatment: Stable optic nerve/RNFL status; Controlled IOP; Stable visual fields Target IOP: Initial target IOP should be 20% lower than pretreatment IOP; the more advanced damage, the lower the IOP target; continued lowering of target IOP with disease progression

American Optometric Association (AOA, 2010)12

Definition of OAG: chronic, progressive disease with characteristic optic nerve (ON) damage, retinal nerve fiber layer (NFL) defects, and subsequent visual field (VF) loss. Goals of Treatment: Reducing or preventing further ON damage Target IOP: 30‐50% lower than the pretreatment level

European Glaucoma Society (EGS, 2008)14

Definition of OAG: Acquired characteristic optic disc or RNFL defects; Glaucomatous VF defects; Age > 35 years; Open angles; Untreated IOP > 21 mm Hg Goals of Treatment: Maintain the patient’s quality of life at a sustainable cost Target IOP: Aim for at least a 20% reduction from initial IOP; target IOP varies according to pretreatment IOP, overall risk of IOP‐related damage, stage of glaucoma, rate of progression, age, life expectancy, and risk factors

South East Asia Glaucoma Interest Group (SEAGIG, 2008)14

Definition of OAG: Chronic progressive optic neuropathy with characteristic changes in the optic nerve or VF; Absence of other causes Goals of Treatment: Tailor treatment to severity of glaucoma, depending on disease stage and risk factors Target IOP: Target IOP is based on the pressure reduction required to slow or stop disease progression; target IOPs set for disease severity with more aggressive targets in advanced disease

Key: OAG = open‐angle glaucoma; RNFL = retinal nerve fiber layer; VF = visual field; IOP = intraocular pressure

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Pharmacology

In 1979, ophthalmic timolol solution (Timoptic) was the first beta-adrenergic antagonist approved for the treatment of intraocular pressure. Since then, a number of additional ophthalmic beta-blocking agents have been approved for use in the US. Carteolol, levobunolol, metipranolol and timolol are non-selective ophthalmic beta-adrenergic antagonists with effects on both beta-1 and beta-2 receptors. Betaxolol is a cardioselective ophthalmic beta-adrenergic antagonist with effects primarily on beta-1 receptors.10-12 The exact mechanism of action of intraocular pressure reduction is unknown however, it is thought the ophthalmic beta-blockers work by reducing aqueous humor production and/or increasing aqueous humor outflow.1,2

Methods

A literature search was conducted to identify articles evaluating the ophthalmic beta-

adrenergic antagonist agents, searching the MEDLINE database (1950 – 2015), the EMBASE database, the Cochrane Library and reference lists of review articles. For the clinical efficacy section, only clinical trials published in English, evaluating the comparative efficacy of the agents are included. Trials evaluating the agents as monotherapy or combination therapy where adjunctive medications remained constant throughout the trial are included. Noncomparative trials and trials comparing monotherapy with combination regimens are excluded.15-25 The following reports were excluded (note: some were excluded for more than 1 reason):

Individual clinical trials which evaluated endpoints other than reduction of symptoms, such

as pharmacokinetics26-28, pharmacodynamics29-38, pharmacoeconomics or other outcomes unrelated to reduction of symptoms.39-46

Individual trials comparing the agents in dose-finding and placebo-controlled studies or in healthy volunteers.47-52

Individual clinical trials evaluating agents or formulations not currently available in the US, protocol templates or clinical trials without access to the full article.49,53-74

Clinical Efficacy

The efficacy of the ophthalmic beta-adrenergic antagonist agents is evaluated in a number of comparative clinical trials. A total of 11 clinical trials were identified for inclusion in this analysis. Each of the 11 trials evaluated the efficacy of timolol versus at least one other ophthalmic beta-adrenergic antagonist. The efficacy of timolol is compared to betaxolol in four trials, to levobunolol in two trials, to carteolol in two trials and to metipranolol in one trial. Three comparative trials evaluating the efficacy of once daily timolol gel to twice daily timolol solution are available for evaluation. One trial evaluating the efficacy of concomitant administration of timolol with dorzolamide compared to a fixed combination of these agents is also available. The clinical safety and efficacy data from these trials is summarized below. See Table 1 in the appendix for the evidence table outlining the included trials.

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Three trials comparing the efficacy of timolol to betaxolol are available for evaluation. In 2004, Miki et al75 published results from a crossover trial of 11 patients who received timolol 0.5% solution administered for 2 years then switched to betaxolol 0.5% solution for 2 additional years. According to the evidence, both agents reduced IOP compared to baseline (p < 0.05) but no differences in IOP reductions were reported between treatment groups. In the same patient group, improvements in visual field changes occurred more frequently in the betaxolol treatment groups compared to the timolol treatment group (p < 0.05). In 2002, Vainio-Jylha76 et al published results from a randomized, double-blind trial of 64 patients with a diagnosis of glaucoma. Patients were randomized to receive betaxolol 0.5% solution or timolol 0.25% solution given twice daily. At the end of the 2 year study period, both agents demonstrated improved rates of efficacy but no differences in the progression of retinal nerve damage or reduction of IOP values were reported between treatment groups. This limited evidence suggests timolol 0.25% ophthalmic solution may be as effective as betaxolol 0.5% ophthalmic solution. A third trial, published in 1998, evaluated the efficacy of betaxolol 0.5% solution, timolol 0.5% solution and pilocarpine 2% in patients with a diagnosis of open-angle glaucoma and an IOP > 24 mmHg. Drance et al77 evaluated the efficacy of the agents over a course of 24 weeks and reported overall improvements in both IOP and visual field values with no differences in rates of efficacy between the agents at the end of the study period. No safety data were provided in the three clinical trials.

One trial evaluating the efficacy of timolol, betaxolol and carteolol is available for

evaluation. In 2001, Watson et al13 published a long-term trial evaluating the efficacy of each of the agents dosed twice daily for up to 7 years. A total of 153 patients (including a total of 280 eyes) were selected for inclusion and, at the end of the study period, 35% (99 eyes) remained in the study. The most frequent reason for study withdrawal was inefficacy. According to the evidence, more patients on betaxolol withdrew from the study within the first year compared to patients on timolol or carteolol (no p value provided). Of those who remained in the study, no differences in mean reduction of IOP were reported between treatment groups at year seven. No significant differences in adverse event rates were reported between treatment groups. Stinging was reported in 0-1% of patients receiving timolol and carteolol and in 20.4% of those receiving betaxolol (p value not provided). Overall, this evidence suggests the ophthalmic beta-adrenergic agents are efficacious in reducing IOP but patients may require switch of therapy or combination therapy over time.

One trial evaluating the efficacy of timolol, carteolol and metipranolol is available for

evaluation. In 2000, Mirza et al78 published a small randomized controlled trial evaluating the efficacy of each of the agents dosed twice daily in 45 patients (n = 15 per treatment group) with a diagnosis of OAG or ocular hypertension. At the end of the 90-day study period, no differences in reduction of IOP or visual field changes were reported between any of the treatment groups. No significant differences in adverse events were reported between treatment groups. Of note, statistically significant increases in triglyceride levels occurred in all treatment groups when compared to baseline (increases of > 40 mg/dL; p < 0.05). This evidence suggests careful monitoring of cholesterol levels in patients receiving ophthalmic beta-adrenergic antagonist agents may be important to avoid complications, especially in patients with underlying heart disease.

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Two trials evaluating the efficacy of timolol and levobunolol are available for evaluation. In 2002, Halper et al79 published a cross-over trial comparing once-daily timolol 0.5% gel to twice daily levobunolol 0.5% solution in 133 adult patients with a diagnosis of OAG or ocular hypertension and an IOP > 22 mmHg. Patients were randomized to receive 6 weeks of each treatment with a 3-week placebo wash-out period in between treatment cycles. At the end of the study period, no differences in reduction of IOP values were reported between treatment groups. The rate of reported burning and stinging was higher in the levobunolol treatment groups (25%) compared to the timolol treatment groups (4%, p < 0.001) and the rate of heartrate changes was greater in the levobunolol treatment groups (reduction of ~4.3-4.5 bpm) compared to the timolol treatment groups (reduction of <1.8 bpm, p < 0.05). No information regarding treatment adherence or patient preference was reported by the authors. In 1998, Walters et al80 published a similar trial comparing the efficacy of once-daily timolol 0.5% gel to twice daily levobunolol 0.5% solution. A total of 152 patients were randomized to receive 6 weeks of each treatment and at the end of the study period, no differences in reduction of IOP were reported between treatment groups. Again, reduced heart rate occurred at a greater rate in the levobunolol treatment groups (reduction of >3 bpm) compared to the timolol treatment groups (reduction of <2 bpm; p =0.001) but no differences in the rate of reported burning and stinging were reported between treatment groups. Of note, blurred vision was reported more frequently in the timolol gel treatment groups (8%) compared to the levobunolol solution treatment groups (1%, p = 0.013). This evidence suggests timolol and levobunolol produce similar rates of efficacy but appear to have different safety profiles.

One trial evaluating the efficacy of the combination product dorzolamide/timolol versus

the individual agents is available for analysis. In 2004, Francis et al81 published a two-part study with part-one, a randomized trial of 131 patients assigned to either the fixed combination product (n = 57) or concomitant administration of the individual products (n = 74) for 4 weeks, followed by part-two, a non-randomized evaluation of all patients switched to the fixed combination product (n = 404). Patients included in the trial had a diagnosis of primary open-angle glaucoma, ocular hypertension or pseudoexfoliation glaucoma in both eyes. At the end of part-one of the trial IOP reduction ranged from -3.2 to -6.5 in the fixed combination group compared to -0.3 to -3.2 in the concomitant treatment group (p = NS). At the end of part-two of the trial, a significant reduction in IOP from baseline was demonstrated (-8.8%, p < 0.0001). No information regarding treatment adherence or patient preference was reported. This evidence suggests administration of the combination agent produces similar rates of IOP lowering as administration of the individual agents in a controlled clinical setting but differences in IOP lowering may occur in a more “real-world” setting as evidenced by part-two of the trial.

Three trials evaluating the efficacy of different timolol products are available for

evaluation. In 2004, Mundorf et al82 compared to the efficacy of timolol LA 0.5% solution (containing potassium sorbate, enhancing ocular bioavailability and reducing administration frequency27) once daily to timolol 0.5% solution twice daily in 332 adult patients with a diagnosis of OAG or ocular hypertension and an IOP > 22 mmHg. At the end of the long-term trial (12 months) mean reductions in IOP values were similar between treatment groups (20-28%, p = NS). Adverse event-related discontinuation rate was similar between the timolol LA and timolol twice daily treatment groups (6% and 4.2%, p = NS) but rate of burning/stinging adverse events were reported more frequently in the timolol LA treatment group (41.6%)

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compared to the timolol twice daily treatment group (22.9%, p = 0.001). In 2001, Shedden et al83 published a trial comparing the efficacy of timolol 0.5% gel-forming solution (gels increase drug contact time with the eye and absorption across the cornea) once daily and timolol 0.5% solution twice daily in a randomized, double-bling trial. A total 286 patients with OAG or ocular hypertension were randomized to receive one of the treatments for a duration of 6 months. At the end of the study period, no differences in reduction of IOP values were reported between treatment groups. Adverse events varied between treatment groups; blurred vision and tearing occurred more frequently in the timolol gel group (p = 0.04) while burning/stinging and reduced heartrate occurred more frequently in the timolol solution group (p < 0.05). No information regarding treatment adherence or patient preference was reported. In 1999, Schenker et al84 published a cross-over trial comparing the timolol 0.5% gel-forming solution once daily and timolol 0.5% solution twice daily. A total of 202 patients with a diagnosis of OAG or ocular hypertension and an IOP > 22 mmHg participated in the study randomized to 6 weeks of treatment with each individual agent. At the end of the 12 week study period, no differences in mean reduction of IOP or drug-related adverse events were reported between treatment groups. Despite similar rates of safety and efficacy for the agents, patients reported greater rates of preference for timolol gel-forming solution compared to the timolol twice daily solution (p < 0.001). Overall, this evidence suggests the different ophthalmic timolol agents produce similar rates of efficacy in patients with OAG and ocular hypertension.

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Adverse Drug Reactions

The ophthalmic beta-adrenergic antagonist agents are generally well-tolerated. The most common ocular adverse events reported with ophthalmic beta-blocker therapy include blepharoconjunctivitis, blurriness, burning/stinging upon administration, corneal anesthesia, diplopia, dry eyes, keratitis and ptosis.1,2,10,11 Benzalkonium chloride is a preservative used in a number of the ophthalmic beta-adrenergic antagonist agents and is also associated with allergic reactions, corneal opacity and keratitis. Topical ophthalmic agents do not generally cause systemic adverse effects, however the rate of systemic adverse effects appears to be slightly more common with the ophthalmic beta-adrenergic antagonists compared to other ophthalmic glaucoma therapies. The most common systemic adverse events reported with ophthalmic beta-blocker therapy include asthma, bradycardia85, cardiac arrhythmia, confusion, depression45, dizziness, dyspnea, hallucinations, impotence, myasthenia and psychosis. .1,2,10,11 The agents have also been associated with changes in cholesterol levels (reduced total cholesterol and HDL levels and increased triglyceride levels).44,86-88 Caution should be used with ophthalmic beta-blocker therapy in patients with chronic-obstructive pulmonary disease, bronchospastic disease, heart failure and diabetes mellitus (as beta-blockers can mask the signs and symptoms of acute hypoglycemia). The use of two ophthalmic beta-blocking therapies is not recommended as the risk of adverse effects greatly increases. Table 4 provides a summary of the adverse events reported with the individual agents, based on package labeling.

A review (2001) of safety data reported in clinical trials reported bronchospasm, adverse cardiovascular effects (including bradycardia) and, less commonly, central nervous system effects (including depression) are reported with ophthalmic beta-blocker therapy.89 According to the evidence, ophthalmic beta-blocker therapy does not appear to be associated with clinically significant adverse metabolic effects. A second review (2002) of the available clinical evidence reported increased rates of cardiopulmonary adverse effects with ophthalmic beta-blocker therapy most frequently in patients with underlying cardiovascular or pulmonary diseases.90 According to the authors, “commonly presumed adverse beta-adrenergic blocker effects observed via systemic or ocular administration are not supported by published randomized clinical trials” and “no scientific studies supporting the development of worsening claudication, depression, hypoglycemic unawareness, or prolonged hypoglycemia” are available for patients receiving ophthalmic beta-blocker therapy. To reduce the risk of systemic adverse events, all patients should receive the lowest effective concentration of medication and receive instruction on proper method of ocular administration.

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Table 4. Rate of Adverse Events Reported with Ophthalmic Beta-Adrenergic Antagonist Therapies*1,2 Agent >10% 1‐10% <1% Frequency not defined

Betaxolol (Betoptic®) Short‐term discomfort (≤25%) NR Alopecia, asthma, bradycardia, bronchial secretions thickened, bronchospasm, depression, dizziness, dyspnea, glossitis, heart block, heart failure, headache, hives, insomnia, lethargy, myasthenia gravis exacerbation, respiratory failure, smell/taste perversion, toxic epidermal necrolysis, vertigo

Ocular: Allergic reaction, anisocoria, blurred vision, choroidal detachment, corneal punctate keratitis, corneal punctate staining (with or without dendritic formations), corneal sensitivity decreased, corneal staining, crusty lashes, discharge, dry eyes, edema, erythema, foreign body sensation, inflammation, itching sensation, keratitis, ocular pain, photophobia, tearing, visual acuity decreased

Carteolol (Ocupress®) Conjunctival hyperemia Ocular: Anisocoria, corneal punctate keratitis, corneal staining, corneal sensitivity decreased, eye pain, vision disturbances

NR NR

Levobunolol (Betagan®) Stinging/burning (up to 33%) Blepharoconjunctivitis (5%) NR Cardiovascular: Arrhythmia, bradycardia, cardiac arrest cerebral ischemia, cerebrovascular accident, chest pain, congestive heart failure, heart block, hypotension, palpitation, syncope; Central nervous system: Ataxia (transient), confusion, depression, dizziness, headache, lethargy; Dermatologic: Alopecia, erythema, pruritus, rash, Stevens‐Johnson syndrome, urticarial; Endocrine & metabolic: Hypoglycemia masked; Gastrointestinal: Diarrhea, nausea; Genitourinary: Impotence; Neuromuscular & skeletal: Myasthenia gravis exacerbation, paresthesia, weakness; Ocular: Blepharoptosis, conjunctivitis, corneal sensitivity decreased, diplopia, iridocyclitis, keratitis, ptosis, visual disturbances; Respiratory: Bronchospasm, dyspnea, nasal congestion, respiratory failure; Miscellaneous: Hypersensitivity

Metipranolol (Optipranolol®) NR NR NR Cardiovascular: Angina, atrial fibrillation, bradycardia, hypertension, MI, palpitation; Central nervous system: Anxiety, depression, dizziness, headache, nervousness, somnolence; Dermatologic: Rash; Gastrointestinal: Nausea; Neuromuscular & skeletal: Arthritis, myalgia, weakness; Ocular: Abnormal vision, blepharitis, blurred vision, browache, conjunctivitis, discomfort, edema, eyelid dermatitis,

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photophobia, tearing, uveitis; Respiratory: Bronchitis, cough, dyspnea, epistaxis, rhinitis; Miscellaneous: Allergic reaction

Timolol (Betimol®, Timoptic®, others)

Burning, stinging NR NR Cardiovascular: Angina pectoris, arrhythmia, bradycardia, cardiac arrest, cardiac failure, cerebral ischemia, cerebral vascular accident, edema, heart block, hypertension, hypotension, palpitation, Raynaud's phenomenon; Central nervous system: Anxiety, confusion, depression, disorientation, dizziness, hallucinations, headache, insomnia, memory loss, nervousness, nightmares, somnolence; Dermatologic: Alopecia, angioedema, pseudopemphigoid, psoriasiform rash, psoriasis exacerbation, rash, urticarial; Endocrine & metabolic: Hypoglycemia masked, libido decreased; Gastrointestinal: Anorexia, diarrhea, dyspepsia, nausea, xerostomia; Genitourinary: Impotence, retoperitoneal fibrosis; Hematologic: Claudication; Neuromuscular & skeletal: Myasthenia gravis exacerbation, paresthesia; Ocular: Blepharitis, blurred vision, cataract, choroidal detachment (following filtration surgery), conjunctival injection, conjunctivitis, corneal sensitivity decreased, cystoid macular edema, diplopia, dry eyes, foreign body sensation, hyperemia, itching, keratitis, ocular discharge, ocular pain, ptosis, tearing, visual acuity decreased refractive changes, visual disturbances; Otic: Tinnitus; Respiratory: Bronchospasm, cough, dyspnea, nasal congestion, pulmonary edema, respiratory failure; Miscellaneous: Allergic reactions, cold hands/feet, Peyronie's disease, systemic lupus erythematosus

Timolol/Brimonidine (Combigan®) *Percentages as reported with combination product. Also see individual agents.

Central nervous system: Drowsiness (children 25% to 83%)

Cardiovascular: Hypertension; Central nervous system: Depression, foreign body sensation of eye, headache; Dermatologic: Erythema of eyelid; Gastrointestinal: Xerostomia; Neuromuscular & skeletal: Weakness; Ophthalmic: Allergic conjunctivitis, burning sensation of eyes, conjunctival

NR NR

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hyperemia, eye pruritus, follicular conjunctivitis, stinging of eyes; Blepharitis, blurred vision, corneal erosion, dry eye syndrome, epiphora, eye discharge, eye irritation, eye pain, eyelid edema, superficial punctate keratitis

Timolol/Dorzolamide (Cosopt®; Cosopt PF®)

Gastrointestinal: Taste perversion (≤30%); Ocular: Burning/stinging (≤30%)

Cardiovascular: Hypertension; Central nervous system: Dizziness, headache; Gastrointestinal: Abdominal pain, dyspepsia, nausea; Genitourinary: Urinary tract infection; Neuromuscular & skeletal: Back pain; Ocular: Blepharitis, cloudy vision, conjunctival discharge, conjunctival edema, conjunctival follicles, conjunctivitis, corneal erosion, corneal staining, cortical lens opacity, dryness, eye debris, eye/eyelid discharge, eye/eyelid pain, eyelid edema, eyelid erythema, eyelid exudate/scales, foreign body sensation, glaucomatous cupping, lens nucleus discoloration, lens opacity, post‐subcapsular cataract, tearing, visual field defect, vitreous detachment; Respiratory: Bronchitis, cough, pharyngitis, sinusitis, upper respiratory infection; Miscellaneous: Flu

Bradycardia, cardiac failure, cerebral vascular accident, chest pain, choroidal detachment (following filtration procedures), depression, diarrhea, dyspnea, heart block, hypotension, iridocyclitis, MI, nasal congestion, paresthesia, photophobia, respiratory failure, skin rash, Stevens‐Johnson syndrome, toxic epidermal necrolysis, urolithiasis, vomiting, xerostomia

NR

*Rates obtained from package inserts and are not meant to be comparative. Key: NR = not reported

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Summary

The ophthalmic beta-adrenergic antagonist agents are commonly used in the treatment of OAG because they are effective in reducing IOP, are well tolerated and are available in generic formulations. Clinical guidelines do not recommend a specific beta-antagonist agent or even a specific class of medications for patients with glaucoma. The majority of published data suggest similar IOP reduction with timolol compared to the four other available agents. Some evidence suggests higher rates of IOP lowering with the non-selective ophthalmic beta-adrenergic antagonist, timolol, compared to the cardioselective ophthalmic beta-adrenergic antagonist, betaxolol, and higher rates of improved visual field changes with betaxolol compared to timolol. This evidence suggests more research is required to determine whether the differences in reported outcomes between nonselective and cardioselective beta-blocker glaucoma therapies result in differences in overall efficacy and disease progression in the treatment of OAG. Differences in adverse effects have been reported between the agents but overall, the adverse events reported with ophthalmic beta-adrenergic antagonist therapy in clinical trials tend to be mild in nature.

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Appendix: Evidence Tables

Evidence Table 1. Clinical Trials Evaluating the Ophthalmic Beta-Adrenergic Antagonists Reference/ Study Design

N Patient Selection Treatment Interventions Results Safety

Miki et al, 200475 Cross‐over trial

22 eyes from 11 patients

Adult patients newly diagnosed with primary open angle glaucoma

Timolol maleate 0.5% twice daily for 2 years then Betaxolol 0.5% twice daily for 2 years Duration: 4 years total

Reduction in mean IOP valueso Timolol > baseline, p < 0.05 o Betaxolol > baseline, p < 0.05 o Timolol = Betaxolol Visual Field changes o Increase in mean deviation

Betaxolol > Timolol , p < 0.05 o Change in corrected pattern

standard deviation Timolol = Betaxolol

Not reported

Francis et al, 200481 Two parts: (1) randomized & (2) non‐randomized multi‐center trials

1: 131 2: 404

Patients with diagnosis of primary open‐angle glaucoma, ocular hypertension or pseudoexfoliation glaucoma in both eyes

Concomitant administration of timolol 0.5% twice daily with dorzolamide 2% three times daily (n = 74) Fixed combination dorzolamide‐timolol (Cosopt) twice daily (n = 57) Duration: (1) 4 weeks, (2) 4 weeks

Part 1: Reduction in IOP values o Fixed combination: ‐3.2 at peak &

‐6.5 at trough o Concomitant: ‐0.3 at peak & ‐3.2

at trough; p = NS Part 2: Reduction in IOP from baseline o Switch to fixed combination:

‐8.8%; p < 0.0001

Not reported

27

Reference/ Study Design


Mundorf et al, 200482 Randomized, double‐blind, multi‐center trial

332 Adult patients with open‐angle glaucoma or ocular hypertension in 1 or both eyes and an unmedicated intraocular pressure of > 22 mm Hg

Timolol‐LA 0.5% solution (timolol maleate containing potassium sorbate, TLA) once daily (n = 166) Timolol maleate 0.5% ophthalmic solution twice daily, TIM (n = 166) Duration: 12 months

Mean reduction in IOPo TLA = TIM

Peak: 25.5–28.7% Trough: 20.8–24.7%

Adverse Event Related Discontinuation Rate o TLA: 10 (6%) o TIM: 7 (4.2%) Burning and Stinging on Instillation o TLA: 41.6% o TIM: 22.9%, p =

0.001

Vainio‐Jylhä et al, 200276 Randomized, double‐blind trial

64 Patients with glaucoma

Betaxolol 0.5% solution twice daily (n = 27) Timolol 0.25 % solution twice daily (n = 28) Duration: 2 years

Progression in retinal nerve fiber layer defects o Timolol = Betaxolol Reduction in mean IOP values o Timolol = Betaxolol

Not reported

Halper et al, 200279 Randomized, double‐blind, multi‐center, cross‐over trial

133 Adult patients with a diagnosis of open‐angle glaucoma or ocular hypertension in one or both eyes and exhibited IOP of >22 mmHg in at least 1 eye following the 3‐week run‐in period

Timolol 0.5% gel‐ forming solution once daily Levobunolol 0.5% solution twice daily Duration: 3‐week placebo run‐in, 6‐week active treatment with each agent and 3‐week placebo wash‐out period

Mean reduction in IOP valueso Timolol = Levobunolol

Peak: 3.7‐3.9 Trough: 5.6‐5.7

Burning and Stinging on Instillation o Timolol: 5 (4%) o Levobunolol: 32

(25%), p < 0.001 Change in Heat Rate o Timolol: ‐1.8 to +

0.4 o Levobunolol: ‐4.5

to ‐4.3, p < 0.05

Watson at al, 200113 Randomized, open‐label trial

153 patients (280 eyes)

Patients with newly diagnosed open‐angle glaucoma

Timolol 0.25% twice daily (n = 51) Carteolol 1% twice daily (n = 48) Betaxolol 0.5% twice daily (n = 54) Duration: 7 years

Mean reduction in IOP valueso At 6 months

Timolol = Carteolol > Betaxolol; no p value provided

o At 7 years Timolol = Carteolol =

Betaxolol

Stinging o Timolol: 1 (1.9%) o Carteolol: 0 (0%) o Betaxolol: 11

(20.4%), no p value reported

28



Shedden et al, 200183 Randomized, double‐blind trial

286 Patients with a diagnosis of open‐angle glaucoma or ocular hypertension

Timolol 0.5% gel‐forming solutiononce daily (n= 191) Timolol 0.5% solution twice daily (n = 95) Duration: 6 months

Mean reduction in IOP valueso Timolol gel = Timolol solution

Blurred vision and tearing o Timolol gel >

Timolol solution, p = 0.04

Burning and Stinging on Instillation o Timolol solution >

Timolol gel, p = 0.04

Rate of reduced heart rate o Timolol solution >

Timolol gel, p < 0.05

Mirza et al, 200078 Randomized, controlled trial


Timolol 0.5% twice daily (n = 15) Carteolol 2% twice daily (n = 15) Metipranolol 0.3% twice daily (n = 15) Duration: 90 days

Reduction in mean IOP valueso Timolol = Carteolol = Metipranolol Visual Field changes o Timolol = Carteolol = Metipranolol

Burning and Stinging on Instillation o Timolol: 2 (13%) o Carteolol: 1

(6.6%) o Metipranolol: 1

(6.6%) Decreases in total cholesterol & HDL and increases in triglyceride levels o Timolol =

Carteolol = Metipranolol > Baseline; p < 0.05 compared to baseline

29



Schenker et al, 199984 Randomized, single‐blind, cross‐over trial

202 Patients with a diagnosis of open‐angle glaucoma or ocular hypertension and an IOP > 22 mmHg

Timolol 0.5% gel‐forming solutiononce daily Timolol 0.5% solution twice daily Duration: 12 weeks, 6 weeks with each treatment

Patient Preference o Timolol gel > Timolol solution; p <

0.001 Mean reduction in IOP o Timolol gel = Timolol solution

Drug‐related adverse events o Timolol gel: 11.4%o Timolol solution:

10.9%

Walters et al, 199880 Randomized, double‐blind, multi‐center, cross‐over trial


Timolol 0.5% gel‐forming solutiononce daily Levobunolol 0.5% twice daily Duration: 3‐week placebo run‐in, 6‐week active treatment with each agent

Reduction in mean IOP valueso Timolol = Levobunolol

Reduced heart ratePeak o Timolol =

Levobunolol Trough o Timolol <

Levobunolol, p = 0.001

Burning and Stinging on Instillation o Timolol =

Levobunolol Blurred vision o Timolol: 8% o Levobunolol: 1%,

p = 0.013

Drance, 199877 Randomized, double‐blind trial

68 Patients with a diagnosis of open‐angle glaucoma with an IOP > 24 mmHg and visual field abnormalities

Betaxolol 0.5% twice daily (n = 27) Timolol 0.5% solution twice daily (n = 27) Pilocarpine 2% four times daily (n = 14) Duration: 24 weeks

Reduction in mean IOP valueso Timolol > Betaxolol Visual Field changes o Timolol = Betaxolol

Not reported

30



Araie et al, 200355 Randomized, double‐blind, multi‐center trial *Data extracted from abstract, access to full trial not available

95 Adult patients with open‐angle glaucoma

Betaxolol Timolol Duration: 2 years

Reduction in mean IOP valueso Timolol > Betaxolol, p < 0.05 Visual Field changes o Increase in mean deviation

Timolol = Betaxolol o Change in corrected pattern

standard deviation Timolol = Betaxolol

Not reported

Stewert et al, 199791 Randomized, double‐blind, multi‐center trial *Data extracted from abstract, access to full trial not available


Carteolol 1% twice daily Timolol 0.5% solution twice daily Duration: 3 months

Reduction in mean IOP valueso Carteolol = Timolol

Heart rate effectso Timolol >

Carteolol, p = 0.039

Ocular adverse effects o Timolol >

Carteolol, p < 0.01

Evidence Table 2. Clinical Trials Evaluating the Ophthalmic Beta-Adrenergic Antagonists in Special Populations Reference/ Study Design


Plager et al, 200915 Randomized, double‐blind, multi‐center trial

105 Pediatric subjects with glaucoma or ocular hypertension < 6 years of age

Betaxolol 0.25% twice daily (n = 34) Timolol Gel‐Forming Solution 0.25% daily (n = 35) Timolol Gel‐Forming Solution 0.5% daily (n = 36) Duration: 12 weeks

Mean reductions in IOP from baselineo Betaxolol: 2.3 o Timolol 0.25%: 2.9 o Timolol 0.5%: 3.7

Adverse event rate

Ocular o Betaxolol: 5/35 o Timolol 0.25%:

2/36 o Timolol 0.5%: 6/36

Cardiovascular o Betaxolol: 2/35 o Timolol 0.25%:

4/36 o Timolol 0.5%: 1/36

Ophthalmic Beta-Adrenergic Antagonists Drug Class … · review focuses on the ophthalmic...

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