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Drug Class Review

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

Betaxolol (Betoptic®) (Ocupress®) (Betagan®) (Optipranolol®) (Betimol®, Timoptic®, others) Timolol/ (Combigan®) Timolol/ (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. Table of Contents

Executive Summary ...... 3

Introduction ...... 5 Table 1. 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 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

2 Executive Summary

Introduction: Five ophthalmic beta-blocking agents are currently available for this use in the United States: (Betoptic®), carteolol (Ocupress®), levobunolol (Betagan®), metipranolol (Optipranolol®) and timolol (Timoptic®). Two combination agents are also available for use: one beta- in combination with an alpha2 (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 in patients with ocular 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 , surgery and laser procedures. Current treatment guidelines from the American Academy of Ophthalmology do not specify a preferred procedure or for treating glaucoma. Topical 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 . 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, , , confusion and . 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

3 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.

4 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.

5 Table 1. Glaucoma Therapies1,4 Characteristic Prostaglandins Beta‐Adrenergic Blockers Carbonic Anhydrase Inhibitors Sympathomimetics Miotic Agents Agents in Class Betaxolol Carteolol Dorzolamide Brimonidine [DSC] Dipivefrin Iodide Levobunolol Metipranolol Timolol Generics Available in Class Yes Yes None Yes Yes Combination Products Latanoprost/Timolol Brimonidine/Timolol Brinzolamide/Brimonidine Brinzolamide/Brimonidine None [NA] Brinzolamide/Timolol [NA] Brinzolamide/Timolol [NA] Brimonidine/Timolol Travoprost/Timolol Dorzolamide/Timolol Dorzolamide/Timolol [NA] Latanoprost/Timolol [NA] Travoprost/Timolol [NA] 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 Not reported Significant effect Significant effect Apraclonidine, Not reported production Brimonidine: Moderate to significant effect

Dipivefrin, : Some effect 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 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% 20 – 30% 8 – 12 hrs: 10% Key adverse effects Ocular Redness, increased iris Stinging, burning Allergic sensitivity, burning, Hyperemia, lid , Stinging, irritation, miosis pigmentation, eyelash stinging itching, foreign‐object changes sensation Systemic Upper Bradycardia, bronchial Altered taste , dry mouth, Headache constriction, pressure fatigue reduction Key: DSC ‐ discontinued, NA ‐ not available in the US

6 Table 2. Summary of Agents*1,4-6 Characteristic Betaxolol Carteolol (Ocupress®) Levobunolol Metipranolol Timolol Timolol/Brimonidine Timolol/Dorzolamide (Betoptic®) (Betagan®) (Optipranolol®) (Betimol®) (Combigan®) (Cosopt®) Concentrations Suspension: 0.25% Solution: 1% Solution: 0.25%, 0.5% Solution: 0.3% Gel Forming Solution: Brimonidine Solution: Dorzolamide Solution: 0.5% Solution: 0.25%, tartrate 0.2% and 2% and timolol 0.5% 0.5% timolol 0.5% Solution, preservative‐ Solution, as free: Dorzolamide 2% hemihydrate: and timolol 0.5% 0.25%, 0.5%

Solution, as maleate: 0.25%, 0.5%

Solution, as maleate, preservative‐free: 0.25%, 0.5% Package Sizes 0.25%: 10mL, 15mL 5mL, 10mL, 15mL 0.25%: 5mL, 10mL 5mL, 10mL 0.25%: 5mL, 5mL, 10mL 10 mL Available 0.5%: 5mL, 10mL, 0.5%: 5mL, 10mL, 10mL, 15mL 15mL 15mL preservative‐free: 60 0.5%: 2.5mL, doses 5mL, 10 mL, 15mL

preservative free: 0.25% (60 doses); 0.5% (60 doses) Generic Available? 0.25%: No Yes Yes Yes Timoptic Ocudose No Yes 0.5%: Yes (preservative‐ Preservative‐free: No free): No Betimol (hemihydrate base): No Others: Yes Labeled Use Chronic open‐angle Open‐angle glaucoma Chronic open‐angle Chronic open‐angle Ocular Elevated intraocular Elevated intraocular glaucoma glaucoma glaucoma hypertension or pressure pressure Intraocular open‐angle hypertension Ocular hypertension Ocular hypertension glaucoma 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 274‐328 260‐330 mOsmol/kg 242‐323 mOsM/kg mOsm/kg

7 Characteristic Betaxolol Carteolol (Ocupress®) Levobunolol Metipranolol Timolol Timolol/Brimonidine Timolol/Dorzolamide (Betoptic®) (Betagan®) (Optipranolol®) (Betimol®) (Combigan®) (Cosopt®) Plasma 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 0.46 ng/mL Concentration after ng/ml Ophthalmic Use Timolol: 0.406 ng/ml Time to Peak 2 hours 2 hours 2‐6 hours 2 hours 1‐2 hours ~1 hour 2 hours Concentration Volume of 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 Distribution products Elimination Route Urine Urine Urine and Feces Urine Urine Urine Urine Plasma Half‐life 14‐22 hours Carteolol: ~6 hours ~20 hours ~3 hours 2.5‐5 hours Brimonidine: 3 hours Up to 4 months 8‐hydroxycarteolol Timolol: 7 hours (active metabolite): ~8‐12 hours Labeled Dosage 1‐2 drops into 1 drop in affected 1‐2 drops into affected 1 drop in the affected 1 drop into 1 drop into affected 1 drop in affected Range, Adults affected eye(s) eye(s) twice daily eye(s) once to twice eye(s) twice daily affected eye(s) eye(s) twice daily eye(s) twice daily twice daily daily once to twice Not indicated in the Not indicated in the daily Pediatric: Glaucoma, Pediatric: Elevated Pediatric: Elevated pediatric population Not indicated in the pediatric population ocular hypertension: intraocular pressure: intraocular pediatric population Pediatric (may be Children ≥2 years: 1 drop Children ≥2 years and pressure: 1 drop off‐label): into affected eye(s) Adolescents: Refer to into affected eye(s) Elevated twice daily adult dosing twice daily intraocular *Note: In the Canadian pressure: Use labeling, use in children lowest effective (at any age) is not dose, gel recommended 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

8 Characteristic Betaxolol Carteolol (Ocupress®) Levobunolol Metipranolol Timolol Timolol/Brimonidine Timolol/Dorzolamide (Betoptic®) (Betagan®) (Optipranolol®) (Betimol®) (Combigan®) (Cosopt®) Preservative in Benzalkonium Benzalkonium benzalkonium chloride Benzalkonium Chloride Benzalkonium Benzalkonium chloride Benzalkonium chloride Product chloride 0.01% Chloride 0.005% 0.004% 0.004% Chloride; 0.005% 0.0075%; preservative‐ preservative‐free free agent available agent available Contraindications ; Hypersensitivity; sinus Hypersensitivity; Hypersensitivity; Hypersensitivity; Hypersensitivity; current Hypersensitivity; ; bradycardia; bronchial ; bronchial asthma; sinus or history of bronchial bronchial asthma or a greater block greater than severe COPD; sinus severe COPD; sinus bradycardia; asthma; severe chronic history of bronchial than first‐degree; first‐degree; bradycardia; second‐ bradycardia; second‐ sinus node obstructive pulmonary asthma; severe cardiogenic ; ; or third‐degree AV and third‐degree AV dysfunction; disease (COPD); sinus chronic obstructive uncompensated bronchial asthma, block; overt cardiac block; cardiac failure; heart block bradycardia; second‐ or pulmonary disease; cardiac failure , or failure; cardiogenic cardiogenic shock greater than first third‐degree sinus bradycardia; COPD; shock degree; ; second‐ or third‐ uncompensated cardiogenic overt cardiac failure; degree atrioventricular cardiac failure; shock; cardiogenic shock; block; overt cardiac pulmonary edema uncompensated children <2 years of age; failure; cardiogenic cardiac failure; also see individual shock bronchospastic agents disease Storage Refrigerator or Room temperature Room temperature Room temperature Room Room temperature (59°F Room temperature room temperature away from light and (59°‐86°F, away from (59°‐86°), away from temperature to 86°F); protect from (59°F to 86°F); protect (36°F to 77°F) moisture light heat, moisture & light (59°‐77°F); light from light protect from light Latest Patent/ expired December expired, generic expired, generic expired, generic Betimol ‐ 7/2010 Apr 19, 2022 Feb 1, 2015 Exclusivity 2010, no generic available available available Timoptic Ocudose Expiration Date product available ‐ expired for 0.25% product *Data summarized based on package labeling. Please see Full Prescribing Information for most up‐to‐date and complete dosing information.

9 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 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

10 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

Definition of OAG: Evidence of either or both: (a) optic disc or RNFL defects; (b) VF American Academy of Ophthalmology defect; Adult‐onset; Open angles; Absence of other causes (AAO, 2010)9 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 Definition of OAG: chronic, progressive disease with characteristic optic nerve (ON) American Optometric Association (AOA, damage, retinal nerve fiber layer (NFL) defects, and subsequent visual field (VF) loss. 2010)12 Goals of Treatment: Reducing or preventing further ON damage Target IOP: 30‐50% lower than the pretreatment level Definition of OAG: Acquired characteristic optic disc or RNFL defects; Glaucomatous VF European Glaucoma Society (EGS, defects; Age > 35 years; Open angles; Untreated IOP > 21 mm Hg 2008)14 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 Definition of OAG: Chronic progressive optic neuropathy with characteristic changes in South East Asia Glaucoma Interest the optic nerve or VF; Absence of other causes Group (SEAGIG, 2008)14 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

11

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 -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.

12 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.

13 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 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%)

14 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.

15 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 , confusion, depression45, dizziness, dyspnea, , 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, and mellitus (as beta-blockers can mask the signs and symptoms of acute ). 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 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.

16 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, Ocular: Allergic reaction, , blurred bronchial secretions thickened, vision, choroidal detachment, corneal punctate bronchospasm, depression, keratitis, corneal punctate staining (with or dizziness, dyspnea, glossitis, heart without dendritic formations), corneal sensitivity block, heart failure, headache, decreased, corneal staining, crusty lashes, hives, , lethargy, discharge, dry eyes, edema, erythema, foreign myasthenia gravis exacerbation, body sensation, inflammation, itching sensation, respiratory failure, smell/taste keratitis, ocular pain, photophobia, tearing, perversion, toxic epidermal visual acuity decreased necrolysis, Carteolol (Ocupress®) Conjunctival hyperemia Ocular: Anisocoria, corneal punctate NR NR keratitis, corneal staining, corneal sensitivity decreased, eye pain, vision disturbances

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, , palpitation, ; : Ataxia (transient), confusion, depression, dizziness, headache, lethargy; Dermatologic: Alopecia, erythema, pruritus, rash, Stevens‐Johnson syndrome, urticarial; Endocrine & metabolic: Hypoglycemia masked; Gastrointestinal: , ; Genitourinary: Impotence; Neuromuscular & skeletal: Myasthenia gravis exacerbation, paresthesia, weakness; Ocular: Blepharoptosis, , corneal sensitivity decreased, diplopia, iridocyclitis, keratitis, ptosis, visual disturbances; Respiratory: Bronchospasm, dyspnea, nasal congestion, respiratory failure; Miscellaneous: Hypersensitivity Metipranolol (Optipranolol®) NR NR NR Cardiovascular: , , bradycardia, hypertension, MI, palpitation; Central nervous system: , 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,

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

Timolol (Betimol®, Timoptic®, Burning, stinging NR NR Cardiovascular: Angina pectoris, arrhythmia, others) 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, , somnolence; Dermatologic: Alopecia, angioedema, pseudopemphigoid, psoriasiform rash, exacerbation, rash, urticarial; Endocrine & metabolic: Hypoglycemia masked, 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 , 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 Central nervous system: Cardiovascular: Hypertension; Central NR NR (Combigan®) Drowsiness (children 25% to nervous system: Depression, foreign body 83%) sensation of eye, headache; Dermatologic: Erythema of eyelid; *Percentages as reported with Gastrointestinal: Xerostomia; combination product. Also see Neuromuscular & skeletal: Weakness; individual agents. Ophthalmic: Allergic conjunctivitis, burning sensation of eyes, conjunctival

18 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 Gastrointestinal: Taste Cardiovascular: Hypertension; Central Bradycardia, cardiac failure, NR (Cosopt®; Cosopt PF®) perversion (≤30%); Ocular: nervous system: Dizziness, headache; cerebral vascular accident, chest Burning/stinging (≤30%) Gastrointestinal: , pain, choroidal detachment dyspepsia, nausea; Genitourinary: Urinary (following filtration procedures), tract ; Neuromuscular & skeletal: depression, diarrhea, dyspnea, Back pain; Ocular: Blepharitis, cloudy heart block, hypotension, vision, conjunctival discharge, iridocyclitis, MI, nasal congestion, conjunctival edema, conjunctival follicles, paresthesia, photophobia, conjunctivitis, corneal erosion, corneal respiratory failure, skin rash, staining, cortical lens opacity, dryness, Stevens‐Johnson syndrome, toxic eye debris, eye/eyelid discharge, epidermal necrolysis, urolithiasis, eye/eyelid pain, eyelid edema, eyelid vomiting, xerostomia 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 *Rates obtained from package inserts and are not meant to be comparative. Key: NR = not reported

19 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.

20

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Appendix: Evidence Tables

Evidence Table 1. Clinical Trials Evaluating the Ophthalmic Beta-Adrenergic Antagonists Reference/ N Patient Selection Treatment Interventions Results Safety Study Design Miki et al, 22 eyes Adult patients newly Timolol maleate 0.5% twice daily Reduction in mean IOP values Not reported 200475 from 11 diagnosed with for 2 years o Timolol > baseline, p < 0.05 patients primary open angle then o Betaxolol > baseline, p < 0.05 Cross‐over trial glaucoma Betaxolol 0.5% twice daily for 2 o Timolol = Betaxolol years Visual Field changes Duration: 4 years total o Increase in mean deviation . Betaxolol > Timolol , p < 0.05 o Change in corrected pattern standard deviation . Timolol = Betaxolol Francis et al, 1: 131 Patients with Concomitant administration of Part 1: Not reported 200481 2: 404 diagnosis of primary timolol 0.5% twice daily with Reduction in IOP values open‐angle dorzolamide 2% three times daily o Fixed combination: ‐3.2 at peak & Two parts: (1) glaucoma, ocular (n = 74) ‐6.5 at trough randomized & hypertension or o Concomitant: ‐0.3 at peak & ‐3.2 (2) non‐ pseudoexfoliation Fixed combination dorzolamide‐ at trough; p = NS randomized glaucoma in timolol (Cosopt) twice daily (n = multi‐center both eyes 57) Part 2: trials Reduction in IOP from baseline Duration: (1) 4 weeks, (2) 4 weeks o Switch to fixed combination: ‐8.8%; p < 0.0001 Reference/ N Patient Selection Treatment Interventions Results Safety Study Design Mundorf et al, 332 Adult patients with Timolol‐LA 0.5% solution (timolol Mean reduction in IOP Adverse Event Related 200482 open‐angle glaucoma maleate containing potassium o TLA = TIM Discontinuation Rate or ocular sorbate, TLA) once daily (n = 166) . Peak: 25.5–28.7% o TLA: 10 (6%) Randomized, hypertension in 1 or . Trough: 20.8–24.7% o TIM: 7 (4.2%) double‐blind, both eyes and an Timolol maleate 0.5% ophthalmic multi‐center trial unmedicated solution twice daily, TIM (n = 166) Burning and Stinging intraocular pressure on Instillation of > 22 mm Hg Duration: 12 months o TLA: 41.6% o TIM: 22.9%, p = 0.001 Vainio‐Jylhä et 64 Patients with Betaxolol 0.5% solution twice daily Progression in retinal nerve fiber layer Not reported al, 200276 glaucoma (n = 27) defects o Timolol = Betaxolol Randomized, Timolol 0.25 % solution twice daily double‐blind trial (n = 28) Reduction in mean IOP values o Timolol = Betaxolol Duration: 2 years Halper et al, 133 Adult patients with a Timolol 0.5% gel‐ forming solution Mean reduction in IOP values Burning and Stinging on 200279 diagnosis of open‐ once daily o Timolol = Levobunolol Instillation angle glaucoma or . Peak: 3.7‐3.9 o Timolol: 5 (4%) Randomized, ocular hypertension Levobunolol 0.5% solution twice . Trough: 5.6‐5.7 o Levobunolol: 32 double‐blind, in one or both eyes daily (25%), p < 0.001 multi‐center, and exhibited IOP of cross‐over trial >22 mmHg in at least Duration: 3‐week placebo run‐in, Change in Heat Rate 1 eye following the 6‐week active treatment with each o Timolol: ‐1.8 to + 3‐week run‐in period agent and 3‐week placebo wash‐ 0.4 out period o Levobunolol: ‐4.5 to ‐4.3, p < 0.05 Watson at al, 153 Patients with newly Timolol 0.25% twice daily (n = 51) Mean reduction in IOP values Stinging 200113 patients diagnosed open‐ o At 6 months o Timolol: 1 (1.9%) (280 angle glaucoma Carteolol 1% twice daily (n = 48) . Timolol = Carteolol > o Carteolol: 0 (0%) Randomized, eyes) Betaxolol; no p value o Betaxolol: 11 open‐label trial Betaxolol 0.5% twice daily (n = 54) provided (20.4%), no p o At 7 years value reported Duration: 7 years . Timolol = Carteolol = Betaxolol 27 Reference/ N Patient Selection Treatment Interventions Results Safety Study Design Shedden et al, 286 Patients with a Timolol 0.5% gel‐forming solution Mean reduction in IOP values Blurred vision and 200183 diagnosis of open‐ once daily (n= 191) o Timolol gel = Timolol solution tearing angle glaucoma or o Timolol gel > Randomized, ocular hypertension Timolol 0.5% solution twice daily Timolol solution, double‐blind trial (n = 95) p = 0.04

Duration: 6 months 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, 45 Patients with a Timolol 0.5% twice daily (n = 15) Reduction in mean IOP values Burning and Stinging on 200078 diagnosis of open‐ o Timolol = Carteolol = Metipranolol Instillation angle glaucoma or Carteolol 2% twice daily (n = 15) o Timolol: 2 (13%) Randomized, ocular hypertension Visual Field changes o Carteolol: 1 controlled trial Metipranolol 0.3% twice daily (n = o Timolol = Carteolol = Metipranolol (6.6%) 15) o Metipranolol: 1 (6.6%) Duration: 90 days Decreases in total cholesterol & HDL and increases in triglyceride levels o Timolol = Carteolol = Metipranolol > Baseline; p < 0.05 compared to baseline

28 Reference/ N Patient Selection Treatment Interventions Results Safety Study Design Schenker et al, 202 Patients with a Timolol 0.5% gel‐forming solution Patient Preference Drug‐related adverse 199984 diagnosis of open‐ once daily o Timolol gel > Timolol solution; p < events angle glaucoma or 0.001 o Timolol gel: 11.4% Randomized, ocular hypertension Timolol 0.5% solution twice daily o Timolol solution: single‐blind, and an IOP > 22 Mean reduction in IOP 10.9% cross‐over trial mmHg Duration: 12 weeks, 6 weeks with o Timolol gel = Timolol solution each treatment Walters et al, 152 Patients with a Timolol 0.5% gel‐forming solution Reduction in mean IOP values Reduced heart rate 199880 diagnosis of open‐ once daily o Timolol = Levobunolol Peak angle glaucoma or o Timolol = Randomized, ocular hypertension Levobunolol 0.5% twice daily Levobunolol double‐blind, Trough multi‐center, Duration: 3‐week placebo run‐in, o Timolol < cross‐over trial 6‐week active treatment with each Levobunolol, p = agent 0.001

Burning and Stinging on Instillation o Timolol = Levobunolol

Blurred vision o Timolol: 8% o Levobunolol: 1%, p = 0.013 Drance, 199877 68 Patients with a Betaxolol 0.5% twice daily (n = 27) Reduction in mean IOP values Not reported diagnosis of open‐ o Timolol > Betaxolol Randomized, angle glaucoma with Timolol 0.5% solution twice daily double‐blind trial an IOP > 24 mmHg (n = 27) Visual Field changes and visual field o Timolol = Betaxolol abnormalities Pilocarpine 2% four times daily (n = 14)

Duration: 24 weeks

29 Reference/ N Patient Selection Treatment Interventions Results Safety Study Design Araie et al, 95 Adult patients with Betaxolol Reduction in mean IOP values Not reported 200355 open‐angle glaucoma o Timolol > Betaxolol, p < 0.05 Timolol Randomized, Visual Field changes double‐blind, Duration: 2 years o Increase in mean deviation multi‐center trial . Timolol = Betaxolol o Change in corrected pattern *Data extracted standard deviation from abstract, . Timolol = Betaxolol access to full trial not available Stewert et al, 176 Patients with a Carteolol 1% twice daily Reduction in mean IOP values Heart rate effects 199791 diagnosis of open‐ o Carteolol = Timolol o Timolol > angle glaucoma or Timolol 0.5% solution twice daily Carteolol, p = Randomized, ocular hypertension 0.039 double‐blind, Duration: 3 months multi‐center trial Ocular adverse effects o Timolol > *Data extracted Carteolol, p < 0.01 from abstract, access to full trial not available

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Evidence Table 2. Clinical Trials Evaluating the Ophthalmic Beta-Adrenergic Antagonists in Special Populations Reference/ N Patient Selection Treatment Interventions Results Safety Study Design Plager et al, 105 Pediatric subjects Betaxolol 0.25% twice daily (n = 34) Mean reductions in IOP from baseline Adverse event rate 200915 with glaucoma or o Betaxolol: 2.3  Ocular ocular hypertension < Timolol Gel‐Forming Solution o Timolol 0.25%: 2.9 o Betaxolol: 5/35 Randomized, 6 years of age 0.25% daily (n = 35) o Timolol 0.5%: 3.7 o Timolol 0.25%: double‐blind, 2/36 multi‐center trial Timolol Gel‐Forming Solution 0.5% o Timolol 0.5%: 6/36 daily (n = 36)  Cardiovascular o Betaxolol: 2/35 Duration: 12 weeks o Timolol 0.25%: 4/36 o Timolol 0.5%: 1/36