Brand names: Betimol, Istalol, Timoptic, Timoptic-XE
Drug class: beta-Adrenergic Blocking Agents
- Beta-Adrenergic Blocking Agents
- β-Adrenergic Blocking Agents
VA class: OP101
CAS number: 91524-16-2

Medically reviewed by Drugs.com on Dec 11, 2023. Written by ASHP.

Introduction

Nonselective β-adrenergic blocking agent.^{104 105 106 107}

Uses for Timolol (EENT)

Ocular Hypertension and Glaucoma

Timolol: Reduction of elevated IOP in patients with open-angle glaucoma or ocular hypertension.^{104 105 106 107}

Current data suggest similar efficacy for timolol maleate and timolol as the hemihydrate.¹⁰⁷ Efficacy of Istalol timolol maleate solution (formulated with potassium sorbate) administered as a 0.5% solution of timolol once daily also similar to that of timolol maleate (formulated without potassium sorbate) administered as a 0.5% solution of timolol twice daily.¹¹⁰

Fixed-combination dorzolamide 2% and timolol 0.5%: Reduction of elevated IOP in patients with open-angle glaucoma or ocular hypertension who have not responded adequately (i.e., failed to achieve target IOP as determined after multiple measurements over time) to a topical β-adrenergic blocking agent.¹⁰⁸ When administered twice daily, IOP-lowering effect was 1–3 mm Hg greater than that of dorzolamide 2% administered 3 times daily or timolol 0.5% administered twice daily and approximately 1 mm Hg less than that achieved with concurrent use of dorzolamide 2% administered 3 times daily and timolol 0.5% administered twice daily.¹⁰⁸

Fixed-combination brimonidine tartrate 0.2% and timolol 0.5%: Reduction of elevated IOP in patients with glaucoma or ocular hypertension who require adjunctive or replacement therapy because of inadequately controlled IOP.¹⁰⁹ When administered twice daily, IOP-lowering effect was 1–3 mm Hg greater than that of brimonidine tartrate 0.2% administered 3 times daily, 1–2 mm Hg greater than that of timolol 0.5% administered twice daily, and approximately 1–2 mm Hg less than that achieved with concurrent use of brimonidine tartrate 0.2% administered 3 times daily and timolol 0.5% administered twice daily.¹⁰⁹

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

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

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

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

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

Timolol (EENT) Dosage and Administration

General

• Since IOP may not stabilize for a few weeks after initiating therapy, determine IOP after about 4 weeks of therapy; thereafter, determine IOP as necessary.^{104 b}

• Because of diurnal variations in IOP, measure IOP at different times during the day to determine if an adequate hypotensive effect is maintained in patients receiving a single daily dose.^{104 106 b}

Administration

Ophthalmic Administration

Apply topically to the eye as an ophthalmic solution containing timolol alone or in fixed combination with brimonidine or dorzolamide.^{104 105 106 107 108 109 110}

Avoid contamination of the solution container.^b (See Bacterial Keratitis under Cautions.)

If more than one topical ophthalmic preparation is used, administer the preparations at least 5 minutes apart^{107 108 109 110} (some manufacturers recommend an interval of at least 10 minutes).¹⁰⁴ Administer other topical preparations at least 10 minutes before a dose of timolol gel-forming solution.¹⁰⁶

Invert and shake containers of timolol ophthalmic gel-forming solution once just prior to administration of each dose.¹⁰⁶

Some timolol ophthalmic solutions contain benzalkonium chloride.^{104 108 109} Remove contact lenses before administering each dose of these solutions; may reinsert lenses 15 minutes after the dose.^{104 108 109} (See Contact Lenses under Cautions.)

Administer preservative-free solutions of timolol or fixed-combination dorzolamide and timolol topically to one or both eyes immediately after opening the container, then immediately discard any solution remaining in the opened single-use container.^{105 111}

Dosage

Available as timolol maleate or timolol (as the hemihydrate); dosage expressed in terms of timolol.^{104 105 107}

Pediatric Patients

Ocular Hypertension and Glaucoma

Ophthalmic

Timolol ophthalmic solution (as timolol maleate) in pediatric patients ≥2 years of age: Initially, 1 drop of a 0.25% solution in the affected eye(s) twice daily.^{104 105} May increase dosage to 1 drop of a 0.5% solution in the affected eye(s) twice daily if necessary.^{104 105} May then reduce dosage to 1 drop of the effective strength in the affected eye(s) once daily if satisfactory IOP is maintained.^{104 105}

Brimonidine tartrate 0.2% and timolol 0.5% ophthalmic solution in pediatric patients ≥2 years of age: 1 drop in the affected eye(s) twice daily (approximately every 12 hours).¹⁰⁹

Dorzolamide 2% and timolol 0.5% ophthalmic solution in pediatric patients ≥2 years of age: 1 drop in the affected eye(s) twice daily.¹⁰⁸

Adults

Ocular Hypertension and Glaucoma

Ophthalmic

Timolol ophthalmic solution (as timolol maleate or hemihydrate): Initially, 1 drop of a 0.25% solution in the affected eye(s) twice daily.^{104 105 107} May increase dosage to 1 drop of a 0.5% solution in the affected eye(s) twice daily if necessary.^{104 105 107} May then reduce dosage to 1 drop of the effective strength in the affected eye(s) once daily if satisfactory IOP is maintained.^{104 105 107}

Istalol (potassium sorbate-containing) timolol ophthalmic solution: 1 drop of a 0.5% solution in the affected eye(s) once daily in the morning.¹¹⁰ (See Bioavailability under Pharmacokinetics.)

Timolol ophthalmic gel-forming solution: 1 drop of a 0.25 or 0.5% solution in the affected eye(s) once daily.¹⁰⁶

Brimonidine tartrate 0.2% and timolol 0.5% ophthalmic solution: 1 drop in the affected eye(s) twice daily (approximately every 12 hours).¹⁰⁹

Dorzolamide 2% and timolol 0.5% ophthalmic solution: 1 drop in the affected eye(s) twice daily.¹⁰⁸

If target IOP not achieved, may initiate additional or alternative ocular hypotensive agents.^{130 131 133} (See Ocular Hypertension and Glaucoma under Uses.) Concomitant use of multiple topical ophthalmic β-adrenergic blocking agents not recommended.^{104 105}

Prescribing Limits

Pediatric Patients

Ocular Hypertension and Glaucoma

Ophthalmic

Timolol ophthalmic solution (as timolol maleate): Dosages >1 drop of a 0.5% solution in the affected eye(s) twice daily generally do not produce further reduction in IOP.^{104 105}

Adults

Ocular Hypertension and Glaucoma

Ophthalmic

Timolol ophthalmic solution (as timolol maleate or hemihydrate): Dosages >1 drop of a 0.5% solution in the affected eye(s) twice daily generally do not produce further reduction in IOP.^{104 105 107}

Timolol ophthalmic gel-forming solution: Dosages >1 drop of a 0.5% solution in the affected eye(s) once daily not studied.¹⁰⁶

Cautions for Timolol (EENT)

Contraindications

• Known hypersensitivity to timolol or any ingredient in the formulation.^{104 105 106 107}

• Asthma, history of asthma, or severe COPD (e.g., severe chronic bronchitis or emphysema).^{104 105 106 107} (See Respiratory Disease under Cautions.)

• Sinus bradycardia or AV block greater than first degree.^{104 105 106 107}

• Overt cardiac failure or cardiogenic shock.^{104 105 106 107} (See Cardiac Failure under Cautions.)

Warnings/Precautions

Sensitivity Reactions

History of Atopy or Anaphylactic Reactions

Patients with a history of atopy or of a severe anaphylactic reaction to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenges with such allergens while taking β-adrenergic blocking agents; such patients may be unresponsive to usual doses of epinephrine used to treat anaphylactic reactions.^{104 105 106 107}

Use of Fixed Combinations

When used in fixed combination with brimonidine or dorzolamide, consider the cautions, precautions, contraindications, and drug interactions associated with each drug in the fixed combination.^{108 109}

Systemic Effects

May be absorbed systemically following topical application to the eye;¹⁰⁴ consider the usual precautions associated with systemic use of β-adrenergic blocking agents when using topical timolol.^b

Cardiac Failure

Severe cardiac reactions, including death associated with cardiac failure, reported in patients receiving systemic or topical (ocular) timolol.^{104 105 106 107} In patients with diminished myocardial contractility, sympathetic stimulation may be essential for circulatory support.¹⁰⁴

May precipitate more severe cardiac failure in patients with preexisting heart failure and may cause cardiac failure in some patients without a history of heart failure.¹⁰⁴

Contraindicated in patients with cardiogenic shock or overt cardiac failure.¹⁰⁴ In patients without a history of cardiac failure, discontinue therapy at the first sign or symptom of cardiac failure.^{104 105 106 107}

Respiratory Disease

Severe respiratory reactions, including death resulting from bronchospasm, reported in patients with asthma receiving systemic or topical (ocular) timolol.^{104 105 106 107}

Contraindicated in patients with asthma, history of asthma, or severe COPD (e.g., severe chronic bronchitis or emphysema).¹⁰⁴ Patients with mild or moderately severe COPD, bronchospastic disease other than asthma, or a history of such bronchospastic disease generally should not receive β-adrenergic blocking agents.^{104 105 106 107}

Muscle Weakness

β-Adrenergic blocking agents reported to potentiate muscle weakness consistent with certain myasthenic manifestations (e.g., diplopia, ptosis, and generalized weakness).^{104 105 106 107}

Timolol reported rarely to increase muscle weakness in patients with myasthenia gravis or myasthenia symptoms.^{104 105 106 107}

Diabetes Mellitus

β-Adrenergic blocking agents may mask signs and symptoms of acute hypoglycemia; administer with caution in patients subject to spontaneous hypoglycemia and in diabetic patients (especially those with labile diabetes) who are receiving hypoglycemic agents.^{104 105 106 107}

Thyrotoxicosis

β-Adrenergic blocking agents may mask signs of hyperthyroidism (e.g., tachycardia).^{104 105 106 107}

Possible thyroid storm if β-adrenergic blocking agent is abruptly withdrawn; carefully monitor patients having or suspected of developing thyrotoxicosis.^{104 105 106 107}

Bacterial Keratitis

Bacterial keratitis reported after inadvertent contamination of multiple-dose containers of topical ophthalmic solutions, principally in patients with concurrent corneal disease or disruption of ocular epithelial surface.^{104 105 106 107}

Improper handling of ophthalmic preparations can result in contamination of the solution by common bacteria known to cause ocular infections.¹⁰⁴ Serious damage to the eye and subsequent loss of vision may result from using contaminated ophthalmic preparations.¹⁰⁴ (See Advice to Patients.)

Major Surgery

Possible increased risks associated with general anesthesia (e.g., severe hypotension, difficulty restarting or maintaining heart beat) due to decreased ability of the heart to respond to reflex β-adrenergic stimuli.^{104 105 106 107}

Need for withdrawal of β-adrenergic blocking agents prior to major surgery is controversial; some clinicians recommend gradual withdrawal of β-adrenergic blocking agents prior to elective surgery.^{104 105 106 107}

If necessary during surgery, may reverse effects of β-adrenergic blocking agents by administering sufficient doses of adrenergic agonists.¹⁰⁴

Angle-closure Glaucoma

Timolol has little or no effect on pupil size; do not use alone in patients with angle-closure glaucoma.^{104 105 106 107}

Cerebrovascular Insufficiency

Caution advised in patients with cerebrovascular insufficiency due to the potential effects of β-adrenergic blocking agents on BP and pulse.^{104 105 106 107} Consider alternative therapy if signs or symptoms suggestive of reduced cerebral blood flow occur.^{104 105 106 107}

Choroidal Detachment

Choroidal detachment after filtration procedures reported.^{104 105 106 107}

Contact Lenses

Some timolol ophthalmic solutions contain benzalkonium chloride, which may be absorbed by soft contact lenses.^{104 108 109} Remove contact lenses before administering each dose of these solutions; may reinsert lenses 15 minutes after the dose.^{104 108 109}

Specific Populations

Pregnancy

Category C.^{107 110}

Use only if potential benefits justify the possible risks to the fetus.¹⁰⁴

Lactation

Distributed into milk following topical application to the eye.¹⁰⁴ Discontinue nursing or the drug.^{104 105 106 107}

Pediatric Use

Timolol maleate ophthalmic solution: Safety and efficacy in pediatric patients ≥2 years of age established based on evidence from adequate and well-controlled studies in children and adults; safety and efficacy not established in pediatric patients <2 years of age.^{104 106} Safety and efficacy of Istalol (timolol maleate solution formulated with potassium sorbate) not established in pediatric patients.¹¹⁰

Timolol (as the hemihydrate) ophthalmic solution: Safety and efficacy not established in pediatric patients.¹⁰⁷

Brimonidine and timolol ophthalmic solution: Safety and efficacy established in pediatric patients 2–16 years of age based on evidence from adequate and well-controlled studies of the fixed combination in adults and additional data from a study evaluating the individually administered drugs (brimonidine tartrate 0.2% administered 3 times daily as an adjunct to timolol therapy) in children 2–7 years of age with glaucoma.¹⁰⁹ Incidence of somnolence appeared to be age and weight related, occurring in 50–83% of children 2–6 years of age and 25% of those 7 years of age who weighed >20 kg.¹⁰⁹

Dorzolamide and timolol ophthalmic solution: Safety and efficacy established (as the individually administered drugs) in pediatric patients ≥2 years of age based on evidence from adequate and well-controlled studies in children and adults.¹⁰⁸ Safety and efficacy not established in pediatric patients <2 years of age.¹⁰⁸

Geriatric Use

No overall differences in safety and efficacy relative to younger patients.^{104 106}

Common Adverse Effects

Burning and stinging on instillation.^{104 105 106 107}

Drug Interactions

Appears to be metabolized partly by CYP2D6.^{104 105 106 107 114}

Drugs Affecting Hepatic Microsomal Enzymes

CYP2D6 inhibitors: Possible increased plasma timolol concentrations and increased systemic β-adrenergic blockade (e.g., decreased heart rate, depression).^{104 105 106 107 114}

Specific Drugs

Timolol (EENT) Pharmacokinetics

Absorption

Bioavailability

Absorbed into systemic circulation following topical administration.^{104 105 106 107}

Systemic bioavailability of Istalol (timolol maleate formulated with potassium sorbate to facilitate absorption into the aqueous humor) similar to that of timolol maleate formulated without potassium sorbate.^{110 113}

Onset

Following topical application to the eye of a 0.25 or 0.5% solution, reduction in IOP usually occurs within 15–30 minutes and reaches a maximum within 1–5 hours.^b

Duration

Reduction in IOP persists about 24 hours.^{104 105 106 107}

Elimination

Metabolism

Appears to be metabolized in the liver partly by CYP2D6.^{104 105 106 107 114}

Stability

Storage

Ophthalmic

Solution

Preserved timolol maleate or timolol (hemihydrate) solution: 15–25°C; protect from light.^{104 107 110} Do not freeze.^{104 107 110}

Preservative-free timolol maleate solution: 15–30°C in the protective foil overwrap; protect from light and freezing.¹⁰⁵ Use the individual unit-dose containers within one month after opening the foil package.¹⁰⁵

Brimonidine tartrate and timolol maleate solution: 15–25°C; protect from light.¹⁰⁹

Preserved dorzolamide and timolol maleate solution: 15–25°C; protect from light.¹⁰⁸

Preservative-free dorzolamide and timolol maleate solution: 20–25°C in the original foil pouch for protection from light; discard any unused containers 15 days after first opening the pouch.¹¹¹ Do not freeze.¹¹¹

Solution, gel-forming

Timolol maleate gel-forming solution: 15–25°C; protect from light and freezing.¹⁰⁶

Actions

• Nonselective β-adrenergic blocking agent that does not have substantial intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic activity.^{104 105 106 107}

• Reduces IOP by about 25–33% in patients with elevated IOP.^b

• Exact mechanism of action not fully elucidated; tonography and fluorophotometric studies suggest that reduced aqueous humor formation is the principal effect.^{104 105 106 107} A slight increase in outflow facility observed in some studies.^{104 105 106 107}

• Tolerance may develop with prolonged use; however, IOP-lowering effect maintained for at least 3 years of continuous use in some patients.^b

Advice to Patients

• Importance of learning and adhering to proper administration techniques to avoid contamination of the solution with common bacteria that can cause ocular infections.^{104 105 106 107} Instruct patients that the tip of the dispensing container should not touch the eye or surrounding structures, or any other surface.¹⁰⁴ Serious damage to the eye and subsequent loss of vision may result from using contaminated ophthalmic solutions.¹⁰⁴

• Advise patients to immediately contact their clinician for advice regarding continued use of the ophthalmic preparation if they experience an intercurrent ocular condition (e.g., trauma, infection) or require ocular surgery.^{104 111}

• When an ophthalmic preparation that contains benzalkonium chloride is used, importance of removing soft contact lenses prior to administering a dose and delaying reinsertion for at least 15 minutes after administration.^{104 108 109}

• If using more than one topical ophthalmic preparation, importance of administering the preparations at least 5 minutes apart^{107 108 109 110} (some manufacturers recommend at least 10 minutes apart).¹⁰⁴ Administer other topical preparations at least 10 minutes before a dose of timolol gel-forming solution.¹⁰⁶

• Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.^{104 105 106 107}

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{104 105 106 107}

• Importance of informing patients of other important precautionary information.^{104 105 106 107} (See Cautions.)

Preparations

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

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

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

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

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