Introduction

Nonselective β-adrenergic blocking agent.

Uses for Timolol (EENT)

Ocular Hypertension and Glaucoma

Timolol: Reduction of elevated IOP in patients with open-angle glaucoma or ocular hypertension.

Current data suggest similar efficacy for timolol maleate and timolol as the hemihydrate. 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.

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. 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.

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. 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.

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). 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.

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.

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

Reduction of pretreatment IOP by ≥25% shown to slow progression of primary open-angle glaucoma. 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. Adjust target IOP up or down as needed over course of disease.

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

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.

• 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.

Administration

Ophthalmic Administration

Apply topically to the eye as an ophthalmic solution containing timolol alone or in fixed combination with brimonidine or dorzolamide.

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

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

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

Some timolol ophthalmic solutions contain benzalkonium chloride. Remove contact lenses before administering each dose of these solutions; may reinsert lenses 15 minutes after the dose. (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.

Dosage

Available as timolol maleate or timolol (as the hemihydrate); dosage expressed in terms of timolol.

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. May increase dosage to 1 drop of a 0.5% solution in the affected eye(s) twice daily if necessary. May then reduce dosage to 1 drop of the effective strength in the affected eye(s) once daily if satisfactory IOP is maintained.

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).

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

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. May increase dosage to 1 drop of a 0.5% solution in the affected eye(s) twice daily if necessary. May then reduce dosage to 1 drop of the effective strength in the affected eye(s) once daily if satisfactory IOP is maintained.

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

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

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

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

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.

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.

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

Contraindications

• Known hypersensitivity to timolol or any ingredient in the formulation.

• Asthma, history of asthma, or severe COPD (e.g., severe chronic bronchitis or emphysema). (See Respiratory Disease under Cautions.)

• Sinus bradycardia or AV block greater than first degree.

• Overt cardiac failure or cardiogenic shock. (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.

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.

Systemic Effects

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

Cardiac Failure

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

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.

Contraindicated in patients with cardiogenic shock or overt cardiac failure. In patients without a history of cardiac failure, discontinue therapy at the first sign or symptom of cardiac failure.

Respiratory Disease

Severe respiratory reactions, including death resulting from bronchospasm, reported in patients with asthma receiving systemic or topical (ocular) timolol.

Contraindicated in patients with asthma, history of asthma, or severe COPD (e.g., severe chronic bronchitis or emphysema). 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.

Muscle Weakness

β-Adrenergic blocking agents reported to potentiate muscle weakness consistent with certain myasthenic manifestations (e.g., diplopia, ptosis, and generalized weakness).

Timolol reported rarely to increase muscle weakness in patients with myasthenia gravis or myasthenia symptoms.

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.

Thyrotoxicosis

β-Adrenergic blocking agents may mask signs of hyperthyroidism (e.g., tachycardia).

Possible thyroid storm if β-adrenergic blocking agent is abruptly withdrawn; carefully monitor patients having or suspected of developing thyrotoxicosis.

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.

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

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.

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

Angle-closure Glaucoma

Timolol has little or no effect on pupil size; do not use alone in patients with angle-closure glaucoma.

Cerebrovascular Insufficiency

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

Choroidal Detachment

Choroidal detachment after filtration procedures reported.

Contact Lenses

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

Specific Populations

Pregnancy

Category C.

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

Lactation

Distributed into milk following topical application to the eye. Discontinue nursing or the drug.

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. Safety and efficacy of Istalol (timolol maleate solution formulated with potassium sorbate) not established in pediatric patients.

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

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. 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.

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. Safety and efficacy not established in pediatric patients <2 years of age.

Geriatric Use

No overall differences in safety and efficacy relative to younger patients.

Common Adverse Effects

Burning and stinging on instillation.

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.

• 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.

Administration

Ophthalmic Administration

Apply topically to the eye as an ophthalmic solution containing timolol alone or in fixed combination with brimonidine or dorzolamide.

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

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

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

Some timolol ophthalmic solutions contain benzalkonium chloride. Remove contact lenses before administering each dose of these solutions; may reinsert lenses 15 minutes after the dose. (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.

Dosage

Available as timolol maleate or timolol (as the hemihydrate); dosage expressed in terms of timolol.

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. May increase dosage to 1 drop of a 0.5% solution in the affected eye(s) twice daily if necessary. May then reduce dosage to 1 drop of the effective strength in the affected eye(s) once daily if satisfactory IOP is maintained.

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).

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

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. May increase dosage to 1 drop of a 0.5% solution in the affected eye(s) twice daily if necessary. May then reduce dosage to 1 drop of the effective strength in the affected eye(s) once daily if satisfactory IOP is maintained.

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

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

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

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

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.

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.

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

Appears to be metabolized partly by CYP2D6.

Drugs Affecting Hepatic Microsomal Enzymes

CYP2D6 inhibitors: Possible increased plasma timolol concentrations and increased systemic β-adrenergic blockade (e.g., decreased heart rate, depression).

Specific Drugs