AHFS Class:

• beta-Adrenergic Blocking Agents 52:40.08

Generic Name(s):

• Timolol Maleate

Timolol is a nonselective β-adrenergic blocking agent.

Ocular Hypertension and Glaucoma

In ophthalmology, topical timolol is used to reduce elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. Dorzolamide hydrochloride and timolol maleate fixed-combination ophthalmic solution is used topically to reduce 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. Brimonidine tartrate and timolol maleate fixed-combination ophthalmic solution is used topically to reduce elevated IOP in patients with glaucoma or ocular hypertension who require adjunctive or replacement therapy because of inadequately controlled IOP.109 Topical timolol also has been used to reduce elevated IOP in patients with aphakic glaucoma† and some secondary glaucomas†. Elevated IOP presents a major risk factor in glaucomatous visual field loss; the higher the level of IOP, the greater the likelihood of optic nerve damage and glaucomatous visual field loss.

Elevated IOP in patients with glaucoma can be reduced by medical treatment, laser therapy, and/or incisional glaucoma surgery; treatment with a topical ocular hypotensive agent frequently is the initial intervention for primary open-angle glaucoma.130 Selection of an initial ocular hypotensive agent is influenced by the extent of the required reduction in IOP, coexisting medical conditions, and the characteristics of the individual drugs (e.g., dosing frequency, adverse effect profile, 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 In the absence of other considerations (e.g., contraindications, cost considerations, intolerance, adverse effects, patient refusal), a prostaglandin analog frequently is considered for initial therapy because of the relatively greater activity, once-daily administration, and low frequency of systemic adverse effects with this drug class; however, ocular adverse effects can occur.130,131,132,134

IOP should be reduced toward a target level that the clinician believes will slow disease progression and avoid visual field losses that would substantially reduce quality of life during the patient's lifetime.130,132 The target level is an estimate and should be individualized based on such factors as the extent of optic nerve damage and/or visual field loss, the baseline IOP at which damage occurred, rate of progression, life expectancy, and other considerations.130,132 Reducing the pretreatment IOP by 25% or more has been shown to slow progression of primary open-angle glaucoma.130,131 The target IOP should be adjusted up or down as needed over the course of the disease.130,131,132 If the target IOP is not achieved with single-agent therapy, alternative or additional ocular hypotensive agents may be selected depending on the patient's response to the initial drug.130 Combination therapy with drugs from different therapeutic classes often is required to achieve adequate control of IOP.131,133

Like other ophthalmic nonselective β-blocking agents (e.g., levobunolol), ophthalmic timolol has been associated with adverse systemic pulmonary and cardiovascular effects. The drug should be used with caution in patients with diminished pulmonary function, and is contraindicated in patients with asthma or a history of asthma and in patients with severe chronic obstructive pulmonary disease.

If timolol is used to reduce IOP in patients with angle-closure glaucoma, the drug should not be used alone but rather in combination with a topical miotic since timolol has little or no effect on pupil size.

Like levobunolol, timolol reduces elevated IOP in patients with chronic open-angle glaucoma without producing the miosis and/or ciliary spasm that are associated with miotic agents.

Clinical Experience

Current data from a limited number of controlled studies suggest similar clinical efficacy for ophthalmic timolol maleate and ophthalmic timolol as the hemihydrate.107 Efficacy of the Istalol^® formulation of timolol maleate ophthalmic solution (formulated with potassium sorbate) administered as a 0.5% solution of timolol once daily also appears to be similar to that of timolol maleate ophthalmic solution (formulated without potassium sorbate) administered as a 0.5% solution of timolol twice daily.110

In double-blind studies in patients with open-angle glaucoma, usual doses of timolol have been found to be at least as effective as therapeutic doses of pilocarpine in reducing elevated IOP without the miosis, ocular irritation, and blurred vision associated with pilocarpine therapy. Timolol maleate also has been found in multiclinic studies to be at least as effective as epinephrine in reducing IOP in patients with open-angle glaucoma.

In clinical studies of 3-15 months' duration, the IOP-lowering effect of the fixed-combination ophthalmic solution containing timolol 0.5% and dorzolamide 2% administered twice daily was 1-3 mm Hg greater than that of dorzolamide 2% administered 3 times daily or timolol 0.5% administered twice daily; the IOP-lowering effect of the fixed combination administered twice daily was slightly (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

In clinical studies evaluating topical timolol 0.5% in fixed combination with brimonidine tartrate 0.2%, the IOP-lowering effect of the fixed-combination ophthalmic solution administered twice daily was 1-3 mm Hg greater than that of brimonidine tartrate 0.2% administered 3 times daily and 1-2 mm Hg greater than that of timolol 0.5% administered twice daily.109 The IOP-lowering effect of the fixed combination administered twice daily was slightly (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 Patients older than 40 years of age receiving the fixed combination twice daily reported less drowsiness than did those receiving concurrent therapy with brimonidine 3 times daily and timolol twice daily.109

Following prolonged therapy with topical timolol, the effect in reducing IOP is generally well maintained, but tolerance has been reported in some patients. In one long-term study in patients receiving timolol for at least 3 years, the reduction in mean IOP was maintained following initial stabilization with the drug.

Administration

Timolol or timolol maleate is applied topically to the eye as an ophthalmic solution. Timolol maleate also is applied topically to the eye as a gel-forming ophthalmic solution.106 Timolol maleate also is commercially available in fixed combination with dorzolamide hydrochloride or brimonidine tartrate (as ophthalmic solutions) for topical application to the eye.108,109 Care should be taken to avoid contamination of the solution container.

Some timolol ophthalmic solutions contain benzalkonium chloride, which may be absorbed by soft contact lenses.104,108,109 Contact lenses should be removed prior to administration of each dose of these solutions, but may be reinserted 15 minutes after the dose.104,108,109

Preservative-free ophthalmic solutions containing timolol alone or in fixed combination with dorzolamide should be administered topically to one or both eyes immediately after the single-use container is opened; since sterility cannot be maintained after the individual unit is opened, any remaining contents should be discarded immediately after administration.105,111

If the patient is receiving more than one ophthalmic preparation, the preparations should be administered at least 5 minutes apart,107,108,109,110 although some manufacturers recommend an interval of at least 10 minutes.104 Containers of timolol maleate ophthalmic gel-forming solution should be inverted and shaken once just prior to administration of each dose.106 Patients receiving ophthalmic gel-forming solutions of the drug who also are receiving other ophthalmic preparations should be instructed that other topical preparations be administered at least 10 minutes before a dose of the gel-forming solution.106

Dosage

Ocular Hypertension and Glaucoma

Dosage of timolol maleate or timolol (as the hemihydrate) is expressed in terms of timolol.

When timolol maleate ophthalmic solution is used for the treatment of open-angle glaucoma or ocular hypertension, the usual initial dosage of timolol in adults and pediatric patients 2 years of age or older is 1 drop of a 0.25% solution in the affected eye(s) twice daily.104,105 If necessary for adequate reduction of intraocular pressure (IOP), dosage may be increased to 1 drop of a 0.5% solution in the affected eye(s) twice daily. The dose may then be reduced to 1 drop of the effective strength in the affected eye(s) once daily if satisfactory IOP is maintained. Dosages exceeding 1 drop of a 0.5% solution twice daily generally have not produced a further reduction in IOP. Alternatively, timolol 0.25 or 0.5% may be administered as the hemihydrate in adults at these same dosages.107

When the Istalol^® formulation of timolol maleate ophthalmic solution is used, the usual adult dosage of timolol is 1 drop of a 0.5% solution in the affected eye(s) once daily in the morning.110

When timolol maleate ophthalmic gel-forming solution is used, the usual adult dosage of timolol is 1 drop of a 0.25 or 0.5% solution in the affected eye(s) once daily.106 Dosages exceeding 1 drop of a 0.5% gel-forming solution once daily have not been studied.106 If further reduction in IOP is needed in patients receiving 1 drop of a timolol 0.5% gel-forming solution once daily, concomitant therapy should be considered.106 When once-daily dosing of timolol ophthalmic gel-forming solution has been substituted for twice-daily dosing of timolol maleate conventional ophthalmic solution, the IOP-lowering effect has remained consistent.106

Because of diurnal variations in IOP, IOP should be measured at different times during the day to determine if an adequate effect is maintained in patients receiving single-daily-dose therapy. Since IOP may not stabilize for a few weeks after initiating timolol therapy in some patients, IOP should also be determined after about 4 weeks of therapy with the drug.

If the target IOP is not achieved, alternative or additional ocular hypotensive agents may be required.130,131,133 Concomitant use of multiple topical ophthalmic β-adrenergic blocking agents is not recommended.104,105

When timolol maleate is used in fixed combination with brimonidine tartrate, the usual dosage in adults and pediatric patients 2 years of age or older is 1 drop of an ophthalmic solution containing brimonidine tartrate 0.2% and timolol 0.5% in the affected eye(s) twice daily at intervals of approximately 12 hours.109

When timolol maleate is used in fixed combination with dorzolamide hydrochloride, the usual dosage in adults and pediatric patients 2 years of age or older is 1 drop of an ophthalmic solution containing dorzolamide 2% and timolol 0.5% in the affected eye(s) twice daily.108

Timolol ophthalmic solutions generally are well tolerated following topical application to the eye; however, adverse effects may occasionally be severe enough to require discontinuance of the drug.

Ocular Effects

In clinical studies, blurred vision (lasting 0.5-5 minutes) upon instillation has been reported in about 33% of patients receiving timolol maleate gel-forming ophthalmic solution.106 Blurred vision requiring discontinuance of the gel-forming solution reportedly occurred in less than 1% of patients.106 The most common adverse effects of ophthalmic timolol solutions, occurring in about 13% of patients, are burning or stinging upon instillation.104,105,106

Signs and symptoms of ocular irritation,104,106 including conjunctivitis,104,106 blepharitis,104,106 keratitis,104,106 ocular pain,104 discharge (e.g., crusting),104,106 itching and tearing,104,106 foreign body sensation,104,106 dry eyes,104,106 eyelid erythema, and blepharoptosis have been reported occasionally in patients receiving topical timolol therapy. Visual disturbances including refractive changes (resulting from withdrawal of miotic therapy in some patients) have been infrequently associated with timolol therapy.104,106 Decreased corneal sensitivity,104,106 diplopia,104,106 cystoid macular edema,104,106 pseudopemphigoid,104,106 choroidal detachment following filtration surgery,104,106 epiphora, photophobia, blurred vision,106 conjunctival injection, corneal fluorescein staining, cataract, retinal vascular disorder, and ptosis106 also have occurred.

Systemic Effects

Cardiovascular Effects

Aggravation or precipitation of certain cardiovascular disorders, presumably related to effects of systemic β-adrenergic blockade, may occur during therapy with topical timolol and may include bradycardia,104,106 arrhythmia,104,106 congestive heart failure, hypotension,104,106 hypertension,104,106 syncope,104,106 heart block,104,106 cerebrovascular accident,104,106 cerebral ischemia,104,106 cardiac failure,104,106 worsening of angina pectoris,104,106 cardiac arrest,104,106 pulmonary edema,104,106 palpitation,104,106 chest pain,104,106 peripheral edema,104,106 edema, claudication,104,106 Raynaud phenomenon,104,106 and cold hands and feet.104,106 Ophthalmic β-adrenergic blocking agents may impair compensatory increases in heart rate and increase the risk of hypotension.109 Slight reduction of resting heart rate may occur, and slightly decreased blood pressure has been reported in some patients receiving high doses of the drug (i.e., 1 drop of a 1% solution to each eye). Rarely, death associated with cardiac failure has been reported in patients receiving systemic or topical (ocular) timolol.104,106

Nervous System Effects

Headache106 and dizziness106 occurred in 1-5% of patients receiving timolol maleate gel-forming ophthalmic solution in clinical studies.106 Other adverse nervous system effects reported with topical (ocular) timolol therapy include exacerbation of myasthenia gravis or myasthenic symptoms (e.g., increased muscle weakness),104,106 paresthesia,104,106 asthenia104,106 and/or fatigue,104,106 somnolence,104,106 insomnia,104,106 nightmares,104,106 behavioral changes104,106 and psychic disturbances104,106 (e.g., depression, 104,106 confusion, 104,106 hallucinations, 104,106 anxiety, disorientation, 104,106 nervousness, 104,106 memory loss).104,106

Respiratory Effects

Aggravation or precipitation of certain respiratory disorders, presumably related to effects of systemic β-adrenergic blockade, may occur during therapy with topical timolol and may include dyspnea,104,106 nasal congestion,104,106 cough,104,106 upper respiratory infections,104,106 sinusitis,104,106 and respiratory failure.104,106 Severe respiratory reactions, including death resulting from bronchospasm (mainly in patients with preexisting bronchospastic disease [e.g., asthma])104,106 have been reported in patients receiving topical timolol therapy.

Dermatologic and Sensitivity Reactions

Hypersensitivity reactions, including anaphylaxis,104,106 angioedema,104,106 urticaria,104,106 and localized or generalized rash104,106 have occurred rarely during topical timolol therapy. Alopecia, 104,106 psoriasiform rash, 104,106 exacerbation of psoriasis, 104,106 and systemic lupus erythematosus104,106 also have been reported.

GI Effects

Diarrhea,104,106 nausea,104,106 dyspepsia,104,106 anorexia, 104,106 and dry mouth104,106 have been reported in patients receiving topical timolol therapy.

Genitourinary Effects

Retroperitoneal fibrosis,104,106 impotence,104,106 decreased libido,104,106 and Peyronie disease104,106 have been reported in some patients receiving topical timolol therapy.

Endocrine Effects

Masked symptoms of hypoglycemia in insulin-dependent diabetics have been reported rarely with topical timolol.104,106

Other Systemic Effects

Common cold and pain in the extremities have been reported in some patients receiving topical timolol therapy. The possibility that other adverse systemic effects associated with systemic timolol or other β-adrenergic blocking agents may occur during topical timolol therapy should be considered.104,106

Precautions and Contraindications

Topical (ocular) timolol shares the toxic potentials of systemically administered timolol, and the usual precautions of systemic timolol therapy should be observed with the topical preparations. In addition, patients receiving topical timolol and a systemic β-adrenergic blocking agent concomitantly should be observed carefully for potential additive effects on intraocular pressure (IOP) and/or systemic effects of β-adrenergic blockade.

Severe cardiac reactions including, rarely, death associated with cardiac failure have been reported in patients receiving systemic or topical timolol.104,105,106 In patients with diminished myocardial contractility, sympathetic stimulation may be essential for circulatory support and more severe cardiac failure may be precipitated by β-adrenergic blockade.104 In some patients without a history of cardiac failure, prolonged β-adrenergic blockade and subsequent myocardial depression may lead to cardiac failure.104 Timolol should be discontinued at the first sign or symptom of impending cardiac failure.104 Topical timolol is contraindicated in patients with cardiogenic shock or overt cardiac failure.104

Severe respiratory reactions, including death resulting from bronchospasm in patients with asthma, have been reported in patients receiving systemic or topical timolol.104,105,106 Topical timolol is contraindicated in patients with asthma or a history of asthma and in patients with severe chronic obstructive pulmonary disease (e.g., severe chronic bronchitis or emphysema).104 Patients with mild or moderately severe chronic obstructive pulmonary disease, bronchospastic disease other than asthma, or a history of such bronchospastic disease generally should not receive β-adrenergic blocking agents.104,105,106,107

Patients who have a history of atopy or of a severe anaphylactic reaction to a variety of allergens reportedly may be more reactive to repeated accidental, diagnostic, or therapeutic challenges with such allergens while taking β-adrenergic blocking agents and may be unresponsive to usual doses of epinephrine used to treat anaphylactic reactions.

β-Adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic manifestations (e.g., diplopia, ptosis, generalized weakness).104

Because β-adrenergic blocking agents may mask the signs and symptoms of acute hypoglycemia, these agents should be administered with caution in patients subject to spontaneous hypoglycemia and in diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents.106,108 Beta-adrenergic blocking agents also may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism.108 Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of β-adrenergic blocking agents that might precipitate a thyroid storm.108

Bacterial keratitis has been reported with the use of multidose containers of topical ophthalmic preparations. These containers had been contaminated inadvertently by patients who, in most cases, had a concurrent corneal disease or disruption of the ocular epithelial surface. Patients should be informed that improper handling of ophthalmic solutions can result in contamination of the solution by common bacteria known to cause ocular infections and should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures or any other surface. Serious damage to the eye and subsequent loss of vision may result from using contaminated ophthalmic solutions. Patients also should be advised 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

Because benzalkonium chloride may be absorbed by soft contact lenses, patients receiving timolol ophthalmic solutions that contain this preservative should be advised to wait at least 15 minutes after instillation of the ophthalmic solution before they insert their soft contact lenses.104

The need to withdraw β-adrenergic blocking agents prior to major surgery is controversial.104β-Adrenergic blocking agents may reduce the ability of the heart to respond to reflex β-adrenergic stimuli, which may increase the risk of general anesthesia.104 Severe, protracted hypotension has occurred during surgery in some patients who received β-adrenergic blocking agents, and difficulty in restarting and maintaining the heartbeat also has been reported.104 Some clinicians recommend gradual withdrawal of β-adrenergic blocking agents prior to administration of general anesthesia.104 If necessary during surgery, the effects of β-adrenergic blocking agents may be reversed by sufficient doses of adrenergic agonists.104

Because timolol has little or no effect on pupil size, the drug should not be used alone in patients with angle-closure glaucoma, but only in combination with a miotic.

Topical timolol should be used with caution in patients with cerebrovascular insufficiency because of the potential effects of β-adrenergic blocking agents on blood pressure and pulse rate.104 If signs or symptoms suggestive of reduced cerebral blood flow develop, alternative ocular hypotensive therapy should be considered.104

When timolol is used in fixed combination with dorzolamide or brimonidine, the cautions, precautions, contraindications, and drug interactions associated with each agent in the fixed combination should be considered.108,109

Topical (ocular) timolol is contraindicated in patients with asthma or a history of asthma and in patients with severe chronic obstructive pulmonary disease, sinus bradycardia, atrioventricular block greater than first degree, overt cardiac failure, or cardiogenic shock. Topical timolol also is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.

Pediatric Precautions

Safety and efficacy of timolol maleate ophthalmic solutions in pediatric patients 2 years of age and older have been established based on evidence from adequate and well-controlled studies in children and adults; safety and efficacy have not been established in pediatric patients younger than 2 years of age.104,106 The manufacturer states that safety and efficacy of the Istalol^® formulation of timolol maleate ophthalmic solution in pediatric patients have not been established.110

The manufacturer states that safety and efficacy of the ophthalmic solution containing timolol as the hemihydrate have not been established in pediatric patients.107

Safety and efficacy of brimonidine tartrate and timolol maleate fixed-combination ophthalmic solution in pediatric patients 2-16 years of age have been established 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 In this pediatric study, the most commonly observed adverse effects were somnolence and decreased mental alertness; approximately 16% of children receiving brimonidine as an adjunct to timolol discontinued therapy because of somnolence.109 The incidence of somnolence generally 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 more than 20 kg.109

Safety and efficacy of the fixed-combination dorzolamide hydrochloride and timolol maleate ophthalmic solution have been established (when the drugs were administered individually) in pediatric patients 2 years of age or older; use of these drugs in this age group is supported by evidence from adequate and well-controlled studies in children and adults.108 Safety and efficacy have not been established in pediatric patients younger than 2 years of age.108

Geriatric Precautions

No overall differences in safety and efficacy of topical ophthalmic timolol have been observed between geriatric patients and younger patients.104,106

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in mice, rats, and rabbits using oral timolol dosages up to 50 mg/kg daily (7000 times the systemic exposure following the maximum recommended human ophthalmic dosage) have not revealed evidence of harm to the fetus. Although delayed fetal ossification was observed at this dosage in rats, no adverse effects on postnatal development occurred in this species. Oral timolol dosages of 1 g/kg daily (142,000 times the systemic exposure following the maximum recommended human ophthalmic dosage) were maternotoxic and resulted in an increased number of fetal resorptions in mice. Increased fetal resorptions were also observed in rabbits receiving oral timolol dosages 14,000 times the systemic exposure following the maximum recommended human ophthalmic dosage.

There are no adequate and controlled studies to date using timolol ophthalmic solution in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

Fertility

Reproduction studies in male and female rats using oral timolol dosages up to 125 times the maximum human oral dosage (based on patient weight of 50 kg) have not revealed evidence of impaired fertility.

Lactation

Timolol is distributed into milk following oral or topical ophthalmic administration. Because of the potential for serious adverse reactions from timolol in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drugs Affecting Hepatic Microsomal Enzymes

Clinical manifestations of enhanced systemic β-adrenergic blockade (e.g., decreased heart rate, depression) have been reported in patients receiving timolol concomitantly with drugs that inhibit cytochrome P-450 (CYP) isoenzyme 2D6 (e.g., cimetidine, quinidine, selective serotonin-reuptake inhibitors).104,114 Sinus bradycardia, which recurred upon rechallenge, has been reported when ophthalmic timolol and oral quinidine were used concomitantly.103 Increased β-adrenergic blockade, manifested as greater reductions in resting heart rate and intraocular pressure (IOP), were observed when oral cimetidine and timolol ophthalmic solution were administered concomitantly in healthy individuals.114 These interactions have been attributed to inhibition of timolol metabolism (via CYP2D6) by cimetidine and quinidine.

Systemic Beta-Adrenergic Blocking Agents

The possibility of an additive effect on IOP and/or systemic β-adrenergic blockade should be considered in patients who are receiving a systemic β-adrenergic blocking agent and topical timolol concomitantly.

Calcium-channel Blocking Agents

Because atrioventricular (AV) conduction disturbances, left ventricular failure, and/or hypotension may occur, caution should be exercised if timolol and a calcium-channel blocking agent are used concomitantly, and such concomitant use should be avoided in patients with impaired cardiac function. Severe bradycardia (e.g., 36 bpm),100,101,102 which was associated with a wandering pacemaker in one patient,100,101 and transient asystole102 have been reported when ophthalmic timolol and oral verapamil were used concomitantly. A single IV dose of atropine was effective in managing serious bradycardia in at least one patient.102 Verapamil should be used with extreme caution in patients receiving ophthalmic timolol;102 when therapy with a calcium-channel blocking agent is indicated (e.g., for angina) in such patients, an agent with minimal effects on SA node and cardiac conduction (e.g., nifedipine) should be used if possible.101,102

Cardiac Glycosides

Concomitant use of β-adrenergic blocking agents with cardiac glycosides and calcium-channel blocking agents may have additive effects on prolonging AV conduction.104

Catecholamine-depleting Drugs

When topical timolol is administered concomitantly with a catecholamine-depleting drug (e.g., reserpine), the patient should be observed closely for possible additive effects and the production of hypotension and/or marked bradycardia, which may result in vertigo, syncope, and/or postural hypotension.

Clonidine

Although oral β-adrenergic blocking agents may exacerbate rebound hypertension that may occur following discontinuance of clonidine, such an effect has not been reported in patients receiving ophthalmic timolol.

Pharmacology

Timolol is a nonselective β-adrenergic blocking agent. Timolol does not have substantial intrinsic sympathomimetic, parasympathomimetic, or local anesthetic activity.

Ocular Effects

Following topical application to the eye, timolol reduces both elevated and normal intraocular pressure (IOP) in patients with or without open-angle (chronic simple, noncongestive) glaucoma or ocular hypertension. Timolol reduces IOP with little or no effect on accommodation or pupillary size. In patients with elevated IOP, timolol reduces mean IOP by about 25-33%. The drug appears to be equally effective in light- and dark-colored eyes.

The exact mechanism by which β-blockers, including timolol, reduce IOP has not been clearly defined. Fluorophotometric studies suggest that reduced aqueous humor formation is the predominant effect. β-Adrenergic blocking agents may block endogenous catecholamine-stimulated increases in cyclic adenosine monophosphate (AMP) concentrations within the ciliary processes and subsequent formation of aqueous humor. Timolol appears to cause little or no change in aqueous humor outflow facility.

In some studies, timolol applied topically to one eye reduced IOP in both eyes; the mechanism of this effect has not been elucidated.

A slight decrease in the intraocular hypotensive effect may occur during the first 3 weeks of timolol therapy, and tolerance may develop with prolonged use; however, the IOP-lowering effect has been maintained for at least 3 years with continuous use of the drug in some patients.

Systemic Effects

Like levobunolol, which is also a nonselective β-adrenergic blocking agent, timolol can produce systemic pulmonary and cardiovascular effects following topical application to the eye. Adverse pulmonary effects (e.g., bronchoconstriction, increased airway resistance) have been reported following ophthalmic application of timolol. Following topical application to the eye, timolol can substantially affect blood pressure and heart rate in some patients.

Pharmacokinetics

The degree of systemic absorption of timolol after topical application to the eye has not been fully elucidated; however, some absorption can apparently occur, since adverse systemic effects have occurred following ophthalmic instillation of the drug. Following topical administration of timolol 0.5% solution twice daily to the eye in a limited number of individuals, mean peak plasma concentrations were 0.46 or 0.35 ng/mL following the morning or afternoon dose, respectively.104 Systemic bioavailability of the Istalol^® formulation of timolol maleate ophthalmic solution (which contains potassium sorbate to facilitate absorption of the drug into the aqueous humor) appears be similar to that of timolol maleate ophthalmic solutions formulated without potassium sorbate; following twice-daily topical administration of these respective formulations of timolol 0.5% to the eye, mean peak plasma timolol concentrations were 0.68 versus 0.6 ng/mL after the first dose and 0.88 versus 0.89 ng/mL at steady state.110,113 In individuals receiving topical timolol 0.5% as the gel-forming ophthalmic solution once daily in the morning, mean peak plasma concentrations following the dose were 0.28 ng/mL.106 Following topical application to the eye of a 0.25 or 0.5% solution of the drug, reduction in intraocular pressure (IOP) usually occurs within 15-30 minutes, reaches a maximum within 1-5 hours, and persists about 24 hours.

Chemistry and Stability

Chemistry

Timolol is a nonselective β-adrenergic blocking agent. The drug, which occurs as the l -isomer, is commercially available as the maleate salt and as the hemihydrate. Timolol maleate and the hemihydrate occur as white, odorless, crystalline powders; timolol maleate is soluble in water and alcohol, and timolol hemihydrate is slightly soluble in water and freely soluble in alcohol. Each 2.56 mg of timolol as the hemihydrate provides about 2.5 mg of timolol. Timolol maleate has a pK_a of approximately 9 in water at 25°C. Each 3.4 mg of timolol maleate provides about 2.5 mg of timolol.

For ophthalmic use, timolol is commercially available as an ophthalmic solution of timolol, timolol maleate, or timolol maleate in fixed combination with brimonidine tartrate or dorzolamide hydrochloride. The commercially available timolol, timolol maleate, and timolol maleate in fixed combination with brimonidine tartrate or dorzolamide hydrochloride ophthalmic preparations are sterile, isotonic aqueous solutions of the drugs. Timolol is a clear colorless solution, whereas timolol maleate is a clear and colorless to light yellow solution. The fixed-combination brimonidine tartrate and timolol maleate ophthalmic solution is a clear, greenish yellow solution,109 and the fixed-combination dorzolamide hydrochloride and timolol maleate ophthalmic solution is a clear, colorless to nearly colorless, slightly viscous solution. The timolol and timolol maleate ophthalmic solutions have a pH of 6.5-7.5, brimonidine tartrate and timolol maleate ophthalmic solution has a pH of 6.5-7.3, and dorzolamide hydrochloride and timolol maleate ophthalmic solution has a pH of approximately 5.65. The commercially available ophthalmic solutions may contain benzalkonium chloride as a preservative. The Istalol^® formulation of timolol maleate ophthalmic solution also contains potassium sorbate; sorbic acid increases lipophilicity of timolol by ion-pairing formation, thereby facilitating absorption of the drug into the aqueous humor,112

Timolol maleate also is available as a gel-forming ophthalmic solution. The commercially available gel-forming ophthalmic solution is a colorless or nearly colorless, slightly opalescent, and slightly viscous sterile, isotonic solution of the drug in water for injection; the solution has a pH of approximately 7 and contains benzododecinium bromide as a preservative. The gel-forming solution contains a purified anionic heteropolysaccharide derived from gellan gum; in the presence of a cation, an aqueous solution of this polysaccharide has the ability to gel. Upon contact with the precorneal tear film, the gel-forming solution forms a gel that subsequently is removed by the flow of tears.

Stability

Solutions of timolol maleate are stable up to a pH of 12. In general, preserved timolol ophthalmic solutions should be stored at 15-25°C104,107,110 and protected from light and freezing.104,107 The 0.3-mL single-use containers of preservative-free timolol maleate ophthalmic solution should be stored at 15-30°C in the protective foil overwrap and protected from light and freezing; the individual unit-dose containers should be used within one month after the foil package is opened.105

Brimonidine tartrate and timolol maleate ophthalmic solution should be stored at 15-25°C and protected from light.109

Preserved dorzolamide hydrochloride and timolol maleate ophthalmic solution should be stored at 20-25°C and protected from light.108 The 0.2-mL single-use containers of preservative-free dorzolamide hydrochloride and timolol maleate ophthalmic solution should be stored at 20-25°C in the original foil pouch for protection from light; any unused containers should be discarded 15 days after the pouch is first opened.111 The preservative-free solution should not be frozen.111

Timolol maleate gel-forming ophthalmic solution should be stored at 15-25°C and protected from light and freezing.106

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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