TIMOPTIC® 0.25% and 0.5% (timolol maleate ophthalmic solution)

TIMOPTIC® 0.25% and 0.5% (timolol maleate ophthalmic solution)

Timolol maleate ophthalmic solution

TIMOPTIC® (timolol maleate ophthalmic solution) is a non-selective beta-adrenergic receptor blocking agent. Its chemical name is (-)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate (1:1) (salt). Timolol maleate possesses an asymmetric carbon atom in its structure and is provided as the levo-isomer. The optical rotation of timolol maleate is:

25° [α] in 1.0N HCl (C = 5%) = -12.2° (-11.7° to -12.5°) 405 nm

Its molecular formula is C13H24N4O3S•C4H4O4.

Timolol maleate has a molecular weight of 432.50. It is a white, odorless, crystalline powder which is soluble in water; sparingly soluble in ethanol; slightly soluble in chloroform; practically insoluble in ether. TIMOPTIC is stable at room temperature.

TIMOPTIC Ophthalmic Solution is supplied as a sterile, isotonic, buffered, aqueous solution of timolol maleate in two dosage strengths. Each mL of TIMOPTIC 0.25% contains 2.5 mg of timolol (3.4 mg of timolol maleate). The pH of the solution is approximately 7, and the osmolality is 260-340 mOsm/kg.

Each mL of TIMOPTIC 0.5% contains 5 mg of timolol (6.8 mg of timolol maleate). Inactive ingredients: monobasic and dibasic sodium phosphate, sodium hydroxide to adjust pH, and purified water. Benzalkonium chloride 0.01% is added as preservative.

Mechanism of Action

Timolol maleate is a beta1 and beta2 (non-selective) adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic(membrane-stabilizing) activity.

Beta-adrenergic receptor blockade reduces cardiac output in both healthy subjects and patients with heart disease. In patients with severe impairment of myocardial function, beta-adrenergic receptor blockade may inhibit the stimulatory effect of the sympathetic nervous system necessary to maintain adequate cardiac function.

Beta-adrenergic receptor blockade in the bronchi and bronchioles results in increased airway resistance from unopposed parasympathetic activity. Such an effect in patients with asthma or other bronchospastic conditions is potentially dangerous.

TIMOPTIC Ophthalmic Solution, when applied topically on the eye, has the action of reducing elevated as well as normal intraocular pressure, whether or not accompanied by glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of glaucomatous visual field loss. The higher the level of intraocular pressure, the greater the likelihood of glaucomatous visual field loss and optic nerve damage.

The onset of reduction in intraocular pressure following administration of TIMOPTIC can usually be detected within one-half hour after a single dose. The maximum effect usually occurs in one to two hours and significant lowering of intraocular pressure can be maintained for periods as long as 24 hours with a single dose. Repeated observations over a period of one year indicate that the intraocular pressure-lowering effect of TIMOPTIC is well maintained.


The precise mechanism of the ocular hypotensive action of TIMOPTIC is not clearly established at this time. Tonography and fluorophotometry studies in man suggest that its predominant action may be related to reduced aqueous formation. However, in some studies a slight increasein outflow facility was also observed.


TIMOPTIC Ophthalmic Solution is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.


TIMOPTIC is contraindicated in patients with (1) bronchial asthma; (2) a history of bronchial asthma; (3) severe chronic obstructive pulmonary disease [see WARNINGS]; (4) sinus bradycardia; (5) second- or third-degree atrioventricular block; (6) overt cardiac failure; (7) cardiogenic shock; or (8) hypersensitivity to any component of this product.


Cardiac Failure: Sympathetic stimulation may be essential for support of the circulation in individuals withdiminished myocardial contractility, and its inhibition of beta-adrenergic receptor blockade mayprecipitate more severe failure.

In Patients Without a History of Cardiac Failure continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of cardiac failure, TIMOPTIC should be discontinued.

Obstructive Pulmonary Disease: Patients with chronic obstructive pulmonary disease (e.g., chronic bronchitis, emphysema) ofmild or moderate severity, bronchospastic disease, or a history of bronchospastic disease (otherthan bronchial asthma or a history of bronchial asthma, in which TIMOPTIC is contraindicatedshould, in general, not receive beta-blockers, includingTIMOPTIC.

Major Surgery: The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to majorsurgery is controversial. Beta-adrenergic receptor blockade impairs the ability of the heart torespond to beta-adrenergically mediated reflex stimuli. This may augment the risk of generalanesthesia in surgical procedures. Some patients receiving beta-adrenergic receptor blockingagents have experienced protracted severe hypotension during anesthesia. Difficulty in restartingand maintaining the heartbeat has also been reported. For these reasons, in patients undergoingelective surgery, some authorities recommend gradual withdrawal of beta-adrenergic receptorblocking agents.

If necessary, during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of adrenergic agonists.

Diabetes Mellitus: Beta-adrenergic blocking agents should be administered with caution in patients subject tospontaneous hypoglycemia or to diabetic patients (especially those with labile diabetes) who arereceiving insulin or oral hypoglycemic agents. Beta-adrenergic receptor blocking agents maymask the signs and symptoms of acute hypoglycemia.

Thyrotoxicosis: Beta-adrenergic blocking agents may mask certain clinical signs (e.g., tachycardia) ofhyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully toavoid abrupt withdrawal of beta-adrenergic blocking agents that might precipitate a thyroidstorm.


Angle-closure glaucoma:In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen theangle. This requires constricting the pupil. Timolol maleate has little or no effect on the pupil.TIMOPTIC should not be used alone in the treatment of angle-closure glaucoma.

Anaphylaxis:While taking beta-blockers, patients with a history of atopy or a history of severe anaphylacticreactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, ortherapeutic challenge with such allergens. Such patients may be unresponsive to the usual dosesof epinephrine used to treat anaphylactic reactions.

Muscle Weakness:Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent withcertain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness). Timolol has been reported rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms.

Drug Interactions

Beta-adrenergic blocking agents:Patients who are receiving a beta-adrenergic blocking agent orally and TIMOPTIC should beobserved for potential additive effects of beta-blockade, both systemic and on intraocularpressure. The concomitant use of two topical beta-adrenergic blocking agents is notrecommended.

Calcium antagonists:Caution should be used in the coadministration of beta-adrenergic blocking agents, such asTIMOPTIC, and oral or intravenous calcium antagonists because of possible atrioventricularconduction disturbances, left ventricular failure, and hypotension. In patients with impairedcardiac function, coadministration should be avoided.

Catecholamine-depleting drugs:Close observation of the patient is recommended when a beta-blocker is administered to patientsreceiving catecholamine-depleting drugs such as reserpine, because of possible additive effectsand the production of hypotension and/or marked bradycardia, which may result in vertigo,syncope, or postural hypotension.

Digitalis and calcium antagonists:The concomitant use of beta-adrenergic blocking agents with digitalis and calcium antagonistsmay have additive effects in prolonging atrioventricular conduction time.

CYP2D6 inhibitors:Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g., quinidine, SSRIs) and timolol.

Clonidine:Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension which can followthe withdrawal of clonidine. There have been no reports of exacerbation of rebound hypertensionwith ophthalmic timolol maleate.

Use in specific populations

Pregnancy: There are no adequate and well-controlled studies in pregnant women. TIMOPTIC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers: Timolol maleate has been detected in human milk following oral and ophthalmic drug administration. Because of the potential for serious adverse reactions from TIMOPTIC in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of timolol maleate ophthalmic solution have been established when administered in pediatric patients aged 2 years and older. Use of timolol maleate ophthalmic solution in these children is supported by evidence from adequate and well controlled studies in children and adults. Safety and efficacy in pediatric patients below the age of 2 years have not been established.

Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Adverse reactions

The most frequently reported adverse experiences have been burning and stinging upon instillation (approximately one in eight patients).

The following additional adverse experiences have been reported less frequently with ocular administration of this or other timolol maleate formulations:

Body as a Whole: Headache, asthenia/fatigue, and chest pain.

Cardiovascular: Bradycardia, arrhythmia, hypotension, hypertension, syncope, heart block, cerebral vascularaccident, cerebral ischemia, cardiac failure, worsening of angina pectoris, palpitation, cardiacarrest, pulmonary edema, edema, claudication, Raynaud’s phenomenon, and cold hands and feet.

Digestive: Nausea, diarrhea, dyspepsia, anorexia, and dry mouth.

Immunologic: Systemic lupus erythematosus.

Nervous System/Psychiatric: Dizziness, increase in signs and symptoms of myasthenia gravis, paresthesia, somnolence,insomnia, nightmares, behavioral changes and psychic disturbances including depression,confusion, hallucinations, anxiety, disorientation, nervousness, and memory loss.

Skin: Alopecia and psoriasiform rash or exacerbation of psoriasis.

Hypersensitivity: Signs and symptoms of systemic allergic reactions, including anaphylaxis, angioedema, urticaria,and localized and generalized rash.

Respiratory: Bronchospasm (predominantly in patients with preexisting bronchospastic disease), respiratoryfailure, dyspnea, nasal congestion, cough and upper respiratory infections.

Endocrine: Masked symptoms of hypoglycemia in diabetic patients [see WARNINGS].

Special Senses: Signs and symptoms of ocular irritation including conjunctivitis, blepharitis, keratitis, ocularpain, discharge (e.g., crusting), foreign body sensation, itching and tearing, and dry eyes; ptosis;decreased corneal sensitivity; cystoid macular edema; visual disturbances including refractive changes and diplopia; pseudopemphigoid; choroidal detachment following filtration; and tinnitus.

Urogenital: Retroperitoneal fibrosis, decreased libido, impotence, and Peyronie’s disease.


There have been reports of inadvertent overdosage with TIMOPTIC Ophthalmic Solution resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest.

Overdosage has been reported with timolol maleate tablets. A 30-year-old female ingested 650 mg of timolol maleate tablets (maximum recommended oral daily dose is 60 mg) and experienced second and third-degree heart block. She recovered without treatment but approximately two months later developed irregular heartbeat, hypertension, dizziness, tinnitus, faintness, increased pulse rate, and borderline first degree heart block.


An in vitro hemodialysis study, using 14C timolol added to human plasma or whole blood, showed that timolol was readily dialyzed from these fluids; however, a study of patients with renal failure showed that timolol did not dialyze readily.


TIMOPTIC Ophthalmic Solution is available in concentrations of 0.25 and 0.5%. The usual starting dose is one drop of TIMOPTIC 0.25% in the affected eye(s) twice a day. If the clinical response is not adequate, the dosage may be changed to one drop of 0.5% solution in the affected eye(s) twice a day.

Since in some patients the pressure-lowering response to TIMOPTIC may require a few weeks to stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with TIMOPTIC.

If the intraocular pressure is maintained at satisfactory levels, the dosage schedule may be changed to one drop once a day in the affected eye(s). Because of diurnal variations in intraocular pressure, satisfactory response to the once-a-day dose is best determined by measuring the intraocular pressure at different times during the day.

Dosages above one drop of TIMOPTIC 0.5% twice a day generally have not been shown to produce further reduction in intraocular pressure. If the patient’s intraocular pressure is still not at a satisfactory level on this regimen, concomitant therapy with other agent(s) for lowering intraocular pressure can be instituted. The concomitant use of two topical beta-adrenergic blocking agents is not recommended.


Store at 15°C to 25°C (59°F to 77°F). Protect from freezing. Protect from light. After opening, TIMOPTIC can be used until the expiration date on the bottle.


Leave a Reply

%d bloggers like this: