Timolol maleate 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 nominal optical rotation of timolol maleate is
in 1.0N HCl (C = 5%) = -12.2° (-11.7° to -12.5°).
Its molecular formula is C 13 H 24 N 4 O 3 S·C 4 H 4 O 4 and its structural formula is:
Timolol maleate has a molecular weight of 432.50. It is a white, odorless, crystalline powder which is soluble in water, methanol, and alcohol. Timolol maleate is stable at room temperature.
Timolol maleate ophthalmic solution is supplied in two formulations: Ophthalmic Solution TIMOPTIC* (timolol maleate ophthalmic solution), which contains the preservative benzalkonium chloride; and Ophthalmic Solution TIMOPTIC* (timolol maleate ophthalmic solution), the preservative-free formulation.
Preservative-free Ophthalmic Solution TIMOPTIC is supplied in OCUDOSE*, a unit dose container, as a sterile, isotonic, buffered, aqueous solution of timolol maleate in two dosage strengths: Each mL of Preservative-free TIMOPTIC in OCUDOSE 0.25% contains 2.5 mg of timolol (3.4 mg of timolol maleate). Each mL of Preservative-free TIMOPTIC in OCUDOSE 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 water for injection.
*Registered trademark of MERCK & CO., INC.
Mechanism of Action
Timolol maleate is a beta 1 and beta 2 (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 (timolol maleate 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 (timolol maleate ophthalmic solution) 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 (timolol maleate ophthalmic solution) is well maintained.
The precise mechanism of the ocular hypotensive action of TIMOPTIC (timolol maleate ophthalmic solution) 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 increase in outflow facility was also observed.
In a study of plasma drug concentration in six subjects, the systemic exposure to timolol was determined following twice daily administration of TIMOPTIC 0.5%. The mean peak plasma concentration following morning dosing was 0.46 ng/mL and following afternoon dosing was 0.35 ng/mL.
In controlled multiclinic studies in patients with untreated intraocular pressures of 22 mmHg or greater, TIMOPTIC (timolol maleate ophthalmic solution) 0.25 percent or 0.5 percent administered twice a day produced a greater reduction in intraocular pressure than 1,2,3, or 4 percent pilocarpine solution administered four times a day or 0.5, 1, or 2 percent epinephrine hydrochloride solution administered twice a day.
In these studies, TIMOPTIC (timolol maleate ophthalmic solution) was generally well tolerated and produced fewer and less severe side effects than either pilocarpine or epinephrine. A slight reduction of resting heart rate in some patients receiving TIMOPTIC (timolol maleate ophthalmic solution) (mean reduction 2.9 beats/minute standard deviation 10.2) was observed.
Preservative-free TIMOPTIC in OCUDOSE is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.
Preservative-free TIMOPTIC in OCUDOSE may be used when a patient is sensitive to the preservative in TIMOPTIC (timolol maleate ophthalmic solution), benzalkonium chloride, or when use of a preservative-free topical medication is advisable.
Preservative-free TIMOPTIC in OCUDOSE is contraindicated in patients with (1) bronchial asthma; (2) a history of bronchial asthma; (3) severe chronic obstructive pulmonary disease (see ); (4) sinus bradycardia; (5) second or third degree atrioventricular block; (6) overt cardiac failure (see ); (7) cardiogenic shock; or (8) hypersensitivity to any component of this product.
As with many topically applied ophthalmic drugs, this drug is absorbed systemically.
Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition by beta-adrenergic receptor blockade may precipitate 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 Preservative-free TIMOPTIC in OCUDOSE should be discontinued.
Obstructive Pulmonary Disease
Patients with chronic obstructive pulmonary disease (e.g., chronic bronchitis, emphysema) of mild or moderate severity, bronchospastic disease, or a history of bronchospastic disease (other than bronchial asthma or a history of bronchial asthma, in which TIMOPTIC in OCUDOSE is contraindicated [see CONTRAINDICATIONS ]) should, in general, not receive beta-blockers, including Preservative-free TIMOPTIC in OCUDOSE.
The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to major surgery is controversial. Beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta-adrenergically mediated reflex stimuli. This may augment the risk of general anesthesia in surgical procedures. Some patients receiving beta-adrenergic receptor blocking agents have experienced protracted severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported. For these reasons, in patients undergoing elective surgery, some authorities recommend gradual withdrawal of beta-adrenergic receptor blocking agents.
If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of adrenergic agonists.
Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic receptor blocking agents may mask the signs and symptoms of acute hypoglycemia.
Beta-adrenergic blocking agents may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents that might precipitate a thyroid storm.
Because of potential effects of beta-adrenergic blocking agents on blood pressure and pulse, these agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow develop following initiation of therapy with Preservative-free TIMOPTIC in OCUDOSE, alternative therapy should be considered.
Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy (e.g. timolol).
Angle-closure glaucoma: In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This requires constricting the pupil. Timolol maleate has little or no effect on the pupil. TIMOPTIC in OCUDOSE 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 anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenge with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.
Muscle Weakness: Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain 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.
Information for Patients
Patients should be instructed about the use of Preservative-free TIMOPTIC in OCUDOSE.
Since sterility cannot be maintained after the individual unit is opened, patients should be instructed to use the product immediately after opening, and to discard the individual unit and any remaining contents immediately after use.
Patients with bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, second or third degree atrioventricular block, or cardiac failure should be advised not to take this product. (See CONTRAINDICATIONS .)
Although TIMOPTIC (timolol maleate ophthalmic solution) used alone has little or no effect on pupil size, mydriasis resulting from concomitant therapy with TIMOPTIC (timolol maleate ophthalmic solution) and epinephrine has been reported occasionally.
Beta-adrenergic blocking agents: Patients who are receiving a beta-adrenergic blocking agent orally and Preservative-free TIMOPTIC in OCUDOSE should be observed for potential additive effects of beta-blockade, both systemic and on intraocular pressure. The concomitant use of two topical beta-adrenergic blocking agents is not recommended.
Calcium antagonists: Caution should be used in the coadministration of beta-adrenergic blocking agents, such as Preservative-free TIMOPTIC in OCUDOSE, and oral or intravenous calcium antagonists, because of possible atrioventricular conduction disturbances, left ventricular failure, and hypotension. In patients with impaired cardiac function, coadministration should be avoided.
Catecholamine-depleting drugs: Close observation of the patient is recommended when a beta blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hyotension 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 antagonists may have additive effects in prolonging atrioventricular conduction time.
Quinidine: Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during combined treatment with quinidine and timolol, possibly because quinidine inhibits the metabolism of timolol via the P-450 enzyme, CYP2D6.
Clonidine: Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. There have been no reports of exacerbation of rebound hypertension with ophthalmic timolol maleate.
Injectable epinephrine: (See PRECAUTIONS , General , Anaphylaxis )
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a two-year oral study of timolol maleate administered orally to rats, there was a statistically significant increase in the incidence of adrenal pheochromocytomas in male rats administered 300 mg/kg/day (approximately 42,000 times the systemic exposure following the maximum recommended human ophthalmic dose). Similar differences were not observed in rats administered oral doses equivalent to approximately 14,000 times the maximum recommended human ophthalmic dose.
In a lifetime oral study in mice, there were statistically significant increases in the incidence of benign and malignant pulmonary tumors, benign uterine polyps and mammary adenocarcinomas in female mice at 500 mg/kg/day (approximately 71,000 times the systemic exposure following the maximum recommended human ophthalmic dose), but not at 5 or 50 mg/kg/day (approximately 700 or 7,000 times, respectively, the systemic exposure following the maximum recommended human ophthalmic dose). In a subsequent study in female mice, in which post-mortem examinations were limited to the uterus and the lungs, a statistically significant increase in the incidence of pulmonary tumors was again observed at 500 mg/kg/day.
The increased occurrence of mammary adenocarcinomas was associated with elevations in serum prolactin which occurred in female mice administered oral timolol at 500 mg/kg/day, but not at doses of 5 or 50 mg/kg/day. An increased incidence of mammary adenocarcinomas in rodents has been associated with administration of several other therapeutic agents that elevate serum prolactin, but no correlation between serum prolactin levels and mammary tumors has been established in humans. Furthermore, in adult human female subjects who received oral dosages of up to 60 mg of timolol maleate (the maximum recommended human oral dosage), there were no clinically meaningful changes in serum prolactin.
Timolol maleate was devoid of mutagenic potential when tested in vivo (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg/kg) and in vitro in a neoplastic cell transformation assay (up to 100 mcg/mL). In Ames tests the highest concentrations of timolol employed, 5000 or 10,000 mcg/plate, were associated with statistically significant elevations of revertants observed with tester strain TA 100 (in seven replicate assays), but not in the remaining three strains. In the assays with tester strain TA 100, no consistent dose response relationship was observed, and the ratio of test to control revertants did not reach 2. A ratio of 2 is usually considered the criterion for a positive Ames test.
Reproduction and fertility studies in rats demonstrated no adverse effect on male or female fertility at doses up to 21,000 times the systemic exposure following the maximum recommended human ophthalmic dose.
Teratogenic Effects-- Pregnancy Category C. Teratogenicity studies with timolol in mice, rats and rabbits at oral doses up to 50 mg/kg/day (7,000 times the systemic exposure following the maximum recommended human ophthalmic dose) demonstrated no evidence of fetal malformations. Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses of 1000 mg/kg/day (142,000 times the systemic exposure following the maximum recommended human ophthalmic dose) were maternotoxic in mice and resulted in an increased number of fetal resorptions. Increased fetal resorptions were also seen in rabbits at doses of 14,000 times the systemic exposure following the maximum recommended human ophthalmic dose, in this case without apparent maternotoxicity.
There are no adequate and well-controlled studies in pregnant women. Preservative-free TIMOPTIC in OCUDOSE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Timolol maleate has been detected in human milk following oral and ophthalmic drug administration. Because of the potential for serious adverse reactions from timolol 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.
Safety and effectiveness in pediatric patients have not been established.
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.
Bradycardia, arrhythmia, hypotension, hypertension, syncope, heart block, cerebral vascular accident, cerebral ischemia, cardiac failure, worsening of angina pectoris, palpitation, cardiac arrest, pulmonary edema, edema, claudication, Raynaud' phenomenon, and cold hands and feet.
Nausea, diarrhea, dyspepsia, anorexia, and dry mouth.
Systemic lupus erythematosus.
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.
Alopecia and psoriasiform rash or exacerbation of psoriasis.
Signs and symptoms of systemic allergic reactions, including angioedema, urticaria, and localized and generalized rash.
Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure, dyspnea, nasal congestion, cough and upper respiratory infections.
Masked symptoms of hypoglycemia in diabetic patients (see ).
Signs and symptoms of ocular irritation including conjunctivitis, blepharitis, keratitis, ocular pain, 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 surgery (see PRECAUTIONS , General ); and tinnitus.
Retroperitoneal fibrosis, decreased libido, impotence, and Peyronie' disease.
The following additional adverse effects have been reported in clinical experience with ORAL timolol maleate or other ORAL beta blocking agents, and may be considered potential effects of ophthalmic timolol maleate: Allergic Erythematous rash, fever combined with aching and sore throat, laryngospasm with respiratory distress; Body as a Whole: Extremity pain, decreased exercise tolerance, weight loss; Cardiovascular Worsening of arterial insufficiency, vasodilatation; Digestive: Gastrointestinal pain, hepatomegaly, vomiting, mesenteric arterial thrombosis, ischemic colitis; Hematologic: Nonthrombocytopenic purpura; thrombocytopenic purpura; agranulocytosis; Endocrine: Hyperglycemia, hypoglycemia; Skin: Pruritus, skin irritation, increased pigmentation, sweating; Musculoskeletal: Arthralgia Nervous System/Psychiatric: Vertigo, local weakness, diminished concentration, reversible mental depression progressing to catatonia, an acute reversible syndrome characterized by disorientation for time and place, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics; Respiratory Rales, bronchial obstruction; Urogenital: Urination difficulties.
There have been reports of inadvertent overdosage with Ophthalmic Solution TIMOPTIC (timolol maleate 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 (see also ADVERSE REACTIONS ).
Overdosage has been reported with Tablets BLOCADREN* (timolol maleate tablets). A 30 year old female ingested 650 mg of BLOCADREN (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 14 C 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.
*Registered trademark of MERCK & CO., Inc.
Preservative-free TIMOPTIC in OCUDOSE is a sterile solution that does not contain a preservative. The solution from one individual unit is to be used immediately after opening for administration to one or both eyes. Since sterility cannot be guaranteed after the individual unit is opened, the remaining contents should be discarded immediately after administration.
Preservative-free TIMOPTIC in OCUDOSE is available in concentrations of 0.25 and 0.5 percent. The usual starting dose is one drop of 0.25 percent Preservative-free TIMOPTIC in OCUDOSE in the affected eye(s) administered twice a day. Apply enough gentle pressure on the individual container to obtain a single drop of solution. If the clinical response is not adequate, the dosage may be changed to one drop of 0.5 percent solution in the affected eye(s) administered twice a day.
Since in some patients the pressure-lowering response to Preservative-free TIMOPTIC in OCUDOSE may require a few weeks to stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with Preservative-free TIMOPTIC in OCUDOSE.
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 0.5 percent TIMOPTIC (timolol maleate ophthalmic solution) 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 taking into consideration that the preparation(s) used concomitantly may contain one or more preservatives. The concomitant use of two topical beta-adrenergic blocking agents is not recommended. (See PRECAUTIONS , Drug Interactions, Beta-adrenergic blocking agents .)
Preservative-free Sterile Ophthalmic Solution TIMOPTIC in OCUDOSE is a clear, colorless to light yellow solution.
No. 9689--Preservative-free TIMOPTIC, 0.25% timolol equivalent, is supplied in OCUDOSE, a clear low density polyethylene unit dose container. Each individual unit contains 0.2 mL of solution, and is available in a foil laminate overwrapped pouch as follows:
NDC 0006-9689-60; 60 Individual Unit Doses
(6505-01-316-8791, 0.25% 60 Individual Unit Doses).
No. 9690--Preservative-free TIMOPTIC, 0.5% timolol equivalent, is supplied in OCUDOSE, a clear low density polyethylene unit dose container. Each individual unit contains 0.2 mL of solution, and is available in a foil laminate overwrapped pouch as follows:
NDC 0006-9690-60; 60 Individual Unit Doses
(6505-01-284-5154, 0.5% 60 Individual Unit Doses).
Store at room temperature, 15-30°C (59-86°F). Protect from freezing. Protect from light.
Because evaporation can occur through the unprotected polyethylene unit dose container and prolonged exposure to direct light can modify the product, the unit dose container should be kept in the protective foil overwrap and used within one month after the foil package has been opened.
9288801 Issued March 2000
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