Timolol Maleate Information
Timolol maleate (Timolol maleate)
Timolol maleate (Timolol maleate) Description
Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution is a non-selective beta-adrenergic receptor blocking agent. Its chemical name is (-)-1-(-butylamino)-3- [(4-morpholino-1, 2, 5-thiadiazol-3-yl)oxy]-2-propanol maleate (1:1) (salt). Timolol maleate (Timolol maleate) possesses an asymmetric carbon atom in its structure and is provided as the levo-isomer. The optical rotation of Timolol maleate (Timolol maleate) is:
Its molecular formula is CHNOS•CHO and its structural formula is:
Timolol maleate (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 (Timolol maleate) Ophthalmic Gel Forming Solution is supplied as a sterile, isotonic, buffered, aqueous solution of Timolol maleate (Timolol maleate) in two dosage strengths. The pH of the solution is approximately 7.0, and the osmolarity is 260-330 mOsm. Each mL of Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution 0.25% contains 2.5 mg of timolol (3.4 mg of Timolol maleate (Timolol maleate) ). Each mL of Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution 0.5% contains 5 mg of timolol (6.8 mg of Timolol maleate (Timolol maleate) ). Inactive ingredients: gellan gum, tromethamine, mannitol, and water for injection. Preservative: benzododecinium bromide 0.012%
The gel forming solution contains a purified anionic heteropolysaccharide derived from gellan gum. An aqueous solution of gellan gum, in the presence of a cation, has the ability to gel. Upon contact with the precorneal tear film, Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution forms a gel that is subsequently removed by the flow of tears.
Timolol maleate (Timolol maleate) Clinical Pharmacology
Timolol maleate (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.
Timolol maleate (Timolol maleate) Ophthalmic Gel Forming 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 and optic nerve damage.
The precise mechanism of the ocular hypotensive action of Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution is not clearly established at this time. Tonography and fluorophotometry studies of Timolol maleate (Timolol maleate) ophthalmic solution 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.
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.
Timolol maleate (Timolol maleate) Clinical Studies
In controlled, double-masked, multicenter clinical studies, comparing Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution 0.25% to Timolol maleate (Timolol maleate) ophthalmic solution 0.25% and Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution 0.5% to Timolol maleate (Timolol maleate) ophthalmic solution 0.5%, Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution administered once a day was shown to be equally effective in lowering intraocular pressure as the equivalent concentration of Timolol maleate (Timolol maleate) ophthalmic solution administered twice a day. The effect of timolol in lowering intraocular pressure was evident for 24 hours with a single dose of Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution. Repeated observations over a period of six months indicate that the intraocular pressure-lowering effect of Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution was consistent. The results from the largest U.S. and international clinical trials comparing Timolol maleate (Timolol maleate) Ophthalmic Gel Forming 0.5% to Timolol maleate (Timolol maleate) ophthalmic solution 0.5% are shown in Figure 1.
Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution administered once daily had a safety profile similar to that of an equivalent concentration of Timolol maleate (Timolol maleate) ophthalmic solution administered twice daily. Due to the physical characteristics of the formulation, there was a higher incidence of transient blurred vision in patients administered Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution. A slight reduction in resting heart rate was observed in some patients receiving Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution 0.5% (mean reduction 24 hours post-dose 0.8 beats/minute, mean reduction 2 hours post-dose 3.8 beats/minute). (See .)
Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution has not been studied in patients wearing contact lenses.
Timolol maleate (Timolol maleate) Indications And Usage
Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.
Timolol maleate (Timolol maleate) Contraindications
Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution 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.
Timolol maleate (Timolol maleate) Warnings
As with many topically applied ophthalmic drugs, this drug is absorbed systemically.
Timolol maleate (Timolol maleate) Precautions
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 Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution, alternative therapy should be considered.
There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface. (See .)
Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy (e.g. timolol).
Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures.
Patients should also be instructed that ocular solutions, if handled improperly or if the tip of the dispensing container contacts the eye or surrounding structures, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions. (See .)
Patients should also be advised that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma or infection), they should immediately seek their physician's advice concerning the continued use of the present multidose container.
Patients should be instructed to invert the closed container and shake once before each use. It is not necessary to shake the container more than once.
Patients requiring concomitant topical ophthalmic medications should be instructed to administer these at least 10 minutes before instilling Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution.
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 .)
Transient blurred vision, generally lasting from 30 seconds to 5 minutes, following instillation, and potential visual disturbances may impair the ability to perform hazardous tasks such as operating machinery or driving a motor vehicle.
In a two-year study of Timolol maleate (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, respectively, times 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 oral 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 (Timolol maleate) (the maximum recommended human oral dosage), there were no clinically meaningful changes in serum prolactin.
Timolol maleate (Timolol maleate) was devoid of mutagenic potential when tested (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg) and in a neoplastic cell transformation assay (up to 100 mcg/mL). In Ames tests, the highest concentrations of timolol employed, 5,000 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.
Timolol maleate (Timolol maleate) Adverse Reactions
In clinical trials, transient blurred vision upon instillation of the drop was reported in approximately one in three patients (lasting from 30 seconds to 5 minutes). Less than 1% of patients discontinued from the studies due to blurred vision. The frequency of patients reporting burning and stinging upon instillation was comparable between Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution and Timolol maleate (Timolol maleate) ophthalmic solution (approximately one in eight patients).
Adverse experiences reported in 1-5% of patients were:
The following additional adverse experiences have been reported with the ocular administration of this or other Timolol maleate (Timolol maleate) formulations:
BODY AS A WHOLE
Asthenia/fatigue, and chest pain.
CARDIOVASCULAR
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's phenomenon, and cold hands and feet.
DIGESTIVE
Nausea, diarrhea, dyspepsia, anorexia, and dry mouth.
IMMUNOLOGIC
Systemic lupus erythematosus.
NERVOUS SYSTEM/PSYCHIATRIC
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, localized and generalized rash.
RESPIRATORY
Bronchospasm (predominantly in patients with preexisting bronchospastic disease), respiratory failure, dyspnea, nasal congestion, cough and upper respiratory infections.
ENDOCRINE
Masked symptoms of hypoglycemia in diabetic patients (see ).
SPECIAL SENSES
Signs and symptoms of ocular irritation including blepharitis, keratitis, and dry eyes; ptosis; decreased corneal sensitivity; cystoid macular edema; visual disturbances including refractive changes and diplopia; pseudopemphigoid; choroidal detachment following filtration surgery (see ); and tinnitus.
UROGENITAL
Retroperitoneal fibrosis, decreased libido, impotence, and Peyronie's disease.
The following additional adverse effects have been reported in clinical experience with ORAL Timolol maleate (Timolol maleate) or other ORAL beta-blocking agents and may be considered potential effects of ophthalmic Timolol maleate (Timolol maleate) : Erythematous rash, fever combined with aching and sore throat, laryngospasm with respiratory distress; Extremity pain, decreased exercise tolerance, weight loss; Worsening of arterial insufficiency, vasodilatation; Gastrointestinal pain, hepatomegaly, vomiting, mesenteric arterial thrombosis, ischemic colitis; Nonthrombocytopenic purpura, thrombocytopenic purpura, agranulocytosis; Hyperglycemia, hypoglycemia; Skin: Pruritus, skin irritation, increased pigmentation, sweating; Arthralgia; 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; Rales, bronchial obstruction; Urination difficulties.
Timolol maleate (Timolol maleate) Overdosage
No data are available in regard to human overdosage with or accidental oral ingestion of Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution.
There have been reports of inadvertent overdosage with Timolol maleate (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 ).
Overdosage has been reported with Timolol maleate (Timolol maleate) tablets. A 30-year-old female ingested 650 mg of Timolol maleate (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 hemodialysis study, using 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.
Timolol maleate (Timolol maleate) Dosage And Administration
Patients should be instructed to invert the closed container and shake once before each use. It is not necessary to shake the container more than once. Other topically applied ophthalmic medications should be administered at least 10 minutes before Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution. (See and accompanying .)
Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution is available in concentrations of 0.25% and 0.5%. The dose is one drop of Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution (either 0.25% or 0.5%) in the affected eye(s) once a day.
Because in some patients the pressure-lowering response to Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution may require a few weeks to stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution.
Dosages higher than one drop of 0.5% Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution once a day have not been studied. If the patient's intraocular pressure is still not at a satisfactory level on this regimen, concomitant therapy can be considered. The concomitant use of two topical beta-adrenergic blocking agents is not recommended. (See .)
When patients have been switched from therapy with Timolol maleate (Timolol maleate) ophthalmic solution administered twice daily to Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution administered once daily, the ocular hypotensive effect has remained consistent.
Timolol maleate (Timolol maleate) How Supplied
Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution is a colorless to nearly colorless, slightly opalescent, and slightly viscous solution.
No. 816– Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution, 0.25% timolol equivalent, is supplied in a white, translucent, HDPE plastic ophthalmic dispenser with a controlled drop tip and a white polystyrene cap as follows:
NDC 25010-816-56, 5 mL.
No. 817 – Timolol maleate (Timolol maleate) Ophthalmic Gel Forming Solution, 0.5% timolol equivalent, is supplied in a white, translucent, HDPE plastic ophthalmic dispenser with a controlled drop tip and a white polystyrene cap as follows:
NDC 25010-817-56, 5 mL.
Timolol maleate (Timolol maleate)
Timolol maleate (Timolol maleate) Timolol Maleate Ophthalmic Gel Forming Solution .% And .%
OPHTHALMIC MEDICATIONS, IF HANDLED IMPROPERLY, CAN BECOME CONTAMINATED BY COMMON BACTERIA KNOWN TO CAUSE EYE INFECTIONS. SERIOUS DAMAGE TO THE EYE AND SUBSEQUENT LOSS OF VISION MAY RESULT FROM USING CONTAMINATED OPHTHALMIC MEDICATIONS. IF YOU THINK YOUR MEDICATION MAY BE CONTAMINATED, OR YOU DEVELOP AN EYE INFECTION, CONTACT YOUR DOCTOR IMMEDIATELY CONCERNING CONTINUED USE OF THIS BOTTLE.
Manuf. for: LawrencevilleNJ 08648USA
By: Laboratories Merck Sharp & Dohme-Chibret63963 Clermont-Ferrand Cedex 9, France
Issued June 2009
50100562
Timolol maleate (Timolol maleate) Principal Display Panel - .% Carton
Timolol Equivalent(Timolol maleate (Timolol maleate) 3.4 mg/mL)
Mfg. for:
By: Laboratories Merck Sharp & Dohme-Chibret63963 Clermont-Ferrand Cedex 9, FranceMade in France
Timolol maleate (Timolol maleate) Principal Display Panel - .% Carton
Timolol Equivalent(Timolol maleate (Timolol maleate) 6.8 mg/mL)
Mfg. for:
By: Laboratories Merck Sharp & Dohme-Chibret63963 Clermont-Ferrand Cedex 9, FranceMade in France
