TIMOLOL MALEATE

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 nominal optical rotation of Timolol Maleate is: 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 ophthalmic solution is stable at room temperature. Timolol Maleate ophthalmic solution is supplied as a sterile, isotonic, buffered, aqueous solution of Timolol Maleate in two dosage strengths: Each mL, for ophthalmic administration, of 0.25% solution contains 2.5 mg of timolol (3.4 mg of Timolol Maleate). The pH of the solution is approximately 7.0. Each mL, for ophthalmic administration, of 0.5% solution contains 5 mg of timolol (6.8 mg of Timolol Maleate). Inactive ingredients: monobasic and dibasic sodium phosphate; hydrochloric acid and/or sodium hydroxide to adjust pH; and purified water. Benzalkonium chloride 0.01% is added as preservative. 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 nominal optical rotation of Timolol Maleate is: The structural formula for 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 ophthalmic solution is stable at room temperature.

Timolol Maleate ophthalmic solution is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

Timolol Maleate ophthalmic solution is available in concentrations of 0.25% and 0.5%. The usual starting dose is one drop of the 0.25% Timolol solution 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 timolol may require a few weeks to stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with timolol. 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 a 0.5% Timolol 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. The concomitant use of two topical beta-adrenergic blocking agents is not recommended (see PRECAUTIONS, Drug Interactions, Beta-adrenergic blocking agents ).

Timolol Maleate 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 (see WARNINGS ); (7) cardiogenic shock; or (8) hypersensitivity to any component of this product.

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 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: 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 pre-existing bronchospastic disease), respiratory failure, 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, 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. 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 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 : Non thrombocytopenic 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.

Although timolol used alone has little or no effect on pupil size, mydriasis resulting from concomitant therapy with timolol and epinephrine has been reported occasionally. Beta-adrenergic blocking agents : Patients who are receiving a beta-adrenergic blocking agent orally and timolol 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 timolol, 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 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 antagonists may 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 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 )