TIMOLOL MALEATE

Drug Interactions Although Timolol Maleate Ophthalmic Solution used alone has little or no effect on pupil size, mydriasis resulting from concomitant therapy with 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 Timolol Maleate Ophthalmic Solution 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 Maleate Ophthalmic Solution, 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 ] .

INDICATIONS AND USAGE Timolol Maleate Sterile Ophthalmic Gel Forming Solution is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

DOSAGE AND ADMINISTRATION Timolol Maleate Ophthalmic Solution is available in concentrations of 0.25 and 0.5%. The usual starting dose is one drop of Timolol Maleate Ophthalmic 0.25% 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 Maleate Ophthalmic 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 Ophthalmic Solution. 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 Timolol Maleate Ophthalmic Solution 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 [see ].

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 Ophthalmic Gel Forming Solution and Timolol Maleate Ophthalmic Solution (approximately one in eight patients). Adverse experiences reported in 1-5% of patients were: Ocular: Pain, conjunctivitis, discharge (e.g., crusting), foreign body sensation, itching and tearing; Systemic: Headache, dizziness, and upper respiratory infections. The following additional adverse experiences have been reported with the ocular administration of this or other timolol maleate formulations: BODY AS A WHOLE Asthenia/fatigue, and chest pain. CARDIOVASCULAR Bradycardia, arrhythmia, hypotension, hypertension, syncope, heart block, cerebrovascular 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 WARNINGS , Diabetes Mellitus ]. 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 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: 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. To report SUSPECTED ADVERSE REACTIONS, contact Bausch & Lomb Incorporated at 1-800-553-5340 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. OVERDOSAGE No data are available in regard to human overdosage with or accidental oral ingestion of Timolol Maleate Ophthalmic Gel Forming Solution. There have been reports of inadvertent overdosage with 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 ADVERSE REACTIONS ]. 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 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.