or intravenous calcium antagonists because of possible atrioventricular conduction disturbances, left ventricular failure, or hypotension. in patients with impaired cardiac function, co-administration should be avoided. 7.3 catecholamine-depleting drugs close observation of the patient is recommended when a beta receptor inhibitor 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. 7.4 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. 7.5 clonidine oral beta-adrenergic receptor inhibiting 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. 7.6 injectable epinephrine [see warnings and precautions (5.11) ]

ications (4) ]. 5.2 cardiac failure 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-adrenergic receptor inhibitors over a period of time can, in some cases, lead to cardiac failure. at the first sign or symptom of cardiac failure, timolol gfs should be discontinued. 5.3 bronchospasm and obstructive pulmonary disease bronchospasm may occur. 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 timolol gfs is contraindicated [see contraindications (4) ]) should, in general, not receive beta-adrenergic receptor inhibitors, including timolol gfs. 5.4 surgical anesthesia the necessity or desirability of withdrawal of beta-adrenergic receptor inhibitors 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 inhibitors have experienced protracted, severe hypotension during anesthesia. difficulty in restarting and maintaining the heartbeat has also been reported. in patients undergoing elective surgery, consider gradual withdrawal of beta-adrenergic receptor inhibitors. if necessary during surgery, the effects of beta-adrenergic receptor inhibitors may be reversed by sufficient doses of adrenergic agonists. 5.5 diabetes mellitus beta-adrenergic receptor inhibitors should be administered with caution in diabetic patients subject to hypoglycemia who are receiving insulin or oral hypoglycemic agents. beta-adrenergic receptor inhibitors may mask the signs and symptoms of acute hypoglycemia. 5.6 thyrotoxicosis beta-adrenergic receptor inhibitors 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 receptor inhibitors that might precipitate a thyroid storm. 5.7 cerebrovascular insufficiency because of potential effects of beta-adrenergic receptor inhibitors 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 gfs, alternative therapy should be considered. 5.8 bacterial keratitis bacterial keratitis may occur with use of multiple dose containers of topical ophthalmic products when these containers are inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface. instruct patients on appropriate instillation techniques [see patient counseling information (17) ]. 5.9 choroidal detachment choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant (e.g., timolol) therapy. 5.10 angle-closure glaucoma in patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. this may require constricting the pupil. timolol gfs has little or no effect on the pupil and should not be used alone in the treatment of angle-closure glaucoma. 5.11 atopy/anaphylaxis while taking beta receptor inhibitors, 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. 5.12 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 to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms.

ody sensation, hyperemia, pruritus and tearing; systemic: headache, hypertension, and upper respiratory infections. in a 3-month, double-masked, active-controlled, multicenter study in pediatric patients, the adverse reactions profile of timolol gfs 0.25% and 0.5% was comparable to that seen in adult patients. 6.2 additional potential adverse reactions associated with timolol maleate 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, cerebral vascular accident, cerebral ischemia, cardiac failure, worsening of angina pectoris, palpitation, cardiac arrest, pulmonary edema, dizziness, 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 confusion, hallucinations, anxiety, depression, 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, and cough. endocrine masked symptoms of hypoglycemia in diabetic patients [see warnings and precautions (5.5) ]. 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 warnings and precautions (5.9 ) ]; and tinnitus. urogenital retroperitoneal fibrosis, decreased libido, impotence and peyronie's disease.

or intravenous calcium antagonists because of possible atrioventricular conduction disturbances, left ventricular failure, or hypotension. in patients with impaired cardiac function, co-administration should be avoided. 7.3 catecholamine-depleting drugs close observation of the patient is recommended when a beta receptor inhibitor 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. 7.4 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. 7.5 clonidine oral beta-adrenergic receptor inhibiting 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. 7.6 injectable epinephrine [see warnings and precautions (5.11) ]

ntial benefit justifies the potential risk to the fetus. 8.3 nursing mothers timolol maleate has been detected in human milk following oral and ophthalmic drug administration. because of the potential for serious adverse reactions in nursing infants from timolol gfs, 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. 8.4 pediatric use safety and iop-lowering effect of timolol gfs 0.25% and 0.5% has been demonstrated in pediatric patients in a 3-month, multicenter, double-masked, active-controlled trial. 8.5 geriatric use no overall differences in safety or effectiveness have been observed between elderly and younger patients.

tential risk to the fetus.

ents with heart disease. in patients with severe impairment of myocardial function beta-adrenergic receptor inhibitors 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 activities. such an effect in patients with asthma or other bronchospastic conditions is potentially dangerous. 12.2 pharmacodynamics because in some patients the intraocular pressure-lowering response to timolol gfs may require a few weeks to stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with timolol gfs. if the patient's intraocular pressure is still not at a satisfactory level on this regimen, concomitant therapy can be considered. 12.3 pharmacokinetics following topical ocular administration of timolol to humans, low concentrations of drug are found in plasma. after bilateral administration of a 0.5% timolol maleate solution to healthy volunteers, maximum plasma concentrations were generally below 5 ng/ml. dosages higher than one drop of 0.5% timolol gfs once daily have not been studied. pharmacokinetic studies in humans using this gel forming solution formulation were not performed. however, systemic uptake from a gel matrix is expected to be slower than from a non-gel forming solution based on studies using other gel forming solutions. the maximum plasma timolol concentration from the gel forming drop is not expected to exceed those of the 0.5% timolol maleate solution.

mum recommended human ophthalmic dose). in a subsequent study in female mice, in which postmortem 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 (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) and in vitro 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.

halmic dose). in a subsequent study in female mice, in which postmortem 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 (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) and in vitro 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.

patients administered timolol gfs [see adverse reactions (6) ]. timolol gfs has not been studied in patients wearing contact lenses. figures

. 9. with the hand holding the bottle, place your index finger on the bottom of the bottle. push the bottom of the bottle to dispense one drop of medication. do not squeeze the sides of the bottle. 10. repeat 6, 7, 8, and 9 with other eye if instructed to do so. 11. replace screw cap by turning until firmly touching the bottle. patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye(s) or surrounding structures. patients should also be instructed that ocular solutions, if handled improperly, could become contaminated by common bacteria known to cause ocular infections. serious damage to the eye(s) and subsequent loss of vision may result from using contaminated solutions. [see warnings and precautions (5.8) ] patients should 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 gfs. 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 (4) ]. patients should be advised that transient blurred vision or visual disturbance, generally lasting from 30 seconds to 5 minutes, following instillation may impair the ability to perform hazardous tasks such as operating machinery or driving a motor vehicle. *timoptic is a registered trademark of merck & co., inc. **drop-tainer® is a registered trademark of alcon research, ltd. manufactured by alcon laboratories, inc. fort worth, texas 76134 for sandoz inc. princeton, nj 08540 9007201-1011 bottle eye