ypotension 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 ]

timolol maleate ophthalmic gel forming solution 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 timolol maleate ophthalmic gel forming solution is contraindicated [see contraindications ] should, in general, not receive beta-blockers, including timolol maleate ophthalmic gel forming solution. major surgery 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. diabetes mellitus 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. thyrotoxicosis 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.

ay require constricting the pupil. timolol maleate has little or no effect on the pupil. timolol maleate ophthalmic gel forming solution 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.

te 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 precautions , drug interactions , beta-adrenergic blocking agents ]. when patients have been switched from therapy with timolol maleate ophthalmic solution administered twice daily to timolol maleate ophthalmic gel forming solution administered once daily, the ocular hypotensive effect has remained consistent.

ascular 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 1-800-321-4576 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.

ypotension 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 ]

es the potential risk to the fetus.

. 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. pharmacokinetics in a study of plasma drug concentration in six subjects, the systemic exposure to timolol was determined following once daily administration of timolol maleate ophthalmic gel forming solution 0.5% in the morning. the mean peak plasma concentration following this morning dose was 0.28 ng/ml. clinical studies in controlled, double-masked, multicenter clinical studies, comparing timolol maleate ophthalmic gel forming solution 0.25% to timolol maleate ophthalmic solution 0.25% and timolol maleate ophthalmic gel forming solution 0.5% to timolol maleate ophthalmic solution 0.5%, 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 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 ophthalmic gel forming solution. repeated observations over a period of six months indicate that the intraocular pressure-lowering effect of timolol maleate ophthalmic gel forming solution was consistent. the results from the largest u.s. and international clinical trials comparing timolol maleate ophthalmic gel forming solution 0.5% to timolol maleate ophthalmic solution 0.5% are shown in figure 1. figure 1 mean iop and std deviation (mm hg) by treatment group u.s. study international study timolol maleate ophthalmic gel forming solution administered once daily had a safety profile similar to that of an equivalent concentration of 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 ophthalmic gel forming solution. a slight reduction in resting heart rate was observed in some patients receiving 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 adverse reactions ]. timolol maleate ophthalmic gel forming solution has not been studied in patients wearing contact lenses. graphs graph2

c 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 (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.

thalmic solution 0.5% are shown in figure 1. figure 1 mean iop and std deviation (mm hg) by treatment group u.s. study international study timolol maleate ophthalmic gel forming solution administered once daily had a safety profile similar to that of an equivalent concentration of 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 ophthalmic gel forming solution. a slight reduction in resting heart rate was observed in some patients receiving 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 adverse reactions ]. timolol maleate ophthalmic gel forming solution has not been studied in patients wearing contact lenses. graphs graph2

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ions should be instructed to administer these at least 10 minutes before instilling 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 contraindications ]. 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.