mpaired 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 )

vative-free timolol maleate ophthalmic solution usp in unit dose vial 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 solution usp is contraindicated [see contraindications ]) should, in general, not receive beta-blockers, including preservative-free timolol maleate ophthalmic solution usp in the unit dose vial. 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.

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.

e-lowering response to preservative-free timolol maleate ophthalmic solution in the unit dose vial may require a few weeks to stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with preservative-free timolol maleate ophthalmic solution in the unit dose vial. 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 0.5% timolol maleate ophthalmic 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 taking into consideration that the preparation(s) used concomitantly may contain one or more preservatives. the concomitant use of two topical beta-adrenergic blocking agents is not recommended. (see precautions , drug interactions , beta-adrenergic blocking agents .)

ucinations, 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 usp or other oral beta blocking agents, and may be considered potential effects of ophthalmic timolol maleate usp: 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 amring pharmaceuticals inc. at 1-844-amring1(1-844-267-4641) or fda at 1-800-fda-1088 or www.fda.gov/medwatch .

mpaired 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 )

enefit justifies the potential risk to the fetus.

whether or not accompanied by glaucoma. elevated intraocular pressure is a major risk factor in the pathogenesis of glaucomatous visual field loss. the higher the level of intraocular pressure, the greater the likelihood of glaucomatous visual field loss and optic nerve damage. the onset of reduction in intraocular pressure following administration of timolol maleate ophthalmic solution usp can usually be detected within one-half hour after a single dose. the maximum effect usually occurs in one to two hours and significant lowering of intraocular pressure can be maintained for periods as long as 24 hours with a single dose. repeated observations over a period of one year indicate that the intraocular pressure-lowering effect of timolol maleate ophthalmic solution usp is well maintained. the precise mechanism of the ocular hypotensive action of timolol maleate ophthalmic solution usp is not clearly established at this time. tonography and fluorophotometry studies 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. pharmacokinetics in a study of plasma drug concentration in six subjects, the systemic exposure to timolol was determined following twice daily administration of timolol maleate ophthalmic solution usp 0.5%. the mean peak plasma concentration following morning dosing was 0.46 ng/ml and following afternoon dosing was 0.35 ng/ml. clinical studies in controlled multiclinic studies in patients with untreated intraocular pressures of 22 mmhg or greater, timolol maleate ophthalmic solution usp 0.25% or 0.5% administered twice a day produced a greater reduction in intraocular pressure than 1, 2, 3, or 4% pilocarpine solution administered four times a day or 0.5, 1, or 2% epinephrine hydrochloride solution administered twice a day. in these studies, timolol maleate ophthalmic solution usp was generally well tolerated and produced fewer and less severe side effects than either pilocarpine or epinephrine. a slight reduction of resting heart rate in some patients receiving timolol maleate ophthalmic solution usp (mean reduction 2.9 beats/minute standard deviation 10.2) was observed.

lmic 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 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 usp (the maximum recommended human oral dosage), there were no clinically meaningful changes in serum prolactin. timolol maleate usp was devoid of mutagenic potential when tested in vivo (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg/kg) 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 ta100 (in seven replicate assays), but not in the remaining three strains. in the assays with tester strain ta100, 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.

nged exposure to direct light can modify the product, the unit dose vial should be kept in the protective foil overwrap and used within one month after the foil package has been opened. keep out of reach of children. manufactured for: amring pharmaceuticals inc. berwyn, pa 19312 www.amringusa.com the amring logo and the “a” logo are trademarks of amring pharmaceuticals inc. manufactured by: holopack verpackungstechnik gmbh, bahnhofstrasse 18, 74429 sulzbach-laufen, germany origin germany rev. 11/2021 006-00423 label1