mine-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 )

ol 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 is contraindicated [see contraindications ]) should, in general, not receive beta-blockers, including timolol. 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.

l maleate has little or no effect on the pupil. timolol maleate 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.

wn 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 ).

lucinations, 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.

mine-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 )

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 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 is well maintained. the precise mechanism of the ocular hypotensive action of timolol 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 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 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 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 (mean reduction 2.9 beats/minute standard deviation 10.2) was observed.

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 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/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 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.

when using timolol maleate. use timolol maleate ophthalmic solution as prescribed by your doctor. 1. if you use other topically applied ophthalmic medications, they should be administered at least 10 minutes before or after timolol maleate. 2. thoroughly wash your hands before each use. 3. before using the medication for the first time be sure the safety celloseal around the cap and top of the bottle neck is unbroken. 4. remove safety seal (figure 1). figure 1 5. to open the bottle, unscrew the cap by turning as indicated by the arrow (figure 2). figure 2 6. sit or stand comfortably, with your head tilted back (figure 3). figure 3 7. open eyes, look up, and draw the lower lid of your eye down gently with your index finger to form a pocket between your eyelid and your eye (figure 4). figure 4 8. hold the timolol maleate bottle upside down. place dropper tip as close as possible to the lower eyelid and gently squeeze until a single drop is dispensed into the eye as directed by your doctor (figure 5). figure 5 do not touch your eye or eyelid with the dropper tip. 9. blink a few times to make sure the eye is covered with the solution. 10. close your eye and remove any excess solution with a clean tissue. 11. repeat steps 6 through 10 with the other eye if instructed to do so by your doctor. 12. replace the cap by turning until it is snug. do not overtighten the cap. 13. do not enlarge the hole of the dispenser tip. special tips 1. do not touch your eye or eyelid with the dropper tip. ophthalmic medications, if handled improperly, can become contaminated by common bacteria known to cause eye infections. serious damage to the eye and subsequent loss of vision may result from using contaminated ophthalmic medications. if you think your medication may be contaminated, or if you develop an eye infection, contact your doctor immediately concerning continued use of this bottle. 2. store at 15-25°c (59-77°f). protect from freezing. protect from light. 3. keep tightly closed when not in use. warning: keep out of the reach of children. if you have any questions about the use of timolol maleate ophthalmic solution, please contact your doctor. revised: 0 4 /201 7 © 2017 allergan. all rights reserved. all trademarks are the property of their respective owners. irvine, ca 92612 made in the u.s.a. timolol maleate ophthalmic solution, 0.25% timolol equivalent, is supplied sterile in opaque white ldpe plastic bottles with droppers with yellow high impact polystyrene (hips) caps as follows: timolol maleate ophthalmic solution, 0.5% timolol equivalent, is supplied sterile in opaque white ldpe plastic bottles with droppers with yellow high impact polystyrene (hips) caps as follows: remove safety seal (figure 1). to open the bottle, unscrew the cap by turning as indicated by the arrow (figure 2). sit or stand comfortably, with your head tilted back (figure 3). open eyes, look up, and draw the lower lid of your eye down gently with your index finger to form a pocket between your eyelid and your eye (figure 4). hold the timolol maleate bottle upside down. place dropper tip as close as possible to the lower eyelid and gently squeeze until a single drop is dispensed into the eye as directed by your doctor (figure 5). pacific pharma

d not to take this product (see contraindications ). patients should be advised that timolol maleate ophthalmic solution contains benzalkonium chloride which may be absorbed by soft contact lenses. contact lenses should be removed prior to administration of the solution. lenses may be reinserted 15 minutes following timolol maleate ophthalmic solution administration.