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Timolol Maleate
Timolol maleate is a non-selective beta-adrenergic receptor blocking agent. The chemical name for timolol maleate tablets is (S)-1-[(1,1-dimethylethyl)amino]-3-[[4-(4-morpholinyl)- 1,2,5-thiadiazol -3 -yl]oxy]-2-propanol, (Z)-2-butenedioate (1:1) salt. The chemical name for timolol maleate ophthalmic solutions and ophthalmic gel forming solution is (-)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate (1:1) (salt). Timolol maleate possesses an asymmetric carbon atom in its structure and is provided as the levo-isomer. Its empirical formula is C13H24N4O3S•C4H4O4. Timolol maleate has a molecular weight of 432.50. It is a white, odorless, crystalline powder which is soluble in water, methanol, and alcohol. Tablets: Blocadren is supplied as tablets in three strengths containing 5 mg, 10 mg or 20 mg timolol maleate for oral administration. Inactive ingredients are cellulose, FD&C blue 2, magnesium stearate, and starch. Ophthalmic Solution: Timoptic is stable at room temperature. Timoptic ophthalmic solution is supplied as a sterile, isotonic, buffered, aqueous solution of timolol maleate in two dosage strengths: each ml of Timoptic 0.25% contains 2.5 mg of timolol (3.4 mg of timolol maleate). Each ml of Timoptic 0.5% contains 5.0 mg of timolol (6.8 mg of timolol maleate). Inactive Ingredients: Monobasic and dibasic sodium phosphate, sodium hydroxide to adjust pH, and water for injection. Benzalkonium chloride 0.01% is added as preservative. Preservative-Free Ophthalmic Solution: Timolol maleate is stable at room temperature. Preservative-free ophthalmic solution Timoptic is supplied in Ocudose, a unit dose container, as a sterile, isotonic, buffered, aqueous solution of timolol maleate in two dosage strengths: Each ml of preservative-free Timoptic in Ocudose 0.25% contains 2.5 mg of timolol (3.4 of timolol maleate). Each ml of preservative-free Timoptic in Ocudose 0.5% contains 5.0 mg of timolol (6.8 mg of timolol maleate). Inactive Ingredients: Monobasic and dibasic sodium phosphate, sodium hydroxide to adjust pH, and water for injection. Ophthalmic Gel Forming Solution: Timoptic-XE sterile ophthalmic gel forming solution is supplied as a sterile, isotonic, buffered, aqueous solution of timolol maleate in two dosage strengths. Each ml of Timoptic-XE 0.25% contains 2.5 mg of timolol (3.4 mg of timolol maleate). Each ml of Timoptic-XE 0.5% contains 5.0 mg of timolol (6.8 mg of timolol maleate). Inactive Ingredients: Gelrite gellan gum, tromethamine, mannitol, and water for injection. Preservative: Benzododecinium bromide 0.012%. Gelrite is a purified anionic heteropolysaccharide derived from gellan
gum. An aqueous solution
of Gelrite, in the presence of a cation, has the ability to gel. Upon
contact with the precorneal
tear film, Timoptic-XE forms
a gel that is subsequently removed
by the wflow of tears.
Tablets Timolol maleate is a beta1 and beta2 (non-selective) adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic activity. Pharmacodynamics Clinical pharmacology studies have confirmed the beta-adrenergic blocking activity as shown by (1) changes in resting heart rate and response of heart rate to changes in posture; (2) inhibition of isoproterenol-induced tachycardia; (3) alteration of the response to the Valsalva maneuver and amyl nitrite administration; and (4) reduction of heart rate and blood pressure changes on exercise. Timolol maleate decreases the positive chronotropic, positive inotropic, bronchodilator, and vasodilator responses caused by beta-adrenergic receptor agonists. The magnitude of this decreased response is proportional to the existing sympathetic tone and the concentration of timolol maleate at receptor sites. In normal volunteers, the reduction in heart rate response to a standard exercise was dose dependent over the test range of 0.5 to 20 mg, with a peak reduction at 2 hours of approximately 30% at higher doses. 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 and Metabolism Timolol maleate is rapidly and nearly completely absorbed (about 90%) following oral ingestion. Detectable plasma levels of timolol occur within one-half hour and peak plasma levels occur in about one to two hours. The drug half-life in plasma is approximately 4 hours and this is essentially unchanged in patients with moderate renal insufficiency. Timolol is partially metabolized by the liver and timolol and its metabolites are excreted by the kidney. Timolol is not extensively bound to plasma proteins; i.e., <10% by equilibrium dialysis and approximately 60% by ultrafiltration. An in vitro hemodialysis study, using 14C 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. Plasma levels following oral administration are about half those following intravenous administration indicating approximately 50% first pass metabolism. The level of beta sympathetic activity varies widely among individuals, and no simple correlation exists between the dose of plasma level of timolol maleate and its therapeutic activity. Therefore, objective clinical measurements such as reduction of heart rate and/or blood pressure should be used as guides in determining the optimal dosage for each patient. Ophthalmic Solutions and Ophthalmic Gel Forming Solution Mechanism of Action Timolol maleate is a beta1 and beta2 (non-selective) adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic (membrane-stabilizing) activity. 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 inpatients with asthma or other bronchospastic conditions is potentially dangerous. Timolol maleate, when applied topically on the eye, has the action of reducing elevated as well as normal intraocular pressure, 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 precise mechanism of the ocular hypotensive action of timolol maleate is not clearly established at this time. Tonography and fluorophotometry studies of timolol maleate 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. Additional Information for Ophthalmic Solutions: The onset of reduction in intraocular pressure following administration of timolol maleate 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 is well maintained. 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 in the morning (twice daily for the preservative-free ophthalmic solution). The mean peak plasma concentration following this morning dose was 0.28 ng/ml for the ophthalmic gel forming solution, and 0.35 ng/ml for the ophthalmic solutions. CLINICAL STUDIESTablets Clinical studies indicate that timolol maleate at a dosage of 20-60 mg/day reduces blood pressure without causing postural hypotension in most patients with essential hypertension. Administration of timolol maleate to patients with hypertension results initially in a decrease in cardiac output, little immediate change in blood pressure, and an increase in calculated peripheral resistance. With continued administration of timolol maleate, blood pressure decreases within a few days, cardiac output usually remains reduced, and peripheral resistance falls toward pretreatment levels. Plasma volume may decrease or remain unchanged during therapy with timolol maleate. In the majority of patients with hypertension timolol maleate also decreases plasma renin activity. Dosage adjustment to achieve optimal antihypertensive effect may require a few weeks. When therapy with timolol maleate is discontinued, the blood pressure tends to return to pretreatment levels gradually. In most patients the antihypertensive activity of timolol maleate is maintained with long-term therapy and is well tolerated. The mechanism of the antihypertensive effects of beta-adrenergic receptor blocking agents is not established at this time. Possible mechanisms of action include reduction in cardiac output, reduction in plasma renin activity, and a central nervous system sympatholytic action. A Norwegian multi-center, double-blind study compared the effects of timolol maleate with placebo in 1884 patients who had survived the acute phase of a myocardial infarction. Patients with systolic blood pressure below 100 mm Hg, sick sinus syndrome and contraindication to beta blockers, including uncontrolled heart failure, second or third degree AV block and bradycardia (<50 beats per minute), were excluded from the multi-center trial. Therapy with timolol maleate, begun 7 to 28 days following infarction, was shown to reduce overall mortality; this was primarily attributable to a reduction in cardiovascular mortality. Timolol maleate significantly reduced the incidence of sudden death (deaths occurring without symptoms or within 24 hours of the onset of symptoms), including those occurring within one hour, and particularly instantaneous deaths (those occurring without preceding symptoms). The protective effect of timolol maleate was consistent regardless of age, sex or site of infarction. The effect was clearest in patients with a first infarction who were considered at a high risk of dying, defined as those with one or more of the following characteristics during the acute phase: transient left ventricular failure, cardiomegaly, newly appearing atrial fibrillation or flutter, systolic hypotension, or SGOT (ASAT) levels greater than four times the upper limit of normal. Therapy with timolol maleate also reduced the incidence of non-fatal reinfarction. The mechanism of the protective effect of timolol maleate is unknown. Timolol maleate was studied for the prophylactic treatment of migraine headache in placebo-controlled clinical trials involving 400 patients, mostly women between the ages of 18 and 66 years. Common migraine was the most frequent diagnosis. All patients had at least two headaches per month at baseline. Approximately 50 percent of patients who received timolol maleate had a reduction in the frequency of migraine headache of at least 50 percent, compared to a similar decrease in frequency in 30 percent of patients receiving placebo. The most common cardiovascular adverse effect was bradycardia (5%). Ophthalmic Solutions In controlled multiclinic studies in patients with untreated intraocular pressures of 22 mmHg or greater, timolol maleate 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 HCl solution administered twice a day. In these studies, timolol maleate 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 (mean reduction 2.9 beats/minute standard deviation 10.2) was observed. Ophthalmic Gel Forming Solution 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. 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. ANIMAL PHARMACOLOGYNo adverse ocular effects were observed in rabbits and dogs administered timolol maleate topically in studies lasting one and two years respectively.
Tablets Hypertension: Timolol maleate is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics. Myocardial Infarction: Timolol maleate is indicated in patients who have survived the acute phase of myocardial infarction, and are clinically stable, to reduce cardiovascular mortality and the risk of reinfarction. Migraine: Timolol maleate is indicated for the prophylaxis of migraine headache. Ophthalmic Solutions and Ophthalmic Gel Forming Solution Timolol maleate is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma. Additional Information for Preservative-Free Ophthalmic Solution: Preservative-free timolol maleate may be used when a patient is sensitive to the preservative in timolol maleate, benzalkonium chloride, or when use of a preservative-free topical medication is advisable.
Tablets Hypertension: The usual initial dosage of timolol maleate is 10 mg twice a day, whether used alone or added to diuretic therapy. Dosage may be increased or decreased depending on heart rate and blood pressure response. The usual total maintenance dosage is 20-40 mg per day. Increases in dosage to a maximum of 60 mg per day divided into two doses may be necessary. There should be an interval of at least seven days between increases in dosages. Timolol maleate may be used with a thiazide diuretic or with other antihypertensive agents. Patients should be observed carefully during initiation of such concomitant therapy. Myocardial Infarction: The recommended dosage for long-term prophylactic use in patients who have survived the acute phase of a myocardial infarction is 10 mg given twice daily (see CLINICAL PHARMACOLOGY). Migraine: The usual initial dosage of timolol maleate is 10 mg twice a day. During maintenance therapy the 20 mg daily dosage may be administered as a single dose. Total daily dosage may be increased to a maximum of 30 mg, given in divided doses, or decreased to 10 mg once per day depending on clinical response and tolerability. If a satisfactory response is not obtained after 6-8 weeks use of the maximum daily dosage, therapy with timolol maleate should be discontinued. Ophthalmic Solutions Timolol maleate ophthalmic solution is available in concentrations of 0.25 and 0.5%. The usual starting dose is one drop of 0.25% timolol maleate 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. Additional Information for Preservative-Free Ophthalmic Solution: Apply enough gentle pressure on the individual container to obtain a single drop of solution. Since in some patients the pressure-lowering response to timolol maleate may require a few weeks to stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with timolol maleate. 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 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 agents(s) for lowering intraocular pressure can be instituted, taking into consideration, for the preservative-free opthalmic solution, 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 DRUG INTERACTIONS, Beta-adrenergic Blocking Agents). Additional Information for Preservative-Free Ophthalmic Solution: Preservative-free Timoptic in Ocudose is a sterile solution that does not contain a preservative. The solution from one individual unit is to used immediately after opening for administration to one or both eyes. Since sterility cannot be guaranteed after the individual unit is opened, the remaining contents should be discarded immediately after administration. Ophthalmic Gel Forming Solution 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. Other topically applied ophthalmic medications should be administered at least 10 minutes before timolol maleate ophthalmic gel forming solution (see PRECAUTIONS, Information for the Patient and PATIENT PACKAGE INSERT). Timolol maleate ophthalmic gel forming solution is available in concentrations of 0.25% and 0.5%. The dose is one drop of timolol maleate ophthalmic gel forming solution (either 0.25% or 0.5%) in the affected eye(s) once a day. Because in some patients the pressure-lowering response to timolol maleate ophthalmic gel forming 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 gel forming solution. Dosages higher than one drop of 0.5% timolol maleate 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 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.
Tablets Timolol maleate is usually well tolerated in properly selected patients. Most adverse effects have been mild and transient. In a multicenter (12-week) clinical trial comparing timolol maleate and placebo in hypertensive patients, the following adverse reactions were reported spontaneously and considered to be causally related to timolol maleate (see TABLE 1).
In patients with migraine the incidence of bradycardia was 5%. In a coronary artery disease population studied in the Norwegian multi-center trial (see CLINICAL PHARMACOLOGY), the frequency of the principal adverse reactions and the frequency with which these resulted in discontinuation of therapy in the timolol and placebo groups were as shown in TABLE 2.
Body as a Whole: Extremity pain, decreased exercise tolerance, weight loss, fever. Cardiovascular: Cardiac arrest, cardiac failure, cerebral vascular accident, worsening of angina pectoris, worsening of arterial insufficiency, Raynaud's phenomenon, palpitations, vasodilatation. Digestive: Gastrointestinal pain, hepatomegaly, vomiting, diarrhea, dyspepsia. Hematologic: Non-thrombocytopenic purpura. Endocrine: Hyperglycemia, hypoglycemia. Skin: Rash, skin irritation, increased pigmentation, sweating, alopecia. Musculoskeletal: Arthralgia. Nervous System: Local weakness, increase in signs and symptoms of myasthenia gravis. Psychiatric: Depression, nightmares, somnolence, insomnia, nervousness, diminished concentration, hallucinations. Respiratory: Cough. Special Senses: Visual disturbances, diplopia, ptosis, dry eyes. Urogenital: Impotence, urination difficulties. There have been reports of retroperitoneal fibrosis in patients receiving timolol maleate and in patients receiving other beta-adrenergic blocking agents. A causal relationship between this condition and therapy with beta-adrenergic blocking agents has not been established. Potential Adverse Effects: In addition, a variety of adverse effects not observed in clinical trials with timolol maleate, but reported with other beta-adrenergic blocking agents, should be considered potential adverse effects of timolol maleate: Nervous System: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics. Cardiovascular: Intensification of AV block (see CONTRAINDICATIONS). Digestive: Mesenteric arterial thrombosis, ischemic colitis. Hematologic: Agranulocytosis, thrombocytopenic purpura. Allergic: Erythematous rash, fever combined with aching and sore throat, laryngospasm with respiratory distress. Miscellaneous: Peyronie's disease. There have been reports of a syndrome comprising psoriasiform skin rash, conjunctivitis sicca, otitis, and sclerosing serositis attributed to the beta-adrenergic receptor blocking agent, practolol. This syndrome has not been reported with timolol maleate. Clinical Laboratory Test Findings: Clinically important changes in standard laboratory parameters were rarely associated with the administration of timolol maleate. Slight increases in blood urea nitrogen, serum potassium, uric acid, and triglycerides, and slight decreases in hemoglobin, hematocrit and HDL cholesterol occurred, but were not progressive or associated with clinical manifestations. Increases in liver function tests have been reported. Ophthalmic Solutions and Ophthalmic Gel Forming Solution The most frequently reported adverse experiences have been burning and stinging upon instillation (approximately 1 in 8 patients). The following additional adverse experiences have been reported less frequently with ocular administration of this or other timolol maleate formulations. Body as a Whole: Headache (not in ophthalmic gel forming solution), asthenia/fatigue, chest pain. Cardiovascular: Bradycardia, arrhythmia, hypotension, (hypertension for the ophthalmic gel forming solution) syncope, heart block, cerebral vascular 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: Dizziness (not in ophthalmic gel forming solution), 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 allergic reactions, including 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 (not in ophthalmic gel forming solution). Endocrine: Masked symptoms of hypoglycemia in diabetic patients (see WARNINGS). Special Senses: Signs and symptoms of ocular irritation including conjunctivitis (not in ophthalmic gel forming solution), blepharitis, keratitis, [ocular pain, discharge (e.g., crusting), foreign body sensation, itching and tearing (not in ophthalmic gel forming solution)], 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. Ophthalmic Gel Forming Solution 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.
Catecholamine-depleting Drugs: Close observation of the patient is recommended when timolol maleate 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 produce vertigo, syncope, or postural hypotension. 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. Tablets Calcium Antagonists: Literature reports suggest that oral calcium antagonists may be used in combination with beta-adrenergic blocking agents when heart function is normal, but should be avoided in patients with impaired cardiac function. Hypotension, AV conduction disturbances, and left ventricular failure have been reported in some patients receiving beta-adrenergic blocking agents when an oral calcium antagonist was added to the treatment regimen. Hypotension was more likely to occur if the calcium antagonist were a dihydropyridine derivative, (e.g., nifedipine) while left ventricular failure and AV conduction disturbances were more likely to occur with either verapamil or diltiazem. Intravenous calcium antagonists should be used with caution in patients receiving beta-adrenergic blocking agents. Digitalis and Either Diltiazem or Verapamil: The concomitant use of beta-adrenergic blocking agents with digitalis and either diltiazem or verapamil may have additive effects in prolonging AV conduction time. Clonidine: Beta adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two drugs are coadministered, the beta adrenergic blocking agent should be withdrawn several days before the gradual withdrawal of clonidine. If replacing clonidine by beta-blocker therapy, the introduction of beta adrenergic blocking agents should be delayed for several days after clonidine administration has stopped. Risk from Anaphylactic Reaction: While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction 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 anaphylactoid reactions. Non-steroidal Anti-inflammatory Drugs: Blunting of the antihypertensive effect of beta-adrenoceptor blocking agents by non-steroidal anti-inflammatory drugs has been reported. When using these agents concomitantly, patients should be observed carefully to confirm that the desired therapeutic effect has been obtained. Ophthalmic Solutions: Although timolol maleate used alone has little or no effect on pupil size, mydriasis resulting from concomitant therapy with timolol maleate and epinephrine has been reported occasionally. Ophthalmic Solutions and Ophthalmic Gel Forming Solution Beta-adrenergic Blocking Agents: Patients who are receiving a beta-adrenergic blocking agent orally and timolol maleate 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, 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. Digitalis and Calcium Antagonists: (Not for preservative-free ophthalmic solution.) The concomitant use of beta-adrenergic blocking agents with digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time. Injectable Epinephrine: (See PRECAUTIONS, General, Anaphylaxis.) Additional Information for Preservative-Free Ophthalmic Solution: Although timolol maleate used alone has little or no effect on pupil size, mydriasis resulting from concomitant therapy with timolol maleate and epinephrine has been reported occasionally.
Ophthalmic Solutions and Ophthalmic Gel Forming Solution Only: As with other topically applied ophthalmic drugs, this drug may be absorbed systemically. The same adverse reactions found with systemic administration of beta-adrenergic blocking agents may occur with topical administration. For example, severe respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma, and rarely death in association with cardiac failure, have been reported following systemic or ophthalmic administration of timolol maleate (see CONTRAINDICATIONS). 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. Tablets Only: Although beta blockers should be avoided in overt congestive heart failure, they can be used, if necessary, with caution in patients with a history of failure who are well-compensated, usually with digitalis and diuretics. Both digitalis and timolol maleate slow AV conduction. If cardiac failure persists, therapy with timolol maleate should be withdrawn. In Patients Without a History of Cardiac Failure Continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of cardiac failure, timolol maleate should be discontinued. Tablets Only: At the first sign or symptom of cardiac failure, patients receiving timolol maleate should be digitalized and/or be given a diuretic, and the response observed closely. If cardiac failure continues, despite adequate digitalization and diuretic therapy, timolol maleate should be withdrawn.
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 IS CONTRAINDICATED, (SEE CONTRAINDICATIONS), SHOULD, IN GENERAL, NOT RECEIVE BETA BLOCKERS, INCLUDING TIMOLOL MALEATE. Additional Information for Tablets: However, if timolol maleate is necessary in such patients, then the drug should be administered with caution since it may block bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta2 receptors. 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 for the ophthalmic solutions and ophthalmic gel forming solution; and such agonists as isoproterenol, dopamine, dobutamine or levarterenol for the tablets (see OVERDOSAGE). 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 hypoglycemia 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 which might precipitate a thyroid storm.
General 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. Tablets Impaired Hepatic or Renal Function: Since timolol maleate is partially metabolized in the liver and excreted mainly by the kidneys, dosage reductions may be necessary when hepatic and/or renal insufficiency is present. Dosing in the Presence of Marked Renal Failure: Although the pharmacokinetics of timolol maleate are not greatly altered by renal impairment, marked hypotensive responses have been seen in patients with marked renal impairment undergoing dialysis after 20 mg doses. Dosing in such patients should therefore be especially cautious. Cerebrovascular Insufficiency: Because of potential effects of beta-adrenergic blocking agents relative to 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 are observed, consideration should be given to discontinuing these agents. Ophthalmic Solutions and Ophthalmic Gel Forming Solution Because of potential effects of beta-adrenergic blocking agents 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 wflow develop following initiation of therapy with timolol maleate, alternative therapy should be considered. Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy (e.g., timolol). Angle-closure Glaucoma: In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This requires constricting the pupil. Timolol 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. Additional Information for Ophthalmic Solution (not including preservative-free) and Ophthalmic Gel Forming Solution: There have been reports of bacterial keratitis associated with the use of multiple dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface (see Information for the Patient). Information for the Patient Ophthalmic Solutions and Ophthalmic Gel Forming Solution Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures. Patients should also be instructed that ocular solutions, if handled improperly or if the tip of the dispensing container contacts the eye or surrounding structures, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions (see General). Additional Information for Ophthalmic Solutions: Patients with bronchia 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 produce (see CONTRAINDICATIONS). Patients should be advised that timolol maleate 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 administration. Additional Information for Ophthalmic Solution: (Not for preservative-free ophthalmic solution.) Patients should also 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. Preservative-Free Ophthalmic Solution Patients should be instructed about the use of preservative-free timolol maleate in Ocudose. Since sterility cannot be maintained after the individual unit is opened, patients should be instructed to use the product immediately after opening, and to discard the individual unit and any remaining contents immediately after use. Ophthalmic Gel Forming Solution 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 maleate. 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. Carcinogenesis, Mutagenesis, and Impairment of Fertility In a two-year study of timolol maleate administered orally to rats, there was a statistically significant increase in the incidence of adrenal pheochromocytomas in male rats administered 300 mg/kg/day (250 times* the maximum recommended human dose for the tablets, and approximately 42,000 times the systemic exposure following the maximum recommended human ophthalmic dose for the ophthalmic solutions and gel forming solution). Similar differences were not observed in rats administered oral doses equivalent to approximately 20 or 80 times* the maximum recommended human dose for the tablets, and approximately 14,000 times the maximum recommended human ophthalmic dose for the ophthalmic solutions and gel forming solution. In a lifetime oral study in mice, there were statistically significant increases in the incidence of benign and malignant pulmonary tumors, benign uterine polyps and mammary adenocarcinoma in female mice at 500 mg/kg/day (approximately 400 times* the maximum recommended human dose for the tablets, and approximately 71,000 times the systemic exposure following the maximum recommended human ophthalmic dose for the ophthalmic solutions and gel forming solution), but not at 5 or 50 mg/kg/day (approximately 700 or 7000, respectively, times, the systemic exposure following the maximum recommended human ophthalmic dose for the ophthalmic solutions and gel forming solution). 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, 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 man. 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 evaluated 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, 5000 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, nor did the ratio of test to control revertants reach 2. A ratio of 2 is usually considered the criterion for a positive Ames test. Reproduction and fertility studies in rats showed no adverse effect on male or female fertility at doses up to 125 times* the maximum recommended human dose for the tablets, and up to 21,000 times the systemic exposure following the maximum recommended human ophthalmic dose for the ophthalmic solutions and gel forming solution. *Based on a patient weight of 50 kg Pregnancy, Teratogenic Effects, Pregnancy Category C Teratogenicity studies with timolol in mice, rats, and rabbits at doses up to 50 mg/kg/day (40 times the maximum recommended human dose for the tablets, and 7000 times the systemic exposure following the maximum recommended human ophthalmic dose for the ophthalmic solutions and gel forming solution) demonstrated no evidence of fetal malformations. Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses of 1000 mg/kg/day (approximately 830 times the maximum recommended human dose for the tablets, and 142,000 times the systemic exposure following the maximum recommended human ophthalmic dose for the ophthalmic solutions and gel forming solution) were maternotoxic in mice and resulted in an increased number of fetal resorptions. Increased fetal resorptions were also seen in rabbits at doses of approximately 40 times the maximum recommended human dose for the tablets, and 14,000 times the systemic exposure following the maximum recommended human ophthalmic dose for the ophthalmic solutions and gel forming solution, in this case without apparent maternotoxicity. There are no adequate and well-controlled studies in pregnant women. Timolol maleate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Timolol maleate has been detected in human milk following oral and ophthalmic drug administration. Because of the potential for serious adverse reactions from timolol maleate in nursing infants, 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. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Tablets, Ophthalmic Solution, and Ophthalmic Gel Forming Solution: (Not for preservative-free ophthalmic solution.) Of the total number of patients in clinical studies of timolol maleate, 46% were 65 years of age and over, while 14% were 75 years of age and over. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals to the product cannot be ruled out.
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