Timolol maleate is a nonselective β-adrenergic blocking agent (β-blocker).
Timolol is used in the management of hypertension1200 and for the prophylaxis of migraine headache.106, 107, 108, 110, 111, 127, 128 Timolol also is used for the management of myocardial infarction (MI) and has been used in the management of angina†.
The choice of a β-adrenergic blocking agent (β-blocker) depends on numerous factors, including pharmacologic properties (e.g., relative β-selectivity, intrinsic sympathomimetic activity, membrane-stabilizing activity, lipophilicity), pharmacokinetics, intended use, and adverse effect profile, as well as the patient's coexisting disease states or conditions, response, and tolerance.176, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193 While specific pharmacologic properties and other factors may appropriately influence the choice of a β-blocker in individual patients,1235 evidence of clinically important differences among the agents in terms of overall efficacy and/or safety is limited.182, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193 Patients who do not respond to or cannot tolerate one β-blocker may be successfully treated with a different agent.184, 185, 186, 187, 190, 192, 193
In the management of hypertension or chronic stable angina pectoris† in patients with chronic obstructive pulmonary disease (COPD) or type I diabetes mellitus, many clinicians prefer to use low dosages of a β1-selective adrenergic blocking agent (e.g., atenolol, metoprolol), rather than a nonselective agent like timolol. However, selectivity of these agents is relative and dose dependent. Some clinicians also will recommend using a β1-selective agent or an agent with intrinsic sympathomimetic activity (e.g., pindolol), rather than a nonselective agent, for the management of hypertension or angina pectoris in patients with peripheral vascular disease, but there is no evidence that the choice of β-blocker substantially affects efficacy. Nonselective β-blockers are preferred for the management of hypertension or angina pectoris in patients with coexisting vascular (e.g., migraine) headache or essential tremor.
Timolol is used alone or in combination with other classes of antihypertensive agents in the management of hypertension.
Current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of drugs from 4 classes of antihypertensive agents (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics).501, 502, 503, 504, 1200 Most guidelines no longer recommend β-blockers as first-line therapy for hypertension because of the lack of established superiority over other recommended drug classes and evidence from at least one study demonstrating that β-blockers may be less effective than angiotensin II receptor antagonists in preventing cardiovascular death, MI, or stroke.194, 501, 503, 504, 515, 1200 However, therapy with a β-blocker may still be considered in hypertensive patients who have a compelling indication (e.g., prior MI, ischemic heart disease, heart failure) for their use or as add-on therapy in those who do not respond adequately to the preferred drug classes.501, 502, 503, 504, 523, 524, 527, 800, 1200 (See Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors under Uses: Hypertension, in Atenolol 24:24 and in Metoprolol 24:24.) Ultimately, choice of antihypertensive therapy should be individualized, considering the clinical characteristics of the patient (e.g., age, ethnicity/race, comorbid conditions, cardiovascular risk factors) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, costs).501, 502, 503, 504, 515, 1200, 1201
A 2017 multidisciplinary hypertension guideline of the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations generally recommends a target blood pressure goal (i.e., blood pressure to achieve with drug therapy and/or nonpharmacologic intervention) of less than 130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.1200 In addition, a systolic blood pressure goal of less than 130 mm Hg generally is recommended for noninstitutionalized ambulatory patients 65 years of age or older with an average systolic blood pressure of at least 130 mm Hg.1200 These blood pressure goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of systolic blood pressure.1200, 1202, 1210 Previous hypertension guidelines, such as those from an expert panel of the Eighth Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8), generally have recommended initiation of antihypertensive treatment in patients with a systolic blood pressure of at least 140 mm Hg or diastolic blood pressure of at least 90 mm Hg, targeted a blood pressure goal of less than 140/90 mm Hg regardless of cardiovascular risk, and used higher systolic blood pressure thresholds and targets in geriatric patients501, 504, 536 compared with those recommended by the 2017 ACC/AHA hypertension guideline.1200 The blood pressure thresholds used to define hypertension, the optimum blood pressure threshold at which to initiate antihypertensive drug therapy, and the ideal target blood pressure values remain controversial.501, 503, 504, 505, 506, 507, 508, 515, 523, 526, 530, 1200, 1201, 1207, 1209, 1222, 1223, 1229
Most patients with hypertension, especially black patients, will require at least 2 antihypertensive drugs to achieve adequate blood pressure control.1200 In general, black hypertensive patients tend to respond better to monotherapy with thiazide diuretics or calcium-channel blocking agents than to monotherapy with β-blockers.176, 180, 181, 501, 504, 1200 Although β-blockers have lowered blood pressure in all races studied, monotherapy with these agents has produced a smaller reduction in blood pressure in black hypertensive patients; however, this population difference in response does not appear to occur during combined therapy with a β-blocker and a thiazide diuretic.500 (See Race under Hypertension: Other Special Considerations for Antihypertensive Drug Therapy, in Uses in Atenolol 24:24 and in Metoprolol 24:24.)
For additional information on the role of β-blockers in the management of hypertension, see Uses: Hypertension, in Atenolol 24:24 and in Metoprolol 24:24. For information on overall principles and expert recommendations for management of hypertension, see Uses: Hypertension in Adults and also see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Timolol is used to reduce the risk of cardiovascular mortality and reinfarction (secondary prevention) in patients who have survived the acute phase of MI. In these patients, administration of timolol within 7-28 days following MI has been shown to reduce cardiovascular mortality and nonfatal reinfarction by approximately 25-40%. The effect of timolol is most apparent in postinfarction patients with transient left ventricular failure, cardiomegaly, atrial fibrillation or flutter of new onset, systolic hypertension, or markedly elevated (e.g., 4 times normal) serum concentrations of AST (SGOT). For information on the use of β-blockers during the acute phase of MI, see Uses in Metoprolol 24:24.
The benefits of long-term β-blocker therapy for secondary prevention of MI have been well established in numerous clinical studies.527, 804, 806, 1101 Patients with MI complicated by heart failure, left ventricular dysfunction, or ventricular arrhythmias appear to derive the most benefit from long-term β-blocker therapy.527 Several large, randomized studies have demonstrated that prolonged oral therapy with a β-blocker can reduce the long-term rates of reinfarction and mortality (e.g., sudden and nonsudden cardiac death) following acute MI.114, 115, 116, 118, 119, 120, 121, 122, 129 It is estimated that such therapy could result in a relative reduction in mortality of about 25% annually for years 1-3 after infarction, with high-risk patients exhibiting the greatest potential benefit;114, 115, 116, 118, 119, 120, 121, 122, 123, 124, 129 the benefit of continued therapy may persist for at least several years beyond this period, although less substantially.114, 118, 126, 129 Therefore, timolol, like other β-blockers, can be used for secondary prevention following acute MI to reduce the risk of reinfarction and mortality.114, 115, 129, 527 The American Heart Association/American College of Cardiology Foundation (AHA/ACCF) secondary prevention guideline recommends β-blocker therapy in all patients with left ventricular systolic dysfunction (ejection fraction of 40% or less) and prior MI; use of a β-blocker with proven mortality benefit (e.g., bisoprolol, carvedilol, or metoprolol succinate) is recommended.525 (See Uses: Heart Failure, in Carvedilol 24:24.) Although the benefits of long-term β-blockade in post-MI patients with normal left ventricular function are less well established, the guideline recommends continued β-blocker therapy for at least 3 years in such patients.525 Further studies are needed to establish the optimal duration of β-blocker therapy for secondary prevention of MI.527, 802, 804
Timolol has been used in the long-term management of chronic stable angina pectoris†. β-Blockers are recommended as the anti-ischemic drugs of choice in most patients with chronic stable angina; despite differences in cardioselectivity, intrinsic sympathomimetic activity, and other clinical factors, all β-blockers appear to be equally effective for this indication.1101 Long-term use of β-blockers in patients with chronic stable angina pectoris has been shown to reduce the frequency of anginal attacks, allow a reduction in nitroglycerin dosage, and increase exercise tolerance.
Combination therapy with a β-blocker and a nitrate appears to be more effective than either drug alone because β-blockers attenuate the increased sympathetic tone and reflex tachycardia associated with nitrate therapy while nitrate therapy (e.g., nitroglycerin) counteracts the potential increase in left-ventricular wall tension associated with a decrease in heart rate.1101 Combined therapy with a β-blocker and a dihydropyridine calcium-channel blocker also may be useful because the tendency to develop tachycardia with the calcium-channel blocker is counteracted by the β-blocker.1101 However, caution should be exercised in the concomitant use of β-blockers and the nondihydropyridine calcium-channel blockers verapamil or diltiazem because of the potential for excessive fatigue, bradycardia, or atrioventricular (AV) block.1101 (See Drug Interactions: Cardiovascular Drugs.)
Timolol is used for the prophylaxis of common or classic migraine headache.106, 107, 108, 110, 111, 127, 128 The US Headache Consortium states that there is good evidence from multiple well-designed clinical trials that timolol has medium to high efficacy for the prophylaxis of migraine headache.171 Efficacy of prophylactic timolol therapy has been established principally in patients with common migraine headache.106, 107, 108, 111 When used prophylactically, chronic therapy with the drug principally reduces the frequency of headaches rather than the severity or duration of those that occur.107, 108, 110, 111, 127 In controlled studies, response (a 50% or greater reduction from baseline in the frequency of headaches) was observed in approximately 50% of patients receiving timolol and in about 30% of patients receiving placebo.107, 108, 111 In addition, timolol maleate (10 mg orally twice daily) appears to be as effective as propranolol hydrochloride (80 mg orally twice daily) for prophylaxis of migraine.107 (For further information on management and classification of migraine headache see Vascular Headaches: General Principles in Migraine Therapy, under Uses in Sumatriptan 28:32.28.)
For ophthalmic uses of timolol maleate, see 52:92.
Timolol maleate is administered orally.
Reductions in heart rate and blood pressure should be monitored as a guide for determining optimum dosage of timolol maleate. If long-term timolol therapy is to be discontinued, dosage of the drug should be gradually reduced over a period of 1-2 weeks. (See Cautions: Precautions and Contraindications.)
For the management of hypertension, the usual initial adult dosage of timolol maleate is 10 mg twice daily, administered alone or in combination with a diuretic. Dosage of timolol maleate may be increased gradually at intervals of not less than 1 week until optimum control of blood pressure is obtained. The usual adult maintenance dosage is 20-40 mg daily, given in 2 divided doses. In some hypertensive patients, once-daily dosing of the drug may be possible. Depending on blood pressure and heart rate response, dosage may be increased to a maximum of 60 mg daily, given in 2 divided doses.
Blood Pressure Monitoring and Treatment Goals
Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved, the dosage may be increased or another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor antagonist, calcium-channel blocker, thiazide diuretic) may be added; if target blood pressure is still not achieved with the use of 2 antihypertensive agents, a third drug may be added.1200, 1216 (See Uses: Hypertension.) In patients who develop unacceptable adverse effects with timolol, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1200, 1216
The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505, 506, 507, 508, 515, 523, 530, 1201, 1207, 1209, 1222 While previous hypertension guidelines have based target blood pressure goals on age and comorbidities,501, 504, 536 the 2017 American College of Cardiology/American Heart Association (ACC/AHA) hypertension guideline incorporates underlying cardiovascular risk into decision making regarding treatment and generally recommends the same target blood pressure (i.e., less than 130/80 mm Hg) for all adults.1200 Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200, 1220
For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the Thiazides General Statement 40:28.20.
When used for secondary prevention after the acute phase of MI, the usual adult dosage of timolol maleate is 10 mg twice daily, initiated within 1-4 weeks after infarction. Although the optimal duration of β-blocker therapy following MI remains to be clearly established, experts generally recommend that such therapy be continued long-term in post-MI patients with left ventricular systolic dysfunction, and for at least 3 years in those with normal left ventricular function.525, 802, 804, 1101
For the management of chronic stable angina pectoris†, timolol maleate dosages of 15-45 mg daily, given in 3 or 4 divided doses, have been used in adults. Dosage of β-blockers in patients with angina usually is adjusted according to clinical response and to maintain a resting heart rate of 55-60 bpm.
For the prevention of migraine headache, the usual initial adult dosage of timolol maleate is 10 mg twice daily.107, 108, 110, 111 During maintenance therapy, the 20-mg daily dosage can be administered as a single rather than divided dose.111 Dosage should be adjusted according to clinical response and patient tolerance, but the manufacturer recommends that it not exceed 30 mg daily, given in divided doses (e.g., 10 mg in the morning and 20 mg in the evening).108, 111 Some patients may respond adequately to 10 mg once daily.111 If an adequate response is not achieved after 6-8 weeks at the maximum recommended dosage, timolol maleate therapy should be discontinued.111
Dosage in Renal and Hepatic Impairment
In patients with renal or hepatic impairment, doses and/or frequency of administration of timolol maleate must be modified in response to the degree of renal or hepatic impairment.
Timolol maleate shares the toxic potentials of β-adrenergic blocking agents (β-blockers). In therapeutic dosage, timolol usually is well tolerated. The incidence and severity of adverse reactions may occasionally be obviated by a reduction in dosage. Abrupt withdrawal of the drug should be avoided, especially in patients with coronary artery disease, since it may exacerbate angina or precipitate myocardial infarction (MI).
Potentially serious adverse cardiovascular effects of timolol include bradycardia, which occurs in 5-9% of patients; hypotension, occurring in 3% or less of patients; arrhythmia and atrioventricular (AV) or sinoatrial (SA) nodal block, occurring in 1% or less of patients; heart failure, occurring in from less than 1% to 8% of patients; pulmonary edema, occurring in 2% or less of patients; and exacerbation of angina pectoris. Other adverse cardiovascular effects include syncope, edema, and chest pain, occurring in about 0.6% of patients; signs of worsening arterial insufficiency including claudication, Raynaud's phenomenon, and coldness or pain in the hands and feet; and palpitation and vasodilation. Cerebrovascular accidents also have occurred in patients receiving timolol.
Adverse CNS effects, occurring in 2-5% of patients, include dizziness, fatigue, and asthenia. Headaches, vertigo, insomnia, nervousness, decreased ability to concentrate, nightmares, somnolence, and mental depression also have occurred. Paresthesia, local weakness and pain in the extremities, arthralgias, visual disturbances, tinnitus, and dryness and irritation of the eyes have occurred. Adverse CNS effects seen with other β-blockers that may occur with timolol include hallucinations, disorientation, short-term memory loss, emotional lability, catatonia, clouded sensorium, and impaired performance on neuropsychometric tests.
Adverse GI reactions of abdominal discomfort, nausea, and constipation reportedly occur in 1-5% of patients. GI pain, elevated liver function test results, hepatomegaly, vomiting, and diarrhea also have been reported. A few cases of mesenteric arterial thrombosis and ischemic colitis have been reported in patients receiving other β-blockers.
Results of a large prospective cohort study of nondiabetic adults 45-64 years of age indicate that use of β-blockers in hypertensive patients is associated with increased risk (about 28%) of developing type 2 diabetes mellitus compared with hypertensive patients who were not receiving hypotensive therapy.160, 161 In this study, the number of new cases of diabetes per 1000 person-years was 33.6 or 26.3 in patients receiving a β-blocker or no drug therapy, respectively.160 The association between the risk of developing type 2 diabetes mellitus and use of β-blockers reportedly was not confounded by weight gain, hyperinsulinemia, or differences in heart rate.160, 161 It is not known if the risk of developing diabetes is affected by β-receptor selectivity.160 Further studies are needed to determine whether concomitant use of ACE inhibitors (which may improve insulin sensitivity) would abrogate β-blocker-induced adverse effects related to glucose intolerance.161 Therefore, until results of such studies are available, the proven benefits of β-blockers in reducing cardiovascular events in hypertensive patients must be weighed carefully against the possible risks of developing type 2 diabetes mellitus.160
Hypoglycemia,159 which may result in loss of consciousness, also may occur in nondiabetic patients receiving β-blockers. Patients most at risk for the development of β-blocker-induced hypoglycemia are those undergoing dialysis, prolonged fasting, or severe exercise regimens.159
β-Blockers may mask signs and symptoms of hypoglycemia (e.g., palpitation, tachycardia, tremor) and potentiate insulin-induced hypoglycemia.159 Although it has been suggested that nonselective β-blockers are more likely to induce hypoglycemia than selective β-blockers, such an adverse effect also has been reported with selective β-blockers (e.g., atenolol).159 In addition, selective β-blockers are less likely to mask symptoms of hypoglycemia or delay recovery from insulin-induced hypoglycemia than nonselective β-blockers because of their vascular sparing effects; however, selective β-blockers can decrease insulin sensitivity by approximately 15-30%, which may result in increased insulin requirements.159
Rales, bronchospasm, and dyspnea have reportedly occurred in 0.6-2% of patients receiving timolol. Irritation, rashes and increased pigmentation of the skin, pruritus, alopecia, increased sweating, decreased libido, impotence, urination difficulties, fever, cough, and retroperitoneal fibrosis also have been reported with timolol. Slight and usually nonprogressive increases in BUN, serum potassium, serum uric acid, serum triglyceride, and blood glucose concentrations and decreases in hemoglobin, serum high-density lipoprotein (HDL)-cholesterol, and blood glucose concentrations and in hematocrit have occurred; these changes generally were not associated with clinical manifestations. Hypokalemia has been reported more frequently in patients receiving timolol in a fixed-combination preparation that includes a thiazide diuretic (no longer commercially available in the US) than in those receiving timolol alone.
The possibility that other adverse effects associated with other β-blockers may occur during timolol therapy should be considered. These include hematologic reactions (e.g., agranulocytosis, nonthrombocytopenic or thrombocytopenic purpura); allergic reactions characterized by fever, sore throat, laryngospasm, and respiratory distress; and Peyronie's disease. Anaphylaxis also has been reported with timolol therapy.111
Precautions and Contraindications
Timolol maleate shares the toxic potentials of β-blockers, and the usual precautions of these agents should be observed.
Timolol should be used with caution in patients with inadequate cardiac function, since heart failure may be precipitated by blockade of β-adrenergic stimulation when timolol therapy is administered. In addition, in patients with latent cardiac insufficiency, prolonged β-adrenergic blockade may lead to heart failure. Although β-blockers should be avoided in patients with overt heart failure, timolol may be administered cautiously, if necessary, to patients with well-compensated heart failure (e.g., those controlled with cardiac glycosides and/or diuretics). Patients receiving timolol therapy should be instructed to consult their physician at the first sign or symptom of impending heart failure and should be adequately treated (e.g., with a heart glycoside and/or diuretic) and observed closely; if heart failure continues, timolol should be discontinued, gradually if possible.
Abrupt withdrawal of timolol may exacerbate angina symptoms or precipitate MI in patients with coronary artery disease, or precipitate thyroid crisis in patients with thyrotoxicosis. Therefore, patients receiving timolol (especially those with ischemic heart disease) should be warned not to interrupt or discontinue therapy without consulting their physician. When discontinuance of long-term timolol therapy is planned, particularly in patients with ischemic heart disease, dosage of the drug should be gradually reduced over a period of 1-2 weeks. When timolol therapy is discontinued, patients should be carefully monitored. If exacerbation of angina occurs or acute coronary insufficiency develops after timolol therapy is interrupted or discontinued, treatment with the drug should be reinstituted promptly, at least temporarily, and appropriate measures for the management of unstable angina pectoris should be initiated. Because coronary artery disease is common and may be unrecognized, the manufacturers caution that it may be prudent not to discontinue timolol therapy abruptly, even in patients being treated only for hypertension.
Since β-blockers may inhibit bronchodilation produced by endogenous catecholamines, the drugs generally should not be used in patients with bronchospastic disease. Timolol should be used with caution in patients with nonallergic bronchospasm (e.g., chronic bronchitis, emphysema) or a history of nonallergic bronchospasm.
It is recommended that timolol be used with caution in patients with diabetes mellitus receiving hypoglycemic agents, especially those with labile disease or those prone to hypoglycemia since the drug may mask the signs and symptoms associated with acute hypoglycemia (e.g., tachycardia and blood pressure changes but not sweating). β-Blockers also may impair glucose tolerance; delay the rate of recovery of blood glucose concentration following drug-induced hypoglycemia; alter the hemodynamic response to hypoglycemia, possibly resulting in an exaggerated hypertensive response; and possibly impair peripheral circulation. (See Cautions: Endocrine Effects.) However, many clinicians state that patients with diabetes mellitus may be particularly likely to experience a reduction in morbidity and mortality with the use of β-blockers.157 (See Uses: Heart Failure, in Metoprolol 24:24.)
The necessity of withdrawing β-blocking therapy prior to major surgery is controversial. Severe, protracted hypotension and difficulty in restarting or maintaining a heart beat have occurred during surgery in some patients who have received β-blockers. Some clinicians recommend gradual withdrawal of β-blockers before elective surgery. The manufacturers recommend administration of β-agonists (e.g., dopamine, dobutamine, isoproterenol) to reverse timolol's β-adrenergic blockade if necessary during surgery.
Timolol should be used with caution in patients with myasthenia, since the drug may increase muscle weakness in some patients with this condition.
Timolol should be used with caution in patients with cerebrovascular insufficiency, since β-blockers may cause cardiovascular effects (e.g., hypotension, bradycardia) that can adversely affect cerebral blood flow. If signs or symptoms suggestive of reduced cerebral blood flow occur in patients receiving timolol, discontinuance of the drug should be considered.
Patients with a history of atopy or severe anaphylactic reactions to a variety of allergens may be more reactive to repeated, accidental, diagnostic, or therapeutic challenge with such allergens while receiving a β-blocker.111 These patients may be less responsive than other patients to usual dosages of epinephrine used to treat anaphylactic reactions.111
Timolol should be used with caution and reduced dosage may be necessary in patients with impaired renal and/or hepatic function. The manufacturers recommend that the drug be used with caution in patients undergoing hemodialysis, since marked hypotension has occurred when 20-mg doses of the drug were administered to these patients.
Timolol is contraindicated in patients with bronchial asthma (or a history of bronchial asthma), allergic bronchospasm, or severe chronic obstructive pulmonary disease; with severe bradycardia, or second- or third-degree AV block; with overt heart failure or cardiogenic shock; or with known hypersensitivity to the drug.
Safety and efficacy of timolol maleate in children have not been established. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Mutagenicity and Carcinogenicity
Timolol maleate was not mutagenic in vivo in the mouse micronucleus test or cytogenetic assay (using doses up to 800 mg/kg) or in vitro in a neoplastic cell transformation assay (using doses up to 100 mcg/mL).111 Although results of an in vitro microbial test system (Ames test) were not considered positive, timolol maleate concentrations of 5000 or 10,000 mcg per plate were associated with statistically significant increases in the number of revertants in some, but not all, test strains.111
In a 2-year study in rats, there was no evidence of carcinogenicity in those that received timolol maleate dosages approximately 20 or 80 times the maximum recommended human dosa however, there was a statistically significant increase in the incidence of adrenal pheochromocytomas in male rats that received a dosage of 300 mg/kg daily (250 times the maximum recommended human dosage).111 In a lifetime study in mice, there was a statistically significant increase in the incidence of benign and malignant pulmonary tumors, benign uterine polyps, and mammary adenocarcinoma in female mice receiving 500 mg/kg daily (approximately 400 times the maximum recommended human dosage); this did not occur with dosages of 5 or 50 mg/kg daily.111 In a subsequent study in female mice receiving 500 mg/kg daily, postmortem examinations (limited to the uterus and lungs) also revealed a statistically significant increase in the incidence of pulmonary tumors.111 The increased incidence of mammary adenocarcinoma in female mice appeared to be associated with elevations in serum prolactin that occurred in those receiving timolol maleate dosages of 500 mg/kg daily, but did not occur in those receiving 5 or 50 mg/kg daily.111 Although an increased incidence of mammary adenocarcinomas in rodents has been associated with administration of several other drugs that elevate serum prolactin, no correlation between serum prolactin concentrations and mammary tumors has been established in humans.111 In addition, clinically important alterations in serum prolactin concentrations have not been reported in adult women receiving the maximum recommended daily dosage of timolol maleate.111
Pregnancy, Fertility, and Lactation
Reproduction studies in mice and rabbits using timolol maleate dosages up to 50 times the maximum human dosage have not revealed evidence of harm to the fetus. Although delayed fetal ossification was observed at this dosage in rats, no adverse effects on postnatal development occurred in this species. In pregnant rabbits and mice receiving timolol maleate dosages 100 and 1000 times the maximum human dosage, respectively, an increased incidence of fetal resorption resulted. There are no adequate and controlled studies to date using timolol in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.
Reproduction studies in male and female rats using timolol maleate dosages up to 125 times the maximum human dosage have not revealed evidence of impaired fertility.111
Timolol is distributed into milk. Because of the potential for serious adverse reactions from timolol in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.
Timolol maleate shares the drug interaction potential of other nonselective β-adrenergic blocking agents (β-blockers), and the usual precautions of these agents should be observed when concomitant therapy with other drugs is considered. In addition to the drug interactions that follow, interactions described for other nonselective β-blockers are likely with timolol. For additional information on the drug interaction potential of timolol, see Drug Interactions, in Propranolol Hydrochloride 24:24.
Concomitant administration of timolol with reserpine may increase the incidence of hypotension and bradycardia as compared with timolol alone, because of reserpine's catecholamine-depleting activity. Timolol also is additive with and may potentiate the hypotensive actions of other hypotensive agents (e.g., hydralazine, methyldopa). This effect usually is used to therapeutic advantage, but dosage should be adjusted carefully when these drugs are used concurrently.
Quinidine may inhibit the metabolism of timolol probably via inhibition of the cytochrome P-450 microsomal enzyme system (CYP2D6) resulting in increased β-adrenergic blockade (e.g., decreased heart rate).145
Because β-blockers may exacerbate rebound hypertension that may occur following discontinuance of clonidine therapy, β-blockers should be discontinued several days before gradual withdrawal of clonidine when clonidine therapy is to be discontinued in patients receiving a β-blocker and clonidine concurrently.145, 146 If clonidine therapy is to be replaced by a β-blocker, administration of the β-blocker should be delayed for several days after clonidine therapy has been discontinued.145, 146
Nonsteroidal Anti-inflammatory Agents
The hypotensive effect of timolol may be antagonized by nonsteroidal anti-inflammatory agents (e.g., ibuprofen, indomethacin).
The oral LD50 of timolol maleate is 1190 and 900 mg/kg in female mice and female rats, respectively.
Limited information is available on the acute toxicity of timolol maleate.111 As with other β-adrenergic blocking agents (β-blockers), symptomatic bradycardia, hypotension, bronchospasm, and acute heart failure may occur with timolol overdosage.111 A 30-year-old woman who ingested 650 mg of the drug experienced second- and third-degree heart block, which initially resolved without treatment.111 However, approximately 2 months later, she developed an irregular heartbeat, hypertension, dizziness, tinnitus, increased pulse rate, and borderline first-degree heart block.111
In acute timolol maleate overdosage, the stomach should be emptied immediately by gastric lavage. Supportive and symptomatic treatment should be initiated. For symptomatic bradycardia, IV atropine may be given; if bradycardia persists, IV isoproterenol hydrochloride may be administered cautiously, and in refractory cases, use of a transvenous cardiac pacemaker should be considered. For second- or third-degree AV block, IV isoproterenol hydrochloride or a transvenous cardiac pacemaker may be used. A vasopressor (e.g., dobutamine, dopamine, norepinephrine) may be given for severe hypotension; IV glucagon may be useful if hypotension is refractory to vasopressors. A β-adrenergic agonist (e.g., isoproterenol) and/or IV aminophylline may be given for bronchospasm. For heart failure, a cardiac glycoside, diuretic, and oxygen should be used. The manufacturers recommend IV aminophylline when heart failure is refractory to conventional therapy; glucagon may also be of some value. Hemodialysis appears to be of little benefit in enhancing elimination of the drug.
Timolol maleate has pharmacologic actions similar to those of other β-adrenergic blocking agents (β-blockers). The principal physiologic action of timolol is to competitively block β-adrenergic receptors within the myocardium (β1-receptors) and within bronchial and vascular smooth muscle (β2-receptors). Unlike atenolol and metoprolol, timolol is not a β1-selective adrenergic blocking agent; timolol is a nonselective β-blocker, inhibiting both β1- and β2-adrenergic receptors. Timolol also does not exhibit the intrinsic sympathomimetic activity seen with pindolol or the membrane-stabilizing activity possessed by propranolol or pindolol.
By inhibiting myocardial β1-adrenergic receptors, timolol produces negative chronotropic and inotropic activity. The negative chronotropic action of timolol on the sinoatrial (SA) node results in a decrease in the rate of SA node discharge and an increase in recovery time, thereby decreasing resting and exercise-stimulated heart rate and reflex orthostatic tachycardia by as much as 30%. High doses of the drug may produce sinus arrest, especially in patients with SA node disease (e.g., sick sinus syndrome). Timolol also slows conduction in the atrioventricular (AV) node. Timolol usually produces a slight reduction in cardiac output, probably secondary to its effect on heart rate. The decrease in myocardial contractility and heart rate produced by timolol leads to a reduction in myocardial oxygen consumption which accounts for the effectiveness of the drug in chronic stable angina pectoris.
Timolol suppresses plasma renin activity and suppresses the renin-aldosterone-angiotensin system. The renin-lowering effect of β-blockers may lead to a minimal reduction in glomerular filtration rate and occasionally may reduce renal blood flow; however, other mechanisms (e.g., decreased cardiac output, unopposed α-mediated renal vasoconstriction) also probably contribute to these effects. Because of the suppression of aldosterone production, β-blockers usually produce no measurable increases in plasma volume or sodium and water retention.
The precise mechanism of timolol's hypotensive effect has not been determined. Timolol may transiently increase peripheral vascular resistance (PVR) at rest and with exercise, but PVR usually returns to baseline with continued administration of the drug. It has been postulated that β-blockers reduce blood pressure by blocking peripheral (especially cardiac) adrenergic receptors (decreasing cardiac output), by decreasing sympathetic outflow from the CNS, and/or by suppressing renin release.
Timolol inhibits β2-adrenergic receptors in the lungs, resulting in an increase in airway resistance, as measured by a decreased forced expiratory volume in 1 second.
Approximately 90% of an oral dose of timolol maleate is rapidly absorbed from the GI tract. Absorption of the drug is not reduced by food. Only about 50% of an oral dose reaches systemic circulation as unchanged drug since timolol undergoes extensive metabolism on first pass through the liver. Peak plasma concentrations of the drug usually are reached within 1-2 hours after oral administration. Considerable interindividual variation in plasma concentrations attained have been reported with a specific oral dose of timolol.
Timolol is 10-60% bound to plasma proteins, depending on the assay method employed. The drug is distributed into milk.
Timolol has a plasma half-life (t½) of 3-4 hours; t½ is essentially unchanged in patients with moderate renal insufficiency. Approximately 80% of a dose of timolol is metabolized in the liver to inactive metabolites. The unchanged drug and its metabolites are excreted in urine. Only small amounts of the drug are removed by hemodialysis.
Timolol maleate is a nonselective β-adrenergic blocking agent (β-blocker). The drug, which is commercially available as the l -isomer, occurs as a white, crystalline powder and is freely soluble in water and soluble in alcohol. Timolol maleate has a pKa of 9 in water at 25°C.
Timolol maleate tablets should be stored in tight, light-resistant containers at a temperature between 15-30°C.111
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 5 mg* | ||
10 mg* | Timolol Maleate Tablets | |||
20 mg* | Timolol Maleate Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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