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Timolol Maleate

Class: beta-Adrenergic Blocking Agents
VA Class: CV100
CAS Number: 26921-17-5

Medically reviewed by Drugs.com. Last updated on Feb 25, 2019.

Introduction

Nonselective β-adrenergic blocking agent (β-blocker).111

Uses for Timolol Maleate

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).111 1200

β-Blockers generally not preferred for first-line therapy of hypertension according to current evidence-based hypertension guidelines, but may be considered in 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 (ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, or thiazide diuretics).194 501 502 503 504 515 523 524 527 800 1200 Timolol is one of several β-blockers (including bisoprolol, carvedilol, metoprolol succinate, metoprolol tartrate, nadolol, and propranolol) recommended by a 2017 ACC/AHA multidisciplinary hypertension guideline as first-line therapy for hypertension in patients with stable ischemic heart disease/angina.1200

Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).501 502 503 504 515 1200 1201

The 2017 ACC/AHA hypertension guideline classifies BP in adults into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension.1200 (See Table 1.)

Source: Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-115.

Individuals with SBP and DBP in 2 different categories (e.g., elevated SBP and normal DBP) should be designated as being in the higher BP category (i.e., elevated BP).

Table 1. ACC/AHA BP Classification in Adults1200

Category

SBP (mm Hg)

DBP (mm Hg)

Normal

<120

and

<80

Elevated

120–129

and

<80

Hypertension, Stage 1

130–139

or

80–89

Hypertension, Stage 2

≥140

or

≥90

The goal of hypertension management and prevention is to achieve and maintain optimal control of BP.1200 However, the BP thresholds used to define hypertension, the optimum BP threshold at which to initiate antihypertensive drug therapy, and the ideal target BP values remain controversial.501 503 504 505 506 507 508 515 523 530 1200 1201 1207 1209 1222 1223 1229

The 2017 ACC/AHA hypertension guideline generally recommends a target BP goal (i.e., BP to achieve with drug therapy and/or nonpharmacologic intervention) <130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.1200 In addition, an SBP goal of <130 mm Hg generally is recommended for noninstitutionalized ambulatory patients ≥65 years of age with an average SBP of ≥130 mm Hg.1200 These BP goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of SBP.1200 1202 1210

Other hypertension guidelines generally have based target BP goals on age and comorbidities.501 504 536 Guidelines such as those issued by the JNC 8 expert panel generally have targeted a BP goal of <140/90 mm Hg regardless of cardiovascular risk and have used higher BP thresholds and target BPs in elderly patients501 504 536 compared with those recommended by the 2017 ACC/AHA hypertension guideline.1200

Some clinicians continue to support previous target BPs recommended by JNC 8 due to concerns about the lack of generalizability of data from some clinical trials (e.g., SPRINT study) used to support the 2017 ACC/AHA hypertension guideline and potential harms (e.g., adverse drug effects, costs of therapy) versus benefits of BP lowering in patients at lower risk of cardiovascular disease.1222 1223 1224 1229

Consider potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs when deciding a patient's BP treatment goal.1200 1220 1229

For decisions regarding when to initiate drug therapy (BP threshold), the 2017 ACC/AHA hypertension guideline incorporates underlying cardiovascular risk factors.1200 1207 ASCVD risk assessment is recommended by ACC/AHA for all adults with hypertension.1200

ACC/AHA currently recommend initiation of antihypertensive drug therapy in addition to lifestyle/behavioral modifications at an SBP ≥140 mm Hg or DBP ≥90 mm Hg in adults who have no history of cardiovascular disease (i.e., primary prevention) and a low ASCVD risk (10-year risk <10%).1200

For secondary prevention in adults with known cardiovascular disease or for primary prevention in those at higher risk for ASCVD (10-year risk ≥10%), ACC/AHA recommend initiation of antihypertensive drug therapy at an average SBP ≥130 mm Hg or an average DBP ≥80 mm Hg.1200

Adults with hypertension and diabetes mellitus, chronic kidney disease (CKD), or age ≥65 years are assumed to be at high risk for cardiovascular disease; ACC/AHA state that such patients should have antihypertensive drug therapy initiated at a BP ≥130/80 mm Hg.1200 Individualize drug therapy in patients with hypertension and underlying cardiovascular or other risk factors.502 1200

In stage 1 hypertension, experts state that it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target BP.1200 Initiation of antihypertensive therapy with 2 first-line agents from different pharmacologic classes recommended in adults with stage 2 hypertension and average BP >20/10 mm Hg above BP goal.1200

Black hypertensive patients generally tend to respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to β-blockers.176 180 181 501 504 1200 However, diminished response to β-blockers is largely eliminated when administered concomitantly with a thiazide diuretic.500

MI

Secondary prevention following acute MI.111

Administration within 7–28 days following MI associated with reductions in cardiovascular mortality and nonfatal reinfarction.a

Experts recommend β-blocker therapy in all patients with left ventricular systolic dysfunction and prior MI; a β-blocker with proven mortality benefit (bisoprolol, carvedilol, or metoprolol succinate) is preferred.525 Although benefits of long-term β-blockade in patients with normal left ventricular function are less well established, experts recommend continuing β-blocker therapy for at least 3 years in such patients.525

Vascular Headache

Prophylaxis of common or classic migraine headache.106 107 108 110 111 127 128

Chronic Stable Angina

Has been used in the management of chronic stable angina pectoris.a

β-Blockers are recommended as first-line anti-ischemic drugs 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 use.1101

Timolol Maleate Dosage and Administration

General

  • Monitor reductions in heart rate and BP as a guide for determining optimum dosage.111

  • If long-term therapy is discontinued, reduce dosage gradually over a period of 1–2 weeks.111 (See Abrupt Withdrawal of Therapy under Cautions.)

BP Monitoring and Treatment Goals

  • Monitor BP regularly (i.e., monthly) during therapy and adjust dosage of the antihypertensive drug until BP controlled.1200

  • If unacceptable adverse effects occur, discontinue drug and initiate another antihypertensive agent from a different pharmacologic class.1216

  • If adequate BP response not achieved with a single antihypertensive agent, either increase dosage of single drug or add a second drug with demonstrated benefit and preferably a complementary mechanism of action (e.g., ACE inhibitor, angiotensin II receptor antagonist, calcium-channel blocker, thiazide diuretic).1200 1216 Many patients will require ≥2 drugs from different pharmacologic classes to achieve BP goal; if goal BP still not achieved, add a third drug.1200 1216

Administration

Oral Administration

Administer orally, usually twice daily.111

For management of hypertension, once-daily dosing may be possible in some patients.a

In patients with chronic stable angina pectoris, administer orally in 3 or 4 divided doses.a

During maintenance therapy in patients with vascular headaches (migraine), may administer daily dosage as a single rather than divided dose.111

Dosage

Available as timolol maleate; dosage expressed in terms of the salt.111

Adults

Hypertension
Oral

Initially, 10 mg twice daily, either alone or in combination with a diuretic.111 a

Increase dosage gradually at weekly (or longer) intervals until optimum effect is obtained.111

Usual maintenance dosage is 20–40 mg daily, given in 2 divided doses; once-daily dosing may be possible in some patients.111 Increases up to a maximum of 60 mg daily (given in 2 divided doses) may be necessary.111

MI
Oral

Secondary prevention after acute phase of MI: Usual dosage is 10 mg twice daily.111

Optimal duration of therapy for secondary prevention remains to be established.527 802 804 Experts generally recommend long-term therapy in post-MI patients with left ventricular dysfunction, and at least 3 years of therapy in those with normal left ventricular function.525 802 804 1101

Chronic Stable Angina
Oral

15–45 mg daily, given in 3 or 4 divided doses.a Adjust dosage according to clinical response and to maintain a resting heart rate of 55–60 bpm.a

Vascular Headaches (Migraine)
Oral

Initially, 10 mg twice daily.107 108 110 111 Adjust dosage according to clinical response and patient tolerance; do not exceed 30 mg daily, given in divided doses (e.g., 10 mg in the morning and 20 mg in the evening).108 111

During maintenance therapy, can administer 20-mg daily dosage as a single rather than divided dose; 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, discontinue therapy.111

Prescribing Limits

Adults

Hypertension
Oral

Maximum 60 mg daily.111

Vascular Headaches (Migraine)
Oral

Maximum 30 mg daily.108 111

Special Populations

Hepatic Impairment

Must modify doses and/or frequency of administration in response to degree of hepatic impairment.111

Renal Impairment

Must modify doses and/or frequency of administration in response to degree of renal impairment.111

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.b Initiate at low end of dosing range.b

Cautions for Timolol Maleate

Contraindications

  • Known hypersensitivity to timolol or any ingredient in the formulation.111

  • Bronchial asthma (or a history of bronchial asthma), allergic bronchospasm, or severe COPD.111

  • Severe bradycardia, heart block greater than first degree, overt cardiac failure, or cardiogenic shock.111

Warnings/Precautions

Warnings

Heart Failure

Possible precipitation of heart failure.111

Avoid use in patients with overt heart failure; may use cautiously in patients with inadequate myocardial function and, if necessary, in patients with well-compensated heart failure (e.g., those controlled with cardiac glycosides and/or diuretics).111

Adequate treatment (e.g., with a cardiac glycoside and/or diuretic) and close observation recommended if signs or symptoms of impending heart failure occur; if heart failure continues, discontinue therapy, gradually if possible.111

Abrupt Withdrawal of Therapy

Abrupt withdrawal of therapy is not recommended as it may exacerbate angina symptoms or precipitate MI in patients with coronary artery disease.111

Gradually decrease dosage over a period of 1–2 weeks and monitor patients carefully; advise patients to temporarily limit their physical activity during withdrawal of therapy.111

If exacerbation of angina occurs or acute coronary insufficiency develops, reinstitute therapy promptly, at least temporarily, and initiate appropriate measures for management of unstable angina pectoris.111

Bronchospastic Disease

Possible inhibition of bronchodilation produced by endogenous catecholamines.111

Generally should not be used in patients with bronchospastic disease, but may use with caution in patients who do not respond to or cannot tolerate alternative treatment.111 a Use with caution in patients with nonallergic bronchospasm (e.g., chronic bronchitis, emphysema) or a history of nonallergic bronchospasm.a (See Contraindications under Cautions.)

Major Surgery

Possible increased risks associated with general anesthesia (e.g., severe hypotension, difficulty restarting or maintaining heart beat) due to decreased ability of the heart to respond to reflex β-adrenergic stimuli.111

Some clinicians recommend gradual withdrawal before elective surgery.111 b Manufacturers recommend administration of β-agonists (e.g., dopamine, dobutamine, isoproterenol) to reverse β-adrenergic blockade if necessary during surgery.111 a b

Diabetes and Hypoglycemia

Possible decreased signs and symptoms of hypoglycemia (e.g., tachycardia, but not sweating or dizziness).111 Use with caution in patients with diabetes mellitus receiving hypoglycemic drugs.111

Thyrotoxicosis

May mask signs of hyperthyroidism (e.g., tachycardia).111 Possible thyroid storm if therapy is abruptly withdrawn; carefully monitor patients having or suspected of developing thyrotoxicosis.111

Sensitivity Reactions

Anaphylactic Reactions

Patients with a history of atopy or anaphylactic reactions to a variety of allergens may be more reactive to repeated, accidental, diagnostic, or therapeutic challenges with such allergens while taking β-blocking agents; such patients may be unresponsive to usual doses of epinephrine.111

General Precautions

Muscle Weakness

β-Adrenergic blockade reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis, generalized weakness).111 b Increased muscle weakness reported rarely in some patients with myasthenia gravis or myasthenic symptoms.111 b

Cerebrovascular Insufficiency

Possible cardiovascular effects (e.g., hypotension, bradycardia) that can adversely affect cerebral blood flow.111 Use with caution in patients with cerebrovascular insufficiency.111 If signs or symptoms suggestive of reduced cerebral blood flow occur, consider discontinuance.111

Other Precautions

Shares the toxic potentials of β-blockers; observe usual precautions of these agents.a

Specific Populations

Pregnancy

Category C.111

Lactation

Distributed into milk.111 Discontinue nursing or the drug.111

Pediatric Use

Safety and efficacy not established.111

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.111

Substantially eliminated by the kidneys; assess renal function periodically and adjust dosage since geriatric patients are more likely to have decreased renal function.111 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Use with caution; dosage adjustment may be necessary.111 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Use with caution; dosage adjustment may be necessary.111 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Fatigue, headache, bradycardia, arrhythmia, pruritus, dizziness, dyspnea, eye irritation.111

Interactions for Timolol Maleate

Appears to be metabolized partly by CYP2D6.540 b

Drugs Affecting Hepatic Microsomal Enzymes

CYP2D6 inhibitors: Potential pharmacodynamic (increased β-adrenergic blockade) and pharmacokinetic interaction (increased plasma timolol concentrations).540 b

Specific Drugs

Drug

Interaction

Comments

Calcium-channel blocking agents

Potential hypotension, AV conduction disturbances, and left ventricular failure111

Avoid concomitant use in patients with impaired cardiac function111

Clonidine

β-Adrenergic blockade may exacerbate rebound hypertension which may occur following clonidine discontinuance145 146

Discontinue β-blockers several days before gradual withdrawal of clonidine145 146

If clonidine therapy is to be replaced by a β-blocker, delay administration for several days after clonidine discontinuance145 146

Digoxin

Possible additive effect in prolonging AV conduction time when used concomitantly with diltiazem or verapamil111

Hypotensive agents (hydralazine, methyldopa)

Possible increased hypotensive effecta

Careful dosage adjustment is recommendeda

NSAIAs

Potential blunting of hypotensive effects111

Monitor patients carefully111

Quinidine

Possible potentiation of β-adrenergic blockade (e.g., decreased heart rate)111

Reserpine

Possible additive effects111

Observe closely for evidence of marked bradycardia or hypotension (may be manifested as vertigo, presyncope or syncope, or orthostatic changes in BP without compensatory tachycardia)111

Timolol Maleate Pharmacokinetics

Absorption

Bioavailability

Absorption from GI tract is rapid; approximately 90% absorbed following oral administration.111 Peak plasma concentration usually attained within 1–2 hours.111

Distribution

Extent

Distributed into milk.111

Plasma Protein Binding

10–60%, depending on assay method employed.111

Elimination

Metabolism

Approximately 80% metabolized in the liver to inactive metabolites.111 a

Elimination Route

Excreted in urine as unchanged drug and metabolites.111

Half-life

3–4 hours.111 a

Special Populations

Only small amounts removed by hemodialysis.111 a

Stability

Storage

Oral

Tablets

Tight containers at 15–30°C.111 Protect from light.111

Actions

  • Inhibits response to adrenergic stimuli by competitively blocking β-adrenergic receptors within the myocardium (β1-receptors) and bronchial and vascular smooth muscle (β2-receptors).111

  • Decreases resting and exercise-stimulated heart rate and reflex orthostatic tachycardia; slows conduction in the AV node; slightly reduces cardiac output, probably secondary to its effect on heart rate.111 a

  • No intrinsic sympathomimetic activity or membrane-stabilizing effect on the heart.111 a

  • Suppresses plasma renin activity and suppresses the renin-aldosterone-angiotensin system.111 a

  • Reduces BP by decreasing cardiac output, decreasing sympathetic outflow from the CNS, and/or suppressing renin release.111 a

  • Increases airway resistance.111 a

Advice to Patients

  • Importance of taking timolol exactly as prescribed.111

  • Importance of not interrupting or discontinuing therapy without consulting clinician;111 advise patients to temporarily limit physical activity when discontinuing therapy.111 a

  • Importance of immediately informing clinician at the first sign or symptom of impending heart failure (e.g., weight gain, increased shortness of breath) or if any difficulty in breathing occurs.111

  • In patients with heart failure, importance of informing clinician of signs or symptoms of exacerbation (e.g., weight gain, difficulty in breathing).111

  • Importance of patients informing anesthesiologist or dentist that they are receiving timolol therapy prior to undergoing major surgery.111

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.111

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.111

  • Importance of informing patients of other important precautionary information.111 (See Cautions.)

Preparations

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.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Timolol Maleate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

5 mg*

Timolol Maleate Tablets

10 mg*

Timolol Maleate Tablets

20 mg*

Timolol Maleate Tablets

AHFS DI Essentials™. © Copyright 2019, Selected Revisions February 25, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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