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Timolol Maleate

Pronunciation

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

Introduction

Nonselective β-adrenergic blocking agent.111

Uses for Timolol Maleate

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).111 500

β-Blockers generally not preferred for initial management of hypertension, 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

Slideshow: Living with Your Migraines: Tips for Treatment and Prevention

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

Acute MI

Secondary prevention following acute MI to reduce the risk of reinfarction and mortality.111

Angina

Management of chronic stable angina pectoris.a

A component of the standard therapeutic measures in the management of unstable angina or non-ST-segment elevation/non-Q-wave MI.143 169 172

Vascular Headache

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

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

  • Carefully monitor BP during initial titration or subsequent upward adjustment in dosage.500 501

  • When available, use evidence-based dosing information (i.e., dosages shown in randomized controlled trials to reduce complications of hypertension) to determine target dosages; target dosages usually can be achieved within 2–4 weeks but may take up to several months.501

  • Goal is to achieve and maintain optimal control of BP; individualize specific target BP based on consideration of multiple factors, including patient age and comorbidities, and currently available evidence from clinical studies.500 501

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

If intolerable adverse effects occur, consider dosage reduction; if adverse effects worsen or fail to resolve, may need to discontinue and switch to another antihypertensive drug class.501

Acute MI
Oral

Usual dosage is 10 mg twice daily.111

Initiation within 7–28 days following MI reduces cardiovascular mortality and nonfatal reinfarction.111 a Some experts recommend initiation within a few days after MI (if not already initiated acutely).112 113 114 116 118 119 120 121 129 143

Optimum benefit may be achieved when oral β-adrenergic blocking agent is continued for at least 1–3 years after infarction (if not contraindicated).112 114 126 Some experts recommend continuing indefinitely unless contraindicated.143

Angina
Chronic Stable Angina Pectoris
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 169

Unstable Angina or Non-ST-segment Elevation MI

In patients at high risk for ischemic events, ACC and AHA suggest initiation with IV loading dose of a β-blocker (in patients who tolerate IV therapy) followed by oral therapy; oral therapy is recommended for lower risk patients.169

Oral

10 mg twice daily.169

The target resting heart rate is 50–60 bpm in the absence of dose-limiting adverse effects.169

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 the timolol or any ingredient in the formulation.111

    Bronchial asthma (or a history of bronchial asthma), allergic bronchospasm, or severe COPD; severe bradycardia, heart block greater than first degree, overt cardiac failure, or cardiogenic shock.111

Warnings/Precautions

Warnings

Cardiac 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 cardiac failure occur; if cardiac 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 Use with caution in patients undergoing major surgery involving general anesthesia.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-adrenergic blocking agents; 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.b d

Drugs Affecting Hepatic Microsomal Enzymes

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

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-adrenergic blocking agents several days before gradual withdrawal of clonidine145 146

If clonidine therapy is to be replaced by a β-adrenergic blocking agent, 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 are 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 of drug are 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 cardiac 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.

* 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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2015. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Timolol Maleate 10MG Tablets (MYLAN): 60/$39.99 or 120/$69.98

Timolol Maleate 20MG Tablets (MYLAN): 60/$65.99 or 180/$169.97

Timolol Maleate 5MG Tablets (MYLAN): 60/$34.99 or 180/$79.97

AHFS DI Essentials. © Copyright, 2004-2015, Selected Revisions February 12, 2015. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

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