Timolol (tablet)

Timolol (tablet)
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, M.D. [2]

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Black Box Warning

WARNING See full prescribing information for complete Boxed Warning. Exacerbation of Ischemic Heart Disease Following Abrupt Withdrawal: Hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy; exacerbation of angina and, in some cases, myocardial infarction have occurred after abrupt discontinuation of such therapy. When discontinuing chronically administered timolol maleate, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of one to two weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, timolol maleate administration should be reinstituted promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Patients should be warned against interruption or discontinuation of therapy without the physician's advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue timolol maleate therapy abruptly even in patients treated only for hypertension.

Overview

Timolol (tablet) is a beta-adrenergic blocker that is FDA approved for the treatment of hypertension, myocardial infarction, migraine. There is a Black Box Warning for this drug as shown here. Common adverse reactions include angina, bradyarrhythmia, heart failure, hypotension, pruritus, rash, urticaria, abdominal pain, diarrhea, indigestion, nausea, vomiting, muscle cramps, confusion, dizziness, headache, dry eyes, hallucinations, psychotic disorder, cough, dyspnea, fatigue.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Hypertension

• Dosing Information

• 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 to 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 7 days between increases in dosages.

Timolol maleate tablets 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

• Dosing Information

• 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.

Migraine

• Dosing information

• 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 to 8 weeks use of the maximum daily dosage, therapy with timolol should be discontinued.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Timolol in adult patients.

Non–Guideline-Supported Use

Angina

• Dosing Information

• 10 to 60 mg/day PO q12-24h.

Anxiety

• Dosing Information

• Outatient surgery: 10 mg (single dose).
• Aerophobia: 20 mg/day.

Essential Tremor

• Dosing Information

• 5 mg PO q12h.

Hyperthyroidism

• Dosing Information

• 10 mg PO q12h.

Supraventricular Arrhythmia

• Dosing Information

• 1 mg IV bolus every 20 minutes up to a total of 3 mg, then 20 mg/day PO.
• Atrial fibrillation: Timolol 20 to 30 mg/day PO + digoxin 0.25 to 0.5 mg/day.
• Premature ventricular beats: 5 to 15 mg PO q12h.
• SVT after coronary artery bypass surgery: 0.5 mg IV 112h, then 10 mg PO q12h.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Timolol (tablet) FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Timolol in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Timolol in pediatric patients.

Contraindications

• Bronchial asthma or with a history of bronchial asthma
• Severe chronic obstructive pulmonary disease
• Sinus bradycardia
• Second-degree atrioventricular block and third-degree atrioventricular block
• Overt cardiac failure
• Cardiogenic shock
• Hypersensitivity to this product.

Warnings

WARNING See full prescribing information for complete Boxed Warning. Exacerbation of Ischemic Heart Disease Following Abrupt Withdrawal: Hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy; exacerbation of angina and, in some cases, myocardial infarction have occurred after abrupt discontinuation of such therapy. When discontinuing chronically administered timolol maleate, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of one to two weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, timolol maleate administration should be reinstituted promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Patients should be warned against interruption or discontinuation of therapy without the physician's advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue timolol maleate therapy abruptly even in patients treated only for hypertension.

Conidition 1

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. 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, patients receiving timolol 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 should be withdrawn.

Obstructive Pulmonary Disease

PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (e.g., CHRONIC BRONCHITIS, EMPHYSEMA) OF MILD OR MODERATE SEVERITY, BRONCHOSPASTIC DISEASE OR A HISTORY OF BRONCHOSPASTIC DISEASE, SHOULD IN GENERAL NOT RECEIVE BETA-BLOCKERS, INCLUDING ‘TIMOLOL’. However, if timolol 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-blocking therapy 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 been subject to 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 such agonists as isoproterenol, dopamine, dobutamine or norepinephrine.

Diabetes Mellitus

Timolol should be administered with caution in patients subject to spontaneous hypoglycemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic receptor blocking agents may mask the signs and symptoms of acute hypoglycemia.

Thyrotoxicosis

Beta-adrenergic blockade 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-blockade which might precipitate a thyroid storm.

Precautions

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.

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.

Risk of 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 anaphylactic reactions.

Adverse Reactions

Clinical Trials Experience

Timolol maleate tablets are usually well tolerated in properly selected patients. Most adverse effects have been mild and transient.

In a multi-center (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:

This image is provided by the National Library of Medicine.

These data are representative of the incidence of adverse effects that may be observed in properly selected patients treated with timolol maleate, i.e., excluding patients with bronchospastic disease, congestive heart failure or other contraindications to beta-blocker therapy.

In patients with migraine the incidence of bradycardia was 5 percent.

In a coronary artery disease population studied in the Norwegian multi-center trial, 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:

This image is provided by the National Library of Medicine.

The following additional adverse effects have been reported in clinical experience with the drug:

• Body as a Whole: Anaphylaxis, 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: Nonthrombocytopenic 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.

• 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.
• 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.

Clinical Laboratory Test Findings

Clinically important changes in standard laboratory parameters were rarely associated with the administration of timolol. 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.

Postmarketing Experience

There is limited information regarding Timolol (tablet) Postmarketing Experience in the drug label.

Drug Interactions

Catecholamine-Depleting Drugs

Close observation of the patient is recommended when timolol 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 orthostatic hypotension.

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.

Calcium Antagonists

Literature reports suggest that oral calcium channel blockers 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 channel blockers was added to the treatment regimen. Hypotension was more likely to occur if the calcium channel blockers 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 channel blockers 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.

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.

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.

Use in Specific Populations

Pregnancy

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Labor and Delivery

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Nursing Mothers

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Geriatic Use

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Race

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Renal Impairment

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Hepatic Impairment

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Females of Reproductive Potential and Males

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Immunocompromised Patients

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Others

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Administration and Monitoring

Administration

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Monitoring

Condition 1

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Condition 2

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Condition 3

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IV Compatibility

Solution

Compatible

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Not Tested

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Variable

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Y-Site

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Variable

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Incompatible

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Admixture

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Variable

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Syringe

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TPN/TNA

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Overdosage

Acute Overdose

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Chronic Overdose

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Pharmacology

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Structure

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Pharmacodynamics

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Pharmacokinetics

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Nonclinical Toxicology

In a 2 year study of timolol maleate in rats, there was a statistically significant increase in the incidence of adrenal pheochromocytomas in male rats administered 300 mg/kg/day (250 times1 the maximum recommended human dose). Similar differences were not observed in rats administered doses equivalent to approximately 20 or 80 times1 the maximum recommended human dose.

In a lifetime 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 times1 the maximum recommended human dose), but not at a 5 or 50 mg/kg/day. In a subsequent study in female mice, in which postmortem examinations were limited to uterus and lungs, a statistically significant increase in the incidence of pulmonary tumors was again observed at 500 mg/kg/day.

The increased occurrence of mammary adenocarcinoma was associated with elevations in serum prolactin that occurred in female mice administered timolol maleate at 500 mg/kg/day, but not at doses of 5 or 50 mg/kg/day. An increased incidence of mammary adenocarcinomas in rodents has been associated with administration of several other therapeutic agents which 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 daily human oral dosage, there were no clinically meaningful changes in serum prolactin.

Timolol maleate was devoid of mutagenic potential when elevated in vivo (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg/kg) and in vitro in a neoplastic cell transformation assay (up to 100 mcg/mL). In Ames tests the highest concentrations of timolol employed, 5,000 or 10,000 mcg/plate, were associated with statistically significant elevations of revertants observed with tester strain TA100 (in seven replicate assays), but not in three additional strains. In the assays with tester strain TA100, 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 times1 the maximum recommended human dose.

Clinical Studies

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How Supplied

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Storage

There is limited information regarding Timolol (tablet) Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

(Patient Counseling Information)

Precautions with Alcohol

Alcohol-Timolol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Timolol (tablet) Brand Names in the drug label.

Look-Alike Drug Names

• (Paired Confused Name 1a) — (Paired Confused Name 1b)
• (Paired Confused Name 2a) — (Paired Confused Name 2b)
• (Paired Confused Name 3a) — (Paired Confused Name 3b)

Drug Shortage Status

Drug Shortage

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References

The contents of this FDA label are provided by the National Library of Medicine.