Timolol (Systemic) (Lexi-Drugs)

ALERT: US Boxed Warning
  Exacerbation of ischemic heart disease following abrupt withdrawal:
Drug Shortages

One or more forms of this drug may be in short supply or unavailable. Refer to the following for additional information:

FDA: https://www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredientDetails.cfm?AI=Timolol Maleate Tablets&st=c

Pronunciation

(TIM oh lol)

Brand Names: Canada

TEVA-Timolol [DSC]

Pharmacologic Category

AntihypertensiveBeta-Blocker, Nonselective

Dosing: Adult

Hypertension (alternative agent): Oral: Initial: 10 mg twice daily; adjust dose based on patient response at intervals of at least every 7 days; usual dosage: 20 to 40 mg/day in 2 divided doses; maximum: 60 mg/day.

Migraine prophylaxis: Oral: Initial: 10 mg twice daily, increase to maximum of 30 mg/day

Myocardial infarction (secondary prevention): Oral: Initial: 5 mg twice daily; may increase to a target dose of 10 mg twice daily (Fonarow 2006; Norwegian Multicenter Study Group 1981). In general, oral beta-blockers should be initiated within the first 24 hours following STEMI (in the absence of contraindications) and continued during and after hospitalization; however, the use of timolol is not routine (ACCF/AHA [O’Gara 2013]).

Atrial fibrillation (rate control) (off-label use): Initial: 10 mg twice daily; increase at weekly intervals as tolerated to 20 mg twice daily, then to a maximum of 30 mg twice daily; may use in combination with digoxin (Ribeiro 1986). Note: Timolol is not commonly used for rate control in atrial fibrillation (AHA/ACC/HRS [January 2014]).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment: Adult

There are no specific dosage adjustments provided in the manufacturer’s labeling. However, timolol is primarily eliminated renally; dosage reduction may be necessary. Significant hypotension has been seen in patients with severe impairment and undergoing dialysis. Use with caution.

Dosing: Hepatic Impairment: Adult

There are no specific dosage adjustments provided in the manufacturer’s labeling. However, timolol is partially metabolized by the liver; dosage reduction may be necessary.

Use: Labeled Indications

Hypertension: Management of hypertension. Note: Beta-blockers are not recommended as first-line therapy (ACC/AHA [Whelton 2017]).

Migraine prophylaxis: Prophylaxis of migraine

Myocardial infarction (secondary prevention): To reduce mortality following MI

Use: Off-Label: Adult

  Atrial fibrillation (rate-control)Level of Evidence [B, G]

Data from a randomized, placebo-controlled trial in patients with atrial fibrillation associated with a rapid ventricular response while receiving digoxin supports the use of oral timolol in patients with chronic atrial fibrillation Ref. Additional trials may be necessary to further define the role of timolol in the treatment of this condition.

Based on the 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation, oral timolol, although not a commonly used agent for this indication, given for rate control in patients with atrial fibrillation is an effective and recommended treatment option among other beta-blockers in patients with this condition.

Level of Evidence Definitions
  Level of Evidence Scale
Clinical Practice Guidelines

Atrial Fibrillation:

AHA/ACC/HRS, “2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation,” March 2014

Coronary Artery Bypass Graft Surgery:

AHA Scientific Statement, “Secondary Prevention After Coronary Artery Bypass Graft Surgery,” February 2015

Hypertension:

“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,” November 2017.

“ACCF/AHA Expert Consensus Document on Hypertension in the Elderly,” 2011

AHA/ACC/CDC, “AHA/ACC/CDC Science Advisory: An Effective Approach to High Blood Pressure Control” November 2013

Eighth Joint National Committee (JNC 8), “2014 Evidence-based Guideline for the Management of High Blood Pressure in Adults,” December 2013

Migraine Prophylaxis:

Neurology, “Evidence-Based Guideline Update: Pharmacologic Treatment for Episodic Migraine Prevention in Adults,” April 2012

Non-ST-Elevation Acute Coronary Syndromes:

“ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction,” August 2007

AHA/ACC, “2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes,” September 2014

Prevention:

“AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and Other Atherosclerotic Vascular Disease: 2011 Update,” November 2011

Valvular Heart Disease:

AHA/ACC, “2014 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease,” March 2014

Administration: Oral

Administer with food at the same time each day.

Dietary Considerations

Should be administered with food at the same time each day.

Storage/Stability

Store at 20°C to 25°C (68°F to 77°F). Protect from light.

Medication Patient Education with HCAHPS Considerations

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea or loss of strength and energy. Have patient report immediately to prescriber severe dizziness, passing out, shortness of breath, excessive weight gain, swelling of arms or legs, angina, bradycardia, abnormal heartbeat, muscle weakness, vision changes, or sensation of cold (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

Medication Safety Issues
  Sound-alike/look-alike issues:
Contraindications

Hypersensitivity to timolol or any component of the formulation; sinus bradycardia; heart block greater than first degree (except in patients with a functioning artificial pacemaker); cardiogenic shock; uncompensated cardiac failure; bronchospastic disease

Documentation of allergenic cross-reactivity for beta-blockers is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Canadian labeling: Additional contraindications (not in US labeling): Right ventricular failure secondary to pulmonary hypertension; significant cardiomegaly; allergic rhinitis; severe chronic obstructive pulmonary disease; anesthesia with agents that produce myocardial depression (eg, ether hypersensitivity to timolol maleate)

Warnings/Precautions

Concerns related to adverse events:

• Anaphylactic reactions: Use caution with history of severe anaphylaxis to allergens; patients taking beta-blockers may become more sensitive to repeated challenges. Treatment of anaphylaxis (eg, epinephrine) in patients taking beta-blockers may be ineffective or promote undesirable effects.

Disease-related concerns:

• Bronchospastic disease: In general, patients with bronchospastic disease should not receive beta-blockers; if used at all, should be used cautiously with close monitoring.

• Conduction abnormality: Consider preexisting conditions such as sick sinus syndrome before initiating.

• Diabetes: Use with caution in patients with diabetes mellitus; may potentiate hypoglycemia and/or mask signs and symptoms.

• Heart failure: Use with caution in patients with compensated heart failure and monitor for a worsening of the condition.

• Myasthenia gravis: Use with caution in patients with myasthenia gravis; can worsen.

• Peripheral vascular disease (PVD) and Raynaud disease: Can precipitate or aggravate symptoms of arterial insufficiency in patients with PVD and Raynaud disease. Use with caution and monitor for progression of arterial obstruction.

• Pheochromocytoma (untreated): Adequate alpha-blockade is required prior to use of any beta-blocker.

• Prinzmetal variant angina: Beta-blockers without alpha1-adrenergic receptor blocking activity should be avoided in patients with Prinzmetal variant angina since unopposed alpha1-adrenergic receptors mediate coronary vasoconstriction and can worsen anginal symptoms (Mayer 1998).

• Psoriasis: Beta-blocker use has been associated with induction or exacerbation of psoriasis, but cause and effect have not been firmly established.

• Renal impairment: Use with caution in patients with severe renal impairment; marked hypotension can occur in patients maintained on hemodialysis.

• Thyroid disease: May mask signs of hyperthyroidism (eg, tachycardia). If thyrotoxicosis is suspected, carefully manage and monitor; abrupt withdrawal may exacerbate symptoms of hyperthyroidism or precipitate thyroid storm.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Bradycardia may be observed more frequently in elderly patients (>65 years of age); dosage reductions may be necessary.

Other warnings/precautions:

• Abrupt withdrawal: [US Boxed Warning]: Beta-blocker therapy should not be withdrawn abruptly (particularly in patients with CAD), but gradually tapered to avoid acute tachycardia, hypertension, and/or ischemia. Severe exacerbation of angina, ventricular arrhythmias, and myocardial infarction (MI) have been reported following abrupt withdrawal of beta-blocker therapy. Temporary but prompt resumption of beta-blocker therapy may be indicated with worsening of angina or acute coronary insufficiency.

• Major surgery: Chronic beta-blocker therapy should not be routinely withdrawn prior to major surgery.

Geriatric Considerations

Since bioavailability increased about twofold in elderly patients, geriatrics may require lower maintenance doses. Also, as serum and tissue concentrations increase beta1 selectivity diminishes. Beta-adrenergic blockade may result in less hemodynamic response than seen in younger adults due to alterations in the beta-adrenergic autonomic system. Studies indicate that despite decreased sensitivity to the chronotropic effects of beta-blockade with age, there appears to be an increased myocardial sensitivity to the negative inotropic effect during stress (ie, exercise). Controlled trials have shown the overall response rate for propranolol to be only 20% to 50% in elderly populations. Therefore, all beta-adrenergic blocking drugs may result in a decreased response as compared to younger adults.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were not observed in the initial animal reproduction studies. Timolol crosses the placenta (Schneider 1988) and decreased fetal heart rate has been observed following maternal use of timolol during pregnancy (Devoe 1986). Adverse events, such as fetal/neonatal hypoglycemia and reduced birth weight, have been observed following in utero exposure to beta-blockers as a class. Adequate facilities for monitoring infants at birth is generally recommended.

Untreated chronic maternal hypertension and preeclampsia are also associated with adverse events in the fetus, infant, and mother (ACOG 2015; Magee 2014). Although beta-blockers may be used when treatment of hypertension in pregnancy is indicated, agents other than timolol are preferred (ACOG 2013; Magee 2014). In addition, other agents are preferred when migraine prophylaxis is needed in pregnant women (Pringsheim 2012).

Breast-Feeding Considerations

Timolol is present in breast milk. Based on data obtained following maternal use of ophthalmic timolol, it is recommended that breastfeeding infants (especially those with cardiorespiratory problems) be monitored for adverse events (Madadi 2008). Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends a decision be made whether to discontinue breastfeeding or the drug, taking into account the importance of treatment to the mother.

Lexicomp Pregnancy & Lactation, In-Depth
Briggs’ Drugs in Pregnancy & Lactation
Adverse Reactions

1% to 10%:

Cardiovascular: Bradycardia

Central nervous system: Dizziness, fatigue

Respiratory: Dyspnea

Frequency not defined:

Cardiovascular: Angina pectoris, cardiac arrhythmia, cardiac failure, cerebral ischemia, cerebrovascular accident, claudication, cold extremities, edema, heart block, hypotension, palpitations, Raynaud’s phenomenon

Central nervous system: Amnesia, anxiety, confusion, depression, disorientation, drowsiness, exacerbation of myasthenia gravis, hallucination, insomnia, nervousness, nightmares, paresthesia

Dermatologic: Alopecia, exacerbation of psoriasis, pemphigoid-like lesion, psoriasiform eruption, skin rash, urticaria

Endocrine & metabolic: Decreased libido, hypoglycemia (masked)

Gastrointestinal: Anorexia, diarrhea, dyspepsia, nausea, xerostomia

Genitourinary: Impotence, Peyronie’s disease, retroperitoneal fibrosis

Hypersensitivity: Angioedema, hypersensitivity reaction

Neuromuscular & skeletal: Systemic lupus erythematosus

Ophthalmic: Blepharoptosis, cystoid macular edema, decreased corneal sensitivity, diplopia, eye discharge, eye pain, keratitis, visual disturbance (including refractive changes), xerophthalmia

Otic: Tinnitus

Respiratory: Bronchospasm, cough, nasal congestion, pulmonary edema, respiratory failure

Toxicology
Metabolism/Transport Effects

Substrate of CYP2D6 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions 

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Risk D: Consider therapy modification

Acetylcholinesterase Inhibitors: May enhance the bradycardic effect of Beta-Blockers. Risk C: Monitor therapy

Ajmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Alpha1-Blockers: Beta-Blockers may enhance the orthostatic hypotensive effect of Alpha1-Blockers. The risk associated with ophthalmic products is probably less than systemic products. Risk C: Monitor therapy

Alpha2-Agonists: May enhance the AV-blocking effect of Beta-Blockers. Sinus node dysfunction may also be enhanced. Beta-Blockers may enhance the rebound hypertensive effect of Alpha2-Agonists. This effect can occur when the Alpha2-Agonist is abruptly withdrawn. Management: Closely monitor heart rate during treatment with a beta blocker and clonidine. Withdraw beta blockers several days before clonidine withdrawal when possible, and monitor blood pressure closely. Recommendations for other alpha2-agonists are unavailable.Exceptions: Apraclonidine. Risk D: Consider therapy modification

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Risk D: Consider therapy modification

Aminoquinolines (Antimalarial): May decrease the metabolism of Beta-Blockers. Risk C: Monitor therapy

Amiodarone: May enhance the bradycardic effect of Beta-Blockers. Possibly to the point of cardiac arrest. Amiodarone may increase the serum concentration of Beta-Blockers. Risk C: Monitor therapy

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy

Antipsychotic Agents (Phenothiazines): May enhance the hypotensive effect of Beta-Blockers. Beta-Blockers may decrease the metabolism of Antipsychotic Agents (Phenothiazines). Antipsychotic Agents (Phenothiazines) may decrease the metabolism of Beta-Blockers. Risk C: Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]).Risk C: Monitor therapy

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk D: Consider therapy modification

Barbiturates: May decrease the serum concentration of Beta-Blockers. Risk C: Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Beta2-Agonists: Beta-Blockers (Nonselective) may diminish the bronchodilatory effect of Beta2-Agonists. Risk X: Avoid combination

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Risk C: Monitor therapy

Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Risk C: Monitor therapy

Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Bromperidol: Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents. Risk X: Avoid combination

Bupivacaine: Beta-Blockers may increase the serum concentration of Bupivacaine. Risk C: Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May enhance the hypotensive effect of Beta-Blockers. Bradycardia and signs of heart failure have also been reported. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Beta-Blockers. Exceptions: Bepridil. Risk C: Monitor therapy

Cardiac Glycosides: Beta-Blockers may enhance the bradycardic effect of Cardiac Glycosides. Risk C: Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Exceptions are discussed in separate monographs. Risk D: Consider therapy modification

Cholinergic Agonists: Beta-Blockers may enhance the adverse/toxic effect of Cholinergic Agonists. Of particular concern are the potential for cardiac conduction abnormalities and bronchoconstriction. Management: Administer these agents in combination with caution, and monitor for conduction disturbances. Avoid methacholine with any beta blocker due to the potential for additive bronchoconstriction. Risk C: Monitor therapy

CloBAZam: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Cobicistat: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates (High risk with Inhibitors). Risk D: Consider therapy modification

Dacomitinib: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Management: Avoid concurrent use of dacomitinib with CYP2D6 subtrates that have a narrow therapeutic index. Risk D: Consider therapy modification

Darunavir: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Dexmethylphenidate: May diminish the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Dipyridamole: May enhance the bradycardic effect of Beta-Blockers. Risk C: Monitor therapy

Disopyramide: May enhance the bradycardic effect of Beta-Blockers. Beta-Blockers may enhance the negative inotropic effect of Disopyramide. Risk C: Monitor therapy

Dronedarone: May enhance the bradycardic effect of Beta-Blockers. Dronedarone may increase the serum concentration of Beta-Blockers. This likely applies only to those agents that are metabolized by CYP2D6. Management: Use lower initial beta-blocker doses; adequate tolerance of the combination, based on ECG findings, should be confirmed prior to any increase in beta-blocker dose. Risk D: Consider therapy modification

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy

EPINEPHrine (Nasal): Beta-Blockers (Nonselective) may enhance the hypertensive effect of EPINEPHrine (Nasal). Risk C: Monitor therapy

EPINEPHrine (Oral Inhalation): Beta-Blockers (Nonselective) may enhance the hypertensive effect of EPINEPHrine (Oral Inhalation). Risk C: Monitor therapy

Epinephrine (Racemic): Beta-Blockers (Nonselective) may enhance the hypertensive effect of Epinephrine (Racemic). Risk C: Monitor therapy

EPINEPHrine (Systemic): Beta-Blockers (Nonselective) may enhance the hypertensive effect of EPINEPHrine (Systemic). Risk C: Monitor therapy

Ergot Derivatives: Beta-Blockers may enhance the vasoconstricting effect of Ergot Derivatives. Exceptions: Nicergoline. Risk D: Consider therapy modification

Fingolimod: Beta-Blockers may enhance the bradycardic effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and beta-blockers if possible. If coadministration is necessary, patients should have overnight continuous ECG monitoring conducted after the first dose of fingolimod. Monitor patients for bradycardia. Risk D: Consider therapy modification

Floctafenine: May enhance the adverse/toxic effect of Beta-Blockers. Risk X: Avoid combination

Grass Pollen Allergen Extract (5 Grass Extract): Beta-Blockers may enhance the adverse/toxic effect of Grass Pollen Allergen Extract (5 Grass Extract). More specifically, Beta-Blockers may inhibit the ability to effectively treat severe allergic reactions to Grass Pollen Allergen Extract (5 Grass Extract) with epinephrine. Some other effects of epinephrine may be unaffected or even enhanced (e.g., vasoconstriction) during treatment with Beta-Blockers. Risk D: Consider therapy modification

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy

Imatinib: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Insulins: Beta-Blockers may enhance the hypoglycemic effect of Insulins. Risk C: Monitor therapy

Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Risk C: Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Risk C: Monitor therapy

Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Risk C: Monitor therapy

Lidocaine (Systemic): Beta-Blockers may increase the serum concentration of Lidocaine (Systemic). Risk C: Monitor therapy

Lidocaine (Topical): Beta-Blockers may increase the serum concentration of Lidocaine (Topical). Risk C: Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Mepivacaine: Beta-Blockers may increase the serum concentration of Mepivacaine. Risk C: Monitor therapy

Methacholine: Beta-Blockers may enhance the adverse/toxic effect of Methacholine. Risk X: Avoid combination

Methoxyflurane: May enhance the hypotensive effect of Beta-Blockers. Risk C: Monitor therapy

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy

Midodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

NIFEdipine: May enhance the hypotensive effect of Beta-Blockers. NIFEdipine may enhance the negative inotropic effect of Beta-Blockers. Risk C: Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May diminish the antihypertensive effect of Beta-Blockers. Risk C: Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Risk D: Consider therapy modification

Opioids (Anilidopiperidine): May enhance the bradycardic effect of Beta-Blockers. Opioids (Anilidopiperidine) may enhance the hypotensive effect of Beta-Blockers. Risk C: Monitor therapy

Panobinostat: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Perhexiline: CYP2D6 Substrates (High risk with Inhibitors) may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Propafenone: May increase the serum concentration of Beta-Blockers. Propafenone possesses some independent beta blocking activity. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

QuiNINE: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Regorafenib: May enhance the bradycardic effect of Beta-Blockers. Risk C: Monitor therapy

Reserpine: May enhance the hypotensive effect of Beta-Blockers. Risk C: Monitor therapy

Rifamycin Derivatives: May decrease the serum concentration of Beta-Blockers. Exceptions: Rifabutin. Risk C: Monitor therapy

Rivastigmine: May enhance the bradycardic effect of Beta-Blockers. Risk X: Avoid combination

Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: May increase the serum concentration of Beta-Blockers. Exceptions: Citalopram; Escitalopram; FluvoxaMINE. Risk C: Monitor therapy

Siponimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia.Risk D: Consider therapy modification

Sulfonylureas: Beta-Blockers may enhance the hypoglycemic effect of Sulfonylureas. Cardioselective beta-blockers (eg, acebutolol, atenolol, metoprolol, and penbutolol) may be safer than nonselective beta-blockers. All beta-blockers appear to mask tachycardia as an initial symptom of hypoglycemia. Ophthalmic beta-blockers are probably associated with lower risk than systemic agents. Risk C: Monitor therapy

Terlipressin: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

Theophylline Derivatives: Beta-Blockers (Nonselective) may diminish the bronchodilatory effect of Theophylline Derivatives. Risk D: Consider therapy modification

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy

Test Interactions

May lead to false-positive aldosterone/renin ratio (ARR) (Funder 2016)

Monitoring Parameters

Blood pressure, heart rate, apical and radial pulses

Hypertension: The 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults (ACC/AHA [Whelton 2017]):

Confirmed hypertension and known CVD or 10-year ASCVD risk ≥10%: Target blood pressure <130/80 mm Hg is recommended.

Confirmed hypertension without markers of increased ASCVD risk: Target blood pressure <130/80 mm Hg may be reasonable.

Advanced Practitioners Physical Assessment/Monitoring

Assess blood pressure and pulse periodically. Dose reduction may be necessary in hepatic and/or renal insufficiency. Obtain serum glucose levels of patients with diabetes since beta-blockers may alter glucose tolerance.

Nursing Physical Assessment/Monitoring

Monitor blood pressure and pulse periodically. Monitor for blunting of signs and symptoms of hypoglycemia in diabetic patients.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral, as maleate:

Generic: 5 mg, 10 mg, 20 mg

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral, as maleate:

Generic: 5 mg, 10 mg, 20 mg

Anatomic Therapeutic Chemical (ATC) Classification
  • C07AA06
Generic Available (US)

Yes

Pricing: US

Tablets (Timolol Maleate Oral)

5 mg (per each): $1.38

10 mg (per each): $1.70

20 mg (per each): $3.14

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer’s AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

Blocks both beta1– and beta2-adrenergic receptors; reduces blood pressure by blocking adrenergic receptors and decreasing sympathetic outflow, produces a negative chronotropic and inotropic activity through an unknown mechanism

Pharmacodynamics/Kinetics

Onset of action: Hypotensive: 15 to 45 minutes

Peak effect: 0.5 to 2.5 hours

Duration: ~4 hours

Absorption: Rapid and complete (~90%)

Distribution: Vd: 1.7 L/kg

Protein binding: 60%

Metabolism: Extensively hepatic via CYP2D6; extensive first-pass effect

Bioavailability: 50%

Half-life elimination: 2 to 2.7 hours; prolonged with renal impairment

Time to peak, plasma: 1 to 2 hours

Excretion: Urine (15% to 20% as unchanged drug)

Local Anesthetic/Vasoconstrictor Precautions

Epinephrine has interacted with nonselective beta-blockers, such as propranolol, to result in initial hypertensive episode followed by bradycardia. Timolol is also a nonselective beta-blocker. The significance of a potential systemic interaction is well known and cautionary use of epinephrine is advised.

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation).

Timolol is a nonselective beta-blocker and may enhance the pressor response to epinephrine, resulting in hypertension and bradycardia. Many nonsteroidal anti-inflammatory drugs, such as ibuprofen and indomethacin, can reduce the hypotensive effect of beta-blockers after 3 or more weeks of therapy with the NSAID. Short-term NSAID use (ie, 3 days) requires no special precautions in patients taking beta-blockers.

Effects on Bleeding

No information available to require special precautions

Index Terms

Timolol Maleate

References

American College of Obstetricians and Gynecologists (ACOG), Committee on Obstetric Practice. Committee Opinion No. 623: emergent therapy for acute-onset, severe hypertension during pregnancy and the postpartum period. Obstet Gynecol. 2015;125(2):521-525.[PubMed 25611642]

American College of Obstetricians and Gynecologists (ACOG), Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013;122(5):1122-1131.[PubMed 24150027]

Brauchli YB, Jick SS, Curtin F, et al, “Association Between Beta-Blockers, Other Antihypertensive Drugs and Psoriasis: Population-Based Case-Control Study,” Br J Dermatol, 2008, 158(6):1299-307.[PubMed 18410416]

Devoe LD, O’Dell BE, Castillo RA, et al, “Metastatic Pheochromocytoma in Pregnancy and Fetal Biophysical Assessment After Maternal Administration of Alpha-Adrenergic, Beta-Adrenergic, and Dopamine Antagonists,” Obstet Gynecol, 1986, 68(3 Suppl):15S-18S.[PubMed 2874538]

Fonarow GC. Beta-blockers for the post-myocardial infarction patient: current clinical evidence and practical considerations. Rev Cardiovasc Med. 2006;7(1):1-9.[PubMed 16534490]

Funder JW, Carey RM, Mantero F, et al. The management of primary aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(5):1889-1916. doi: 10.1210/jc.2015-4061.[PubMed 26934393]

Go AS, Bauman M, King SM, et al. An effective approach to high blood pressure control: a science advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention [published online November 15, 2013]. Hypertension.[PubMed 24243703]

James PA, Oparil S, Carter BL, et al. 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults: Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-520.[PubMed 24352797]

January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation. 2014;130:e199-267. doi: 10.1161/CIR.0000000000000041.[PubMed 24682347]

Lang DM, “Anaphylactoid and Anaphylactic Reactions. Hazards of Beta-Blockers,” Drug Saf, 1995, 12(5):299-304.[PubMed 7669259]

Madadi P, Koren G, Freeman DJ, et al, “Timolol Concentrations in Breast Milk of a Woman Treated for Glaucoma: Calculation of Neonatal Exposure,” J Glaucoma, 2008, 17(4):329-31.[PubMed 18552619]

Magee LA, Pels A, Helewa M, Rey E, von Dadelszen P, Canadian Hypertensive Disorders of Pregnancy Working Group. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy: executive summary. J Obstet Gynaecol Can. 2014;36(5):416-441.[PubMed 24927294]

Mayer S, Hillis LD. Prinzmetal’s variant angina. Clin Cardiol. 1998;21(4):243-246.[PubMed 9562933]

Mundorf TK, Ogawa T, Naka H, et al, “A 12-Month, Multicenter, Randomized, Double-Masked, Parallel-Group Comparison of Timolol-LA Once Daily and Timolol Maleate Ophthalmic Solution Twice Daily in the Treatment of Adults With Glaucoma or Ocular Hypertension,” Clin Ther, 2004, 26(4):541-51.[PubMed 15189751]

Nishimura RA, Otto CM, Bonow RO, et al, 2014 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(23):2440-92. doi: 10.1161/CIR.0000000000000029.[PubMed 24589852]

Norwegian Multicenter Study Group. Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med. 1981;304(14):801-807.[PubMed 7010157]

O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(4):e362-e425.[PubMed 23247304]

Pringsheim T, Davenport W, Mackie G, et al. Canadian Headache Society guideline for migraine prophylaxis. Can J Neurol Sci. 2012;39(2 Suppl 2):S1-59.[PubMed 22683887]

Ribeiro LG, Kasdin SL, Snyder DL, Fisher MB, Irvin JD.l. Beneficial effects of timolol in digitalized patients with atrial fibrillation and a rapid ventricular response. Arq Bras Cardiol. 1986;46(3):211-215.[PubMed 3548664]

Schneider H and Proegler M, “Placental Transfer of Beta-Adrenergic Antagonists Studied in an in vitro Perfusion System of Human Placental Tissue,” Am J Obstet Gynecol, 1988, 159(1):42-7.[PubMed 2899395]

Schön MP and Boehncke WH, “Psoriasis,” N Eng J Med, 2005, 352(18):1899-1912.[PubMed 15872205]

Smith SC Jr, Benjamin EJ, Bonow RO, et al, “AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients With Coronary and Other Atherosclerotic Vascular Disease: 2011 Update: A Guideline From the American Heart Association and American College of Cardiology Foundation,” Circulation, 2011, 124(22):2458-73.[PubMed 22052934]

Timolol (prescribing information). Mylan Pharmaceuticals, Inc: Morgantown, WV; August 2006.

Timolol [product monograph]. Vaughan, Ontario, Canada: AA Pharma Inc; February 2018.

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Brand Names: International

Arutimol (UA); Blocadren (AT, IT, LB, QA); Blocadren Depot (NO); Normatin (UA)

Timolol (Systemic) (Patient Education – Adult Medication)
You must carefully read the “Consumer Information Use and Disclaimer” below in order to understand and correctly use this information
Pronunciation

(TIM oh lol)

Warning
  • Do not stop taking this drug all of a sudden. If you do, chest pain that is worse and in some cases heart attack may occur. The risk may be greater if you have certain types of heart disease. To avoid side effects, you will want to slowly stop this drug as ordered by your doctor. Call your doctor right away if you have new or worse chest pain or if other heart problems occur.
What is this drug used for?
  • It is used to treat high blood pressure.
  • It is used after a heart attack to help prevent future heart attacks and lengthen life.
  • It is used to prevent migraine headaches.
  • It may be given to you for other reasons. Talk with the doctor.
What do I need to tell my doctor BEFORE I take this drug?
  • If you have an allergy to timolol or any other part of this drug.
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If you have any of these health problems: Asthma or other breathing problems like COPD (chronic obstructive pulmonary disease).
  • If you have any of these health problems: Heart block, shock caused by heart problems, or slow heartbeat.
  • If you have heart failure (weak heart).
  • If you are breast-feeding or plan to breast-feed.
  • This is not a list of all drugs or health problems that interact with this drug.
  • Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this drug with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.
What are some things I need to know or do while I take this drug?
  • Tell all of your health care providers that you take this drug. This includes your doctors, nurses, pharmacists, and dentists.
  • Avoid driving and doing other tasks or actions that call for you to be alert until you see how this drug affects you.
  • To lower the chance of feeling dizzy or passing out, rise slowly if you have been sitting or lying down. Be careful going up and down stairs.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • Check blood pressure and heart rate as the doctor has told you. Talk with the doctor.
  • Talk with your doctor before you drink alcohol.
  • This drug may hide the signs of low blood sugar. Talk with the doctor.
  • If you have high blood sugar (diabetes), you will need to watch your blood sugar closely.
  • If you are taking this drug and have high blood pressure, talk with your doctor before using OTC products that may raise blood pressure. These include cough or cold drugs, diet pills, stimulants, ibuprofen or like products, and some natural products or aids.
  • This drug may make it harder to tell if you have signs of an overactive thyroid like fast heartbeat. If you have an overactive thyroid and stop taking this drug all of a sudden, it may get worse and could be life-threatening. Talk with your doctor.
  • Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this drug while you are pregnant.
What are some side effects that I need to call my doctor about right away?
  • WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:
  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Very bad dizziness or passing out.
  • Shortness of breath, a big weight gain, or swelling in the arms or legs.
  • Chest pain or pressure.
  • Slow heartbeat.
  • A heartbeat that does not feel normal.
  • Muscle weakness.
  • Change in eyesight.
  • Feeling cold.
What are some other side effects of this drug?
  • All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:
  • Dizziness.
  • Feeling tired or weak.
  • Upset stomach.
  • These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.
  • You may report side effects to your national health agency.
How is this drug best taken?
  • Use this drug as ordered by your doctor. Read all information given to you. Follow all instructions closely.
  • To gain the most benefit, do not miss doses.
  • Keep taking this drug as you have been told by your doctor or other health care provider, even if you feel well.
What do I do if I miss a dose?
  • Take a missed dose as soon as you think about it.
  • If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
  • Do not take 2 doses at the same time or extra doses.
How do I store and/or throw out this drug?
  • Store at room temperature.
  • Protect from light.
  • Store in a dry place. Do not store in a bathroom.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.
General drug facts
  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else’s drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. If you have any questions about this drug, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.