Timolol eent

Pronunciation

Class: beta-Adrenergic Blocking Agents
VA Class: OP101
CAS Number: 91524-16-2
Brands: Betimol, Cosopt Ocumeter Plus, Timoptic Ocudose, Timoptic Ocumeter Plus, Timoptic-XE Ocumeter

Introduction

Nonselective β-adrenergic blocking agent.104 105 106 107

Uses for Timolol

Ocular Hypertension and Glaucoma

Reduction of elevated IOP in patients with open-angle glaucoma or ocular hypertension.104 105 106 107 Used alone or in conjunction with another IOP-lowering drug (e.g., latanoprost, a carbonic anhydrase inhibitor).104 105 106 107 108

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Fixed-combination preparation containing timolol maleate and dorzolamide hydrochloride used to reduce elevated IOP in patients with open-angle glaucoma or ocular hypertension who have not responded adequately (i.e., failed to achieve target IOP as determined after multiple measurements over time) to a topical β-adrenergic blocking agent.108

Fixed-combination preparation associated with slightly smaller decrease in IOP than combination therapy with timolol (administered twice daily) and dorzolamide (administered 3 times daily).108

Timolol Dosage and Administration

Administration

Ocular Administration

Applied topically to the eye as an ophthalmic solution.104 105 106 107 108

Avoid contamination of the solution container.a

If more than one ophthalmic drug is used, administer the drugs at least 10 minutes apart.104 106

Invert and shake containers of timolol ophthalmic gel-forming solution once just prior to administration of each dose.106

Dosage

Available as timolol maleate or timolol (as the hemihydrate); dosage is expressed in terms of timolol.104 105 107

Adults

Ocular Hypertension and Glaucoma
Ocular Administration

Timolol ophthalmic solution: initially, 1 drop of a 0.25% solution in the affected eye(s) twice daily.104 105 107 May increase dosage to 1 drop of a 0.5% solution in the affected eye(s) twice daily if necessary.104 105 107 May then reduce dosage to 1 drop of the effective strength in the affected eye(s) once daily if satisfactory IOP is maintained.104 105 107

Timolol ophthalmic gel-forming solution: 1 drop of a 0.25 or 0.5% solution in the affected eye(s) once daily.106

Fixed-combination timolol/dorzolamide solution: 1 drop in the affected eye(s) twice daily.108

Prescribing Limits

Adults

Ocular Hypertension and Glaucoma
Ocular Administration

Timolol ophthalmic solution: Dosages >1 drop of a 0.5% solution in the affected eye(s) twice daily generally do not produce further reduction in IOP.104 105 107

Timolol ophthalmic gel-forming solution: Dosages >1 drop of a 0.5% solution in the affected eye(s) once daily not studied.106

Cautions for Timolol

Contraindications

  • Known hypersensitivity to timolol or any ingredient in the formulation.104 105 106 107

  • Bronchial asthma or a history of bronchial asthma, severe COPD, sinus bradycardia, AV block greater than first degree, overt cardiac failure, or cardiogenic shock.104 105 106 107

Warnings/Precautions

Warnings

Cardiovascular Effects

Severe cardiac reactions, including death associated with cardiac failure, have been reported in patients receiving systemic or topical (ocular) timolol.104 105 106 107 Discontinue therapy at the first sign or symptom of cardiac failure.104 105 106 107

Respiratory Effects

Severe respiratory reactions, including death resulting from bronchospasm, have been reported in patients receiving systemic or topical (ocular) timolol.104 105 106 107

Patients with mild or moderately severe COPD (e.g., chronic bronchitis, emphysema), bronchospastic disease, or a history of bronchospastic disease (other than bronchial asthma or a history of bronchial asthma, in which condition timolol is contraindicated) generally should not receive β-adrenergic blocking agents.104 105 106 107

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.104 105 106 107 Some clinicians recommend gradual withdrawal of β-adrenergic blocking agents prior to elective surgery.104 105 106 107

Diabetes Mellitus

β-Adrenergic blocking agents may mask signs and symptoms of acute hypoglycemia; administer with caution in patients subject to spontaneous hypoglycemia and in diabetic patients (especially those with labile diabetes) who are receiving hypoglycemic agents.104 105 106 107

Thyrotoxicosis

β-Adrenergic blocking agents may mask signs of hyperthyroidism (e.g., tachycardia).104 105 106 107

Possible thyroid storm if β-adrenergic blocking agent is abruptly withdrawn; carefully monitor patients having or suspected of developing thyrotoxicosis.104 105 106 107

Sensitivity Reactions

Patients with a history of atopy or of a severe anaphylactic reaction to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenges with such allergens while taking β-adrenergic blocking agents; such patients may be unresponsive to usual doses of epinephrine used to treat anaphylactic reactions.104 105 106 107

General Precautions

Dorzolamide Component

When using fixed-combination preparation containing dorzolamide hydrochloride, consider the warnings, cautions, precautions, and contraindications associated with dorzolamide.108

Bacterial Keratitis

Bacterial keratitis reported after inadvertent contamination of multiple dose containers for topical ophthalmic use, principally in patients with concurrent corneal disease or disruption of ocular epithelial surface.104 105 106 107 Avoid contamination of solution container.104 105 106 107 (See Advice to Patients.)

Ocular effects

Choroidal detachment after filtration procedures reported.104 105 106 107

Angle-closure Glaucoma

Timolol has little or no effect on pupil size; do not use alone in patients with angle-closure glaucoma.104 105 106 107

Muscle Weakness

β-Adrenergic blocking agents reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness).104 105 106 107

Timolol reported rarely to increase muscle weakness in patients with myasthenia gravis or myasthenia symptoms.104 105 106 107

Cerebrovascular Insufficiency

Caution advised in patients with cerebrovascular insufficiency due to the potential effects of β-adrenergic blocking agents on blood pressure and pulse.104 105 106 107

Consider alternative therapy if signs or symptoms suggestive of reduced cerebral blood flow occur.104 105 106 107

Specific Populations

Pregnancy

Category C.104 105 106 107

Lactation

Distributed into milk following topical application to the eye.104 Discontinue nursing or the drug.104 105 106 107

Pediatric Use

Safety and efficacy not established.104 105 106 107

Geriatric Use

Safety and efficacy in those ≥65 years of age similar to those in younger adults; however, possibility exists of greater sensitivity to the drug in some geriatric patients.104 106

Common Adverse Effects

Burning and stinging on instillation.104 105 106 107

Interactions for Timolol

Appears to be metabolized partly by CYP2D6.104 105 106 107 c

Drugs Affecting Hepatic Microsomal Enzymes

CYP2D6 inhibitors: Potential pharmacodynamic (increased β-adrenergic blockade) and pharmacokinetic interaction (increased plasma timolol concentrations).104 105 106 107 c

Specific Drugs

Drug

Interaction

Comments

β-Adrenergic blocking agents, systemic

Additive systemic and ocular effects104 105 106 107 108

Calcium-channel blocking agents

Potential hypotension, AV conduction disturbances, and left ventricular failure101 102 104 105 106 107

Caution advised104 105 106 107

Avoid concomitant use in patients with impaired cardiac function104 105 106 107

Cimetidine

Possible additive reductions in resting heart rate and IOPc

Digitalis

Possible additive effect in prolonging AV conduction time when used concomitantly with calcium-channel blocking agents (diltiazem, verapamil)104 105 106 107

Catecholamine-depleting drugs (e.g., reserpine)

Possible additive effects104 105 106 107

Observe closely for evidence of marked bradycardia or hypotension (may be manifested as vertigo, syncope, or postural hypotension)104 105 106 107

Clonidine

Oral β-adrenergic blocking agents may exacerbate rebound hypertension following discontinuance of clonidine104 105 106 107

Not reported with ophthalmic use of timolol104 105 106 107

Epinephrine

Mydriasis possible following concomitant ocular administration104 105 106 107

Atopic individuals and those with a history of severe anaphylactic reactions may not respond to usual doses of epinephrine used in the treatment of anaphylactic reactions104 105 106 107

Ocular hypotensive agents

Additive IOP-lowering effects104 105 106 107 108

Used to therapeutic advantage104 105 106 107 108

If more than one topical ophthalmic drug is used, administer at least 10 minutes apart104 106

Quinidine

Potential increase in plasma timolol concentrations and in β-blockade (bradycardia)103 104 105 106 107

Timolol Pharmacokinetics

Absorption

Bioavailability

Absorbed into systemic circulation following topical administration.104 105 106 107

Onset

Following topical application to the eye of a 0.25 or 0.5% solution, reduction in IOP usually occurs within 15–30 minutes and reaches a maximum within 1–5 hours.b

Duration

Reduction in IOP persists about 24 hours.104 105 106 107

Elimination

Metabolism

Appears to be metabolized in the liver partly by CYP2D6.104 105 106 107 c

Stability

Storage

Ophthalmic

Solution

Timolol maleate or timolol (hemihydrate) solutions: 15–30°C; protect from light.104 105 107 Do not freeze.104 107

Fixed-combination timolol/dorzolamide solution: 15–25°C.108 Protect from light.108

Solution, gel-forming

15–25°C; protect from light.106

Actions

  • Nonselective β-adrenergic blocking agent that does not have substantial intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic activity.104 105 106 107

  • Potent ocular hypotensive agent; reduces IOP by about 25–33% in patients with elevated IOP.b

  • Exact mechanism of action not fully elucidated; tonography and fluorophotometric studies suggest that reduced aqueous humor formation is the principal effect.104 105 106 107 A slight increase in outflow facility observed in some studies.104 105 106 107

  • Tolerance may develop with prolonged use; however, IOP-lowering effect maintained for at least 3 years of continuous use in some patients.b

Advice to Patients

  • Importance of learning and adhering to proper administration techniques to avoid contamination of the product.104 105 106 107 If more than one topical ophthalmic drug is used, importance of administering the drugs at least 10 minutes apart.104 106

  • When an ophthalmic preparation that contains benzalkonium chloride is used, importance of removing soft contact lenses prior to administering a dose and for at least 15 minutes after administration.104

  • Advise patients to consult a clinician immediately regarding the continued use of ophthalmic preparations if an intercurrent ocular condition (e.g., trauma, infection) occurs.104 105 106 107

  • Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.104 105 106 107

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.104 105 106 107

  • Importance of informing patients of other important precautionary information.104 105 106 107 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Timolol (Hemihydrate)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Ophthalmic

Solution

0.25% (of anhydrous timolol)

Betimol (with benzalkonium chloride)

Vistakon

0.5% (of anhydrous timolol)

Betimol (with benzalkonium chloride)

Vistakon

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

Timolol Maleate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Ophthalmic

Solution

0.25% (of timolol)*

Timolol Maleate Ophthalmic Solution

Apotex, Bausch & Lomb, Falcon

Timoptic Ocumeter Plus (with benzalkonium chloride)

Merck

Timoptic Ocudose (preservative-free)

Merck

0.5% (of timolol)*

Timolol Maleate Ophthalmic Solution

Apotex, Bausch & Lomb, Falcon

Timoptic Ocumeter Plus (with benzalkonium chloride)

Merck

Timoptic Ocudose (preservative-free)

Merck

Solution, gel-forming

0.25% (of timolol)*

Timolol GFS (with benzalkonium chloride)

Falcon

Timoptic-XE Ocumeter (with benzododecinium bromide)

Merck

0.5% (of timolol)*

Timolol GFS (with benzalkonium chloride)

Falcon

Timoptic-XE Ocumeter (with benzododecinium bromide)

Merck

Timolol Maleate Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Ophthalmic

Solution

0.5% (of timolol) with Dorzolamide Hydrochloride 2% (of dorzolamide)

Cosopt Ocumeter Plus (with benzalkonium chloride)

Merck

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Betimol 0.25% Solution (VISTAKON PHARMACEUTICALS): 5/$55.99 or 15/$149.97

Betimol 0.5% Solution (VISTAKON PHARMACEUTICALS): 5/$60.99 or 15/$169.98

Betimol 0.5% Solution (VISTAKON PHARMACEUTICALS): 10/$113.99 or 30/$326.96

Betimol 0.5% Solution (VISTAKON PHARMACEUTICALS): 15/$175.99 or 45/$499.99

Combigan 0.2-0.5% Solution (ALLERGAN): 5/$90.85 or 15/$255.25

Cosopt 2-0.5% Solution (MERCK SHARP & DOHME): 10/$135.99 or 30/$392.95

Dorzolamide-Timolol 2-0.5% Solution (HI-TECH): 10/$99.99 or 30/$279.97

Istalol 0.5% Solution (ISTA PHARMACEUTICALS): 5/$185.98 or 15/$515.96

Timolol Maleate 0.25% Solution (APOTEX): 15/$19.99 or 45/$49.97

Timolol Maleate 0.25% Solution (SANDOZ): 5/$12.99 or 15/$30.99

Timolol Maleate 0.25% Solution (SANDOZ): 5/$59.71 or 15/$126.86

Timolol Maleate 0.25% Solution (SANDOZ): 10/$16.99 or 30/$40.98

Timolol Maleate 0.5% Solution (SANDOZ): 5/$15.99 or 15/$34.99

Timolol Maleate 0.5% Solution (SANDOZ): 5/$55.99 or 15/$145.96

Timolol Maleate 0.5% Solution (SANDOZ): 10/$19.99 or 30/$44.97

Timolol Maleate 0.5% Solution (SANDOZ): 15/$20.99 or 45/$53.98

Timoptic 0.5% Solution (VALEANT): 5/$109.99 or 10/$215.97

Timoptic Ocudose 0.5% Solution (VALEANT): 60/$277.00 or 180/$810.02

Timoptic-XE 0.5% Solution (VALEANT): 5/$133.94 or 15/$389.45

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 1, 2005. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

100. Knoll Pharmaceuticals. Isoptin SR (verapamil HCl) sustained release oral tablets prescribing information. Whippany, NJ; 1992 Aug.

101. Pringle SD, MacEwen CJ. Severe bradycardia due to interaction of timolol eye drops and verapamil. BMJ. 1987; 294:155-6. [IDIS 225511] [PubMed 3109547]

102. Sinclair NI, Benzie JL. Timolol eye drops and verapamil–a dangerous combination. Med J Aust. 1983; 1:548. [IDIS 175967] [PubMed 6343813]

103. Dinai Y, Sharir M, Naveh N et al. Bradycardia induced by interaction between quinidine and ophthalmic timolol. Ann Intern Med. 1985; 103:890-1. [IDIS 208000] [PubMed 4062090]

104. Merck and Co. Timoptic 0.25% and 0.5% (timolol maleate) ophthalmic solution, prescribing information. West Point, PA; 2001 Apr.

105. Merck and Co. Timoptic 0.25% and 0.5% (timolol maleate) ophthalmic solution in OCUDOSE (dispenser), prescribing information. West Point, PA; 2000 Mar.

106. Merck and Co. Timoptic-XE 0.25% and 0.5% (timolol maleate) ophthalmic gel forming solution prescribing information. West Point, PA; 2001 Mar.

107. Ciba Vision Ophthalmics. Betimol (timolol) ophthalmic solution 0.25%, 0.5% prescribing information. In: Physician’s desk reference for ophthalmology. 24th ed. Montvale, NJ: Medical Economics Company, Inc; 1996:261-3.

108. Merck & Company. Cosopt (dorzolamide hydrochloride and timolol maleate) sterile ophthalmic solution prescribing information. West Point, PA; 2000 Aug.

a. AHFS drug information 2003. McEvoy GK, ed. Timolol Maleate. Bethesda, MD: American Society of Health-System Pharmacists; 2003: page 1793-7.

b. AHFS drug information 2003. McEvoy GK, ed. Timolol. Bethesda, MD: American Society of Health-System Pharmacists; 2003: page 2720-3.

c. Ishii Y, Nakamura K, Tsutsumi K et al. Drug interaction between cimetidine and timolol ophthalmic solution: effect on heart rate and intraocular pressure in healthy Japanese volunteers. J Clin Pharmacol. 2000; 40:193-9. [PubMed 10664926]

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