Levobunolol (Monograph)

Brand name: Betagan
Drug class: beta-Adrenergic Blocking Agents
- Beta-Adrenergic Blocking Agents
- β-Adrenergic Blocking Agents
VA class: OP101
Chemical name: (-)-5-(3-tert-Butylamino-2-hydroxypropoxy)-1,2,3,4-tetrahydronaphthalen-1-one hydrochloride
Molecular formula: C₁₇H₂₅NO₃•ClH [Molecular Formula]
CAS number: 27912-14-7[CAS number]

Medically reviewed by Drugs.com on Nov 21, 2024. Written by ASHP.

Introduction

Nonselective β-adrenergic blocking agent.

Uses for Levobunolol

Ocular Hypertension and Glaucoma

Reduction of elevated IOP in patients with chronic open-angle glaucoma or ocular hypertension. When administered twice daily, usual dosages of levobunolol are as effective as usual dosages of timolol in reducing IOP.

When selecting an initial ocular hypotensive agent, consider extent of the required IOP reduction, coexisting medical conditions, and drug characteristics (e.g., dosing frequency, adverse effects, cost). With single-agent regimens, the reduction in IOP is approximately 25–33% with topical prostaglandin analogs; 20–25% with topical β-adrenergic blocking agents, α-adrenergic agonists, or miotic (parasympathomimetic) agents; 20–30% with oral carbonic anhydrase inhibitors; 18% with topical rho kinase inhibitors; and 15–20% with topical carbonic anhydrase inhibitors.

A prostaglandin analog frequently is considered for initial therapy in the absence of other considerations (e.g., contraindications, cost considerations, intolerance, adverse effects, patient refusal) because of relatively greater activity, once-daily administration, and low frequency of systemic adverse effects; however, ocular adverse effects can occur.

Goal is to maintain an IOP at which visual field loss is unlikely to substantially reduce quality of life during the patient's lifetime.

Reduction of pretreatment IOP by ≥25% shown to slow progression of primary open-angle glaucoma. Set an initial target IOP (based on extent of optic nerve damage and/or visual field loss, baseline IOP at which damage occurred, rate of progression, life expectancy, and other considerations) and reduce IOP toward this goal. Adjust target IOP up or down as needed over course of disease.

Combination therapy with drugs from different therapeutic classes often required to control IOP.

Levobunolol Dosage and Administration

General

• Adjust dosage to individual requirements and response of patient as determined by tonometric readings before and during therapy.

• Because of diurnal variations in IOP, measure IOP at different times during the day to determine if an adequate hypotensive effect is maintained. Since IOP may not stabilize for a few weeks after initiating therapy, determine IOP after about 4 weeks of therapy; thereafter, determine IOP as necessary.

Administration

Ophthalmic Administration

Apply topically to the eye as an ophthalmic solution.

Avoid contamination of the solution container. (See Bacterial Keratitis under Cautions.)

Remove soft contact lenses before administering each dose; may reinsert lenses 15 minutes after the dose. (See Contact Lenses under Cautions.)

Dosage

Available as levobunolol hydrochloride; dosage expressed in terms of the salt.

Adults

Ocular Hypertension and Glaucoma

Ophthalmic

Initially, 1 or 2 drops of a 0.5% ophthalmic solution in the affected eye(s) once daily or, alternatively, 1 or 2 drops of a 0.25% ophthalmic solution twice daily.

May increase dosage, if necessary, to 1 drop of a 0.5% ophthalmic solution in the affected eye(s) twice daily in patients with more severe or uncontrolled glaucoma.

If target IOP not achieved, may initiate additional or alternative ocular hypotensive agents. (See Ocular Hypertension and Glaucoma under Uses.) Generally avoid concomitant use of multiple topical ophthalmic β-adrenergic blocking agents.

Prescribing Limits

Adults

Ocular Hypertension and Glaucoma

Ophthalmic

Dosages >1 drop of a 0.5% ophthalmic solution twice daily generally have not been more effective.

Cautions for Levobunolol

Contraindications

Cardiogenic shock or overt cardiac failure that is not adequately compensated. (See Cardiac Failure under Cautions.)

Asthma, history of asthma, or severe COPD (e.g., severe chronic bronchitis or emphysema). (See Respiratory Disease under Cautions.)

Sinus bradycardia or AV block greater than first degree.

Known hypersensitivity to levobunolol or any ingredient in the formulation.

Warnings/Precautions

Sensitivity Reactions

History of Anaphylactic or Hypersensitivity Reactions

Patients with a history of 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.

Use with caution in patients with known hypersensitivity to other β-adrenergic blocking agents.

Sulfite Sensitivity

Levobunolol hydrochloride ophthalmic solution contains sulfites, which may cause allergic-type reactions (including anaphylaxis and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.

Systemic Effects

May be absorbed systemically following topical application to the eye; consider the usual precautions associated with systemic use of β-adrenergic blocking agents when using topical levobunolol.

Hypotension

Ophthalmic β-adrenergic blocking agents may impair compensatory increases in heart rate and increase risk of hypotension.

Cardiac Failure

Severe cardiac reactions, including death associated with cardiac failure, reported in patients receiving topical (ocular) β-adrenergic blocking agents. May precipitate more severe cardiac failure in patients with preexisting heart failure and may cause cardiac failure in some patients without a history of heart failure. (See Actions.)

Contraindicated in patients with cardiogenic shock or with overt cardiac failure that is not adequately compensated (e.g., treated with cardiac glycosides and/or diuretics). In patients without a history of cardiac failure, discontinue therapy at the first sign or symptom of cardiac failure.

Respiratory Disease

Severe respiratory reactions, including death resulting from bronchospasm, reported in patients with asthma receiving topical (ocular) β-adrenergic blocking agents.

Contraindicated in patients with asthma, history of asthma, or severe COPD (e.g., severe chronic bronchitis or emphysema). Patients with mild or moderately severe COPD, bronchospastic disease other than asthma, or a history of such bronchospastic disease generally should not receive β-adrenergic blocking agents. If levobunolol is required, use with caution in such patients since it may antagonize bronchodilation produced by endogenous and exogenous catecholamines.

Use with caution in other patients with diminished pulmonary function.

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.

Need for withdrawal of β-adrenergic blocking agents prior to major surgery is controversial; in some patients, gradual withdrawal of β-adrenergic blocking agents prior to elective surgery may be appropriate.

If necessary during surgery, may reverse effects of β-adrenergic blocking agents by administering sufficient doses of β-adrenergic agonists (e.g., isoproterenol, dopamine, dobutamine, norepinephrine).

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.

Thyrotoxicosis

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

Possible thyroid storm if β-adrenergic blocking agent is abruptly withdrawn; carefully monitor patients suspected of developing thyrotoxicosis.

Choroidal Detachment

Choroidal detachment after filtration procedures reported with the administration of aqueous suppressant therapy.

Vascular Insufficiency

Caution advised in patients with cerebrovascular insufficiency due to the potential effects of β-adrenergic blocking agents on BP and pulse. Consider alternative therapy if signs or symptoms of reduced cerebral blood flow occur.

Caution also advised in patients with other syndromes associated with vascular insufficiency (i.e., Raynaud phenomenon); levobunolol may potentiate these syndromes.

Angle-closure Glaucoma

Levobunolol has little or no effect on pupil size. Do not use alone in patients with angle-closure glaucoma; use only in combination with a miotic in these patients.

Muscle Weakness

β-Adrenergic blocking agents reported to potentiate muscle weakness consistent with certain myasthenic manifestations (e.g., diplopia, ptosis, generalized weakness).

Bacterial Keratitis

Bacterial keratitis reported with use of multiple-dose containers of topical ophthalmic solutions. Containers were inadvertently contaminated by patients, most of whom had concurrent corneal disease or disruption of the ocular epithelial surface.

Improper handling of ophthalmic solutions can result in contamination of the solution by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated ophthalmic preparations. (See Advice to Patients.)

Contact Lenses

Levobunolol ophthalmic solution contains benzalkonium chloride, which may be absorbed by soft contact lenses. Remove soft contact lenses before administering each dose; may reinsert lenses 15 minutes after the dose.

Specific Populations

Pregnancy

No evidence of maternal toxicity or fetal harm in reproduction studies using oral levobunolol in rats. Fetotoxicity (increased resorptions) observed in rabbits (animals that may be particularly sensitive to β-adrenergic blocking agents).

No adequate and controlled studies in pregnant women; use only if potential benefits justify the possible risks to the fetus.

Lactation

Not known whether levobunolol is distributed into milk following topical application to the eye. Caution if used in nursing women.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in safety and efficacy relative to younger adults.

Common Adverse Effects

Ocular stinging or burning on instillation, blepharoconjunctivitis.

Drug Interactions

Specific Drugs

Levobunolol Pharmacokinetics

Absorption

Bioavailability

Some systemic absorption occurs following topical administration.

Onset

Following topical application to the eye, reduction in IOP is usually evident within 1 hour and reaches a maximum within about 2–6 hours.

Duration

Reduction in IOP may persist for up to 24 hours.

Distribution

Extent

Following topical application in rabbits, rapidly distributed throughout ocular tissues and fluids (e.g., cornea, iris, ciliary body, aqueous humor).

Levobunolol crosses the placenta in some animals; not known whether distributed into human milk.

Elimination

Metabolism

Extensively metabolized in the liver principally to dihydrolevobunolol, an active metabolite.

Elimination Route

Approximately 93% of topically applied dose is excreted in urine and feces in rabbits.

Half-life

Following ophthalmic administration of racemic bunolol in rabbits: 60–90 min.

Stability

Storage

Ophthalmic

Solution

Light-resistant containers at 15–25°C.

Actions

• Nonselective β-adrenergic blocking agent that has some direct myocardial depressant activity but does not have substantial local anesthetic activity or intrinsic sympathomimetic activity.

• Reduces both elevated and normal IOP with little or no effect on pupillary size or accommodation.

• Reduces IOP by about 25–40% from baseline in patients with elevated IOP.

• Exact mechanism of action not fully elucidated; fluorophotometric studies suggest that reduced aqueous humor formation is the predominant effect.

• May block endogenous catecholamine-stimulated increases in cyclic adenosine monophosphate (AMP) concentrations within the ciliary processes and subsequent formation of aqueous humor.

• Does not appear to affect aqueous humor outflow facility.

• Tolerance may develop with prolonged use; however, IOP-lowering effect maintained for at least 2 years with continuous use in some patients.

Advice to Patients

• Importance of learning and adhering to proper administration techniques to avoid contamination of the solution with common bacteria that can cause ocular infections. Instruct patients that the tip of the dispensing container should not touch the eye or surrounding structures. Serious damage to the eye and subsequent loss of vision may result from using contaminated ophthalmic solutions.

• Advise patients to immediately contact their clinician for advice regarding continued use of the current multidose container if they experience an intercurrent ocular condition (e.g., trauma, infection) or require ocular surgery.

• Importance of removing contact lenses before administering each dose and delaying reinsertion for at least 15 minutes after the dose.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., cardiovascular disease, bronchospastic disease).

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

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

Preparations

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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

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