Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, Ophthalmic, as hydrochloride:
Betagan: 0.5% (5 mL [DSC], 10 mL [DSC], 15 mL [DSC])
Generic: 0.5% (5 mL, 10 mL [DSC], 15 mL [DSC])
Pharmacology
Mechanism of Action
Blocks both beta1- and beta2-adrenergic receptors and reduces intraocular pressure by reducing aqueous humor production or possibly increases the outflow of aqueous humor.
Pharmacokinetics/Pharmacodynamics
Onset of Action
Within 1 hour; Peak effect: 2 to 6 hours
Duration of Action
Up to 24 hours
Use: Labeled Indications
Elevated intraocular pressure: Treatment of elevated intraocular pressure in patients with ocular hypertension or chronic open-angle glaucoma
Contraindications
Hypersensitivity to levobunolol or any component of the formulation; bronchial asthma or history of bronchial asthma; severe COPD; sinus bradycardia; second- or third-degree atrioventricular block; overt heart failure; cardiogenic shock
Documentation of allergenic cross-reactivity for ophthalmic beta-adrenergic blocking agents is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.
Dosage and Administration
Dosing: Adult
Elevated intraocular pressure: Ophthalmic: Instill 1 to 2 drops into affected eye(s) once daily; may increase to 1 drop twice daily in patients with severe or uncontrolled glaucoma. Doses >1 drop twice daily are generally not more effective.
Dosing: Geriatric
Refer to adult dosing.
Administration
For topical ophthalmic use only. Wash hands before and after use. Some solutions contain benzalkonium chloride; remove contact lens prior to administration. Wait 15 minutes before reinserting. Do not touch tip of applicator to eye or other surfaces. Do not administer 2 or more ophthalmic beta-adrenergic blocking agents simultaneously.
Storage
Store at 15°C to 25°C (59°F to 77°F). Protect from light.
Drug Interactions
Beta2-Agonists: Beta-Blockers (Nonselective) may diminish the bronchodilatory effect of Beta2-Agonists. Avoid combination
Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Monitor therapy
Bupivacaine: Beta-Blockers may increase the serum concentration of Bupivacaine. 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. 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. 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. Consider therapy modification
EPINEPHrine (Nasal): Beta-Blockers (Nonselective) may enhance the hypertensive effect of EPINEPHrine (Nasal). Monitor therapy
EPINEPHrine (Oral Inhalation): Beta-Blockers (Nonselective) may enhance the hypertensive effect of EPINEPHrine (Oral Inhalation). Monitor therapy
Epinephrine (Racemic): Beta-Blockers (Nonselective) may enhance the hypertensive effect of Epinephrine (Racemic). Monitor therapy
EPINEPHrine (Systemic): Beta-Blockers (Nonselective) may enhance the hypertensive effect of EPINEPHrine (Systemic). Monitor therapy
Ergot Derivatives: Beta-Blockers may enhance the vasoconstricting effect of Ergot Derivatives. Exceptions: Nicergoline. Consider therapy modification
Fexinidazole [INT]: Bradycardia-Causing Agents may enhance the arrhythmogenic effect of Fexinidazole [INT]. Avoid combination
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. Consider therapy modification
Floctafenine: May enhance the adverse/toxic effect of Beta-Blockers. 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. Consider therapy modification
Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Monitor therapy
Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy
Lidocaine (Systemic): Beta-Blockers may increase the serum concentration of Lidocaine (Systemic). Monitor therapy
Lidocaine (Topical): Beta-Blockers may increase the serum concentration of Lidocaine (Topical). Monitor therapy
Mepivacaine: Beta-Blockers may increase the serum concentration of Mepivacaine. Monitor therapy
Methacholine: Beta-Blockers may enhance the adverse/toxic effect of Methacholine. Monitor therapy
Methoxyflurane: May enhance the hypotensive effect of Beta-Blockers. Monitor therapy
Midodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy
NIFEdipine: May enhance the hypotensive effect of Beta-Blockers. NIFEdipine may enhance the negative inotropic effect of Beta-Blockers. Monitor therapy
Opioids (Anilidopiperidine): May enhance the bradycardic effect of Beta-Blockers. Opioids (Anilidopiperidine) may enhance the hypotensive effect of Beta-Blockers. Monitor therapy
Regorafenib: May enhance the bradycardic effect of Beta-Blockers. Monitor therapy
Reserpine: May enhance the hypotensive effect of Beta-Blockers. Monitor therapy
Rivastigmine: May enhance the bradycardic effect of Beta-Blockers. 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. Monitor therapy
Siponimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. Consider therapy modification
Terlipressin: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy
Theophylline Derivatives: Beta-Blockers (Nonselective) may diminish the bronchodilatory effect of Theophylline Derivatives. Monitor therapy
Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy
Adverse Reactions
>10%: Ophthalmic: Burning sensation of eyes (≤33%), stinging of eyes (≤33%)
1% to 10%: Ophthalmic: Blepharoconjunctivitis (5%)
Frequency not defined:
Cardiovascular: Bradycardia, cardiac arrhythmia, cardiac failure, cerebral ischemia, cerebrovascular accident, chest pain, heart block, hypotension, palpitations, syncope
Central nervous system: Ataxia (transient), confusion, depression, dizziness, exacerbation of myasthenia gravis, foreign body sensation of eye, headache, lethargy, paresthesia
Dermatologic: Alopecia, pruritus, skin rash, Stevens-Johnson syndrome, urticaria
Endocrine & metabolic: Hypoglycemia (masked)
Gastrointestinal: Diarrhea, nausea
Genitourinary: Impotence
Hypersensitivity: Hypersensitivity reaction
Neuromuscular & skeletal: Weakness
Ophthalmic: Blepharoptosis, decreased corneal sensitivity, diplopia, iridocyclitis, keratitis, ocular allergy, visual disturbance
Respiratory: Bronchospasm, dyspnea, nasal congestion, respiratory failure
Warnings/Precautions
Concerns related to adverse events:
- Anaphylactic reactions: Instill with caution in patients with history of severe anaphylaxis to a variety of 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.
- Choroidal detachment: Beta-blockade and/or other aqueous suppressive therapy has been associated with choroidal detachment following filtration procedures.
Disease-related concerns:
- Cerebrovascular disease: Use with caution in cerebrovascular insufficiency; consider alternative therapy for patients with signs/symptoms of decreased cerebral blood flow after therapy initiation.
- Diabetes: Use with caution in patients with diabetes mellitus (especially labile diabetes); 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; may lead to heart failure in patients without a history of heart failure (discontinue use at first sign or symptoms of heart failure). Use is contraindicated in overt heart failure. In a scientific statement from the AHA, levobunolol has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: major) (AHA [Page 2016]).
- Myasthenia gravis: Use with caution in patients with myasthenia gravis; may worsen disease or other myasthenic symptoms (eg, diplopia, ptosis, generalized weakness).
- Peripheral vascular disease and Raynaud disease: Can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease or Raynaud disease. Use with caution and monitor for progression of arterial obstruction.
- Respiratory disease: In general, patients with bronchospastic disease should not receive beta-blockers; if used at all, should be used cautiously with close monitoring. Severe respiratory reactions, including fatalities due to bronchospasm in patients with asthma, have been reported with ophthalmic use. Use is contraindicated in bronchial asthma or history of bronchial asthma and severe COPD.
- 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:
- Contact lens wearers: Some products may contain benzalkonium chloride, which may be absorbed by soft contact lenses. Remove lens prior to administration and wait 15 minutes before reinserting.
Dosage form specific issues:
- Metabisulfite: Ophthalmic solutions may contain metabisulfite, which may cause allergic reactions in susceptible individuals.
Other warnings/precautions:
- Absorption: Systemic absorption of levobunolol and adverse effects may occur with ophthalmic use, including respiratory and cardiovascular effects (including bradycardia and/or hypotension). Beta-blocker therapy should not be withdrawn abruptly in order to avoid acute tachycardia, hypertension, and/or ischemia.
- Appropriate use: Should not be used alone in angle-closure glaucoma (has no effect on pupillary constriction). Concomitant use of 2 topical beta-blockers is not recommended. Multidose vials have been associated with development of bacterial keratitis; avoid contamination.
- Surgery: May block systemic effects of beta agonists (eg, epinephrine, norepinephrine); notify anesthesiologist if patient is receiving ophthalmic beta-blocker therapy. Patients undergoing planned major surgery should be gradually tapered off therapy (if possible) prior to procedure. If necessary during surgery, effects of beta-blocker therapy may be reversed by adrenergic agonists.
Monitoring Parameters
Intraocular pressure, heart rate, funduscopic exam, visual field testing
Pregnancy
Pregnancy Considerations
The same adverse effects observed with systemic administration of beta-blockers may occur following ophthalmic use of levobunolol. If ophthalmic agents are needed for the treatment of glaucoma during pregnancy, the minimum effective dose should be used in combination with punctal occlusion to decrease potential exposure to the fetus (Johnson 2001; Salim 2014; Samples 1988).
Patient Education
- 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 burning or stinging. Have patient report immediately to prescriber vision changes, eye pain, severe eye irritation, muscle weakness, severe dizziness, passing out, slow heartbeat, shortness of breath, excessive weight gain, or swelling of arms or legs (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.
