VA Class:OP101
ATC Class:S01ED03
Levobunolol hydrochloride is a nonselective β-adrenergic blocking agent.1, 2, 3, 9, 10, 11, 12, 13, 14, 15, 16, 17, 20, 21, 22, 23, 27, 28
Ocular Hypertension and Glaucoma
In ophthalmology, topical levobunolol hydrochloride is used to reduce elevated intraocular pressure (IOP) in patients with chronic open-angle glaucoma1, 2, 51, 52, 53, 54, 55, 56, 58, 92, 113 or ocular hypertension.1, 2, 51, 52, 53, 54, 55, 56, 57, 58, 92, 113 Elevated IOP presents a major risk factor in glaucomatous field loss; the higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss.1
Elevated IOP in patients with glaucoma can be reduced by medical treatment, laser therapy, and/or incisional glaucoma surgery; treatment with a topical ocular hypotensive agent frequently is the initial intervention for primary open-angle glaucoma.130 Selection of an initial ocular hypotensive agent is influenced by the extent of the required reduction in IOP, coexisting medical conditions, and the characteristics of the individual drugs (e.g., dosing frequency, adverse effect profile, cost).130, 132 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.130, 131 In the absence of other considerations (e.g., contraindications, cost considerations, intolerance, adverse effects, patient refusal), a prostaglandin analog frequently is considered for initial therapy because of the relatively greater activity, once-daily administration, and low frequency of systemic adverse effects with this drug class; however, ocular adverse effects can occur.130, 131, 132, 134
IOP should be reduced toward a target level that the clinician believes will slow disease progression and avoid visual field losses that would substantially reduce quality of life during the patient's lifetime.130, 132 The target level is an estimate and should be individualized based on such factors as the extent of optic nerve damage and/or visual field loss, the baseline IOP at which damage occurred, rate of progression, life expectancy, and other considerations.130, 132 Reducing the pretreatment IOP by 25% or more has been shown to slow progression of primary open-angle glaucoma.130, 131 The target IOP should be adjusted up or down as needed over the course of the disease.130, 131, 132 If the target IOP is not achieved with single-agent therapy, alternative or additional ocular hypotensive agents may be selected depending on the patient's response to the initial drug.130 Combination therapy with drugs from different therapeutic classes often is required to achieve adequate control of IOP.131, 133
If levobunolol is used to reduce IOP in patients with angle-closure glaucoma,7, 98, 104, 105, 106, 107, 108 the drug should not be used alone but rather in combination with a topical miotic since levobunolol has little or no effect on pupil size.1, 2, 51, 52, 53, 54, 55, 56, 58
Like timolol,2, 51, 52, 54, 55, 56, 58, 92 ophthalmic levobunolol has been associated with adverse systemic pulmonary1, 2, 51 and cardiovascular effects.1, 2, 51, 52, 53, 54, 55, 56, 58, 92 Increased airway resistance can occur following topical application of levobunolol to the eye.1, 2, 51 The drug should be used with caution in patients with diminished pulmonary function, and is contraindicated in patients with asthma or a history of asthma and in patients with severe chronic obstructive pulmonary disease.1, 2 (See Cautions: Precautions and Contraindications.)
In controlled studies of 3 months' or up to 12 months' duration, IOP was controlled in 64-70% of patients receiving topical levobunolol hydrochloride 0.25% twice daily; the mean reduction in IOP from baseline was approximately 5 mm Hg.113 In an open-label study, IOP was controlled in 72% of patients receiving topical levobunolol hydrochloride 0.25% once daily; the mean reduction in IOP from baseline was approximately 6 mm Hg.113
In a clinical study of 3 months' duration, IOP was controlled in 72% of patients receiving topical levobunolol hydrochloride 0.5% once daily; the mean reduction in IOP from baseline was 7 mm Hg.1 In clinical studies of approximately 2 years' duration, IOP was well controlled in approximately 80% of patients receiving topical levobunolol hydrochloride 0.5% twice daily; the mean reduction in IOP from baseline was 7-8 mm Hg.1
When administered twice daily, usual dosages of levobunolol appear to be as effective as usual dosages of timolol in reducing IOP in patients with chronic open-angle glaucoma or ocular hypertension.2, 51, 52, 54, 55, 56, 58, 92
During prolonged therapy with topical levobunolol, the effect in reducing IOP is generally well maintained,1, 2, 51, 52, 54, 58, 92 but tolerance has been reported in some patients.51, 52, 54 In long-term studies in patients receiving levobunolol for up to 2 years, the reduction in mean IOP was maintained following initial stabilization with the drug.1, 2, 51
Levobunolol hydrochloride is applied topically to the eye as an ophthalmic solution.1, 2, 51, 52, 53, 54, 55, 56, 57, 58, 92, 113 Care should be taken to avoid contamination of the solution container.80 (See Cautions: Precautions and Contraindications.)
Levobunolol ophthalmic solution contains benzalkonium chloride, which may be absorbed by soft contact lenses.1, 113 The manufacturers state that soft contact lenses should be removed prior to administration of each dose but may be reinserted 15 minutes after the dose.1, 113
Ocular Hypertension and Glaucoma
For the treatment of open-angle glaucoma or ocular hypertension, the therapeutic regimen must be adjusted according to the individual requirements and response of the patient as determined by tonometric readings before and during therapy.1, 7
For the initial treatment of open-angle glaucoma1, 2, 51, 52, 53, 54, 55, 56, 58, 92 or ocular hypertension,1, 2, 51, 52, 53, 54, 55, 56, 57, 58, 92 the usual dosage of levobunolol hydrochloride is 1 or 2 drops of a 0.5% ophthalmic solution in the affected eye(s) once daily1, 2, 51, 52, 53, 54, 55, 56, 58, 92, 93 or, alternatively, 1 or 2 drops of a 0.25% ophthalmic solution may be used twice daily.113 If necessary for adequate reduction of intraocular pressure (IOP) in patients with more severe or uncontrolled glaucoma, dosage may be increased to 1 drop of a 0.5% solution in the affected eye(s) twice daily.1 Dosages exceeding 1 drop of levobunolol hydrochloride 0.5% solution twice daily generally have not been more effective.1
Because of diurnal variations in IOP, IOP should be measured at different times during the day to determine if an adequate hypotensive effect is maintained.76, 92 Since IOP may not stabilize for a few weeks after initiating levobunolol hydrochloride therapy in some patients, IOP should also be determined after about 4 weeks of therapy with levobunolol;92, 95, 96 thereafter, IOP should be determined as necessary.7, 92
If the target IOP is not achieved, alternative or additional ocular hypotensive agents may be required.130, 131, 133 (See Uses: Ocular Hypertension and Glaucoma.) Patients generally should not receive multiple topical ophthalmic β-adrenergic blocking agents concomitantly.1
Levobunolol hydrochloride ophthalmic solution is generally well tolerated following topical application to the eye;1, 2, 51, 52, 53, 54, 55, 56, 57, 58, 92 however, adverse effects may occasionally be severe enough to require discontinuance of the drug.1, 2, 54, 58
The most frequent adverse effects of topical ophthalmic levobunolol are mild ocular stinging1, 2, 52, 53, 58 or burning1, 2, 51, 52, 53, 58 and discomfort following instillation of the solution,2, 51, 52, 53, 58 which occur in about 33% of patients but are usually transient.1 Blepharoconjunctivitis1, 2, 51 occurs in about 5% of patients,1 and blepharitis,2, 52, 54 decreased visual acuity,2, 51, 52, 53, 54, 56, 58 conjunctivitis,2 iridocyclitis,1, 2 band keratopathy,2 erythema,2, 54 and itching sensation2 occur in about 4% of patients.2 Decreased corneal sensitivity1, 2, 51, 52, 54, 58 and tearing2 have been reported rarely.1 Choroidal detachment following filtration procedures also has been reported with the administration of aqueous suppressant therapy.1 Keratitis, ocular allergy,1 blepharoptosis, visual disturbances (e.g., refractive changes [secondary to withdrawal of miotic therapy in some cases], diplopia, ptosis), and foreign body sensation have been reported with ophthalmic use of levobunolol or other β-blocking agents.1
Use of levobunolol hydrochloride ophthalmic solution has occasionally been associated with adverse systemic effects.1, 2, 51, 52, 53, 54, 55, 56, 58, 92 Evidence of adverse pulmonary1, 2, 51 or cardiovascular1, 2, 51, 52, 53, 54, 55, 56, 58, 92 effects following topical application of the drug to the eye has been reported. Aggravation or precipitation of certain cardiovascular,1, 2, 51, 52, 53, 54, 55, 56, 58 pulmonary,1, 2, 51 and other disorders,1, 2 presumably related to effects of systemic β-adrenergic blockade,1, 2 may occur during therapy with topical levobunolol. Bradycardia,1, 2, 56, 58 arrhythmia,1 hypotension,1, 2 syncope,1 heart block,1 cerebral ischemia,1 cerebrovascular accident,1 congestive heart failure,1 palpitation,1 cardiac arrest,1 dyspnea,1 and bronchospasm (mainly in patients with preexisting bronchospastic disease and in geriatric patients)1, 2 have been reported in patients receiving topical therapy with levobunolol or other β-blocking agents.1 Severe respiratory and cardiac reactions,1, 2 including death resulting from bronchospasm in patients with asthma, and rarely death in association with cardiac failure,1 have been reported in patients receiving topical therapy with a β-blocking agent.1 Ophthalmic β-blocking agents also may impair compensatory increases in heart rate and increase the risk of hypotension.1 Reduction of resting heart rate (about 5-10 beats/minute)1, 2, 51, 52, 53, 54, 55, 56, 58, 92 may occur, and decreased diastolic (about 2-10 mm Hg)1, 2, 51, 52, 53, 54, 55, 56, 58, 92 and systolic (about 4-20 mm Hg)1, 2, 51, 52, 53, 54, 55, 56, 58, 92 blood pressures have been reported in some patients receiving ophthalmic levobunolol. Rarely, headache,1, 2, 51, 53, 54, 55 transient ataxia,1, 53 dizziness,1, 2 and lethargy1, 2 have been reported following topical application of levobunolol to the eye.
Nausea,1 heartburn,2, 51, 54 diarrhea,1, 2, 51, 54 nasal congestion,1 alopecia,1 impotence,1 dizziness,1, 2, 51 mental depression,1 confusion,1 increased manifestations of myasthenia gravis,1 paresthesia,1 asthenia,1 chest pain,1 and elevated serum ALT (SGPT) and bilirubin2 concentrations have been reported in patients receiving topical ophthalmic therapy with levobunolol or other β-blocking agents.1 Masking of hypoglycemic symptoms in insulin-dependent diabetics and respiratory failure also have been reported.1 The possibility that other adverse effects associated with systemic use of nonselective β-adrenergic blocking agents may occur during topical levobunolol therapy should be considered.1, 2
Hypersensitivity reactions, including urticaria1, 2 and pruritus,1 have occurred rarely during ophthalmic levobunolol therapy. Localized and generalized rash and Stevens-Johnson syndrome1 have been reported in patients receiving topical therapy with levobunolol or other β-blocking agents.1
Precautions and Contraindications
Levobunolol hydrochloride may be absorbed systemically following topical application to the eye,1, 2 and the usual precautions associated with systemic use of β-adrenergic blocking agents should be considered when using topical levobunolol.1 In addition, patients receiving topical levobunolol and a systemic β-adrenergic blocking agent concomitantly should be observed carefully for potential additive effects on intraocular pressure (IOP) and/or systemic effects of β-adrenergic blockade.1
The commercially available formulations of levobunolol hydrochloride ophthalmic solution contain sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals.1, 110, 113 The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.110
Severe cardiac reactions including rare reports of death associated with cardiac failure have been reported in patients receiving systemic or topical β-blocking agents.1 In patients with diminished myocardial contractility, sympathetic stimulation may be essential for circulatory support and more severe cardiac failure may be precipitated by β-adrenergic blockade.1 In some patients without cardiac failure, prolonged β-adrenergic blockade and subsequent myocardial depression may lead to cardiac failure.1 Levobunolol should be discontinued at the first sign or symptom of impending cardiac failure.1 Ophthalmic levobunolol is contraindicated in patients with cardiogenic shock or with overt cardiac failure1 that is not adequately compensated (e.g., treated with cardiac glycosides and/or diuretics).98, 99
β-Adrenergic blockade may lead to an increase in airway resistance and bronchospasm, particularly in patients with a history of asthma.1, 5 Severe respiratory reactions, including death resulting from bronchospasm in patients with asthma, have been reported in patients receiving systemic or ophthalmic β-blocking agents.1 Ophthalmic levobunolol is contraindicated in patients with asthma or a history of asthma and in patients with severe chronic obstructive pulmonary disease (e.g., severe chronic bronchitis or emphysema).1 Patients with mild or moderately severe chronic obstructive pulmonary disease, bronchospastic disease other than asthma, or a history of such bronchospastic disease generally should not receive β-blocking agents; however, if use of ophthalmic levobunolol cannot be avoided in such patients, caution is advised since β-blocking agents may interfere with the bronchodilation produced by endogenous and exogenous catecholamines.1 Levobunolol also should be used with caution in other patients with diminished pulmonary function.1
Ophthalmic levobunolol should be used with caution in patients with diabetes mellitus, especially those with labile disease who are receiving hypoglycemic agents or those prone to hypoglycemia, since β-blocking agents may mask the signs and symptoms of hypoglycemia (e.g., tachycardia and blood pressure changes but not sweating).1, 64 Patients having or suspected of developing thyrotoxicosis should be monitored closely during ophthalmic levobunolol therapy, since β-blocking agents may mask certain signs (e.g., tachycardia) and symptoms of hyperthyroidism and abrupt withdrawal of these agents can precipitate thyroid storm.1
The need to withdraw β-blocking agents prior to major surgery is controversial.1, 60, 93β-Blocking agents may reduce the ability of the heart to respond to reflex β-adrenergic stimuli, which may increase the risk of general anesthesia.1 Severe, protracted hypotension has occurred during surgery in some patients who received β-blocking agents, and difficulty in restarting and maintaining the heartbeat also has been reported.1 Therefore, the manufacturer states that gradual withdrawal of levobunolol prior to administration of general anesthesia should be considered.1 If necessary during surgery, the effects of β-blockers may be reversed by sufficient doses of β-agonists (e.g., isoproterenol, dopamine, dobutamine, norepinephrine).1
Ophthalmic levobunolol should be used with caution in patients with cerebrovascular insufficiency because of the potential effects of β-blocking agents on blood pressure and pulse rate.1 If signs or symptoms suggestive of reduced cerebral blood flow develop, alternative ocular hypotensive therapy should be considered.1 Ophthalmic levobunolol also should be used with caution in patients with other syndromes associated with vascular insufficiency (i.e., Raynaud phenomenon) since the drug may potentiate these syndromes.1
Patients who have a history 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-blocking agents and may be unresponsive to usual doses of epinephrine used to treat anaphylactic reactions.1
Bacterial keratitis has been reported with the use of multiple-dose containers of topical ophthalmic solutions.114 These containers were contaminated inadvertently by patients who, in most cases, had concurrent corneal disease or disruption of the ocular epithelial surface.114 Patients should be informed that improper handling of ophthalmic solutions can result in contamination of the solution by common bacteria known to cause ocular infections and that they should avoid allowing the tip of the dispensing container to contact the eye or surrounding structures.114 Serious damage to the eye and subsequent loss of vision may result from using contaminated ophthalmic solutions.114 Patients also should be advised 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.114
Patients who wear soft contact lenses should be instructed to remove their lenses prior to administering each dose of levobunolol ophthalmic solution since the solution contains benzalkonium chloride, which may be absorbed by soft contact lenses.1, 113 The lenses may be reinserted 15 minutes after the dose.1, 113
Ophthalmic levobunolol should be used with caution in patients with known hypersensitivity to other β-blocking agents.1
β-Blocking agents have been reported to potentiate muscle weakness consistent with certain myasthenic manifestations (e.g., diplopia, ptosis, generalized weakness).1
Because levobunolol has little or no effect on pupil size,1, 2, 51, 52, 53, 54, 55, 56, 58 the drug should not be used alone in patients with angle-closure glaucoma, but only in combination with a miotic.1, 7, 98, 104, 105, 106, 107, 108
Levobunolol hydrochloride ophthalmic solution is also contraindicated in patients with sinus bradycardia1, 52 or atrioventricular block greater than first-degree,1, 18 and in patients with known hypersensitivity to the drug or any ingredient in the formulation.1
Safety and efficacy of levobunolol hydrochloride ophthalmic solution in children have not been established.1
No overall differences in safety or efficacy of topical ophthalmic levobunolol have been observed between geriatric patients and younger adults.1
Mutagenicity and Carcinogenicity
In vitro and in vivo microbial and mammalian test systems using levobunolol have not revealed evidence of mutagenicity.1, 2
An increased incidence of benign uterine leiomyomas was observed in lifetime studies in mice receiving oral levobunolol hydrochloride dosages of 200 mg/kg daily (about 14,000 times the usual human daily ocular dose) but not in those receiving oral dosages of 12 or 50 mg/kg daily.1, 2 In a 2-year study in rats, there was an increased incidence of benign hepatomas in male rats receiving an oral levobunolol hydrochloride dosage 12,800 times the usual human daily ocular dose but not in those receiving dosages 350-2000 times the usual human dose.1
Pregnancy, Fertility, and Lactation
Reproduction studies in rats using oral levobunolol hydrochloride dosages up to 1800 times (i.e., 25 mg/kg) the usual human daily ocular dose have not revealed evidence of maternal toxicity or harm to the fetus.1, 2 Fetotoxicity, as manifested by increased number of resorption sites, has been observed in rabbits using oral dosages of 1, 3, or 10 mg/kg daily, but it appears that rabbits may be particularly sensitive to β-adrenergic blocking agents.1, 2 Reproduction studies in pregnant ewes using IV racemic bunolol hydrochloride doses of 0.05 mg/kg revealed evidence of maternal and fetal bradycardia and inhibition of isoproterenol-induced agonist activity in both ewe and fetus.2
There are no adequate and controlled studies to date using levobunolol hydrochloride ophthalmic solution in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1
Reproduction studies in male and female rats using oral levobunolol hydrochloride dosages up to 1800 times (i.e., 25 mg/kg daily) the usual human daily ocular dose for up to 6 months did not reveal evidence of impaired fertility;1, 2 however, 6-week studies in male and female mice using intraperitoneal racemic bunolol hydrochloride dosages of 10 mg/kg daily revealed a 35% decrease in fertility in the females.2
It is not known whether levobunolol hydrochloride is distributed into milk.1 Because systemically administered β-blockers and topical timolol maleate are distributed into milk, levobunolol should be used with caution in nursing women.1
Systemic Beta-Adrenergic Blocking Agents
The possibility of an additive effect on intraocular pressure (IOP) and/or systemic β-adrenergic blockade should be considered in patients who are receiving a systemic β-blocking agent and topical levobunolol concomitantly.1 Ophthalmic levobunolol should be used with caution in patients receiving systemic β-blocking agents.1
Calcium-channel Blocking Agents
Concomitant use of β-adrenergic blocking agents with calcium-channel blocking agents may have additive effects on prolonging atrioventricular (AV) conduction.1 Patients receiving levobunolol concomitantly with a calcium-channel blocking agent should be monitored for AV conduction disturbances, left ventricular failure, and/or hypotension; such concomitant use should be avoided in patients with impaired cardiac function.1
Concomitant use of β-adrenergic blocking agents with cardiac glycosides and calcium-channel blocking agents may have additive effects on prolonging AV conduction.1
The manufacturer states that when topical levobunolol is administered concomitantly with a catecholamine-depleting drug (e.g, reserpine), the patient should be observed closely for possible additive effects and the production of hypotension and/or bradycardia, which may result in vertigo, syncope, and/or postural hypotension.1
Although topical levobunolol used alone has little or no effect on pupil size,1, 2 mydriasis resulting from concomitant therapy with topical levobunolol and epinephrine has been reported occasionally.1
The manufacturer states that phenothiazines and β-adrenergic blocking agents may have additive hypotensive effects, which may result from inhibition of each other's metabolism.1
There currently is no information available on overdosage of levobunolol in humans.1
The oral LD50 of levobunolol hydrochloride is 273-1530, 700-800, 400-500, and 100 mg/kg in mice, rats, hamsters, and dogs, respectively,2 and the IV LD50 of the drug is 78-84 and 25-28 mg/kg in mice and rats, respectively.2
In general, overdosage of levobunolol may be expected to produce effects associated with systemic β-adrenergic blocking agents (e.g., bradycardia, hypotension, bronchospasm, cardiac failure, heart block).1
Treatment of levobunolol overdosage generally involves symptomatic and supportive care.1 In case of topical overdosage of levobunolol hydrochloride ophthalmic solution, the eye(s) should be flushed with adequate amounts75 of water or 0.9% sodium chloride solution.1 Following acute ingestion of the drug, usual measures to prevent further absorption of drug from the GI tract (e.g., gastric lavage) should be considered.1 For symptomatic bradycardia, IV atropine may be given; if bradycardia persists, IV isoproterenol hydrochloride may be administered cautiously, and in refractory cases, use of a transvenous cardiac pacemaker should be considered.1 A vasopressor (e.g., dopamine, dobutamine, norepinephrine) may be given for severe hypotension.1 For acute heart failure, appropriate therapy, including a cardiac glycoside, diuretics, and oxygen, should be initiated immediately.1 Glucagon may also be useful for the management of myocardial depression and hypotension.1 For atrioventricular block greater than first degree, IV isoproterenol hydrochloride may be administered cautiously, or use of a transvenous cardiac pacemaker should be considered.1 A β-adrenergic agonist (e.g., isoproterenol hydrochloride) and/or a theophylline derivative may be used for bronchospasm.1
Levobunolol hydrochloride is a nonselective β-adrenergic blocking agent.1, 2, 3, 10, 11, 12, 13, 14, 15, 16, 17, 19, 20, 21, 22, 23, 27, 28 On a weight basis, the β-adrenergic blocking activity of IV levobunolol as measured by antagonism of isoproterenol-induced tachycardia is approximately 2-6 times that of IV propranolol,2, 11, 13, 14, 16, 48 2-3 times that of IV racemic bunolol,2, 13, 16 and more than 60 times that of IV dextrobunolol.1, 16 Oral levobunolol is 20-49 times more potent than oral propranolol2, 11, 14, 16 and 2-4 times more potent than racemic bunolol.2, 11, 14, 15
In addition to its ocular effects, levobunolol competitively blocks β-adrenergic receptors within the myocardium (β1-receptors)1, 2, 11, 12, 13, 15, 17, 22, 23, 24, 25, 26, 28 and within bronchial and vascular smooth muscle (β2-receptors).1, 2, 27, 28 Levobunolol has some direct myocardial depressant activity1, 2, 14 but does not have substantial membrane-stabilizing (local anesthetic) activity1, 2, 23 or intrinsic β-agonist activity.1, 2, 14, 20, 21, 23 Through its myocardial β-adrenergic blocking action, levobunolol decreases cardiac output in both healthy individuals and patients with heart disease.1
Following topical application to the eye, levobunolol hydrochloride reduces both elevated1, 2, 51, 52, 53, 54, 55, 56, 57, 58, 92 and normal1, 2 intraocular pressure (IOP) in patients with1, 2, 51, 52, 53, 54, 55, 56, 58, 92 or without glaucoma.1, 2, 51, 52, 53, 54, 55, 56, 57, 58, 92 Levobunolol reduces IOP with little or no effect on pupillary size1, 2, 51, 52, 53, 54, 55, 56, 92 or accommodation.1 In patients with elevated IOP, levobunolol reduces mean IOP by about 25-40% from baseline.2, 51, 52, 53, 54, 55, 56, 57, 58, 92 The drug appears to be equally effective in light- and dark-colored eyes.51, 52, 53, 54, 58, 92
The exact mechanism by which β-blockers, including levobunolol, reduce IOP has not been clearly defined.1, 2, 7, 8, 29, 34, 50, 59 Fluorophotometric studies suggest that reduced aqueous humor formation is the predominant effect.1, 2, 7, 8, 97, 98β-Adrenergic blocking agents may block endogenous catecholamine-stimulated increases in cyclic adenosine monophosphate (AMP) concentrations within the ciliary processes and subsequent formation of aqueous humor.2, 6, 7, 8, 30, 32, 34, 59 The drugs do not appear to affect aqueous humor outflow facility,8, 34, 59 although β-blockers may block the increase in outflow facility that occurs following ophthalmic use of epinephrine.34, 59, 98
There is some evidence that levobunolol may also reduce IOP in the contralateral, untreated eye, although to a lesser extent than in the hypertensive eye.55, 57 The drug appears to cause minimal changes in tear secretion.1, 2, 52, 54 Levobunolol appears to have minimal local anesthetic effect on the cornea.1, 2, 51, 52, 54
Tolerance to the intraocular hypotensive effect may develop with prolonged use of ophthalmic levobunolol;98, 99 however, the IOP-lowering effect has been maintained for at least 2 years with continuous use of the drug in some patients.1, 2
Like timolol,33, 35, 61, 62, 63, 65, 66, 67, 68, 69, 70, 71, 72, 73, 90, 91 which is also a nonselective β-adrenergic blocking agent, levobunolol can produce systemic pulmonary1, 2, 51 and cardiovascular1, 2, 51, 52, 53, 54, 55, 56, 58, 92 effects following topical application to the eye. Adverse pulmonary effects (e.g., bronchoconstriction, increased airway resistance) have been reported rarely following ophthalmic application of levobunolol.1, 2, 51 Following topical application to the eye, levobunolol can substantially affect blood pressure1, 2, 51, 52, 53, 54, 55, 56, 58, 92 and heart rate in some patients.1, 2, 51, 52, 53, 54, 55, 56, 58, 92 Decreases in mean systolic (about 4-20 mm Hg)1, 2, 51, 52, 53, 54, 55, 56, 58, 92 and diastolic blood pressures (about 2-10 mm Hg)1, 2, 51, 52, 53, 54, 55, 56, 58, 92 and in heart rate (about 5-10 beats/minute)1, 2, 51, 52, 53, 54, 55, 56, 58, 92 have been observed in some patients following ophthalmic application of levobunolol.12, 18
The extent of ocular and systemic absorption of levobunolol hydrochloride following topical application to the eye in humans has not been elucidated; however, some systemic absorption can apparently occur, since systemic β-adrenergic blocking effects (e.g., reduction in heart rate, reduction in systolic and diastolic blood pressures) have occurred following topical application of the drug.1, 2, 51, 52, 53, 54, 55, 56, 58, 92
Following topical application to the eye of a 0.25 or 0.5% solution of levobunolol hydrochloride, reduction in intraocular pressure (IOP) is usually evident with 1 hour, reaches a maximum within about 2-6 hours, and may persist for up to 24 hours.1, 55, 57, 111 The effect of a single dose of levobunolol hydrochloride on IOP usually dissipates within 24 hours after instillation;1 however, as with other ophthalmic β-blocking agents,77, 78, 79 some reduction in IOP may persist for up to a week or longer after discontinuance of levobunolol.98, 99 In patients with open-angle glaucoma or ocular hypertension, the maximal lowering of IOP occurs after approximately 2-3 weeks of twice-daily instillation of the drug.53, 55, 56
Following topical application to the eye of radiolabeled racemic bunolol hydrochloride in rabbits, radioactivity was observed in the cornea and iris 15 minutes after instillation; peak drug concentrations were reached within 30 minutes and were 90, 12, 10, and 3 mcg/g in the cornea, iris, ciliary body, and aqueous humor, respectively.2 Substantial accumulation of racemic bunolol in ocular tissue does not appear to occur during multiple-dose administration.2
Levobunolol hydrochloride is rapidly and almost completely absorbed following oral administration.44, 45, 47 Following oral administration of a single 3-mg dose of levobunolol hydrochloride in healthy adults, peak blood concentrations of about 16 ng/mL occur within approximately 1-3 hours.45, 47 Following oral administration of levobunolol hydrochloride, β-adrenergic blocking activity (e.g., as measured by a decrease in exercise-induced heart rate) begins within 4-8 hours and generally persists for 24 hours or longer following oral administration.25 Substantial accumulation of the drug does not appear to occur during multiple-dose administration.45
Distribution of levobunolol hydrochloride into human ocular tissues and fluids has not been characterized to date.98 Following topical application in rabbits, racemic bunolol hydrochloride is rapidly distributed throughout ocular tissues and fluids, including the cornea, iris, ciliary body, and aqueous humor.2
Following oral administration in animals, levobunolol hydrochloride is widely distributed, with highest concentrations attained in GI tract, heart, liver, muscles, kidneys, and spleen; the drug is also distributed into the CNS.43 Following IV administration in healthy adults, the apparent volume of distribution of levobunolol is reportedly about 5.5 L/kg.45
Levobunolol crosses the placenta in some animals.2 It is not known whether the drug is distributed into milk.1
The metabolic fate and elimination characteristics of levobunolol hydrochloride following topical application to the eye in humans have not been described to date.
Following ophthalmic administration of racemic bunolol hydrochloride in rabbits, the elimination half-life of bunolol in the aqueous humor, cornea, iris, and ciliary body ranged from 60-90 minutes. Following ophthalmic application of levobunolol in rabbits, dihydrolevobunolol was the major metabolite found in the aqueous humor.98, 109 Approximately 93% of the dose applied to the eye was excreted in urine and feces in these animals.2, 99
Following oral or IV administration of a 3-mg dose of levobunolol hydrochloride in healthy adults, the drug has a plasma elimination half-life of about 5-6 hours.45, 47 Total body clearance of levobunolol from plasma has been reported to average 11 mL/minute per kg in adults with normal renal and hepatic function.45
The exact metabolic fate of levobunolol has not been clearly established, but the drug is extensively metabolized to several metabolites in the liver.36, 38, 39, 40, 41, 42, 43, 46, 47, 98, 99 The principal metabolite is dihydrolevobunolol.36, 39, 40, 44, 45, 46, 47, 48, 99, 109 Both levobunolol and dihydrolevobunolol undergo conjugation via glucuronic and sulfuric acids.36, 39, 40, 43, 47, 99, 109 Levobunolol also undergoes oxidative dealkylation and subsequent oxidation yielding 2 minor acidic metabolites, β-5-oxytetralonyl lactic acid and 5-oxytetralonyl acetic acid.36, 37, 39, 41, 43, 47 Small amounts of a hydroxydihydrolevobunolol are formed by oxidation of dihydrolevobunolol.36, 39, 40, 99 Only dihydrolevobunolol has β-Adrenergic blocking activity,36, 38, 42 and this metabolite may be present in plasma in amounts up to 65% those of levobunolol.36, 44, 47 Dihydrolevobunolol is a nonselective β-blocker with no β-agonist activity and has a pharmacologic profile38 and potency36, 38, 42, 46 similar to that of levobunolol. It has been postulated that hydrogenation of levobunolol to dihydrolevobunolol takes place in the cytosol, whereas the other metabolic pathways are microsomal reactions yielding compounds that lack β-adrenergic blocking activity.38, 42
Levobunolol hydrochloride is a nonselective β-adrenergic blocking agent.1, 2, 3, 9, 10, 11, 12, 13, 14, 15, 16, 17, 20, 21, 22, 23, 27, 28 Levobunolol is structurally related to propranolol and nadolol.18
Levobunolol is the levorotatory isomer of bunolol.11, 13, 14, 15, 16, 17, 20, 28 The l -isomer is more than 60 times as potent as dextrobunolol in β-adrenergic blocking activity1, 16 but equipotent in direct myocardial depressant activity.1, 14, 36 (See Pharmacology.)
Levobunolol hydrochloride occurs as a white, crystalline powder2 which is odorless and bitter-tasting; it has solubilities of 300 mg/mL in water2 and 24 mg/mL in alcohol2 at 25°C. The drug has a pKa of 9.4.99
Levobunolol hydrochloride ophthalmic solution is a colorless to slightly light yellow, sterile, isotonic solution of the drug in purified water;1 hydrochloric acid and/or sodium hydroxide is added to adjust pH.1, 2 The ophthalmic solution also contains benzalkonium chloride as a preservative, sodium chloride to adjust tonicity, polyvinyl alcohol to adjust viscosity, monobasic potassium phosphate and dibasic sodium phosphate as a buffer, and sodium metabisulfite.1
Levobunolol hydrochloride ophthalmic solution should be stored in light-resistant containers at 15-25°C.1
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Ophthalmic | Solution | 0.25%* | Levobunolol Hydrochloride Ophthalmic Solution | |
0.5%* | Betagan® | Allergan | ||
Levobunolol Hydrochloride Ophthalmic Solution |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions December 1, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Allergan. Betagan® (levobunolol hydrochloride) ophthalmic solution prescribing information. Irvine, CA; 2017 Dec.
2. Allergan Pharmaceuticals, Inc. Betagan® product monograph. Irvine, CA; 1985.
3. Reynolds JEF, ed. Martindale: the extra pharmacopoeia. 28th ed. London: The Pharmaceutical Press; 1982:1341.
4. Taylor P. Anticholinesterase agents. In: Gilman AG, Goodman LS, Rall TW et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 7th ed. New York: Macmillan Publishing Company; 1985:110-27.
5. Weiner N. Drugs that inhibit adrenergic nerves and block adrenergic receptors. In: Gilman AG, Goodman LS, Rall TW et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 7th ed. New York: Macmillan Publishing Company; 1985:181-214.
6. Remis LL, Epstein DL. Treatment of glaucoma. Annu Rev Med . 1984; 35:195-205. [PubMed 6426371]
7. Havener WH. Ocular pharmacology. 5th ed. St. Louis: CV Mosby Co; 1983:261-417,656-7.
8. Neufeld AH. Epinephrine and timolol: how do these drugs lower intraocular pressure? Ann Ophthalmol . 1981; 13:1109-11.
9. Schwender CF, Pike RE, Shavel J Jr. Derivatives of 3,4-dihydro-1(2 H )-naphthalenone as β-adrenergic blocking agents: 2. Aromatic-substituted analogs of bunolol. J Med Chem . 1973; 16:254-7. [PubMed 4147388]
10. Rzeszotarski WJ, Gibson RE, Eckelman WC et al. Cardioselectivity of β-adrenoceptor blocking agents: 1. 1-[(4-hydroxyphenethyl)amino]-3-(aryloxy)propan-2-ols. J Med Chem . 1979; 22:735-7. [PubMed 37339]
11. Commarato MA, Giardino EC, Kopia GA et al. Levo-bunolol and propranolol: further evaluation of oral β-blocking activity in conscious dogs. Arch Int Pharmacodyn Ther . 1977; 226:205-13. [PubMed 327960]
12. Shapiro W, Park J. The effect of a new beta-blocking agent, levo-bunolol, on exercise-induced or augmented ventricular arrhythmias. Am Heart J . 1978; 96:417-8. [PubMed 356571]
13. Kaplan HR, Commarato MA. Relative beta adrenergic receptor blocking activity in dogs after intravenous and intraportal vein administration: bunolol, propranolol, their levo isomers and sotalol. J Pharmacol Exp Ther . 1973; 185:395-405. [PubMed 4145046]
14. Robson RD, Kaplan HR. The cardiovascular pharmacology of bunolol, a new beta adrenergic blocking agent. J Pharmacol Exp Ther . 1970; 175:157-67. [PubMed 4394301]
15. Kaplan HR, LaSala SA, Robson RD. Oral β-adrenoceptor blocking activity of bunolol and its optical isomers. Eur J Pharmacol . 1971; 16:237-40. [PubMed 4405784]
16. Kaplan HR, LaSala SA. Oral and intravenous beta adrenergic blocking potency of bunolol d,1-5-[3-tert.-butylamino)-2-hydroxypropoxy)-3,4 dihydro-1-(2 H ) naphthalenone hydrochloride, the isomers and propranolol. Fed Proc . 1970; 29:477.
17. Kaplan HR, Commarato MA, Lattime EC. l -Bunolol and propranolol: oral and intravenous β-adrenoceptor blocking activity in rats compared to dogs and humans. J Pharm Sci . 1978; 67:132-3. [PubMed 22739]
18. Hammer RH. Cardiovascular drugs. In: Foye WO, ed. Principles of medicinal chemistry. 2nd ed. Philadelphia: Lea & Febiger; 1981:395-429.
19. Arce-Gomez E, Alcocer L. Aspe J. Antihypertensive effect of L-bunolol a new beta -adrenergic blocking agent. Curr Ther Res . 1976; 19:386-96. [PubMed 817869]
20. Covi G, Capuzzo MG, Corsato M et al. Comparison of levo-bunolol and atenolol in the treatment of mild or moderate hypertension. Curr Ther Res . 1984; 36:516-21.
21. Gavras H, Gavras I, Brunner HR et al. Effect of a new beta-adrenergic blocker, l -bunolol, on blood pressure and on the renin-aldosterone system. J Clin Pharmacol . 1977; 17:350-7. [PubMed 323300]
22. Podrid PJ, Lown B, Graboys TB. Effect of levo-bunolol on ventricular arrhythmia. Circulation . 1977; 56(Suppl III):III-8. [PubMed 902386]
23. Kaplan HR, Robson RD. Antiarrhythmic activity of bunolol, a new beta adrenergic blocking agent. J Pharmacol Exp Ther . 1970; 175:168-77. [PubMed 4394302]
24. Bray JS. Pilot single-blind evaluation of the effects of levo-bunolol on exercise tolerance and angina attack rate in patients with proven ischemic heart disease. Clin Res . 1977; 25:544A.
25. Shapiro W, Park J. Comparison of duration of action of levo-bunolol and propranolol at rest and during exercise in angina pectoris. Clin Res . 1978; 26:47A.
26. Palmieri G, Nazzari M, Ambrosi G et al. A crossover randomized comparison of levobunolol and propranolol in the treatment of angina of effort. Curr Ther Res . 1985; 37:524-9.
27. Giles RE, Finkel MP. Effects of alprenolol, bunolol and propranolol on pulmonary resistance in the anaesthetized dog. Eur J Pharmacol . 1971; 16:156-63.
28. Quast U, Vollmer KO. Binding of β-adrenergic antagonists to rat and rabbit lung: special reference to levobunolol. Arzneimittelforschung . 1984; 34:579-84. [PubMed 6147147]
29. Coakes RL, Brubaker RF. The mechanism of timolol in lowering intraocular pressure: in the normal eye. Arch Ophthalmol . 1978; 96:2045-8. [PubMed 363105]
30. Watanabe K, Chiou GCY. Action mechanism of timolol to lower the intraocular pressure in rabbits. Ophthalmic Res . 1983; 15:160-7. [PubMed 6314218]
31. Boger WP III. Timolol: short term “escape” and long term “drift.” Ann Ophthalmol . 1979; 11:1239-42. Editorial.
32. Remis LL, Epstein DL. Treatment of glaucoma. Glaucoma . 1984; 35:195-205.
33. Chiou GCY. Recent advances in antiglaucoma drugs. Biochem Pharmacol . 1981; 30:103-6. [PubMed 7248025]
34. Schenker HI, Yablonski ME, Podos SM et al. Fluorophotometric study of epinephrine and timolol in human subjects. Arch Ophthalmol . 1981; 99:1212-6. [PubMed 7259595]
35. Polack BCP. Drugs used in ocular treatment. In: Dukes MNG, ed. Side effects of drugs. New York: Elsevier/North Holland Inc; 1981:425-9.
36. Leinweber FJ, Szpiech JM, DiCarlo FJ. l -Bunolol metabolites in human urine. Pharmacology . 1978; 16:70-7. [PubMed 339235]
37. Leinweber FJ, Greenough RC, DiCarlo FJ. Bunolol metabolism by dogs: urinary excretion of 5-hydroxytetralone. Xenobiotica . 1978; 8:239-43. [PubMed 347724]
38. Leinweber FJ, Greenough RC, Schwender CF et al. Bunolol metabolism by cell-free preparations of human liver: biosynthesis of dihydrobunolol. Xenobiotica . 1972; 2:191-202. [PubMed 4560367]
39. Leinweber FJ, Szpiech JM, DiCarlo FJ. l -Bunolol metabolism in rats: identification of urinary metabolites. J Pharm Sci . 1978; 67:129-31. [PubMed 338886]
40. Leinweber FJ, Greenough RC, DiCarlo FJ. Bunolol metabolism by dogs: identification of basic metabolites and their conjugates. J Pharm Sci . 1977; 66:1570-5. [PubMed 335043]
41. Leinweber FJ, Greenough RC, Schwender CF et al. Bunolol metabolism by dogs: isolation and identification of two acidic metabolites. J Pharm Sci . 1971; 60:1516-9. [PubMed 4399678]
42. Leinweber FJ, Greenough RC, Schwender CF et al. Bunolol metabolism by cell-free preparations of human liver: biosynthesis of dihydrobunolol. Fed Proc . 1972; 31:537.
43. Leinweber FJ, Haynes LJ, Crew MC et al. Absorption, tissue distribution, and excretion of bunolol-14C by dogs. J Pharm Sci . 1971; 60:1512-5. [PubMed 4399677]
44. DiCarlo FJ, Leinweber FJ, Szpiech JM et al. Metabolism of l -bunolol in man. Fed Proc . 1976; 35:566.
45. Kölle EU, Hengy H, Thomann P. Pharmacokinetics of levobunolol and dihydrolevobunolol in man. Naunyn-Schmiedeberg's Arch Pharmacol . 1983; 322:R9.
46. Hengy H, Kölle EU. Determination of levobunolol and dihydrolevobunolol in blood and urine by high-performance liquid chromatography using fluorescence detection. J Chromatogr . 1985; 338:444-9. [PubMed 3889026]
47. DiCarlo FJ, Leinweber FJ, Szpiech JM et al. Metabolism of l -bunolol. Clin Pharmacol . 1977; 22:858-63.
48. Schwender CF, Farber S, Blaum C et al. Derivatives of 3,4-dihydro-1(2 H )-naphthalenone as β-adrenergic blocking agents: 1. bunolol and related analogs. J Med Chem . 1970; 13:684-8. [PubMed 4393796]
49. Shell JW. Pharmacokinetics of topically applied ophthalmic drugs. Surv Ophthalmol . 1982; 26:207-18. [PubMed 7041308]
50. Zimmerman TJ. Timolol maleate—a new glaucoma medication? Invest Ophthalmol Visual Sci . 1977; 16:687-8. Editorial.
51. Levobunolol Study Group. Levobunolol: a beta-adrenoceptor antagonist effective in the long-term treatment of glaucoma. Ophthalmology . 1985; 92:1271-6. [PubMed 2865710]
52. Berson FG, Cohen HB, Foerster RJ et al. Levobunolol compared with timolol for the long-term control of elevated intraocular pressure. Arch Ophthalmol . 1985; 103:379-82. [PubMed 3883972]
53. Bensinger RE, Keates EU, Gofman JD et al. Levobunolol: a three-month efficacy study in the treatment of glaucoma and ocular hypertension. Arch Ophthalmol . 1985; 103:375-8. [PubMed 3883971]
54. Ober M, Scharrer A, David R et al. Long-term ocular hypotensive effect of levobunolol: results of a one-year study. Br J Ophthalmol . 1985; 69:593-9. [PubMedCentral][PubMed 3893528]
55. Duzman E, Ober M, Scharrer A et al. A clinical evaluation of the effects of topically applied levobunolol and timolol on increased intraocular pressure. Am J Ophthalmol . 1982; 94:318-27. [PubMed 6751091]
56. Long D, Zimmerman T, Spaeth G et al. Minimum concentration of levobunolol required to control intraocular pressure in patients with primary open-angle glaucoma or ocular hypertension. Am J Ophthalmol . 1985; 99:18-22. [PubMed 3881033]
57. Partamian LG, Kass MA, Gordon M. A dose-respone study of the effect of levobunolol on ocular hypertension Am J Ophthalmol . 1983; 95:229-32.
58. Cinotti A, Cinotti D, Grant W et al. Levobunolol vs timolol for open-angle glaucoma and ocular hypertension. Am J Ophthalmol . 1985; 99:11-7. [PubMed 3881032]
59. Thomas JV, Epstein DL. Timolol and epinephrine in primary open angle glaucoma. Arch Ophthalmol . 1981; 99:91-5. [PubMed 7006581]
60. Martin DE, Kammerer WS. The hypertensive surgical patient: controversies in management. Surg Clin North Am . 1983; 63:1017-33. [PubMed 6138862]
61. Zimmerman TJ, Leader BJ, Golob DS. Potential side effects of timolol therapy in the treatment of glaucoma. Ann Ophthalmol . 1981; 13:683-9. [PubMed 7020551]
62. Van Buskirk M. Adverse reactions from timolol administration. Ophthalmology . 1980; 87:447-50. [PubMed 7402590]
63. McMahon CD, Shaffer RN, Hoskins HD Jr et al. Adverse effects experienced by patients taking timolol. Am J Ophthalmol . 1979; 88:736-8. [PubMed 507146]
64. Jackson JE, Bressler R. Clinical pharmacology of sulphonylurea hypoglycaemic agents: part 2. Drugs . 1981; 22:295-320. [PubMed 7030708]
65. Anon. Additions to Timoptic contraindications. FDA Drug Bull . 1981; 11:17-8. [PubMed 7319166]
66. Schoene RB, Abuan T, Ward RL et al. Effects of topical betaxolol, timolol, and placebo on pulmonary function in asthmatic bronchitis. Am J Ophthalmol . 1984; 97:86-92. [PubMed 6141730]
67. Hernandez y Hernandez HH, Cervantes R, Frati A et al. Cardiovascular effects of topical glaucoma therapies in normal subjects. J Toxicol Cutaneous Ocul Toxicol . 1983; 2:99-106.
68. McMahon CD, Shaffer RN, Hoskins HD Jr et al. Adverse effects experienced by patients taking timolol. Am J Ophthalmol . 1979; 88:736-8. [PubMed 507146]
69. Van Buskirk M. Adverse reactions from timolol administration. Ophthalmology . 1980; 87:447-50. [PubMed 7402590]
70. Zimmerman TJ, Leader BJ, Golob DS. Potential side effects of timolol therapy in the treatment of glaucoma. Ann Ophthalmol . 1981; 13:683-9. [PubMed 7020551]
71. Levy NS, Boone L, Ellis E. A controlled comparison of betaxolol and timolol with long-term evaluation of safety and efficacy. Glaucoma . 1985; 7:54-62.
72. Munroe WP, Rindone JP, Kershner RM. Systemic side effects associated with the ophthalmic administration of timolol. Drug Intell Clin Pharm . 1985; 19:85-9. [PubMed 3882377]
73. Leier CV, Baker ND, Weber PA. Cardiovascular effects of ophthalmic timolol. Ann Intern Med . 1986; 104:197-9. [PubMed 3946944]
74. Schwender CF, Farber S, Blaum C et al. Derivatives of 3,4-dihydro-1(2H)-naphthalenone as β-adrenergic blocking agents. 1. bunolol and related analogs. J Med Chem . 1970; 13:684-8. [PubMed 4393796]
75. Gosselin RE, Smith RP, Hodge HC. Clinical toxicology of commercial products. 5th ed. Baltimore, MD: Williams & Wilkins; 1984:I-6.
76. Kitazawa Y, Horie T. Diurnal variation of intraocular pressure in primary open-angle glaucoma. Am J Ophthalmol . 1975; 79:557-66. [PubMed 1168023]
77. Caldwell DR, Salisbury CR, Guzek JP. Effects of topical betaxolol in ocular hypertensive patients. Arch Ophthalmol . 1984; 102:539-40. [PubMed 6704008]
78. Radius RL. Use of betaxolol in the reduction of elevated intraocular pressure. Arch Ophthalmol . 1983; 101:898-900. [PubMed 6860201]
79. Levy NS, Boone L. Effect of 0.25% betaxolol placebo. Glaucoma . 1985; 5:230-2.
80. American Society of Health-System Pharmacists, Inc.. Medication Teaching Manual . 2nd ed. Bethesda, MD: American Society of Hospital Pharmacists; 1980:300.
81. Fraunfelder FT. Extraocular fluid dynamics: how best to apply topical ocular medication. Trans Am Ophthalmol . 1976; 74:457-87.
82. Anon. Sulfites in foods and drugs. FDA Drug Bull . 1983; 13:12. [PubMed 6604672]
83. Sogn D. The ubiquitous sulfites. JAMA . 1984; 251:2986-7. [PubMed 6716628]
84. Koepke JW, Christopher KL, Chai H et al. Dose-dependent bronchospasm from sulfites in isoetharine. JAMA . 1984; 251:2982-3. [PubMed 6716626]
85. Twarog FJ, Leung DYM. Anaphylaxis to a component of isoetharine (sodium bisulfite). JAMA . 1982; 248:2030-1. [PubMed 7120631]
86. Baker GJ, Collett P, Allen DH. Bronchospasm induced by metabisulphite-containing foods and drugs. Med J Aust . 1981; 2:614-7. [PubMed 7334982]
87. Koepke JW, Selner JC, Dunhill AL. Presence of sulfur dioxide in commonly used bronchodilator solutions. J Allergy Clin Immunol . 1983; 72(5 Part 1):504-8. [PubMed 6630799]
88. US Food and Drug Administration. Sulfiting agents; labeling in drugs for human use: warning statement (Docket No. 84N-0113). Fed Regist . 1985; 50:47558-63.
89. US Food and Drug Administration Center for Food Safety and Applied Nutrition. Tentative report on the reexamination of the GRAS status of sulfiting agents, October 1984. Bethesda, MD: FASEB Life Sciences Research Office. (in press)
90. Spiritus EM, Casciari R. Effects of topical betaxolol, timolol, and placebo on pulmonary function in asthmatic bronchitis. Am J Ophthalmol . 1985; 100:492-3. [PubMed 4037047]
91. Schoene RB, Abuan T, Ward RL et al. Effects of topical betaxolol, timolol, and placebo on pulmonary function in asthmatic bronchitis. Am J Ophthalmol . 1985; 100:493-4.
92. Silverstone DE, Arkfeld D, Cowan G et al. Long-term diurnal control of intraocular pressure with levobunolol and timolol. Glaucoma . 1985; 7:138-40.
93. Wandel T, Charap AD, Lewis RA et al. Glaucoma treatment with once-daily levobunolol. Am J Ophthalmol . 1986; 101:298-304. [PubMed 3513594]
94. Matthys H, Pohl M, Braig H et al. The cardiopulmonary effects of celiprolol and propranolol in asymptomatic bronchial asthmatics. Br J Clin Pract . 1985; 40(Suppl):33.
95. Alcon Laboratories. Betoptic® prescribing information. Fort Worth, TX; 1985 Nov.
96. Merck Sharpe & Dohme. Timoptic® prescribing information. West Point, PA; 1985 Oct.
97. Schwartz HJ, Scher TH. Biosulfite intolerance manifest as bronchospasm following topical dipivefrin hydrochloride therapy for glaucoma. Arch Ophthalmol . 1985; 103:14-5. [PubMed 3977669]
98. Reviewers' comments (personal observations), 1986 Aug.
99. Novack G. (Allergan Pharmaceuticals, Inc, Irvine, CA): personal communication; 1986 Jul 17.
100. Meekins BB, Tsoy EA, Shields BM. Comparison of two treatment schedules for combined timolol and dipivefrin therapy. Invest Ophthalmol Vis Sci . 1986; 27(Suppl):161.
101. Allen R, Long D, Robin A et al. Efficacy and safety of levobunolol compared with timolol in combination with dipivefrin in glaucoma. Invest Ophthalmol Vis Sci . 1986; 27(Suppl):161.
102. Kass MA, Meltzer DW, Gordon M et al. Compliance with topical pilocarpine treatment. Am J Ophthalmol . 1986; 101:515-23. [PubMed 3706455]
103. Goldberg I, Ashburn FS Jr, Palmberg PF et al. Timolol and epinephrine: a clinical study of ocular interactions. Arch Ophthalmol . 1980; 98:484-6. [PubMed 7362504]
104. Goethals M, Missotten L. Long term trial of timolol in different forms of glaucoma. Bull Soc Belg Ophthalmol . 1977; 179:95-101.
105. Kramer P, Ritch R. The treatment of acute angle-closure glaucoma revisited. Ann Ophthalmol . 1984; 16:1101-3. [PubMed 6532284]
106. Phillips CI. Timolol in operated closed-angle glaucoma. Br J Ophthalmol . 1980: 64:240-6.
107. Airaksinen PJ, Saari KM, Tiainen TJ et al. Management of acute closed-angle glaucoma with miotics and timolol. Br J Ophthalmol . 1979; 63:822-5. [PubMedCentral][PubMed 526463]
108. Levine L. Clinical implications of reported timolol-induced side effects. Am J Optom Physiol Optics . 1982; 59:523-8.
109. Tang-Liu DDS, Liu S, Richman J et al. HPLC quantitation of levobunolol and its metabolite, dihydrolevobunolol, in biological fluids. J Liq Chromatogr . (in press)
110. Food and Drug Administration. Sulfiting agents; labeling in drugs for human use; warning statements. [21 CFR Part 201] Fed Regist . 1986; 51:43900-5.
111. Garbe D. (Allergan Pharmaceuticals, Inc, Irvine, CA): personal communication; 1990 Feb 13.
112. Alward WLM. Medical management of glaucoma. N Engl J Med . 1998; 339:1298-307. [PubMed 9791148]
113. Allergan. Levobunolol hydrochloride ophthalmic solution prescribing information. Madison, NJ; 2018 Dec.
114. Alcon Laboratories. Betoptic® S (betaxolol hydrochloride) suspension prescribing information. Fort Worth, TX; 2018 Nov.
130. Prum BE Jr, Rosenberg LF, Gedde SJ et al. Primary open-angle glaucoma preferred practice pattern® guideline [published corrigendum appears in Ophthalmology . 2018; 125: 949]. San Francisco, CA: American Academy of Ophthalmology; 2015. From the American Academy of Ophthalmology website. [Web]
131. Liebmann JM, Lee JK. Current therapeutic options and treatments in development for the management of primary open-angle glaucoma. Am J Manag Care . 2017; 23(15 Suppl):S279-S292. [PubMed 29164845]
132. Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA . 2014; 311:1901-11. [PubMed 24825645]
133. Gupta D, Chen PP. Glaucoma. Am Fam Physician . 2016; 93:668-74. [PubMed 27175839]
134. Inoue K. Managing adverse effects of glaucoma medications. Clin Ophthalmol . 2014; 8:903-13. [PubMed 24872675]