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PACIFIC/GREENST
SKU
60758006015

levobunolol 0.5% eye drops

Generic
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Uses

Ocular Hypertension and Glaucoma

In ophthalmology, topical levobunolol hydrochloride is used to reduce elevated IOP in various conditions, including chronic open-angle glaucoma and ocular hypertension. Reduction in IOP may reduce or prevent glaucomatous visual field loss or optic nerve damage and obviate surgery.

Levobunolol may be used alone or in conjunction wth a topical miotic (e.g., pilocarpine), topical dipivefrin, topical epinephrine, and/or a systemic carbonic anhydrase inhibitor. When used in conjunction with these agents, levobunolol may have an additive IOP-lowering effect. If levobunolol is used to reduce IOP in patients with angle-closure glaucoma, 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.

Like timolol, levobunolol reduces elevated IOP in patients with chronic open-angle glaucoma without producing the miosis and/or ciliary spasm that are associated with miotic agents. In addition, use of levobunolol in patients with central lenticular opacities can avoid the visual impairment caused by a constricted pupil. 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, and like timolol, ophthalmic levobunolol has been associated with adverse systemic pulmonary and cardiovascular effects. Increased airway resistance can occur following topical application of levobunolol to the eye. 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.(See Cautions: Precautions and Contraindications.)

During prolonged therapy with topical levobunolol, the effect in reducing IOP is generally well maintained, but tolerance has been reported in some patients. 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.

Dosage and Administration

Administration

Levobunolol hydrochloride is applied topically to the eye as an ophthalmic solution. Care should be taken to avoid contamination of the solution container. The patient instructions provided by the manufacturer should be consulted for use of the compliance cap attached to the container of levobunolol hydrochloride ophthalmic solution.

Dosage

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.

For the initial treatment of open-angle glaucoma or ocular hypertension, the usual dosage of levobunolol hydrochloride is 1 or 2 drops of a 0.5% solution in the affected eye(s) once daily or, alternatively, 1 or 2 drops of a 0.25% solution may be used twice daily. If necessary for adequate reduction of 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.

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. 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; thereafter, IOP should be determined as necessary.

Dosages exceeding 1 drop of levobunolol hydrochloride 0.5% solution twice daily generally have not been more effective. If further reduction of IOP is required in patients receiving 1 drop of 0.5% levobunolol hydrochloride ophthalmic solution twice daily, a topical miotic, and/or a systemically administered carbonic anhydrase inhibitor may be added to the levobunolol hydrochloride regimen.

Cautions

Levobunolol hydrochloride ophthalmic solution is generally well tolerated following topical application to the eye; however, adverse effects may occasionally be severe enough to require discontinuance of the drug.

Ocular Effects

The most frequent adverse effects of topical levobunolol are mild ocular stinging or burning and discomfort following instillation of the solution, which occur in about 33% of patients but are usually transient. Blepharoconjunctivitis occurs in about 5% of patients, and blepharitis, decreased visual acuity, conjunctivitis, iridocyclitis, band keratopathy, erythema, and itching sensation occur in about 4% of patients. Decreased corneal sensitivity and tearing have been reported rarely. Keratitis, blepharoptosis, and visual disturbances (e.g., refractive changes [secondary to withdrawal of miotic therapy in some cases], diplopia, ptosis) have been reported with ophthalmic use of other nonselective β-blocking agents.

Systemic Effects

Use of levobunolol hydrochloride ophthalmic solution has occasionally been associated with adverse systemic effects. Evidence of adverse pulmonary or cardiovascular effects following topical application of the drug to the eye has been reported. Aggravation or precipitation of certain cardiovascular, pulmonary, and other disorders, presumably related to effects of systemic β-adrenergic blockade, may occur during therapy with topical levobunolol and may include bradycardia, arrhythmia, hypotension, syncope, heart block, cerebral ischemia, cerebrovascular accident, and bronchospasm (mainly in patients with preexisting bronchospastic disease and geriatric patients). Severe respiratory and cardiac reactions, including death resulting from bronchospasm in patients with asthma, and rarely death in association with cardiac failure, have been reported in patients receiving topical therapy with a nonselective β-blocking agent. Reduction of resting heart rate (about 5-10 beats/minute) may occur, and decreased diastolic (about 2-10 mm Hg) and systolic (about 4-20 mm Hg) blood pressures have been reported in some patients receiving ophthalmic levobunolol. Rarely, headache, transient ataxia, dizziness, and lethargy have been reported following topical application of levobunolol.

Nausea, heartburn, diarrhea, dizziness, mental depression, and elevated serum ALT (SGPT) and bilirubin concentrations have been reported in patients receiving topical therapy with a nonselective β-blocking agent. Masking of hypoglycemic symptoms in insulin-dependent diabetics, respiratory failure, and congestive heart failure have also been reported. The possibility that other adverse effects associated with systemic levobunolol or other β-adrenergic blocking agents may occur during topical levobunolol therapy should be considered.

Sensitivity Reactions

Hypersensitivity reactions, including urticaria and pruritus, have occurred rarely during ophthalmic levobunolol therapy. Localized and generalized rash have been reported in patients receiving topical therapy with a β-blocking agent.

Precautions and Contraindications

Levobunolol hydrochloride may be absorbed systemically following topical application to the eye, and the usual precautions associated with systemic use of nonselective β-adrenergic blocking agents should be considered when using topical levobunolol. In addition, patients receiving topical levobunolol and a systemic β-adrenergic blocking agent concomitantly should be observed carefully for potential additive effects on IOP and/or systemic effects of β-adrenergic blockade.

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. 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.

Levobunolol hydrochloride ophthalmic solution should be used with caution in patients with inadequate cardiac function, since congestive heart failure may be precipitated by blockade of β-adrenergic stimulation when levobunolol therapy is administered. In addition, in patients with latent cardiac insufficiency, prolonged β-adrenergic blockade and subsequent myocardial depression may lead to cardiac failure. The drug should be discontinued at the first sign or symptom of impending cardiac failure. Ophthalmic levobunolol is 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).

Ophthalmic levobunolol should be used with caution in patients with diminished pulmonary function and in patients with nonallergic bronchospasm (e.g., chronic bronchitis, emphysema), since β-blocking agents may interfere with the bronchodilation produced by endogenous and exogenous catecholamines and other β2-adrenergic agonists. β-adrenergic blockade may lead to an increase in airway resistance and bronchospasm, particularly in patients with a history of asthma. Ophthalmic levobunolol is contraindicated in patients with asthma or a history of asthma and in patients with severe chronic obstructive pulmonary disease.

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). 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.

The need to withdraw β-blocking agents prior to major surgery is controversial. The manufacturer states that gradual withdrawal of levobunolol prior to administration of general anesthesia should be considered, since severe, protracted hypotension has occurred during surgery in some patients who received β-adrenergic blocking agents and because β-blocking agents may reduce the ability of the heart to respond to reflex β-adrenergic stimuli. If necessary during surgery, the effects of β-blockers may be reversed by sufficient doses of β-agonists (e.g., isoproterenol, dopamine, dobutamine, norepinephrine).

Ophthalmic levobunolol should be used with caution in patients with myasthenia gravis, since β-blockers have been reported to potentiate muscle weakness (manifested as diplopia, ptosis, and generalized weakness) in some patients with this condition.

Because levobunolol has little or no effect on pupil size, the drug should not be used alone in patients with angle-closure glaucoma, but only in combination with a miotic.

Levobunolol hydrochloride ophthalmic solution is also contraindicated in patients with sinus bradycardia or atrioventricular block greater than first-degree, and in patients with known hypersensitivity to the drug or any ingredient in the formulation.

Pediatric Precautions

Safety and efficacy of levobunolol hydrochloride ophthalmic solution in children have not been established.

Mutagenicity and Carcinogenicity

In vitro and in vivo microbial and mammalian test systems using levobunolol have not revealed evidence of mutagenicity.

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. 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.

Pregnancy, Fertility, and Lactation

Pregnancy

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. 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. 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. 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.

Fertility

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; 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.

Lactation

It is not known whether levobunolol hydrochloride is distributed into milk. Because systemically administered β-blockers and topical timolol maleate are distributed into milk, levobunolol should be used with caution in nursing women.

Drug Interactions

Ocular Hypotensive Agents

When used in conjunction with topical miotics and/or systemically administered carbonic anhydrase inhibitors, the effect of levobunolol hydrochloride in lowering IOP may be additive. This effect may be used to therapeutic advantage in the treatment of glaucoma or ocular hypertension. However, some evidence suggests that combined therapy with a topical nonselective adrenergic agonist and a topical nonselective β-adrenergic blocking agent (e.g., timolol) generally has a less than additive effect. Although topical levobunolol used alone has little or no effect on pupil size, mydriasis resulting from concomitant therapy with topical levobunolol and epinephrine has been reported occasionally.

Systemic β-Adrenergic Blocking Agents

The possibility of an additive effect on IOP and/or systemic β-adrenergic blockade should be considered in patients who are receiving a systemic β-blocking agent and topical levobunolol concomitantly.

Catecholamine-depleting Drugs

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.

Pharmacokinetics

Absorption

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.

Following topical application to the eye of a 0.25 or 0.5% solution of levobunolol hydrochloride, reduction in IOP is usually evident with 1 hour, reaches a maximum within about 2-6 hours, and may persist for up to 24 hours. The effect of a single dose of levobunolol hydrochloride on IOP usually dissipates within 24 hours after instillation; however, as with other ophthalmic β-blocking agents, some reduction in IOP may persist for up to a week or longer after discontinuance of levobunolol. 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.

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. Substantial accumulation of racemic bunolol in ocular tissue does not appear to occur during multiple-dose administration.

Levobunolol hydrochloride is rapidly and almost completely absorbed following oral administration. 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. 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. Substantial accumulation of the drug does not appear to occur during multiple-dose administration.

Distribution

Distribution of levobunolol hydrochloride into human ocular tissues and fluids has not been characterized to date. 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.

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. Following IV administration in healthy adults, the apparent volume of distribution of levobunolol is reportedly about 5.5 L/kg.

Levobunolol crosses the placenta in some animals. It is not known whether the drug is distributed into milk.

Elimination

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. Approximately 93% of the dose applied to the eye was excreted in urine and feces in these animals.

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. 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.

The exact metabolic fate of levobunolol has not been clearly established, but the drug is extensively metabolized to several metabolites in the liver. The principal metabolite is dihydrolevobunolol. Both levobunolol and dihydrolevobunolol undergo conjugation via glucuronic and sulfuric acids. Levobunolol also undergoes oxidative dealkylation and subsequent oxidation yielding 2 minor acidic metabolites, β-5-oxytetralonyl lactic acid and 5-oxytetralonyl acetic acid. Small amounts of a hydroxydihydrolevobunolol are formed by oxidation of dihydrolevobunolol. Only dihydrolevobunolol has β-Adrenergic blocking activity, and this metabolite may be present in plasma in amounts up to 65% those of levobunolol. Dihydrolevobunolol is a nonselective β-blocker with no β-agonist activity and has a pharmacologic profile and potency 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.

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