Prescription Drug Information: Levobunolol Hydrochloride

LEVOBUNOLOL HYDROCHLORIDE- levobunolol hydrochloride solution/ drops
Bausch & Lomb Incorporated

DESCRIPTION

Levobunolol hydrochloride ophthalmic solution USP, 0.5% is a noncardioselective beta-adrenoceptor blocking agent for ophthalmic use.

Levobunolol hydrochloride is represented by the following structural formula:

BETAGAN ® (levobunolol hydrochloride ophthalmic solution, USP) s terile

Mol. Formula C17 H25 NO3 •HCl

Mol. Wt. 327.85

Chemical Name: (–)-5-[3-(tert -Butylamino)-2-hydroxypropoxy]-3,4-dihydro-1(2H)- naphthalenone hydrochloride.

Each mL of 0.5% contains:

Active: levobunolol hydrochloride 0.5%; Inactives: polyvinyl alcohol 1.4%, sodium chloride, dibasic sodium phosphate, edetate disodium, sodium metabisulfite, monobasic potassium phosphate, and purified water. Hydrochloric acid and/or sodium hydroxide may be added to adjust pH (5.5 — 7.5); Preservative: benzalkonium chloride (0.004%).

CLINICAL PHARMACOLOGY

Levobunolol hydrochloride is a noncardioselective beta-adrenoceptor blocking agent, equipotent at both beta1 and beta2 receptors. Levobunolol hydrochloride is greater than 60 times more potent than its dextro isomer in its beta-blocking activity, yet equipotent in its potential for direct myocardial depression. Accordingly, the levo isomer, levobunolol hydrochloride, is used. Levobunolol hydrochloride does not have significant local anesthetic (membrane-stabilizing) or intrinsic sympathomimetic activity.

Beta-adrenergic receptor blockade reduces cardiac output in both healthy subjects and patients with heart disease. In patients with severe impairment of myocardial function, beta-adrenergic receptor blockade may inhibit the stimulatory effect of the sympathetic nervous system necessary to maintain adequate cardiac function.

Beta-adrenergic receptor blockade in the bronchi and bronchioles results in increased airway resistance from unopposed parasympathetic activity. Such an effect in patients with asthma or other bronchospastic conditions is potentially dangerous.

Levobunolol hydrochloride ophthalmic solution, USP has been shown to be an active agent in lowering elevated as well as normal intraocular pressure (IOP) whether or not accompanied by glaucoma. 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.

The onset of action with one drop of levobunolol hydrochloride ophthalmic solution can be detected within one hour after treatment, with maximum effect seen between 2 and 6 hours.

A significant decrease in IOP can be maintained for up to 24 hours following a single dose.

In controlled clinical studies of approximately two years duration, intraocular pressure was well-controlled in approximately 80% of subjects treated with levobunolol hydrochloride ophthalmic solution 0.5% twice a day. The mean IOP decrease from baseline was between 7 mm Hg and 8 mm Hg. No significant effects on pupil size, tear production or corneal sensitivity were observed. Levobunolol hydrochloride ophthalmic solution at the concentrations tested, when applied topically, decreased heart rate and blood pressure in some patients. The IOP-lowering effect of levobunolol hydrochloride ophthalmic solution was well maintained over the course of these studies.

In a three-month clinical study, a single daily application of 0.5% levobunolol hydrochloride ophthalmic solution controlled the IOP of 72% of subjects achieving an overall mean decrease in IOP of 7.0 mm Hg.

The primary mechanism of the ocular hypotensive action of levobunolol hydrochloride in reducing IOP is most likely a decrease in aqueous humor production. Levobunolol hydrochloride ophthalmic solution reduces IOP with little or no effect on pupil size or accommodation.

INDICATIONS AND USAGE

Levobunolol hydrochloride ophthalmic solution has been shown to be effective in lowering intraocular pressure and may be used in patients with chronic open-angle glaucoma or ocular hypertension.

CONTRAINDICATIONS

Levobunolol hydrochloride ophthalmic solution is contraindicated in those individuals with bronchial asthma, or with a history of bronchial asthma, or severe chronic obstructive pulmonary disease (see WARNINGS); sinus bradycardia; second and third degree atrioventricular block; overt cardiac failure (see WARNINGS); cardiogenic shock; or hypersensitivity to any component of these products.

WARNINGS

As with other topically applied ophthalmic drugs, levobunolol hydrochloride ophthalmic solution may be absorbed systemically. The same adverse reactions found with systemic administration of beta-adrenergic blocking agents may occur with topical administration. For example, severe respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma, and rarely death in association with cardiac failure, have been reported with topical application of beta-adrenergic blocking agents (see CONTRAINDICATIONS). Additionally, ophthalmic beta-blockers may impair compensatory tachycardia and increase risk of hypotension.

Cardiac Failure

Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition by beta-adrenergic receptor blockade may precipitate more severe failure.

In Patients Without a History of Cardiac Failure

Continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of cardiac failure, levobunolol hydrochloride ophthalmic solution should be discontinued (see CONTRAINDICATIONS).

Potentiation of Vascular Insufficiency

Levobunolol hydrochloride ophthalmic solution may potentiate syndromes associated with vascular insufficiency (i.e. Raynaud’s phenomenon), and therefore, should be used with caution in these patients.

Obstructive Pulmonary Disease

PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (e.g., CHRONIC BRONCHITIS, EMPHYSEMA) OF MILD OR MODERATE SEVERITY, BRONCHOSPASTIC DISEASE OR A HISTORY OF BRONCHOSPASTIC DISEASE (OTHER THAN BRONCHIAL ASTHMA OR A HISTORY OF BRONCHIAL ASTHMA, IN WHICH LEVOBUNOLOL HYDROCHLORIDE OPHTHALMIC SOLUTION IS CONTRAINDICATED, SEE CONTRAINDICATIONS), SHOULD IN GENERAL NOT RECEIVE BETA BLOCKERS, INCLUDING LEVOBUNOLOL HYDROCHLORIDE OPHTHALMIC SOLUTION. However, if levobunolol hydrochloride ophthalmic solution is deemed necessary in such patients, then it should be administered cautiously since it may block bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta2 receptors.

Major Surgery

The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to major surgery is controversial. Beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta-adrenergically mediated reflex stimuli. This may augment the risk of general anesthesia in surgical procedures. Some patients receiving beta-adrenergic receptor blocking agents have been subject to protracted severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported. For these reasons, in patients undergoing elective surgery, gradual withdrawal of beta-adrenergic blocking agents may be appropriate.

If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of such agonists as isoproterenol, dopamine, dobutamine or levarterenol (see OVERDOSAGE).

Diabetes Mellitus

Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic blocking agents may mask the signs and symptoms of acute hypoglycemia.

Thyrotoxicosis

Beta-adrenergic blocking agents may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blocking agents which might precipitate a thyroid storm.

Choroidal Detachment

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

These products contain sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

PRECAUTIONS

General

Levobunolol hydrochloride ophthalmic solution, USP should be used with caution in patients with known hypersensitivity to other beta-adrenoceptor blocking agents.

Use with caution in patients with known diminished pulmonary function.

Levobunolol hydrochloride ophthalmic solution should be used with caution in patients who are receiving a beta-adrenergic blocking agent orally, because of the potential for additive effects on systemic beta-blockade or on intraocular pressure. Patients should not typically use two or more topical ophthalmic beta-adrenergic blocking agents simultaneously.

Because of the potential effects of beta-adrenergic blocking agents on blood pressure and pulse rates, these medications must be used cautiously in patients with cerebrovascular insufficiency. Should signs or symptoms develop that suggest reduced cerebral blood flow while using levobunolol hydrochloride ophthalmic solution, alternative therapy should be considered.

In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This requires, in most cases, constricting the pupil with a miotic. Levobunolol hydrochloride ophthalmic solution has little or no effect on the pupil. When levobunolol hydrochloride ophthalmic solution is used to reduce elevated intraocular pressure in angle-closure glaucoma, it should be followed with a miotic and not alone.

The preservative in levobunolol hydrochloride ophthalmic solution, benzalkonium chloride, may be absorbed by soft contact lenses. Patients wearing soft (hydrophilic) contact lenses should be instructed to remove contact lenses before administration of the solution and wait at least 15 minutes after instilling levobunolol hydrochloride ophthalmic solution before reinserting soft contact lenses.

Muscle Weakness

Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis and generalized weakness).

Drug Interactions

Although levobunolol hydrochloride ophthalmic solution used alone has little or no effect on pupil size, mydriasis resulting from concomitant therapy with levobunolol hydrochloride ophthalmic solution and epinephrine may occur.

Close observation of the patient is recommended when a beta-blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.

Patients receiving beta-adrenergic blocking agents along with either oral or intravenous calcium antagonists should be monitored for possible atrioventricular conduction disturbances, left ventricular failure and hypotension. In patients with impaired cardiac function, simultaneous use should be avoided altogether.

The concomitant use of beta-adrenergic blocking agents with digitalis and calcium antagonists may have additive effects on prolonging atrioventricular conduction time.

Phenothiazine-related compounds and beta-adrenergic blocking agents may have additive hypotensive effects due to the inhibition of each other’s metabolism.

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