Levobunolol Hydrochloride Ophthalmic Solution

Levobunolol Hydrochloride Ophthalmic Solution USP is a noncardioselective beta-adrenoceptor blocking agent for ophthalmic use.

Levobunolol hydrochloride is represented by the following structural formula:

C₁₇H₂₅NO₃•HCl

Mol. Wt. 327.85

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

Each mL of 0.25% and 0.5% contains:

ACTIVE: Levobunolol Hydrochloride 2.5 mg (0.25%) and 5 mg (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 ADDED: Benzalkonium Chloride (0.004%).

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 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 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 two separate, controlled studies (one three month and one up to 12 months duration) levobunolol hydrochloride ophthalmic solution 0.25% b.i.d. controlled the IOP of approximately 64% and 70% of the subjects. The overall mean decrease from baseline was 5.4 mm Hg and 5.1 mm Hg respectively. In an open-label study levobunolol hydrochloride ophthalmic solution 0.25% q.d. controlled the IOP of 72% of the subjects while achieving an overall mean decrease of 5.9 mm Hg.

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% b.i.d. The mean IOP decrease from baseline was between 6.87 mm Hg and 7.81 mm Hg. No significant effects on pupil size, tear production or corneal sensitivity were observed. Levobunolol hydrochloride at the concentrations tested, when applied topically, decreased heart rate and blood pressure in some patients. The IOP-lowering effect of levobunolol was well maintained over the course of these studies.

In a three month clinical study, a single daily application of levobunolol hydrochloride ophthalmic solution 0.5% 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 reduces IOP with little or no effect on pupil size or accommodation in contrast to the miosis which cholinergic agents are known to produce. The blurred vision and night blindness often associated with miotics would not be expected and have not been reported with the use of levobunolol. This is particularly important in cataract patients with central lens opacities who would experience decreased visual acuity with pupillary constriction.

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.

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.

As with other topically applied ophthalmic drugs, levobunolol 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). 

In clinical trials the use of levobunolol hydrochloride has been associated with transient ocular burning and stinging in up to 1 in 3 patients, and with blepharoconjunctivitis in up to 1 in 20 patients. Decreases in heart rate and blood pressure have been reported (see CONTRAINDICATIONS and WARNINGS).

The following adverse effects have been reported rarely with the use of levobunolol: iridocyclitis, headache, transient ataxia, dizziness, lethargy, urticaria and pruritus.

Decreased corneal sensitivity has been noted in a small number of patients. Although levobunolol has minimal membrane-stabilizing activity, there remains a possibility of decreased corneal sensitivity after prolonged use.

The following additional adverse reactions have been reported either with levobunolol or ophthalmic use of other beta-adrenergic receptor blocking agents: BODY AS A WHOLE: Headache, asthenia, chest pain. CARDIOVASCULAR: Bradycardia, arrhythmia, hypotension, syncope, heart block, cerebral vascular accident, cerebral ischemia, congestive heart failure, palpitation, cardiac arrest. DIGESTIVE: Nausea, diarrhea. PSYCHIATRIC: Depression, confusion, increase in signs and symptoms of myasthenia gravis, paresthesia. SKIN: Hypersensitivity, including localized and generalized rash, alopecia, Stevens-Johnson Syndrome. RESPIRATORY: Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure, dyspnea, nasal congestion. UROGENITAL: Impotence. ENDOCRINE: Masked symptoms of hypoglycemia in insulin-dependent diabetics (see WARNINGS). SPECIAL SENSES: Signs and symptoms of keratitis, blepharoptosis, visual disturbances including refractive changes (due to withdrawal of miotic therapy in some cases), diplopia, ptosis.

Other reactions associated with the oral use of non-selective adrenergic receptor blocking agents should be considered potential effects with ophthalmic use of these agents.

No data are available regarding overdosage in humans. Should accidental ocular overdosage occur, flush eye(s) with water or normal saline. If accidentally ingested, efforts to decrease further absorption may be appropriate (gastric lavage).

The most common signs and symptoms to be expected with overdosage with administration of a systemic beta-adrenergic blocking agent are symptomatic bradycardia, hypotension, bronchospasm, and acute cardiac failure. Should these symptoms occur, discontinue levobunolol therapy and initiate appropriate supportive therapy. The following supportive measures should be considered:

1. Symptomatic bradycardia: Use atropine sulfate intravenously in a dosage of 0.25 mg to 2 mg to induce vagal blockade. If bradycardia persists, intravenous isoproterenol hydrochloride should be administered cautiously. In refractory cases the use of a transvenous cardiac pacemaker should be considered.

2. Hypotension: Use sympathomimetic pressor drug therapy, such as dopamine, dobutamine or levarterenol. In refractory cases, the use of glucagon hydrochloride may be useful.

3. Bronchospasm: Use isoproterenol hydrochloride. Additional therapy with aminophylline may be considered.

4. Acute cardiac failure: Conventional therapy with digitalis, diuretics and oxygen should be instituted immediately. In refractory cases the use of intravenous aminophylline is suggested. This may be followed, if necessary, by glucagon hydrochloride which may be useful.

5. Heart block (second or third degree): Use isoproterenol hydrochloride or a transvenous cardiac pacemaker.

The recommended starting dose is one to two drops of levobunolol hydrochloride ophthalmic solution 0.5% in the affected eye(s) once a day. Typical dosing with levobunolol hydrochloride ophthalmic solution 0.25% is one to two drops twice daily. In patients with more severe or uncontrolled glaucoma, levobunolol hydrochloride ophthalmic solution 0.5% can be administered b.i.d. As with any new medication, carefully monitoring of patients is advised.

Dosages above one drop of levobunolol hydrochloride ophthalmic solution 0.5% b.i.d. are not generally more effective. If the patient's IOP is not at a satisfactory level on this regimen, concomitant therapy with dipivefrin and/or epinephrine, and/or pilocarpine and other miotics, and/or systemically administered carbonic anhydrase inhibitors, such as acetazolamide, can be instituted. Patients should not typically use two or more topical ophthalmic beta-adrenergic blocking agents simultaneously.

Levobunolol hydrochloride ophthalmic solution USP, is supplied in a plastic bottle with a controlled drop tip in the following sizes:

0.5%      5 mL bottles - NDC 54868-3363-1

Store between 15°-30°C (59°-86°F). Protect from light. Replace cap immediately after use.

DO NOT USE IF IMPRINTED NECKBAND IS NOT INTACT

KEEP OUT OF REACH OF CHILDREN

STERILE OPHTHALMIC SOLUTION

Rx only

FOR USE IN THE EYES ONLY

Bausch & Lomb Incorporated

Tampa, Florida 33637 ©Bausch & Lomb Incorporated

9117400 (Folded)

9117500 (Flat)

NDC 54868-3363-1

Levobunolol Hydrochloride Ophthmalic Solution USP,
0.5% (Sterile)

Rx only