As with other topically applied ophthalmic drugs, BETAGAN 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].

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 aHistory 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, BETAGAN should be discontinued.

Obstructive Pulmonary Disease

PATIENTS WITH CHRONIC OBSTRUCTlVE PULMONARY DISEASE (e.g., CHRONIC BRONCHITIS, EMPHYSEMA) OF MILD OR MODERATE SEVERITY, BRONCHOSPASTlC DISEASE OR A HISTORY OF BRONCHOSPASTlC DISEASE (OTHER THAN BRONCHIAL ASTHMA OR A HISTORY OF BRONCHIAL ASTHMA, IN WHICH BETAGAN IS CONTRAINDICATED, See CONTRAINDICATIONS), SHOULD IN GENERAL NOT RECEIVE BETA BLOCKERS, INCLUDING BETAGAN. However, if BETAGAN 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.

These products contains 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.

General

BETAGAN (levobunolol HCl) Liquifilm sterile ophthalmic solution 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.

BETAGAN 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 BETAGAN, 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. BETAGAN has liffle or no effect on the pupil. When BETAGAN is used to reduce elevated intraocular pressure in angle-closure glaucoma, it should be followed with a miotic and not alone.

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

Animal Studies

No adverse ocular effects were observed in rabbits administered BETAGAN topically in studies lasting one year in concentrations up to 10 times the human dose concentration.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a lifetime oral study in mice, there were statistically significant (p<e;0.05) increases in the incidence of benign leiomyomas in female mice at 200 mg/kg/day (14,300 times the recommended human dose for glaucoma), but not at 12 or 50 mg /kg/day (850 and 3,500 times the human dose). In a two year oral study of levobunolol HCl in rats, there was a statistically significant (p<e;O.05) increase in the incidence of benign hepatomas in male rats administered 12,800 times the recommended human dose for glaucoma. Similar differences were not observed in rats administered oral doses equivalent to 350 times to 2,000 times the recommended human dose for glaucoma.

Levobunolol did not show evidence of mutagenic activity in a battery of microbiological and mammalian in vitro and in vivo assays.

Reproduction and fertility studies in rats showed no adverse effect on male or female fertility at doses up to 1,800 times the recommended human dose for glaucoma.

Pregnancy Category C

Fetotoxicity (as evidenced by a greater number of resorption sites) has been observed in rabbits when doses of levobunolol HCl equivalent to 200 and 700 times the recommended dose for the treatment of glaucoma were given. No fetotoxic effects have been observed in similar studies with rats at up to 1,800 times the human dose for glaucoma. Teratogenic studies with levobunolol in rats at doses up to 25 mq/kg/day (1,800 times the recommended human dose for glaucoma) showed no evidence of fetal malformations. There were no adverse effects on postnatal development of offspring. It appears when results from studies using rats and studies with other beta-adrenergic blockers are examined, that the rabbit may be a particularly sensitive species. There are no adequate and well-controlled studies in pregnant women. BETAGAN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Systemic beta-blockers and topical timolol maleate are known to be excreted in human milk. Caution should be exercised when BETAGAN is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use:

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

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