Betaxolol 10 mg Tablet, Film Coated, 100-count — NDC 24658-700-01 (Billing 24658-0700-01)

WARNINGS Cardiac Failure Sympathetic stimulation may be a vital component supporting circulatory function in congestive heart failure, and beta-adrenergic receptor blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe heart failure. In hypertensive patients who have congestive heart failure controlled by digitalis and diuretics, beta-blockers should be administered cautiously. Both digitalis and beta-adrenergic receptor blocking agents slow AV conduction.

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. Therefore at the first sign or symptom of cardiac failure, discontinuation of betaxolol should be considered. In some cases beta-blocker therapy can be continued while cardiac failure is treated with cardiac glycosides, diuretics, and other agents, as appropriate.

Exacerbation of Angina Pectoris Upon Withdrawal Abrupt cessation of therapy with certain beta-blocking agents in patients with coronary artery disease has been followed by exacerbations of angina pectoris and, in some cases, myocardial infarction has been reported. Therefore, such patients should be warned against interruption of therapy without the physician's advice. Even in the absence of overt angina pectoris, when discontinuation of betaxolol is planned, the patient should be carefully observed and therapy should be reinstituted, at least temporarily, if withdrawal symptoms occur.

Bronchospastic diseases PATIENTS WITH BRONCHOSPASTIC DISEASE SHOULD NOT IN GENERAL RECEIVE BETA-BLOCKERS. Because of its relative β 1 -selectivity (cardioselectivity), low doses of betaxolol may be used with caution in patients with bronchospastic disease who do not respond to or cannot tolerate alternative treatment. Since β 1 -selectivity is not absolute and is inversely related to dose, the lowest possible dose of betaxolol should be used (5 to 10 mg once daily) and a bronchodilator should be made available.

If dosage must be increased, divided dosage should be considered to avoid the higher peak blood levels associated with once-daily dosing. Major Surgery Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery, however the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures (see Precautions, Drug Interactions ). Titrate betaxolol dose to maintain effective heart rate control while avoiding frank hypotension and bradycardia.

Diabetes and Hypoglycemia Beta-blockers should be used with caution in diabetic patients. Beta-blockers may mask tachycardia occurring with hypoglycemia (patients should be warned of this), although other manifestations such as dizziness and sweating may not be significantly affected. Unlike nonselective beta-blockers, betaxolol does not prolong insulin-induced hypoglycemia.

Thyrotoxicosis Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism (eg, tachycardia). Abrupt withdrawal of beta-blockade might precipitate a thyroid storm; therefore, patients known or suspected of being thyrotoxic from whom betaxolol is to be withdrawn should be monitored closely (See Dosage and Administration, Cessation of Therapy ). Betaxolol should not be given to patients with untreated pheochromocytoma.

ADVERSE REACTIONS Most adverse reactions have been mild and transient and are typical of beta-adrenergic blocking agents, eg, bradycardia, fatigue, dyspnea, and lethargy. Withdrawal of therapy in U.S. and European controlled clinical trials has been necessary in about 3.5% of patients, principally because of bradycardia, fatigue, dizziness, headache, and impotence. Frequency estimates of adverse events were derived from controlled studies in which adverse reactions were volunteered and elicited in U.S. studies and volunteered and/or elicited in European studies.

In the U.S., the placebo-controlled hypertension studies lasted for 4 weeks, while the active-controlled hypertension studies had a 22- to 24-week double-blind phase. The following doses were studied: betaxolol—5, 10, 20, and 40 mg once daily; atenolol—25, 50, and 100 mg once daily; and propranolol—40, 80, and 160 mg b.i.d. Betaxolol, like other beta-blockers, has been associated with the development of antinuclear antibodies (ANA) (e.g., lupus erythematosus).

In controlled clinical studies, conversion of ANA from negative to positive occurred in 5.3% of the patients treated with betaxolol, 6.3% of the patients treated with atenolol, 4.9% of the patients treated with propranolol, and 3.2% of the patients treated with placebo. Betaxolol adverse events reported with a 2% or greater frequency, and selected events with lower frequency, in U.S. controlled studies are: Dose Range Body System/Adverse Reaction Betaxolol (N=509) 5-40 mg q.d.* (%) Propranolol (N=73) 40-160 mg b.i.d.

(%) Atenolol (N=75) 25-100 mg q.d. (%) Placebo (N=109) (%) Cardiovascular Bradycardia (heart rate <50 BPM) Symptomatic bradycardia Edema 8.1 0.8 1.8 4.1 1.4 0 12.0 0 0 0 0

1.8Central Nervous System Headache Dizziness Fatigue Lethargy 6.5 4.5 2.9 2.8 4.1 11.0 9.6 4.1 5.3 2.7 4.0 2.7 15.6 5.5 0

0.9Psychiatric Insomnia Nervousness Bizarre dreams Depression 1.2 0.8 1.0 0.8 8.2 1.4 2.7 2.7 2.7 2.7 1.3 4.0 0 0 0 0 Autonomic Impotence 1.2† 0 0 0 Respiratory Dyspnea Pharyngitis Rhinitis Upper respiratory infection 2.4 2.0 1.4 2.6 2.7 0 0 0 1.3 4.0 4.0 0 0.9 0.9 0.9

5.5Gastrointestinal Dyspepsia Nausea Diarrhea 4.7 1.6 2.0 6.8 1.4 6.8 2.7 4.0 8.0 0.9 0

0.9Musculoskeletal Chest pain Arthralgia 2.4 3.1 1.4 0 2.7 4.0 0.9

1.8Skin Rash 1.2 0 0 0 *Five patients received 80 mg q.d. †N=336 males; impotence is a known possible adverse effect of this pharmacological class. Of the above adverse reactions associated with the use of betaxolol, only bradycardia was clearly dose related, but there was a suggestion of dose relatedness for fatigue, lethargy, and dyspepsia. In Europe, the placebo-controlled study lasted for 4 weeks, while the comparative studies had a 4-52-week double-blind phase.

The following doses were studied: betaxolol 20 and 40 mg once daily and atenolol 100 mg once daily. From European controlled hypertension clinical trials, the following adverse events reported by 2% or more patients and selected events with lower frequency are presented: Dose Range Body System/Adverse Reaction Betaxolol (N=155) 20-40 mg q.d. (%) Atenolol (N=81) 100 mg q.d.

(%) Placebo (N=60) (%) Cardiovascular Bradycardia (heartrate <50 BPM) Symptomatic bradycardia Palpitation Edema Cold extremities 5.8 1.9 1.9 1.3 1.9 5.0 2.5 3.7 1.2 0 0 0 1.7 0 0 Central Nervous System Headache Dizziness Fatigue Asthenia Insomnia Paresthesia 14.8 14.8 9.7 7.1 5.0 1.9 9.9 17.3 18.5 0 3.7 2.5 23.3 15.0 0 16.7 3.3 0 Gastrointestinal Nausea Dyspepsia Diarrhea 5.8 3.9 1.9 1.2 7.4 3.7 0 3.3 0 Musculoskeletal Chest pain Joint pain Myalgia 7.1 5.2 3.2 6.2 4.9 3.7 5.0 1.7

3.3The only adverse event whose frequency clearly rose with increasing dose was bradycardia. Elderly patients were especially susceptible to bradycardia, which in some cases responded to dose-reduction (see Precautions ). The following selected (potentially important) adverse events have been reported at an incidence of less than 2% in U.S. controlled and open, long-term clinical stu… [Excerpted — this section continues on DailyMed.]

Drug Interactions The following drugs have been coadministered with betaxolol and have not altered its pharmacokinetics: cimetidine, nifedipine, chlorthalidone, and hydrochlorothiazide. Concomitant administration of betaxolol with the oral anticoagulant warfarin has been shown not to potentiate the anticoagulant effect of warfarin. Catecholamine-depleting drugs (eg, reserpine) may have an additive effect when given with beta-blocking agents.

Patients treated with a beta-adrenergic receptor blocking agent plus a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension. Should it be decided to discontinue therapy in patients receiving beta-blockers and clonidine concurrently, the beta-blocker should be discontinued slowly over several days before the gradual withdrawal of clonidine. Literature reports suggest that oral calcium antagonists may be used in combination with beta-adrenergic blocking agents when heart function is normal, but should be avoided in patients with impaired cardiac function.

Hypotension, AV conduction disturbances, and left ventricular failure have been reported in some patients receiving beta-adrenergic blocking agents when an oral calcium antagonist was added to the treatment regimen. Hypotension was more likely to occur if the calcium antagonist were a dihydropyridine derivative, eg, nifedipine, while left ventricular failure and AV conduction disturbances, including complete heart block, were more likely to occur with either verapamil or diltiazem. Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate.

Concomitant use can increase the risk of bradycardia. Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with beta blockers. Disopyramide is a Type I antiarrhythmic drug with potent negative inotropic and chronotropic effects.

Disopyramide has been associated with severe bradycardia, asystole and heart failure when administered with beta blockers. Particular care should be taken when using anesthetic agents which depress the myocardium, such as ether, cyclopropane, and trichloroethylene (see Warnings, Major surgery ).

PRECAUTIONS General Beta-adrenoceptor blockade can cause reduction of intraocular pressure. Since betaxolol hydrochloride is marketed as an ophthalmic solution for treatment of glaucoma, patients should be told that betaxolol may interfere with the glaucoma-screening test. Withdrawal may lead to a return of increased intraocular pressure.

Patients receiving beta-adrenergic blocking agents orally and beta-blocking ophthalmic solutions should be observed for potential additive effects either on the intraocular pressure or on the known systemic effects of beta-blockade. The value of using beta-blockers in psoriatic patients should be carefully weighed since they have been reported to cause an aggravation in psoriasis. Impaired Hepatic or Renal Function Betaxolol is primarily metabolized in the liver to metabolites that are inactive and then excreted by the kidneys; clearance is somewhat reduced in patients with renal failure but little changed in patients with hepatic disease.

Dosage reductions have not routinely been necessary when hepatic insufficiency is present (see Dosage and Administration ) but patients should be observed. Patients with severe renal impairment and those on dialysis require a reduced dose. (See Dosage and Administration ).

Information for Patients Patients, especially those with evidence of coronary artery insufficiency, should be warned against interruption or discontinuation of betaxolol therapy without the physician's advice. Although cardiac failure rarely occurs in appropriately selected patients, patients being treated with beta-adrenergic blocking agents should be advised to consult a physician at the first sign or symptom of failure. Patients should know how they react to this medicine before they operate automobiles and machinery or engage in other tasks requiring alertness.

Patients should contact their physician if any difficulty in breathing occurs, and before surgery of any type. Patients should inform their physicians, ophthalmologists, or dentists that they are taking betaxolol. Patients with diabetes should be warned that beta-blockers may mask tachycardia occurring with hypoglycemia.

Drug Interactions The following drugs have been coadministered with betaxolol and have not altered its pharmacokinetics: cimetidine, nifedipine, chlorthalidone, and hydrochlorothiazide. Concomitant administration of betaxolol with the oral anticoagulant warfarin has been shown not to potentiate the anticoagulant effect of warfarin. Catecholamine-depleting drugs (eg, reserpine) may have an additive effect when given with beta-blocking agents.

Patients treated with a beta-adrenergic receptor blocking agent plus a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension. Should it be decided to discontinue therapy in patients receiving beta-blockers and clonidine concurrently, the beta-blocker should be discontinued slowly over several days before the gradual withdrawal of clonidine. Literature reports suggest that oral calcium antagonists may be used in combination with beta-adrenergic blocking agents when heart function is normal, but should be avoided in patients with impaired cardiac function.

Hypotension, AV conduction disturbances, and left ventricular failure have been reported in some patients receiving beta-adrenergic blocking agents when an oral calcium antagonist was added to the treatment regimen. Hypotension was more likely to occur if the calcium antagonist were a dihydropyridine derivative, eg, nifedipine, while left ventricular failure and AV conduction disturbances, including complete heart block, were more likely to occur with either verapamil or diltiazem. Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate.

Concomitant use can increase the risk of bradycardia. Amiodarone is an antiarrhythmic agent with negative chronotropic properties… [Excerpted — this section continues on DailyMed.]