Pharmacokinetics and Metabolism

In man, absorption of an oral dose is complete. There is a small and consistent first-pass effect resulting in an absolute bioavailability of 89% ± 5% that is unaffected by the concomitant ingestion of food or alcohol. Mean peak blood concentrations of 21.6 ng/ml (range 16.3 to 27.9 ng/ml) are reached between 1.5 and 6 (mean about 3) hours after a single oral dose, in healthy volunteers, of 10 mg of betaxolol. Peak concentrations for 20-mg and 40-mg doses are 2 and 4 times that of a 10-mg dose and have been shown to be linear over the dose range of 5 to 40 mg. The peak to trough ratio of plasma concentrations over 24 hours is 2.7. The mean elimination half-life in various studies in normal volunteers ranged from about 14 to 22 hours after single oral doses and is similar in chronic dosing. Steady state plasma concentrations are attained after 5 to 7 days with once-daily dosing in persons with normal renal function.

Betaxolol is approximately 50% bound to plasma proteins. It is eliminated primarily by liver metabolism and secondarily by renal excretion. Following oral administration, greater than 80% of a dose is recovered in the urine as betaxolol and its metabolites. Approximately 15% of the dose administered is excreted as unchanged drug, the remainder being metabolites whose contribution to the clinical effect is negligible.

Steady state studies in normal volunteers and hypertensive patients found no important differences in kinetics. In patients with hepatic disease, elimination half-life was prolonged by about 33%, but clearance was unchanged, leading to little change in AUC. Dosage reductions have not routinely been necessary in these patients. In patients with chronic renal failure undergoing dialysis, mean elimination half-life was approximately doubled, as was AUC, indicating the need for a lower initial dosage (5 mg) in these patients. The clearance of betaxolol by hemodialysis was 0.015 L/h/kg and by peritoneal dialysis, 0.010 L/h/kg. In one study (n=8), patients with stable renal failure, not on dialysis, with mean creatinine clearance of 27 ml/min showed slight increases in elimination half-life and AUC, but no change in Cmax. In a second study of 30 hypertensive patients with mild to severe renal impairment, there was a reduction in clearance of betaxolol with increasing degrees of renal insufficiency. Inulin clearance (mL/min/1.73 m2) ranged from 70 to 107 in 7 patients with mild impairment, 41 to 69 in 14 patients with moderate impairment, and 8 to 37 in 9 patients with severe impairment. Clearance following oral dosing was reduced significantly in patients with moderate and severe renal impairment (26% and 35%, respectively) when compared with those with mildly impaired renal function. In the severely impaired group, the mean Cmax and the mean elimination half-life tended to increase (28% and 24%, respectively) when compared with the mildly impaired group. A starting dose of 5 mg is recommended in patients with severe renal impairment (See Dosage and Administration).

Studies in elderly patients (n=10) gave inconsistent results but suggest some impairment of elimination, with one small study (n=4) finding a mean half-life of 30 hours. A starting dose of 5 mg is suggested in older patients.

Pharmacodynamics

Clinical pharmacology studies have demonstrated the beta-adrenergic receptor blocking activity of betaxolol by (1) reduction in resting and exercise heart rate, cardiac output, and cardiac work load, (2) reduction of systolic and diastolic blood pressure at rest and during exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) reduction of reflex orthostatic tachycardia.

The β1-selectivity of betaxolol in man was shown in three ways: (1) In normal subjects, 10- and 40-mg oral doses of betaxolol, which reduced resting heart rate at least as much as 40 mg of propranolol, produced less inhibition of isoproterenol-induced increases in forearm blood flow and finger tremor than propranolol. In this study, 10 mg of betaxolol was at least comparable to 50 mg of atenolol. Both doses of betaxolol, and the one dose of atenolol, however, had more effect on the isoproterenol-induced changes than placebo (indicating some β2 effect at clinical doses) and the higher dose of betaxolol was more inhibitory than the lower. (2) In normal subjects, single intravenous doses of betaxolol and propranolol, which produced equal effects on exercise-induced tachycardia, had differing effects on insulin-induced hypoglycemia, with propranolol, but not betaxolol, prolonging the hypoglycemia compared with placebo. Neither drug affected the maximum extent of the hypoglycemic response. (3) In a single-blind crossover study in asthmatics (n=10), intravenous infusion over 30 minutes of low doses of betaxolol (1.5 mg) and propranolol (2 mg) had similar effects on resting heart rate but had differing effects on FEV1 and forced vital capacity, with propranolol causing statistically significant (10% to 20%) reductions from baseline in mean values for both parameters while betaxolol had no effect on mean values. While blood levels were not measured, the dose of betaxolol used in this study would be expected to produce blood concentrations, at the time of the pulmonary function studies, considerably lower than those achieved during antihypertensive therapy with recommended doses of betaxolol. In a randomized double-blind, placebo-controlled crossover (4X4 Latin Square) study in 10 asthmatics, betaxolol (about 5 or 10 mg IV) had little effect on isoproterenol-induced increases in FEV1; in contrast, propranolol (about 7 mg IV) inhibited the response.

Consistent with its negative chronotropic effect, due to beta-blockade of the SA node, and lack of intrinsic sympathomimetic activity, betaxolol increases sinus cycle length and sinus node recovery time. Conduction in the AV node is also prolonged.

Significant reductions in blood pressure and heart rate were observed 24 hours after dosing in double-blind, placebo-controlled trials with doses of 5 to 40 mg administered once daily. The antihypertensive response to betaxolol was similar at peak blood levels (3 to 4 hours) and at trough (24 hours). In a large randomized, parallel dose-response study of 5, 10, and 20 mg, the antihypertensive effects of the 5-mg dose were roughly half of the effects of the 20-mg dose (after adjustment for placebo effects) and the 10-mg dose gave more than 80% of the antihypertensive response to the 20-mg dose. The effect of increasing the dose from 10 mg to 20 mg was thus small. In this study, while the antihypertensive response to betaxolol showed a dose-response relationship, the heart rate response (reduction in HR) was not dose related. In other trials, there was little evidence of a greater antihypertensive response to 40 mg than to 20 mg. The maximum effect of each dose was achieved within 1 or 2 weeks. In comparative trials against propranolol, atenolol, and chlorthalidone, betaxolol appeared to be at least as effective as the comparative agent.

Betaxolol has been studied in combination with thiazide-type diuretics and the blood pressure effects of the combination appear additive. Betaxolol has also been used concurrently with methyldopa, hydralazine, and prazosin.

The mechanism of the antihypertensive effects of beta-adrenergic receptor blocking agents has not been established. Several possible mechanisms have been proposed, however, including: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic-neuronal sites, leading to decreased cardiac output, (2) a central effect leading to reduced sympathetic outflow to the periphery, and (3) suppression of renin activity.

The results from long-term studies have not shown any diminution of the antihypertensive effect of betaxolol with prolonged use.

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 β1-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 β1-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.

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.

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.

Risk of Anaphylactic Reaction

Although it is known that patients on beta-blockers may be refractory to epinephrine in the treatment of anaphylactic shock, beta-blockers can, in addition, interfere with the modulation of allergic reaction and lead to an increased severity and/or frequency of attacks. Severe allergic reactions including anaphylaxis have been reported in patients exposed to a variety of allergens either by repeated challenge, or accidental contact, and with diagnostic or therapeutic agents while receiving beta-blockers. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Lifetime studies with betaxolol HCl in mice at oral dosages of 6, 20, and 60 mg/kg/day (up to 90 × the maximum recommended human dose [MRHD] based on 60-kg body weight) and in rats at 3, 12, or 48 mg/kg/day (up to 72 × MRHD) showed no evidence of a carcinogenic effect. In a variety of in vitro and in vivo bacterial and mammalian cell assays, betaxolol HCl was nonmutagenic. Betaxolol did not adversely affect fertility or mating performance of male or female rats at doses up to 256 mg/kg/day (380 × MRHD).

Pregnancy

Neonatal Period

The beta-blocker action persists in the neonate for several days after birth to a treated mother: there is an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period. Bradycardia, respiratory distress and hypoglycemia have also been reported. Accordingly, attentive surveillance of the neonate (heart rate and blood glucose for the first 3 to 5 days of life) in a specialized setting is recommended.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Elderly Patients

Betaxolol may produce bradycardia more frequently in elderly patients. In general, patients 65 years of age and older had a higher incidence rate of bradycardia (heart rate < 50 BPM) than younger patients in U.S. clinical trials. In a double-blind study in Europe, 19 elderly patients (mean age = 82) received betaxolol 20 mg daily. Dosage reduction to 10 mg or discontinuation was required for 6 patients due to bradycardia (See Dosage and Administration).

Potential Adverse Effects

Although not reported in clinical studies with betaxolol, a variety of adverse effects have been reported with other beta-adrenergic blocking agents and may be considered potential adverse effects of betaxolol:

Central nervous system: Reversible mental depression progressing to catatonia, an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability with slightly clouded sensorium, and decreased performance on neuropsychometric tests.

Allergic: Fever combined with aching and sore throat, laryngospasm, respiratory distress.

Hematologic: Agranulocytosis, thrombocytopenic purpura, and nonthrombocytopenic purpura.

Gastrointestinal: Mesenteric arterial thrombosis, ischemic colitis.

Metabolic: Hypoglycemia.

Miscellaneous: Raynaud's phenomena. There have been reports of skin rashes and/or dry eyes associated with the use of beta-adrenergic blocking drugs. The reported incidence is small, and in most cases, the symptoms have cleared when treatment was withdrawn. Discontinuation of the drug should be considered if any such reaction is not otherwise explicable. Patients should be closely monitored following cessation of therapy.

The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with betaxolol during investigational use and extensive foreign experience. However, dry eyes have been reported.

Hypotension

Use sympathomimetic pressor drug therapy, such as dopamine, dobutamine, or norepinephrine. In refractory cases of overdosage of other beta-blockers, the use of glucagon hydrochloride has been reported to be useful.

Bradycardia

Atropine should be administered. If there is no response to vagal blockade, isoproterenol should be administered cautiously (See Warnings: Major Surgery). In refractory cases the use of a transvenous cardiac pacemaker may be considered.

Acute cardiac failure

Conventional therapy including digitalis, diuretics, and oxygen should be instituted immediately.

Bronchospasm

Use a β2-agonist. Additional therapy with aminophylline may be considered.

Heart block (2nd- or 3rd-degree)

Use isoproterenol or a transvenous cardiac pacemaker.

Dosage Adjustments for Specific Patients

Cessation of therapy

If withdrawal of betaxolol therapy is planned, it should be achieved gradually over a period of about 2 weeks. Patients should be carefully observed and advised to limit physical activity to a minimum.