"Nov. 1, 2012 -- Having even mildly elevated blood pressure at midlife prematurely ages the brain, a new study shows.
Researchers say the early changes seen with higher blood pressure may set the stage for problems with thinking, memor"...
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 Kerledex should be considered. In some cases Kerledex therapy can be continued while cardiac failure is treated with cardiac glycosides, additional diuretics, and other agents, as appropriate.
Renal and hepatic diseases and electrolyte disturbances
In patients with renal disease, chlorthalidone or related drugs may precipitate azotemia. Cumulative effects may develop in the presence of impaired renal function. If progressive renal impairment becomes evident, Kerledex therapy should be reappraised.
In patients with impaired hepatic function or progressive liver disease, minor alterations in fluid and electrolyte balance may precipitate hepatic coma. Kerledex should be used with caution in these patients.
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 Kerledex is planned, it should be done gradually over about 2 weeks and the patient should be carefully observed. A beta-blocker 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.
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 Kerledex 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.
During chlorthalidone administration insulin requirements in diabetic patients may be increased, decreased, or unchanged and latent diabetes mellitus may become manifest.
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.
Systemic lupus erythematosus
The possibility of exacerbation or activation of systemic lupus erythematosus has been reported with thiazide diuretics, which are structurally related to chlorthalidone. However, systemic lupus erythematosus has not been reported following chlorthalidone administration.
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 Kerledex 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.
In patients receiving chlorthalidone, hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or during concomitant use of corticosteroids or ACTH. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (eg, increased ventricular irritability). Hypokalemia may be avoided or treated by use of potassium supplements or foods with a high potassium content. The hypokalemic effect of chlorthalidone is dose-related.
Any chloride deficit during chlorthalidone therapy is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease). Hypochloremic alkalosis often precedes other evidence of severe potassium deficiency. Frequently, therefore, more sensitive indicators than the serum potassium level are the serum bicarbonate and chloride concentrations. Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt, except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Increases in serum glucose may occur in patients on chlorthalidone. Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving chlorthalidone. The antihypertensive effects of the drug may be enhanced in the post-sympathectomy patient.
Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia. Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium even in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function. Pathologic changes in the parathyroid glands, with hypercalcemia and hypophosphatemia, have been observed in a few patients on prolonged thiazide therapy; however, the common complications of hyperparathyroidism such as renal lithiasis, bone resorption, and peptic ulceration have not been seen. Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.
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 but patients should be observed. Patients with severe renal impairment and those on dialysis require a reduced dose.
Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. All patients receiving chlorthalidone should be observed for clinical signs of fluid or electrolyte imbalance: namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids.
Carcinogenesis, mutagenesis, impairment of fertility
Betaxolol: Lifetime studies with betaxolol HCl in mice at oral dosages of 6, 20, and 60 mg/kg/day (up to 90 X the maximum recommended human dose (MRHD) based on 60-kg body weight or 7.4 X MRHD based on body surface area) and in rats at 3, 12, or 48 mg/kg/day (up to 72 X MRHD, based on body weight, or 11.8 X MRHD based on body surface area) 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 caused no adverse effects on fertility or general reproductive performance of male or female rats at doses up to 256 mg/kg/day (380 X MRHD, based on body weight; 62.9 X MRHD, based on body surface area).
Chlorthalidone: No information is available concerning the carcinogenic effects of chlorthalidone or its effects on fertility. Mutagenicity studies with chlorthalidone in mammalian cell assays demonstrated that the drug causes chromosomal aberrations when tested at high concentrations in vitro in the presence of hepatic metabolizing enzymes. The clinical significance of these findings has not been established.
Betaxolol and Chlorthalidone: The effects of the combination of betaxolol and chlorthalidone on carcinogenicity and impairment of fertility have not been assessed. The mutagenic effects of chlorthalidone do not appear to be altered by betaxolol.
Pregnancy Category C. Reproduction and teratology studies were conducted with the combination betaxolol/chlorthalidone in rats and rabbits. No teratologic effects were noted at doses up to 540 times the MRHD (based on 60 kg body weight; or 88 X MRHD based on body area) in rats and up to 72 times the MRHD in rabbits (or 15.6 X MRHD based on body area). Embryotoxicity in the form of post-implantation loss (primarily embryonic resorption) was observed at doses 120 times the MRHD in the rat (or 20 X MRHD, based on body area) and at doses 72 times the MRHD in the rabbit (15.6 X MRHD, based on body area). There was no embryotoxicity at doses up to 6 times the MRHD in the rat (or 1 X MRHD, based on body area) and 24 times the MRHD in the rabbit (or 5.2 X MRHD, based on body area).
Betaxolol: In a study in which pregnant rats received betaxolol at doses of 4, 40, or 400 mg/kg, the highest dose (600 X MRHD based on body weight, 98 X MRHD based on body surface area) was associated with increased postimplantation loss, reduced litter size and weight, and an increased incidence of skeletal and visceral abnormalities, which may have been a consequence of drug-related maternal toxicity. Other than a possible increased incidence of incomplete descent of testes and sternebral reductions, betaxolol at 4 mg/kg/day and 40 mg/kg/day (60 X MRHD based on body weight; 9.8 X MRHD, based on body surface area) caused no fetal abnormalities. In a second study with a different strain of rat, 200 mg betaxolol/kg/day (300 X MRHD based on body weight, or 49 X MRHD based on body area) was associated with maternal toxicity and an increase in resorptions, but no teratogenicity. In a study in which pregnant rabbits received doses of 1, 4, 12 or 36 mg betaxolol/kg/day (54 X MRHD based on body weight, or 12 X MRHD based on body area), a marked increase in postimplantation loss occurred at the highest dose, but no drug-related teratogenicity was observed. The rabbit is more sensitive to betaxolol than other species because of higher bioavailability resulting from saturation of the first-pass effect. In a peri- and postnatal study in rats at doses of 4, 32 and 256 mg betaxolol/kg/day (380 X MRHD based on body weight, or 62.8 X MRHD based on body area), the highest dose was associated with a marked increase in total litter loss within 4 days postpartum. In surviving offspring, growth and development were also affected.
Chlorthalidone: Thiazides cross the placental barrier and appear in cord blood. The use of chlorthalidone and related drugs in pregnant women requires that the anticipated benefits of the drug be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult.
There are no adequate and well-controlled studies in pregnant women. Kerledex should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Each component of Kerledex is excreted in human milk. Because of the potential for serious adverse reactions from Kerledex in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Safety and efficacy in children have not been established.
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.
Last reviewed on RxList: 9/6/2011
This monograph has been modified to include the generic and brand name in many instances.
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