KERLONE Tablet Ref.[51024] Active ingredients: Betaxolol

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 Kerlone 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 Kerlone 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 ß1 selectivity (cardioselectivity), low doses of Kerlone 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 Kerlone 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Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery, however the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and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 Kerlone 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, Kerlone 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 Kerlone is to be withdrawn should be monitored closely (see Dosage and Administration: Cessation of therapy).

Kerlone should not be given to patients with untreated pheochromocytoma.

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.

Kerlone, 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:

^* 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- to 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:

The 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 studies, European controlled clinical trials, or in marketing experience. It is not known whether a causal relationship exists between betaxolol and these events; they are listed to alert the physician to a possible relationship:

Autonomic: flushing, salivation, sweating.

Body as a whole: allergy, fever, malaise, pain, rigors.

Cardiovascular: angina pectoris, arrhythmia, atrioventricular block, heart failure, hypertension, hypotension, myocardial infarction, thrombosis, syncope. Central and peripheral nervous system: ataxia, neuralgia, neuropathy, numbness, speech disorder, stupor, tremor, twitching.

Gastrointestinal: anorexia, constipation, dry mouth, increased appetite, mouth ulceration, rectal disorders, vomiting, dysphagia.

Hearing and Vestibular: earache, labyrinth disorders, tinnitus, deafness.

Hematologic: anemia, leucocytosis, lymphadenopathy, purpura, thrombocytopenia.

Liver and biliary: increased AST, increased ALT.

Metabolic and nutritional: acidosis, diabetes, hypercholesterolemia, hyperglycemia, hyperkalemia, hyperlipemia, hyperuricemia, hypokalemia, weight gain, weight loss, thirst, increased LDH.

Musculoskeletal: arthropathy, neck pain, muscle cramps, tendonitis.

Psychiatric: abnormal thinking, amnesia, impaired concentration, confusion, emotional lability, hallucinations, decreased libido.

Reproductive disorders: Female: breast pain, breast fibroadenosis, menstrual disorder;

Male: Peyronie’s disease, prostatitis.

Respiratory: bronchitis, bronchospasm, cough, epistaxis, flu, pneumonia, sinusitis.

Skin: alopecia, eczema, erythematous rash, hypertrichosis, pruritus, skin disorders.

Special senses: abnormal taste, taste loss.

Urinary system: cystitis, dysuria, micturition disorder, oliguria, proteinuria, abnormal renal function, renal pain.

Vascular: cerebrovascular disorder, intermittent claudication, leg cramps, peripheral ischemia, thrombophlebitis.

Vision: abnormal lacrimation, abnormal vision, blepharitis, ocular hemorrhage, conjunctivitis, dry eyes, iritis, cataract, scotoma.

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 Kerlone during investigational use and extensive foreign experience. However, dry eyes have been reported.

Impaired hepatic or renal function

Kerlone 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).

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.

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 Kerlone 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.

Patients, especially those with evidence of coronary artery insufficiency, should be warned against interruption or discontinuation of Kerlone 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 Kerlone. Patients with diabetes should be warned that beta-blockers may mask tachycardia occurring with hypoglycemia.

The following drugs have been coadministered with Kerlone and have not altered its pharmacokinetics: cimetidine, nifedipine, chlorthalidone, and hydrochlorothiazide. Concomitant administration of Kerlone 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).

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 betablockers. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.

Pregnancy Category C. In a study in which pregnant rats received betaxolol at doses of 4, 40, or 400 mg/kg/day, the highest dose (600 x MRHD) 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 (6 x MRHD and 60 x MRHD) caused no fetal abnormalities. In a second study with a different strain of rat, 200 mg betaxolol/kg/day (300 x MRHD) 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), a marked increase in post-implantation 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), 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.

There are no adequate and well-controlled studies in pregnant women. Kerlone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Beta-blockers reduce placental perfusion, which may result in intrauterine fetal death, immature and premature deliveries. In addition, adverse effects (especially hypoglycemia and bradycardia) may occur in fetus.

Since Kerlone is excreted in human milk in sufficient amounts to have pharmacological effects in the infant, caution should be exercised when Kerlone is administered to a nursing mother.

Safety and effectiveness in pediatric patients have not been established.

Kerlone 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).