Kerledex

Betaxolol Hydrochloride:

• Description
• Clinical pharmacology
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Kerledex (Betaxolol Hydrochloride) reviews

DESCRIPTION

Kerledex (Betaxolol Hydrochloride) is a β₁-selective (cardioselective) adrenergic receptor blocking agent available as 10-mg and 20-mg tablets for oral administration. Kerledex (Betaxolol Hydrochloride) is chemically described as 2-propanol,1-[4-[2-(cyclopropylmethoxy)ethyl]phenoxy]-3-[(1-methylethyl)amino]-,hydrochloride,(±). It has the following chemical structure:

Kerledex (Betaxolol Hydrochloride) hydrochloride is a water-soluble white crystalline powder with a molecular formula of C₁₈H₂₉NO₃-HCl and a molecular weight of 343.9. It is freely soluble in water, ethanol, chloroform, and methanol, and has a pKa of 9.4.

The inactive ingredients are anhydrous lactose, carnauba wax, hypromellose, microcrystalline cellulose, polyethylene glycol, polysorbate 80, pregeletanized starch (corn), sodium starch glycolate, stearic acid and titanium dioxide.

Molecular Weight 343.9

CLINICAL PHARMACOLOGY

Kerledex is a β₁-selective (cardioselective) adrenergic receptor blocking agent that has weak membrane-stabilizing activity and no intrinsic sympathomimetic (partial agonist) activity. The preferential effect on β₁ receptors is not absolute, however, and some inhibitory effects on β₂ receptors (found chiefly in the bronchial and vascular musculature) can be expected at higher doses.

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 Kerledex (Betaxolol Hydrochloride). 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.

Kerledex (Betaxolol Hydrochloride) 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 Kerledex (Betaxolol Hydrochloride) 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 Kerledex (Betaxolol Hydrochloride) 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 Kerledex (Betaxolol Hydrochloride) 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 Kerledex (Betaxolol Hydrochloride) 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 Kerledex (Betaxolol Hydrochloride) in man was shown in three ways: (1) In normal subjects, 10- and 40-mg oral doses of Kerledex (Betaxolol Hydrochloride), 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 Kerledex (Betaxolol Hydrochloride) was at least comparable to 50 mg of atenolol. Both doses of Kerledex (Betaxolol Hydrochloride), 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 Kerledex (Betaxolol Hydrochloride) was more inhibitory than the lower. (2) In normal subjects, single intravenous doses of Kerledex (Betaxolol Hydrochloride) and propranolol, which produced equal effects on exercise-induced tachycardia, had differing effects on insulin-induced hypoglycemia, with propranolol, but not Kerledex (Betaxolol Hydrochloride), 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 Kerledex (Betaxolol Hydrochloride) (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 Kerledex (Betaxolol Hydrochloride) had no effect on mean values. While blood levels were not measured, the dose of Kerledex (Betaxolol Hydrochloride) 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 Kerledex (Betaxolol Hydrochloride). In a randomized double-blind, placebo-controlled crossover (4X4 Latin Square) study in 10 asthmatics, Kerledex (Betaxolol Hydrochloride) (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, Kerledex (Betaxolol Hydrochloride) 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 Kerledex (Betaxolol Hydrochloride) 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 Kerledex (Betaxolol Hydrochloride) 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, Kerledex (Betaxolol Hydrochloride) appeared to be at least as effective as the comparative agent.

Kerledex (Betaxolol Hydrochloride) has been studied in combination with thiazide-type diuretics and the blood pressure effects of the combination appear additive. Kerledex (Betaxolol Hydrochloride) 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 Kerledex (Betaxolol Hydrochloride) with prolonged use.

INDICATIONS AND USAGE

Kerledex (Betaxolol Hydrochloride) is indicated in the management of hypertension. It may be used alone or concomitantly with other antihypertensive agents, particularly thiazide-type diuretics.

CONTRAINDICATIONS

Kerledex (Betaxolol Hydrochloride) is contraindicated in patients with known hypersensitivity to the drug.

Kerledex (Betaxolol Hydrochloride) is contraindicated in patients with sinus bradycardia, heart block greater than first degree, cardiogenic shock, and overt cardiac failure. (see Warnings).

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 Kerledex 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 Kerledex (Betaxolol Hydrochloride) 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, low doses of Kerledex (Betaxolol Hydrochloride) 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 Kerledex (Betaxolol Hydrochloride) 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. Titrate Kerledex (Betaxolol Hydrochloride) 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, although other manifestations such as dizziness and sweating may not be significantly affected. Unlike nonselective beta-blockers, Kerledex (Betaxolol Hydrochloride) 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 Kerledex (Betaxolol Hydrochloride) is to be withdrawn should be monitored closely (see Dosage and Administration: Cessation of therapy).

Kerledex (Betaxolol Hydrochloride) should not be given to patients with untreated pheochromocytoma.

PRECAUTIONS

General

Beta-adrenoceptor blockade can cause reduction of intraocular pressure. Since Kerledex hydrochloride is marketed as an ophthalmic solution for treatment of glaucoma, patients should be told that Kerledex (Betaxolol Hydrochloride) 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

Kerledex (Betaxolol Hydrochloride) 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 Kerledex 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 Kerledex (Betaxolol Hydrochloride). Patients with diabetes should be warned that beta-blockers may mask tachycardia occurring with hypoglycemia.

Drug Interactions

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

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 Kerledex 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, Kerledex (Betaxolol Hydrochloride) HCl was nonmutagenic. Kerledex (Betaxolol Hydrochloride) did not adversely affect fertility or mating performance of male or female rats at doses up to 256 mg/kg/day (380 × MRHD).

Pregnancy

Pregnancy Category C

In a study in which pregnant rats received Kerledex at doses of 4, 40, or 400 mg/kg/day, the highest dose (600 × 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, Kerledex (Betaxolol Hydrochloride) at 4 mg/kg/day and 40 mg/kg/day (6 × MRHD and 60 × MRHD) caused no fetal abnormalities. In a second study with a different strain of rat, 200 mg betaxolol/kg/day (300 × 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 × 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 Kerledex (Betaxolol Hydrochloride) 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 × 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. Kerledex (Betaxolol Hydrochloride) 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.

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.

Nursing Mothers

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

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Elderly Patients

Kerledex (Betaxolol Hydrochloride) 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 Kerledex (Betaxolol Hydrochloride) 20 mg daily. Dosage reduction to 10 mg or discontinuation was required for 6 patients due to bradycardia (See Dosage and Administration ).

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.

Kerledex, 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 Kerledex (Betaxolol Hydrochloride), 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.

Kerledex (Betaxolol Hydrochloride) adverse events reported with a 2% or greater frequency, and selected events with lower frequency, in U.S. controlled studies are:

Of the above adverse reactions associated with the use of Kerledex (Betaxolol Hydrochloride), 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: Kerledex (Betaxolol Hydrochloride) 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 Kerledex (Betaxolol Hydrochloride) 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 Kerledex (Betaxolol Hydrochloride), a variety of adverse effects have been reported with other beta-adrenergic blocking agents and may be considered potential adverse effects of Kerledex (Betaxolol Hydrochloride):

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 Kerledex (Betaxolol Hydrochloride) during investigational use and extensive foreign experience. However, dry eyes have been reported.

table-1 table-2

OVERDOSAGE

No specific information on emergency treatment of overdosage with Kerledex is available. The most common effects expected are bradycardia, congestive heart failure, hypotension, bronchospasm, and hypoglycemia. In one acute overdosage of Kerledex (Betaxolol Hydrochloride), a 16-year-old female recovered fully after ingesting 460 mg.

Oral LD₅₀s are 350 to 400 mg betaxolol/kg in mice and 860 to 980 mg/kg in rats.

In the case of overdosage, treatment with Kerledex (Betaxolol Hydrochloride) should be stopped and the patient carefully observed. Hemodialysis or peritoneal dialysis does not remove substantial amounts of the drug. In addition to gastric lavage, the following therapeutic measures are suggested if warranted:

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.. 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

Use isoproterenol or a transvenous cardiac pacemaker.

DOSAGE AND ADMINISTRATION

The initial dose of Kerledex in hypertension is ordinarily 10 mg once daily either alone or added to diuretic therapy. The full antihypertensive effect is usually seen within 7 to 14 days. If the desired response is not achieved the dose can be doubled after 7 to 14 days. Increasing the dose beyond 20 mg has not been shown to produce a statistically significant additional antihypertensive effect; but the 40-mg dose has been studied and is well tolerated. An increased effect (reduction) on heart rate should be anticipated with increasing dosage. If monotherapy with Kerledex (Betaxolol Hydrochloride) does not produce the desired response, the addition of a diuretic agent or other antihypertensive should be considered (see, Drug Interactions ).

Dosage Adjustments for Specific Patients

Patients with renal failure

In patients with renal impairment, clearance of Kerledex declines with decreasing renal function.

In patients with severe renal impairment and those undergoing dialysis the initial dose of Kerledex (Betaxolol Hydrochloride) is 5 mg once daily. If the desired response is not achieved, dosage may be increased by 5 mg/day increments every 2 weeks to a maximum dose of 20 mg/day.

Patients with hepatic disease

Patients with hepatic disease do not have significantly altered clearance. Dosage adjustments are not routinely needed.

Elderly patients

Consideration should be given to reduction in the starting dose to 5 mg in elderly patients. These patients are especially prone to beta-blocker-induced bradycardia, which appears to be dose related and sometimes responds to reductions in dose.

Cessation of therapy

If withdrawal of Kerledex (Betaxolol Hydrochloride) 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.

HOW SUPPLIED

Kerledex (Betaxolol Hydrochloride) Tablets USP, 10 mg* contains 10 mg Kerledex (Betaxolol Hydrochloride) hydrochloride (equivalent to 8.94 mg Kerledex (Betaxolol Hydrochloride)) are white, round biconvex, film-coated tablets, debossed “Є” above and “38” below bisect on one side and plain on the other side, available in bottles of 100 and 1000.

Kerledex (Betaxolol Hydrochloride) Tablets USP, 20 mg* contains 20 mg Kerledex (Betaxolol Hydrochloride) hydrochloride (equivalent to 17.88 mg Kerledex (Betaxolol Hydrochloride)) are white, round biconvex, film-coated tablets, debossed “Є” above “39” on one side and plain on the other side, available in bottles of 100 and 1000.

Store at 20°–25°C (68°–77°F).

Manufactured by:

Epic Pharma, LLC

Laurelton, NY 11413

Manufactured in USA

Revised February 2016

MF038REV02/16

OE1091

Kerledex (Betaxolol Hydrochloride) Tablets USP, 10 mg

100 Film-Coated Tablets

Rx Only

betaxolol-10mg-100-count-rev-02-16

Kerledex (Betaxolol Hydrochloride) Tablets USP, 20 mg

100 Film-Coated Tablets

Rx Only

betaxolol-20mg-100-count-rev-02-16

Chlorthalidone:

• Indications and usage:
• Contraindications:
• Warnings:
• Precautions:
• Information for patients
• Laboratory tests
• Drug interactions
• Drug/laboratory test interactions
• Carcinogenesis, mutagenesis, impairment of fertility
• Pregnancy
• Nursing mothers
• Pediatric use
• Adverse reactions:
• Overdosage
• Dosage and administration:
• How supplied:
• Animal pharmacology:
• Kerledex (Chlorthalidone) reviews

INDICATIONS AND USAGE:

Diuretics such as Kerledex are indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effect of other antihypertensive drugs in the more severe forms of hypertension.

Kerledex (Chlorthalidone) is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy.

Kerledex (Chlorthalidone) has also been found useful in edema due to various forms of renal dysfunction, such as nephrotic syndrome, acute glomerulonephritis, and chronic renal failure.

Usage in Pregnancy:

The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developed toxemia. Edema during pregnancy may arise from pathologic causes or from the physiologic and mechanical consequences of pregnancy. Kerledex (Chlorthalidone) is indicated in pregnancy when edema is due to pathologic causes, just as it is in the absence of pregnancy (however, see PRECAUTIONS, below). Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is illogical and unnecessary. There is hypervolemia during normal pregnancy that is harmful to neither the fetus nor the mother (in the absence of cardiovascular disease), but that is associated with edema, including generalized edema, in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort that is not relieved by rest. In these cases, a short course of diuretics may provide relief and be appropriate.

CONTRAINDICATIONS:

Anuria.

Known hypersensitivity to Kerledex (Chlorthalidone) or other sulfonamide-derived drugs.

WARNINGS:

Kerledex (Chlorthalidone) should be used with caution in severe renal disease. In patients with renal disease, Kerledex (Chlorthalidone) or related drugs may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.

Kerledex (Chlorthalidone) should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Sensitivity reactions may occur in patients with a history of allergy or bronchial asthma.

The possibility of exacerbation or activation of systemic lupus erythematosus has been reported with thiazide diuretics, which are structurally related to Kerledex (Chlorthalidone). However, systemic lupus erythematosus has not been reported following Kerledex (Chlorthalidone) administration.

PRECAUTIONS:

General

Hypokalemia may develop with Kerledex (Chlorthalidone) as with any other diuretic, 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. Digitalis therapy may exaggerate metabolic effects of hypokalemia especially with reference to myocardial activity.

Any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease). 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.

Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving Kerledex (Chlorthalidone). Thiazide-like diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

The antihypertensive effects of the drug may be enhanced in the post-sympathectomy patient.

If progressive renal impairment becomes evident, as indicated by a rising nonprotein nitrogen or blood urea nitrogen, a careful reappraisal of therapy is necessary with consideration given to withholding or discontinuing diuretic therapy.

Calcium excretion is decreased by thiazide-like drugs. Pathological changes in the parathyroid gland with hypercalcemia and hypophosphatemia have been observed in few patients on thiazide therapy. The common complications of hyperparathyroidism such as renal lithiasis, bone resorption and peptic ulceration have not been seen.

Information for Patients

Patients should inform their physician if they have: (1) had an allergic reaction to Kerledex (Chlorthalidone) or other diuretics or have asthma, (2) kidney disease, (3) liver disease, (4) gout, (5) systemic lupus erythematosus, or (6) been taking other drugs such as cortisone, digitalis, lithium carbonate, or drugs for diabetes.

Patients should be cautioned to contact their physician if they experience any of the following symptoms of potassium loss: excess thirst, tiredness, drowsiness, restlessness, muscle pains or cramps, nausea, vomiting, or increased heart rate or pulse.

Patients should also be cautioned that taking alcohol can increase the chance of dizziness occurring.

Laboratory Tests

Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

All patients receiving Kerledex (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.

Drug Interactions

Kerledex (Chlorthalidone) may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs with ganglionic peripheral adrenergic blocking drugs.

Medication such as digitalis may also influence serum electrolytes. Warning signs, irrespective of cause, are: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Insulin requirements in diabetic patients may be increased, decreased, or unchanged. Higher dosage of oral hypoglycemic agents may be required. Latent diabetes mellitus may become manifest during Kerledex (Chlorthalidone) administration.

Kerledex (Chlorthalidone) and related drugs may increase the responsiveness to tubocurarine.

Kerledex (Chlorthalidone) and related drugs may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.

Drug/Laboratory Test Interactions

Kerledex (Chlorthalidone) and related drugs may decrease serum PBI levels without signs of thyroid disturbance.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No information available.

Pregnancy

Reproduction studies have been performed in the rat and the rabbit at doses up to 420 times the human dose and have revealed no evidence of harm to the fetus due to Kerledex. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nonteratogenic Effects

Thiazides cross the placental barrier and appear in cord blood. The use of Kerledex (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 that have occurred in the adult.

Nursing Mothers

Thiazides are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Kerledex (Chlorthalidone), 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.

Pediatric Use

Safety and effectiveness in children has not been established.

ADVERSE REACTIONS:

To report SUSPECTED ADVERSE REACTIONS, please call RiconPharma LLC at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

The following adverse reactions have been observed, but there is not enough systematic collection of data to support an estimate of their frequency.

Gastrointestinal System Reactions: anorexia, gastric irritation, nausea, vomiting, cramping, diarrhea, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis.

Central Nervous System Reactions: dizziness, vertigo, paresthesias, headache, xanthopsia.

Hematologic Reactions: leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia.

Dermatologic-Hypersensitivity Reactions: purpura, photosensitivity, rash, urticaria, necrotizing angiitis (vasculitis, cutaneous vasculitis), Lyell’s syndrome (toxic epidermal necrolysis).

Cardiovascular Reactions: orthostatic hypotension may occur and may be aggravated by alcohol, barbiturates, or narcotics.

Other Adverse Reactions: hyperglycemia, glycosuria, hyperuricemia, muscle spasm, weakness, restlessness, impotence.

Whenever adverse reactions are moderate or severe, Kerledex (Chlorthalidone) dosage should be reduced or therapy withdrawn.

OVERDOSAGE

Symptoms of acute overdosage include nausea, weakness, dizziness, and disturbances of electrolyte balance. The oral LD₅₀ of the drug in the mouse and the rat is more than 25,000 mg/kg body weight. The minimum lethal dose (MLD) in humans has not been established. There is no specific antidote, but gastric lavage is recommended, followed by supportive treatment. Where necessary, this may include intravenous dextrose-saline with potassium, administered with caution.

DOSAGE AND ADMINISTRATION:

Therapy should be initiated with the lowest possible dose. This dose should be titrated according to individual patient response to gain maximal therapeutic benefit while maintaining lowest dosage possible. A single dose given in the morning with food is recommended; divided daily doses are unnecessary.

Hypertension

Initiation: Therapy, in most patients, should be initiated with a single daily dose of 25 mg. If the response is insufficient after a suitable trial, the dosage may be increased to a single daily dose of 50 mg. If additional control is required, the dosage of Kerledex (Chlorthalidone) may be increased to 100 mg once daily or a second antihypertensive drug (step 2 therapy) may be added. Dosage above 100 mg daily usually does not increase effectiveness. Increases in serum uric acid and decreases in serum potassium are dose-related over the 25 to 100 mg/day range.

Maintenance: Maintenance doses may be lower than initial doses and should be adjusted according to individual patient response. Effectiveness is well sustained during continued use.

Edema

Initiation: Adults, initially 50 to 100 mg daily, or 100 mg on alternate days. Some patients may require 150 to 200 mg at these intervals or up to 200 mg daily. Dosages above this level, however, do not usually produce a greater response.

Maintenance: Maintenance doses may often be lower than initial doses and should be adjusted according to individual patient response. Effectiveness is well sustained during continued use.

HOW SUPPLIED:

Kerledex (Chlorthalidone) Tablets, USP are available containing 25 mg or 50 mg of Kerledex (Chlorthalidone), USP.

The 25 mg tablets are green colored, biconvex, round shaped tablets debossed with ‘010’ on one side, and plain on the other side. They are available as follows:

NDC 51125-010-06

Bottles of 100 tablets

NDC 51125-010-09

Bottles of 1000 tablets

The 50 mg tablets are green colored, capsule shaped tablets debossed with ‘011’ on one side, and a break-line on the other side. They are available as follows:

NDC 51125-011-06

Bottles of 100 tablets

NDC 51125-011-09

Bottles of 1000 tablets

Store at 20ºC to 25º C (68º to 77º F).

Protect from light.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

ANIMAL

Pharmacology:

Biochemical studies in animals have suggested reasons for the prolonged effect of Kerledex (Chlorthalidone). Absorption from the gastrointestinal tract is slow due to its low solubility. After passage to the liver, some of the drug enters the general circulation, while some is excreted in the bile, to be reabsorbed later. In the general circulation, it is distributed widely to the tissue, but is taken up in highest concentrations by the kidneys, where amounts have been found 72 hours after ingestion, long after it has disappeared from other tissues. The drug is excreted unchanged in the urine.

Manufactured for:

RiconPharma LLC.

Denville, NJ, 07834

Made in U.S.A

PC143 Revised: 03/17