Get your patient on Atenolol And Chlorthalidone - Atenolol And Chlorthalidone tablet (Atenolol And Chlorthalidone)
Atenolol And Chlorthalidone - Atenolol And Chlorthalidone tablet prescribing information
INDICATIONS AND USAGE
Atenolol and chlorthalidone is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including atenolol and chlorthalidone.
Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.
This fixed dose combination drug is not indicated for initial therapy of hypertension. If the fixed dose combination represents the dose appropriate to the individual patient's needs, it may be more convenient than the separate components.
DOSAGE AND ADMINISTRATION
DOSAGE MUST BE INDIVIDUALIZED. (See INDICATIONS AND USAGE . )
Chlorthalidone is usually given at a dose of 25 mg daily; the usual initial dose of atenolol is 50 mg daily. Therefore, the initial dose should be one atenolol and chlorthalidone 50 mg/25 mg tablet given once a day. If an optimal response is not achieved, the dosage should be increased to one atenolol and chlorthalidone 100 mg/25 mg tablet given once a day.
When necessary, another antihypertensive agent may be added gradually beginning with 50 percent of the usual recommended starting dose to avoid an excessive fall in blood pressure.
Since atenolol is excreted via the kidneys, dosage should be adjusted in cases of severe impairment of renal function. No significant accumulation of atenolol occurs until creatinine clearance falls below 35 mL/min/1.73 m 2 (normal range is 100 mL/min/1.73 m 2 to 150 mL/min/1.73 m 2 ); therefore, the following maximum dosages are recommended for patients with renal impairment.
| Creatinine Clearance | Atenolol Elimination | |
|---|---|---|
| (mL/min/1.73m 2 ) | Half-Life (hrs) | Maximum Dosage |
| 15-35 | 16-27 | 50 mg daily |
| <15 | >27 | 50 mg every other day |
CONTRAINDICATIONS
Atenolol and chlorthalidone tablets are contraindicated in patients with: sinus bradycardia; heart block greater than first degree; cardiogenic shock; overt cardiac failure (see WARNINGS ); anuria; hypersensitivity to this product or to sulfonamide-derived drugs.
ADVERSE REACTIONS
Atenolol and chlorthalidone tablets are usually well tolerated in properly selected patients. Most adverse effects have been mild and transient. The adverse effects observed for atenolol and chlorthalidone are essentially the same as those seen with the individual components.
Atenolol
The frequency estimates in the following table were derived from controlled studies in which adverse reactions were either volunteered by the patient (US studies) or elicited, e.g., by checklist (foreign studies). The reported frequency of elicited adverse effects was higher for both atenolol and placebo-treated patients than when these reactions were volunteered. Where frequency of adverse effects for atenolol and placebo is similar, causal relationship to atenolol is uncertain.
| Volunteered | Total–Volunteered and Elicited | |||
|---|---|---|---|---|
| (US Studies) | (Foreign + US Studies) | |||
| Atenolol | Placebo | Atenolol | Placebo | |
| (n = 164) | (n = 206) | (n = 399) | (n = 407) | |
| % | % | % | % | |
| CARDIOVASCULAR | ||||
| Bradycardia | 3 | 0 | 3 | 0 |
| Cold Extremities | 0 | 0.5 | 12 | 5 |
| Postural Hypotension | 2 | 1 | 4 | 5 |
| Leg Pain | 0 | 0.5 | 3 | 1 |
| CENTRAL NERVOUS SYSTEM/ | ||||
| NEUROMUSCULAR | ||||
| Dizziness | 4 | 1 | 13 | 6 |
| Vertigo | 2 | 0.5 | 2 | 0.2 |
| Light-Headedness | 1 | 0 | 3 | 0.7 |
| Tiredness | 0.6 | 0.5 | 26 | 13 |
| Fatigue | 3 | 1 | 6 | 5 |
| Lethargy | 1 | 0 | 3 | 0.7 |
| Drowsiness | 0.6 | 0 | 2 | 0.5 |
| Depression | 0.6 | 0.5 | 12 | 9 |
| Dreaming | 0 | 0 | 3 | 1 |
| GASTROINTESTINAL | ||||
| Diarrhea | 2 | 0 | 3 | 2 |
| Nausea | 4 | 1 | 3 | 1 |
| RESPIRATORY (see WARNINGS ) | ||||
| Wheeziness | 0 | 0 | 3 | 3 |
| Dyspnea | 0.6 | 1 | 6 | 4 |
During postmarketing experience, the following have been reported in temporal relationship to the use of the drug: elevated liver enzymes and/or bilirubin, hallucinations, headache, impotence, Peyronie’s disease, postural hypotension which may be associated with syncope, psoriasiform rash or exacerbation of psoriasis, psychoses, purpura, reversible alopecia, thrombocytopenia, visual disturbance, sick sinus syndrome, and dry mouth. Atenolol, like other beta-blockers, has been associated with the development of antinuclear antibodies (ANA), lupus syndrome, and Raynaud’s phenomenon.
Chlorthalidone
Cardiovascular: orthostatic hypotension; Gastrointestinal: anorexia, gastric irritation, vomiting, cramping, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis; CNS: vertigo, paresthesia, xanthopsia; Hematologic: leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia; Hypersensitivity: purpura, photosensitivity, rash, urticaria, necrotizing angiitis (vasculitis) (cutaneous vasculitis), Lyell’s syndrome (toxic epidermal necrolysis); Miscellaneous: hyperglycemia, glycosuria, hyperuricemia, muscle spasm, weakness, restlessness. Clinical trials of atenolol and chlorthalidone conducted in the United States (89 patients treated with atenolol and chlorthalidone) revealed no new or unexpected adverse effects.
Drug Interactions
Atenolol and chlorthalidone may potentiate the action of other antihypertensive agents used concomitantly. Patients treated with atenolol and chlorthalidone plus a catecholamine depletor (e.g., reserpine) should be closely observed for evidence of hypotension and/or marked bradycardia which may produce vertigo, syncope or postural hypotension.
Calcium channel blockers may also have an additive effect when given with atenolol and chlorthalidone. (See WARNINGS . )
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.
Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with beta-blockers.
Thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude the therapeutic effectiveness of norepinephrine. Thiazides may increase the responsiveness to tubocurarine.
Concomitant use of prostaglandin synthase inhibiting drugs, e.g., indomethacin, may decrease the hypotensive effects of beta-blockers.
Lithium generally should not be given with diuretics because they reduce its renal clearance and add a high risk of lithium toxicity. Read prescribing information for lithium preparations before use of such preparations with atenolol and chlorthalidone.
Beta-blockers may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two drugs are coadministered, the beta-blocker should be withdrawn several days before the gradual withdrawal of clonidine. If replacing clonidine by beta-blocker therapy, the introduction of beta-blockers should be delayed for several days after clonidine administration has stopped.
While taking beta-blockers, patients with a history of anaphylactic reaction to a variety of allergens may have a more severe reaction on repeated challenge, either accidental, diagnostic or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat the allergic reaction.
Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
DESCRIPTION
Atenolol and chlorthalidone tablets, USP are for the treatment of hypertension. It combines the antihypertensive activity of two agents: a beta 1 -selective (cardioselective) hydrophilic blocking agent (atenolol), and a monosulfonamyl diuretic (chlorthalidone). Atenolol, USP is Benzeneacetamide, 4-[2’-hydroxy-3’-[(1-methylethyl)amino]propoxy]-. It has the following structural formula:
C 14 H 22 N 2 O 3 M.W. 266.34
Atenolol, USP (free base) is a relatively polar hydrophilic compound with a water solubility of 26.5 mg/mL at 37°C. It is freely soluble in 1N HCl (300 mg/mL at 25°C) and less soluble in chloroform (3 mg/mL at 25°C).
Chlorthalidone, USP is 2-Chloro-5-(1-hydroxy-3-oxo-1-isoindolinyl) benzene sulfonamide. Chlorthalidone, USP has a water solubility of 12 mg/100 mL at 20°C. It has the following structural formula:
C 14 H 11 ClN 2 O 4 S M.W. 338.77
Each atenolol and chlorthalidone tablet, USP 50 mg/25 mg for oral administration contains: atenolol USP, 50 mg and chlorthalidone USP, 25 mg.
Each atenolol and chlorthalidone tablet, USP 100 mg/25 mg for oral administration contains: atenolol USP, 100 mg and chlorthalidone USP, 25 mg.
Atenolol and chlorthalidone tablets USP, 50 mg/25 mg and 100 mg/25 mg, contain the following inactive ingredients: magnesium stearate, microcrystalline cellulose, povidone and sodium starch glycolate.
CLINICAL PHARMACOLOGY
Atenolol and Chlorthalidone
Atenolol and chlorthalidone have been used singly and concomitantly for the treatment of hypertension. The antihypertensive effects of these agents are additive, and studies have shown that there is no interference with bioavailability when these agents are given together in the single combination tablet. Therefore, this combination provides a convenient formulation for the concomitant administration of these two entities. In patients with more severe hypertension, atenolol and chlorthalidone may be administered with other antihypertensives such as vasodilators.
Atenolol
Atenolol is a beta 1 -selective (cardioselective) beta-adrenergic receptor blocking agent without membrane stabilizing or intrinsic sympathomimetic (partial agonist) activities. This preferential effect is not absolute, however, and at higher doses, atenolol inhibits beta 2 -adrenoreceptors, chiefly located in the bronchial and vascular musculature.
Pharmacodynamics
In standard animal or human pharmacological tests, beta-adrenoreceptor blocking activity of atenolol has been demonstrated by: (1) reduction in resting and exercise heart rates and cardiac output, (2) reduction of systolic and diastolic blood pressure at rest and on exercise, (3) inhibition of isoproterenol induced tachycardia and (4) reduction in reflex orthostatic tachycardia.
A significant beta-blocking effect of atenolol, as measured by reduction of exercise tachycardia, is apparent within one hour following oral administration of a single dose. This effect is maximal at about 2 to 4 hours and persists for at least 24 hours. The effect at 24 hours is dose related and also bears a linear relationship to the logarithm of plasma atenolol concentration. However, as has been shown for all beta-blocking agents, the antihypertensive effect does not appear to be related to plasma level.
In normal subjects, the beta 1 -selectivity of atenolol has been shown by its reduced ability to reverse the beta 2 -mediated vasodilating effect of isoproterenol as compared to equivalent beta-blocking doses of propranolol. In asthmatic patients, a dose of atenolol producing a greater effect on resting heart rate than propranolol resulted in much less increase in airway resistance. In a placebo controlled comparison of approximately equipotent oral doses of several beta-blockers, atenolol produced a significantly smaller decrease of FEV 1 than nonselective beta-blockers, such as propranolol and unlike those agents did not inhibit bronchodilation in response to isoproterenol.
Consistent with its negative chronotropic effect due to beta blockade of the SA node, atenolol increases sinus cycle length and sinus node recovery time. Conduction in the AV node is also prolonged. Atenolol is devoid of membrane stabilizing activity, and increasing the dose well beyond that producing beta blockade does not further depress myocardial contractility. Several studies have demonstrated a moderate (approximately 10%) increase in stroke volume at rest and exercise.
In controlled clinical trials, atenolol given as a single daily dose, was an effective antihypertensive agent providing 24-hour reduction of blood pressure. Atenolol has been studied in combination with thiazide-type diuretics and the blood pressure effects of the combination are approximately additive. Atenolol is also compatible with methyldopa, hydralazine and prazosin, the combination resulting in a larger fall in blood pressure than with the single agents. The dose range of atenolol is narrow, and increasing the dose beyond 100 mg once daily is not associated with increased antihypertensive effect. The mechanisms of the antihypertensive effects of beta-blocking agents have not been established. Several mechanisms have been proposed and include: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron 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 efficacy of atenolol with prolonged use.
Pharmacokinetics and Metabolism
In man, absorption of an oral dose is rapid and consistent but incomplete. Approximately 50% of an oral dose is absorbed from the gastrointestinal tract, the remainder being excreted unchanged in the feces. Peak blood levels are reached between 2 and 4 hours after ingestion. Unlike propranolol or metoprolol, but like nadolol, hydrophilic atenolol undergoes little or no metabolism by the liver, and the absorbed portion is eliminated primarily by renal excretion. Atenolol also differs from propranolol in that only a small amount (6% to 16%) is bound to proteins in the plasma. This kinetic profile results in relatively consistent plasma drug levels with about a fourfold interpatient variation. There is no information as to the pharmacokinetic effect of atenolol on chlorthalidone.
The elimination half-life of atenolol is approximately 6 to 7 hours and there is no alteration of the kinetic profile of the drug by chronic administration. Following doses of 50 mg or 100 mg, both beta-blocking and antihypertensive effects persist for at least 24 hours. When renal function is impaired, elimination of atenolol is closely related to the glomerular filtration rate; but significant accumulation does not occur until the creatinine clearance falls below 35 mL/min/1.73 m 2 (see prescribing information for atenolol).
Atenolol Geriatric Pharmacology
In general, elderly patients present higher atenolol plasma levels with total clearance values about 50% lower than younger subjects. The half-life is markedly longer in the elderly compared to younger subjects. The reduction of atenolol clearance follows the general trend that the elimination of renally excreted drugs is decreased with increasing age.
Chlorthalidone:
Chlorthalidone is a monosulfonamyl diuretic which differs chemically from thiazide diuretics in that a double ring system is incorporated in its structure. It is an oral diuretic with prolonged action and low toxicity. The diuretic effect of the drug occurs within 2 hours of an oral dose. It produces diuresis with greatly increased excretion of sodium and chloride. At maximal therapeutic dosage, chlorthalidone is approximately equal in its diuretic effect to comparable maximal therapeutic doses of benzothiadiazine diuretics. The site of action appears to be the cortical diluting segment of the ascending limb of Henle’s loop of the nephron.
HOW SUPPLIED
Atenolol and chlorthalidone tablets USP, 50 mg/25 mg are white, round, scored tablets imprinted with “DAN 5782” on one side and plain on the other side. Supplied in bottles of 100 (NDC 0591-5782-01).
Atenolol and chlorthalidone tablets USP, 100 mg/25 mg are white, round tablets imprinted with “DAN 5783” on one side and plain on the other side. Supplied in bottles of 100 (NDC 0591-5783-01)
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a well-closed, light-resistant container with a child-resistant closure. Protect from heat, light and moisture.
Manufactured In India By: Watson Pharma Private Limited Verna, Salcette Goa 403 722 INDIA
Manufactured For: Teva Pharmaceuticals Parsippany, NJ 07054
Rev. A 3/2024
