ATENOLOL: 12,327 Adverse Event Reports & Safety Profile

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. 1 2

INDICATIONS AND USAGE Hypertension Atenolol tablets are 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. 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. Atenolol tablets may be administered with other antihypertensive agents.

Angina Pectoris

Due to Coronary Atherosclerosis Atenolol tablets are indicated for the long-term management of patients with angina pectoris.

Acute Myocardial Infarction

Atenolol tablets are indicated in the management of hemodynamically stable patients with definite or suspected acute myocardial infarction to reduce cardiovascular mortality. Treatment can be initiated as soon as the patient's clinical condition allows. (See Error! Hyperlink reference not valid., Error! Hyperlink reference not valid. , and WARNINGS .) In general, there is no basis for treating patients like those who were excluded from the ISIS-1 trial (blood pressure less than 100 mm Hg systolic, heart rate less than 50 bpm) or have other reasons to avoid beta blockade. As noted above, some subgroups (e.g., elderly patients with systolic blood pressure below 120 mm Hg) seemed less likely to benefit.

DOSAGE AND ADMINISTRATION Hypertension The initial dose of atenolol tablets USP is 50 mg given as one tablet a day either alone or added to diuretic therapy. The full effect of this dose will usually be seen within one to two weeks. If an optimal response is not achieved, the dosage should be increased to atenolol tablets USP 100 mg given as one tablet a day. Increasing the dosage beyond 100 mg a day is unlikely to produce any further benefit. Atenolol tablets USP may be used alone or concomitantly with other antihypertensive agents including thiazide-type diuretics, hydralazine, prazosin, and alpha-methyldopa.

Angina Pectoris

The initial dose of atenolol tablets USP is 50 mg given as one tablet a day. If an optimal response is not achieved within one week, the dosage should be increased to atenolol tablets USP 100 mg given as one tablet a day. Some patients may require a dosage of 200 mg once a day for optimal effect. Twenty-four hour control with once daily dosing is achieved by giving doses larger than necessary to achieve an immediate maximum effect. The maximum early effect on exercise tolerance occurs with doses of 50 to 100 mg, but at these doses the effect at 24 hours is attenuated, averaging about 50% to 75% of that observed with once a day oral doses of 200 mg.

Acute Myocardial

Infarction In patients with definite or suspected acute myocardial infarction, treatment with atenolol I.V. injection should be initiated as soon as possible after the patient's arrival in the hospital and after eligibility is established. Such treatment should be initiated in a coronary care or similar unit immediately after the patient's hemodynamic condition has stabilized. Treatment should begin with the intravenous administration of 5 mg atenolol over 5 minutes followed by another 5 mg intravenous injection 10 minutes later. Atenolol I.V. injection should be administered under carefully controlled conditions including monitoring of blood pressure, heart rate, and electrocardiogram. Dilutions of atenolol I.V. injection in Dextrose Injection USP, Sodium Chloride Injection USP, or Sodium Chloride and Dextrose Injection may be used. These admixtures are stable for 48 hours if they are not used immediately. In patients who tolerate the full intravenous dose (10 mg), atenolol tablets USP, 50 mg should be initiated 10 minutes after the last intravenous dose followed by another 50 mg oral dose 12 hours later. Thereafter, atenolol tablets USP can be given orally either 100 mg once daily or 50 mg twice a day for a further 6 to 9 days or until discharge from the hospital. If bradycardia or hypotension requiring treatment or any other untoward effects occur, atenolol tablets USP should be discontinued (see full prescribing information prior to initiating therapy with atenolol tablets USP). Data from other beta blocker trials suggest that if there is any question concerning the use of IV beta blocker or clinical estimate that there is a contraindication, the IV beta blocker may be eliminated and patients fulfilling the safety criteria may be given atenolol tablets USP, 50 mg twice daily or 100 mg once a day for at least seven days (if the IV dosing is excluded). Although the demonstration of efficacy of atenolol tablets USP is based entirely on data from the first seven postinfarction days, data from other beta blocker trials suggest that treatment with beta blockers that are effective in the postinfarction setting may be continued for one to three years if there are no contraindications. Atenolol tablets USP is an additional treatment to standard coronary care unit therapy.

Elderly

Patients or Patients With Renal Impairment Atenolol tablets USP are excreted by the kidneys; consequently dosage should be adjusted in cases of severe impairment of renal function. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Evaluation of patients with hypertension or myocardial infarction should always include assessment of renal function. Atenolol excretion would be expected to decrease with advancing age. No significant accumulation of atenolol tablets USP occurs until creatinine clearance falls below 35 mL/min/1.73 m 2 . Accumulation of atenolol and prolongation of its half-life were studied in subjects with creatinine clearance between 5 and 105 mL/min. Peak plasma levels were significantly increased in subjects with creatinine clearances below 30 mL/min. The following maximum oral dosages are recommended for elderly, renally-impaired patients and for patients with renal impairment due to other causes: Creatinine Clearance (mL/min/1.73 m 2 )

Atenolol Elimination

Half-Life (h)

Maximum Dosage

15 to 35 16 to 27 50 mg daily < 15 > 27 25 mg daily Some renally-impaired or elderly patients being treated for hypertension may require a lower starting dose of atenolol tablets USP: 25 mg given as one tablet a day. If this 25 mg dose is used, assessment of efficacy must be made carefully. This should include measurement of blood pressure just prior to the next dose ("trough" blood pressure) to ensure that the treatment effect is present for a full 24 hours. Although a similar dosage reduction may be considered for elderly and/or renally-impaired patients being treated for indications other than hypertension, data are not available for these patient populations. Patients on hemodialysis should be given 25 mg or 50 mg after each dialysis; this should be done under hospital supervision as marked falls in blood pressure can occur. Cessation of Therapy in Patients With Angina Pectoris If withdrawal of atenolol tablet USP therapy is planned, it should be achieved gradually and patients should be carefully observed and advised to limit physical activity to a minimum.

CONTRAINDICATIONS Atenolol tablets are contraindicated in sinus bradycardia, heart block greater than first degree, cardiogenic shock, and overt cardiac failure. (See WARNINGS .) Atenolol tablets are contraindicated in those patients with a history of hypersensitivity to the atenolol or any of the drug product’s components.

ADVERSE REACTIONS Most adverse effects have been mild and transient. The frequency estimates in the following table were derived from controlled studies in hypertensive patients in which adverse reactions were either volunteered by the patient (U.S. studies) or elicited, e.g., by checklist (foreign studies). The reported frequency of elicited adverse effects was higher for both atenolol tablets and placebo-treated patients than when these reactions were volunteered. Where frequency of adverse effects of atenolol tablets and placebo is similar, causal relationship to atenolol tablets is uncertain. Volunteered (U.S. Studies) Total-Volunteered and Elicited (Foreign + U.S. Studies) Atenolol (n = 164) % Placebo (n = 206) % Atenolol (n = 399) % Placebo (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 Acute Myocardial Infarction In a series of investigations in the treatment of acute myocardial infarction, bradycardia and hypotension occurred more commonly, as expected for any beta-blocker, in atenolol-treated patients than in control patients. However, these usually responded to atropine and/or to withholding further dosage of atenolol. The incidence of heart failure was not increased by atenolol. Inotropic agents were infrequently used. The reported frequency of these and other events occurring during these investigations is given in the following table. In a study of 477 patients, the following adverse events were reported during either intravenous and/or oral atenolol administration: Conventional Therapy Plus Atenolol (n = 244)

Conventional Therapy

Alone (n = 233)

Bradycardia

43 (18%) 24 (10%)

Hypotension

60 (25%) 34 (15%)

Bronchospasm

3 (1.2%) 2 (0.9%)

Heart Failure

46 (19%) 56 (24%)

Heart Block

11 (4.5%) 10 (4.3%) BBB + Major Axis Deviation 16 (6.6%) 28 (12%)

Supraventricular Tachycardia

28 (11.5%) 45 (19%)

Atrial Fibrillation

12 (5%) 29 (11%)

Atrial Flutter

4 (1.6%) 7 (3%)

Ventricular Tachycardia

39 (16%) 52 (22%)

Cardiac Reinfarction

0 (0%) 6 (2.6%)

Total Cardiac Arrests

4 (1.6%) 16 (6.9%)

Nonfatal Cardiac Arrests

4 (1.6%) 12 (5.1%)

Deaths

7 (2.9%) 16 (6.9%)

Cardiogenic Shock

1 (0.4%) 4 (1.7%) Development of Ventricular Septal Defect 0 (0%) 2 (0.9%) Development of Mitral Regurgitation 0 (0%) 2 (0.9%)

Renal Failure

1 (0.4%) 0 (0%)

Pulmonary Emboli

3 (1.2%) 0 (0%) In the subsequent International Study of Infarct Survival (ISIS-1) including over 16,000 patients of whom 8,037 were randomized to receive atenolol treatment, the dosage of intravenous and subsequent oral atenolol was either discontinued or reduced for the following reasons: Reasons for Reduced Dosage I.V.

Atenolol Reduced

Dose (< 5 mg) Full dosage was 10 mg and some patients received less than 10 mg but more than 5 mg.

Oral Partial Dose Hypotension/Bradycardia

105 (1.3%) 1168 (14.5%)

Cardiogenic Shock

4 (.04%) 35 (.44%)

Reinfarction

0 (0%) 5 (.06%)

Cardiac Arrest

5 (.06%) 28 (.34%)

Heart

Block (> first degree) 5 (.06%) 143 (1.7%)

Cardiac Failure

1 (.01%) 233 (2.9%)

Arrhythmias

3 (.04%) 22 (.27%)

Bronchospasm

1 (.01%) 50 (.62%) During postmarketing experience with atenolol tablets, 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 tablets, like other beta-blockers, has been associated with the development of antinuclear antibodies (ANA), lupus syndrome, and Raynaud’s phenomenon.

Potential Adverse Effects

In addition, a variety of adverse effects have been reported with other beta-adrenergic blocking agents, and may be considered potential adverse effects of atenolol tablets. Hematologic: Agranulocytosis. Allergic: Fever, combined with aching and sore throat, laryngospasm, and respiratory distress.

Central Nervous

System: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation of time and place; short-term memory loss; emotional lability with slightly clouded sensorium; and, decreased performance on neuropsychometrics. Gastrointestinal: Mesenteric arterial thrombosis, ischemic colitis. Other: Erythematous rash. Miscellaneous: 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. Discontinuance of the drug should be considered if any such reaction is not otherwise explicable. Patients should be closely monitored following cessation of therapy. (See DOSAGE AND ADMINISTRATION .) The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with atenolol tablets. Furthermore, a number of patients who had previously demonstrated established practolol reactions were transferred to atenolol tablets therapy with subsequent resolution or quiescence of the reaction. To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch for voluntary reporting of adverse reactions.

WARNINGS Cardiac Failure Sympathetic stimulation is necessary in supporting circulatory function in congestive heart failure, and beta blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. 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. At the first sign or symptom of impending cardiac failure, patients should be treated appropriately according to currently recommended guidelines, and the response observed closely. If cardiac failure continues despite adequate treatment, atenolol and chlorthalidone tablets should be withdrawn (See DOSAGE AND ADMINISTRATION ). Renal and Hepatic Disease and Electrolyte Disturbances Since atenolol is excreted via the kidneys, atenolol and chlorthalidone tablets should be used with caution in patients with impaired renal function. In patients with renal disease, thiazides may precipitate azotemia. Since cumulative effects may develop in the presence of impaired renal function, if progressive renal impairment becomes evident, atenolol and chlorthalidone tablets should be discontinued. In patients with impaired hepatic function or progressive liver disease, minor alterations in fluid and electrolyte balance may precipitate hepatic coma. Atenolol and chlorthalidone tablets should be used with caution in these patients.

Ischemic Heart Disease

Following abrupt cessation of therapy with certain beta-blocking agents in patients with coronary artery disease, exacerbations of angina pectoris and, in some cases, myocardial infarction have been reported. Therefore, such patients should be cautioned against interruption of therapy without the physician's advice. Even in the absence of overt angina pectoris, when discontinuation of atenolol and chlorthalidone tablets is planned, the patient should be carefully observed and should be advised to limit physical activity to a minimum. Atenolol and chlorthalidone tablets should be reinstated if withdrawal symptoms occur. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue atenolol and chlorthalidone tablets therapy abruptly even in patients treated only for hypertension.

Concomitant

Use of Calcium Channel Blockers Bradycardia and heart block can occur and the left ventricular end diastolic pressure can rise when beta-blockers are administered with verapamil or diltiazem. Patients with pre-existing conduction abnormalities or left ventricular dysfunction are particularly susceptible (See PRECAUTIONS ).

Bronchospastic

Diseases PATIENTS WITH BRONCHOSPASTIC DISEASE SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of its relative beta 1 -selectivity, however, atenolol and chlorthalidone tablets may be used with caution in patients with bronchospastic disease who do not respond to or cannot tolerate, other antihypertensive treatment. Since beta 1 -selectivity is not absolute, the lowest possible dose of atenolol and chlorthalidone tablets should be used and a beta 2 -stimulating agent (bronchodilator) should be made available. If dosage must be increased, dividing the dose should be considered in order to achieve lower peak blood levels.

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. Metabolic and Endocrine Effects Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting). If severe hypoglycemia occurs, patients should be instructed to seek emergency treatment. Insulin requirements in diabetic patients may be increased, decreased or unchanged; latent diabetes mellitus may become manifest during chlorthalidone administration. Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Abrupt withdrawal of beta blockade might precipitate a thyroid storm; therefore, patients suspected of developing thyrotoxicosis from whom atenolol and chlorthalidone tablets therapy is to be withdrawn should be monitored closely. Because calcium excretion is decreased by thiazides, atenolol and chlorthalidone tablets 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. Hyperuricemia may occur, or acute gout may be precipitated in certain patients receiving thiazide therapy.

Untreated Pheochromocytoma

Atenolol and chlorthalidone tablets should not be given to patients with untreated pheochromocytoma. Pregnancy and Fetal Injury Atenolol can cause fetal harm when administered to a pregnant woman. Atenolol crosses the placental barrier and appears in cord blood. Administration of atenolol, starting in the second trimester of pregnancy, has been associated with the birth of infants that are small for gestational age. No studies have been performed on the use of atenolol in the first trimester and the possibility of fetal injury cannot be excluded. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Neonates born to mothers who are receiving atenolol at parturition or breastfeeding may be at risk for hypoglycemia and bradycardia. Caution should be exercised when atenolol and chlorthalidone tablets are administered during pregnancy or to a woman who is breastfeeding (See PRECAUTIONS, Nursing Mothers ). Atenolol and chlorthalidone tablets were studied for teratogenic potential in the rat and rabbit. Doses of atenolol/chlorthalidone of 8/2 mg/kg/day, 80/20 mg/kg/day, and 240/60 mg/kg/day were administered orally to pregnant rats with no evidence of embryofetotoxicity observed. Two studies were conducted in rabbits. In the first study, pregnant rabbits were dosed with 8/2 mg/kg/day, 80/20 mg/kg/day, and 160/40 mg/kg/day of atenolol/chlorthalidone. No teratogenic effects were noted, but embryonic resorptions were observed at all dose levels (ranging from approximately 5 times to 100 times the maximum recommended human dose * ). In the second rabbit study, doses of atenolol/chlorthalidone were 4/1 mg/kg/day, 8/2 mg/kg/day, and 20/5 mg/kg/day. No teratogenic or embryotoxic effects were demonstrated.

Atenolol

Atenolol has been shown to produce a dose-related increase in embryo/fetal resorptions in rats at doses equal to or greater than 50 mg/kg/day or 25 or more times the maximum recommended human antihypertensive dose. * Although similar effects were not seen in rabbits, the compound was not evaluated in rabbits at doses above 25 mg/kg/day or 12.5 times the maximum recommended human antihypertensive dose. * 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. * Based on the maximum dose of 100 mg/day in a 50 kg patient.

PRECAUTIONS General Atenolol and chlorthalidone may aggravate peripheral arterial circulatory disorders. Electrolyte and Fluid Balance Status Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. Patients should be observed for clinical signs of fluid or electrolyte imbalance; i.e., hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Measurement of potassium levels is appropriate especially in elderly patients, those receiving digitalis preparations for cardiac failure, patients whose dietary intake of potassium is abnormally low, or those suffering from gastrointestinal complaints. 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 (e.g., increased ventricular irritability). Hypokalemia may be avoided or treated by use of potassium supplements or foods with a high potassium content. Any chloride deficit during thiazide therapy 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.

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.

Other

Precautions In patients receiving thiazides, sensitivity reactions may occur with or without a history of allergy or bronchial asthma. The possible exacerbation or activation of systemic lupus erythematosus has been reported. The antihypertensive effects of thiazides may be enhanced in the postsympathectomy patient. Carcinogenesis, Mutagenesis, Impairment of Fertility Two long-term (maximum dosing duration of 18 or 24 months) rat studies and one long-term (maximum dosing duration of 18 months) mouse study, each employing dose levels as high as 300 mg/kg/day or 150 times the maximum recommended human antihypertensive dose*, did not indicate a carcinogenic potential of atenolol. A third (24 month) rat study, employing doses of 500 mg/kg/day and 1,500 mg/kg/day (250 and 750 times the maximum recommended human antihypertensive dose*) resulted in increased incidences of benign adrenal medullary tumors in males and females, mammary fibroadenomas in females, and anterior pituitary adenomas and thyroid parafollicular cell carcinomas in males. No evidence of a mutagenic potential of atenolol was uncovered in the dominant lethal test (mouse), in vivo cytogenetics test (Chinese hamster) or Ames test ( S typhimurium ). Fertility of male or female rats (evaluated at dose levels as high as 200 mg/kg/day or 100 times the maximum recommended human dose*) was unaffected by atenolol administration. *Based on the maximum dose of 100 mg/day in a 50 kg patient.

Animal Toxicology

Six month oral administration studies were conducted in rats and dogs using atenolol and chlorthalidone doses up to 12.5 mg/kg/day (atenolol/chlorthalidone 10/2.5 mg/kg/day -- approximately five times the maximum recommended human antihypertensive dose*). There were no functional or morphological abnormalities resulting from dosing either compound alone or together other than minor changes in heart rate, blood pressure and urine chemistry which were attributed to the known pharmacologic properties of atenolol and/or chlorthalidone. Chronic studies of atenolol performed in animals have revealed the occurrence of vacuolation of epithelial cells of Brunner's glands in the duodenum of both male and female dogs at all tested dose levels (starting at 15 mg/kg/day or 7.5 times the maximum recommended human antihypertensive dose*) and increased incidence of atrial degeneration of hearts of male rats at 300 mg atenolol/kg/day but not 150 mg atenolol/kg/day (150 and 75 times the maximum recommended human antihypertensive dose,* respectively). *Based on the maximum dose of 100 mg/day in a 50 kg patient. Use in Pregnancy See WARNINGS, Pregnancy and Fetal Injury .

Nursing Mothers

Atenolol is excreted in human breast milk at a ratio of 1.5 to 6.8 when compared to the concentration in plasma. Caution should be exercised when atenolol is administered to a nursing woman. Clinically significant bradycardia has been reported in breastfed infants. Premature infants, or infants with impaired renal function, may be more likely to develop adverse effects. Neonates born to mothers who are receiving atenolol at parturition or breastfeeding may be at risk for hypoglycemia and bradycardia. Caution should be exercised when atenolol and chlorthalidone is administered during pregnancy or to a woman who is breastfeeding. (See WARNINGS, Pregnancy and Fetal Injury .)

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of atenolol and chlorthalidone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy.

Electrolyte and Fluid Balance Status Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. Patients should be observed for clinical signs of fluid or electrolyte imbalance; i.e., hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Measurement of potassium levels is appropriate especially in elderly patients, those receiving digitalis preparations for cardiac failure, patients whose dietary intake of potassium is abnormally low, or those suffering from gastrointestinal complaints. 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 (e.g., increased ventricular irritability). Hypokalemia may be avoided or treated by use of potassium supplements or foods with a high potassium content. Any chloride deficit during thiazide therapy 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.

Other

Precautions In patients receiving thiazides, sensitivity reactions may occur with or without a history of allergy or bronchial asthma. The possible exacerbation or activation of systemic lupus erythematosus has been reported. The antihypertensive effects of thiazides may be enhanced in the postsympathectomy patient.

Use in Pregnancy See WARNINGS, Pregnancy and Fetal Injury .

Drug Interactions Atenolol and chlorthalidone tablets may potentiate the action of other antihypertensive agents used concomitantly. Patients treated with atenolol and chlorthalidone tablets 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 tablets (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 tablets. 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.