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 and placebo-treated patients than when these reactions were volunteered. Where frequency of adverse effects of atenolol and placebo is similar, causal relationship to atenolol 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 (seeWARNINGS)
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:

Full dosage was 10 mg and some patients received less than 10 mg but more than 5 mg.
	Reasons for Reduced Dosage
IV Atenolol Reduced Dose (< 5 mg)*	Oral Partial Dose
Hypotension/Bradycardia	105	(1.3%)	1168	(14.5%)
Cardiogenic Shock	4	(0.04%)	35	(0.44%)
Reinfarction	0	(0%)	5	(0.06%)
Cardiac Arrest	5	(0.06%)	28	(0.34%)
Heart Block (> first degree)	5	(0.06%)	143	(1.7%)
Cardiac Failure	1	(0.01%)	233	(2.9%)
Arrhythmias	3	(0.04%)	22	(0.27%)
Bronchospasm	1	(0.01%)	50	(0.62%)

During postmarketing experience with atenolol, 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.

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 with acute myocardial infarction, cardiac failure which is not promptly and effectively controlled by 80 mg of intravenous furosemide or equivalent therapy is a contraindication to beta blocker treatment.

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 should be withdrawn. (SeeDOSAGE AND ADMINISTRATION).

CESSATION OF THERAPY WITH ATENOLOL

Patients with coronary artery disease, who are being treated with atenolol, should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in angina patients following the abrupt discontinuation of therapy with beta blockers. The last two complications may occur with or without preceding exacerbation of the angina pectoris. As with other beta blockers, when discontinuation of atenolol is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. If the angina worsens or acute coronary insufficiency develops, it is recommended that atenolol be promptly reinstituted, at least temporarily. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue atenolol therapy abruptly even in patients treated only for hypertension. (SeeDOSAGE AND ADMINISTRATION).

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. (SeePRECAUTIONS).

Bronchospastic Diseases

PATIENTS WITH BRONCHOSPASTIC DISEASE SHOULD, IN GENERAL, NOT RECEIVE BETA BLOCKERS. Because of its relative beta1 selectivity, however, atenolol may be used with caution in patients withbronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Since beta1 selectivity is not absolute, the lowest possible dose of atenolol should be used with therapy initiated at 50 mg and a beta2-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.

Diabetes and Hypoglycemia

Atenolol should be used with caution in diabetic patients if a beta-blocking agent is required. Beta blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected. At recommended doses, atenolol does not potentiate insulin-induced hypoglycemia and, unlike non-selective beta-blockers, does not delay recovery of blood glucose to normal levels.

Thyrotoxicosis

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 therapy is to be withdrawn should be monitored closely. (See DOSAGE AND ADMINISTRATION).

Untreated Pheochromocytoma

Atenolol 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 breast- feeding may be at risk for hypoglycemia and bradycardia. Caution should be exercised when atenolol is administered during pregnancy or to a woman who is breast-feeding. (See**PRECAUTIONS****,**Nursing Mothers.)

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.1 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.2

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1

Based on the maximum dose of 100 mg/day in a 50 kg patient.

2

Based on the maximum dose of 100 mg/day in a 50 kg patient.

PRECAUTIONS

General

Patients already on a beta blocker must be evaluated carefully before atenolol is administered. Initial and subsequent atenolol dosages can be adjusted downward depending on clinical observations including pulse and blood pressure. Atenolol may aggravate peripheral arterial circulatory disorders.

Impaired Renal Function

The drug should be used with caution in patients with impaired renal function. (SeeDOSAGE AND ADMINISTRATION).

Drug Interactions

Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients treated with atenolol plus a catecholamine depletor should therefore 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. (SeeWARNINGS).

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.

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.

Concomitant use of prostaglandin synthase inhibiting drugs, e.g., indomethacin, may decrease the hypotensive effects of beta-blockers.

Information on concurrent usage of atenolol and aspirin is limited. Data from several studies, i.e., TIMI-II, ISIS-2, currently do not suggest any clinical interaction between aspirin and beta blockers in the acute myocardial infarction setting.

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.

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,3 did not indicate a carcinogenic potential of atenolol. A third (24 month) rat study, employing doses of 500 and 1,500 mg/kg/day (250 and 750 times the maximum recommended human antihypertensive dose4) 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 dose5) was unaffected by atenolol administration.

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3

Based on the maximum dose of 100 mg/day in a 50 kg patient.

4

Based on the maximum dose of 100 mg/day in a 50 kg patient.

5

Based on the maximum dose of 100 mg/day in a 50 kg patient.

Animal Toxicology

Chronic studies employing oral 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 of atenolol (starting at 15 mg/kg/day or 7.5 times the maximum recommended human antihypertensive dose6) and increased incidence of atrial degeneration of hearts of male rats at 300 but not 150 mg atenolol/kg/day (150 and 75 times the maximum recommended human antihypertensive dose,7 respectively).

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6

Based on the maximum dose of 100 mg/day in a 50 kg patient.

7

Based on the maximum dose of 100 mg/day in a 50 kg patient.

Usage in Pregnancy

Pregnancy Category D

SeeWARNINGS: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 breast fed 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 breast- feeding may be at risk for hypoglycemia and bradycardia. Caution should be exercised when atenolol is administered during pregnancy or to a woman who is breast-feeding (see**WARNINGS****,**Pregnancy and Fetal Injury).

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Hypertension and Angina Pectoris Due to Coronary Atherosclerosis

Clinical studies of atenolol did not include sufficient number of patients 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 of concomitant disease or other drug therapy.

Acute Myocardial Infarction

Of the 8,037 patients with suspected acute myocardial infarction randomized to atenolol in the ISIS-1 trial (seeCLINICAL PHARMACOLOGY), 33% (2,644) were 65 years of age and older. It was not possible to identify significant differences in efficacy and safety between older and younger patients; however, elderly patients with systolic blood pressure <120 mmHg seemed less likely to benefit (seeINDICATIONS AND USAGE).

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.