Atenolol tablet

Description

Atenolol, a synthetic, beta 1-selective (cardioselective) adrenoreceptor blocking agent, may be chemically described as benzeneacetamide, 4 -[2-hydroxy-3-[(1- methylethyl) amino] propoxy]-. The molecular and structural formulas are:

Atenolol Structure

Atenolol (free base) has a molecular weight of 266. It is a relatively polar hydrophilic compound with a water solubility of 26.5 mg/mL at 37C and a log partition coefficient (octanol/water) of 0.23. It is freely soluble in 1N HCl (300 mg/mL at 25C) and less soluble in chloroform (3 mg/mL at 25C).

Atenolol tablets, USP is available as 25, 50 and 100 mg tablets for oral administration.

Inactive Ingredients: Magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, hydroxypropyl methylcellulose, titanium dioxide and glycerine

Clinical pharmacology

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 rate 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. Maximum reduction in exercise tachycardia occurs within 5 minutes of an intravenous dose. For both orally and intravenously administered drug, the duration of action is dose related and also bears a linear relationship to the logarithm of plasma atenolol concentration. The effect on exercise tachycardia of a single 10 mg intravenous dose is largely dissipated by 12 hours, whereas beta-blocking activity of single oral doses of 50 mg and 100 mg is still evident beyond 24 hours following administration. 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 1selectivity 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 1than 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 during exercise.

In controlled clinical trials, atenolol, given as a single daily oral 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, each 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 possible 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.

By blocking the positive chronotropic and inotropic effects of catecholamines and by decreasing blood pressure, atenolol generally reduces the oxygen requirements of the heart at any given level of effort, making it useful for many patients in the long-term management of angina pectoris. On the other hand, atenolol can increase oxygen requirements by increasing left ventricular fiber length and end diastolic pressure, particularly in patients with heart failure.

In a multicenter clinical trial (ISIS-1) conducted in 16,027 patients with suspected myocardial infarction, patients presenting within 12 hours (mean = 5 hours) after the onset of pain were randomized to either conventional therapy plus atenolol (n = 8,037), or conventional therapy alone (n = 7,990). Patients with a heart rate of < 50 bpm or systolic blood pressure < 100 mm Hg, or with other contraindications to beta-blockade were excluded. Thirty-eight percent of each group were treated within 4 hours of onset of pain. The mean time from onset of pain to entry was 5.0 2.7 hours in both groups. Patients in the atenolol group were to receive atenolol I.V. Injection 5 to 10 mg given over 5 minutes plus atenolol tablets 50 mg every 12 hours orally on the first study day (the first oral dose administered about 15 minutes after the IV dose) followed by either atenolol tablets 100 mg once daily or atenolol tablets 50 mg twice daily on days 2-7. The groups were similar in demographic and medical history characteristics and in electrocardiographic evidence of myocardial infarction, bundle branch block, and first degree atrioventricular block at entry.

During the treatment period (days 0-7), the vascular mortality rates were 3.89% in the atenolol group (313 deaths) and 4.57% in the control group (365 deaths). This absolute difference in rates, 0.68%, is statistically significant at the P < 0.05 level. The absolute difference translates into a proportional reduction of 15% (3.89 to 4.57/4.57 = -0.15). The 95% confidence limits are 1% to 27%. Most of the difference was attributed to mortality in days 0 to 1 (atenolol - 121 deaths; control - 171 deaths).

Despite the large size of the ISIS-1 trial, it is not possible to identify clearly subgroups of patients most likely or least likely to benefit from early treatment with atenolol. Good clinical judgment suggests, however, that patients who are dependent on sympathetic stimulation for maintenance of adequate cardiac output and blood pressure are not good candidates for beta-blockade. Indeed, the trial protocol reflected that judgment by excluding patients with blood pressure consistently below 100 mm Hg systolic. The overall results of the study are compatible with the possibility that patients with borderline blood pressure (less than 120 mm Hg systolic), especially if over 60 years of age, are less likely to benefit.

The mechanism through which atenolol improves survival in patients with definite or suspected acute myocardial infarction is unknown, as is the case for other beta-blockers in the postinfarction setting. Atenolol, in addition to its effects on survival, has shown other clinical benefits including reduced frequency of ventricular premature beats, reduced chest pain, and reduced enzyme elevation.

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 in atenolol clearance follows the general trend that the elimination of renally excreted drugs is decreased with increasing age.

Indications and usage

Atenolol tablets USP 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 USP may be administered with other antihypertensive agents.

Spl unclassified section

Angina Pectoris Due to Coronary Atherosclerosis:Atenolol is indicated for the long-term management of patients with angina pectoris.

Spl unclassified section

Acute Myocardial Infarction:Atenolol is 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 DOSAGE AND ADMNISTRATION, CONTRAINDICATIONS 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.

Contraindications

Atenolol is contraindicated in sinus bradycardia, heart block greater than first degree, cardiogenic shock, and overt cardiac failure (see WARNINGS).

Atenolol is contraindicated in those patients with a history of hypersensitivity to the atenolol or any of the drug products components.

Warnings

Boxed warning section

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 (see DOSAGE AND ADMINISTRATION).

Precautions

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 (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.

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.

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 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

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 (see CLINICAL 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 mm Hg seemed less likely to benefit (see INDICATIONS 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.

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
(USStudies)

Total-Volunteered
andElicited (Foreign+U.S.Studies)

Atenolol
(n=164)
%
Placebo
(n=206)
%

Atenolol
(n=339)
%
Placebo
(n=407)
%
CARDIOVASCULAR





Bradycardia
3


3

ColdExtremities

0.5

12
5
PosturalHypotension
2
1

4
5
LegPain

0.5

3
1
CENTRALNERVOUSSYSTEM/
NEUROMUSCULAR





Dizziness
4
1

13
6
Vertigo
2
0.5

2
0.2
Lightheadedness
1


3
0.7
Tiredness
0.6
0.5

26
13
Fatigue
3
1

6
5
Lethargy
1


3
0.7
Drowsiness
0.6


2
0.5
Depression
0.6
0.5

12
9
Dreaming



3
1
GASTROINTESTINAL





Diarrhea
2


3
2
Nausea
4
1

3
1
RESPIRATORY (see WARNINGS)




Wheeziness



3
3
Dyspnea
0.6
1

6
4

Overdosage

Overdosage with atenolol has been reported with patients surviving acute doses as high as 5 g. One death was reported in a man who may have taken as much as 10 g acutely.

The predominant symptoms reported following atenolol overdose are lethargy, disorder of respiratory drive, wheezing, sinus pause and bradycardia. Additionally, common effects associated with overdosage of any beta-adrenergic blocking agent and which might also be expected in atenolol overdose are congestive heart failure, hypotension, bronchospasm and/or hypoglycemia.

Treatment of overdose should be directed to the removal of any unabsorbed drug by induced emesis, gastric lavage, or administration of activated charcoal. Atenolol can be removed from the general circulation by hemodialysis. Other treatment modalities should be employed at the physicians discretion and may include:

BRADYCARDIA: Atropine intravenously. If there is no response to vagal blockade, give isoproterenol cautiously. In refractory cases, a transvenous cardiac pacemaker may be indicated.

HEART BLOCK (SECOND OR THIRD DEGREE): Isoproterenol or transvenous cardiac pacemaker.

CARDIAC FAILURE: Digitalize the patient and administer a diuretic. Glucagon has been reported to be useful.

HYPOTENSION: Vasopressors such as dopamine or norepinephrine (levarterenol). Monitor blood pressure continuously.

BRONCHOSPASM: A beta 2stimulant such as isoproterenol or terbutaline and/or aminophylline.

HYPOGLYCEMIA: Intravenous glucose.

Based on the severity of symptoms, management may require intensive support care and facilities for applying cardiac and respiratory support.

Dosage and administration

How supplied

Atenolol Tablets USP:

Tablets of 25 mg atenolol, NDC 16571-430-11 (circular, biconvex, film coated white to offwhite tablets identified with ATN engraved on one side and 25 engraved on the other side) are supplied in bottles of 1000 tablets.

Tablets of 50 mg atenolol, NDC 16571-431-11 (circular, biconvex, film coated white to offwhite tablets identified with ATN and 50 engraved on one side and lip like score engraved on the other side) are supplied in bottles of 1000 tablets.

Tablets of 100 mg atenolol, NDC 16571-441-11 (circular, biconvex, film coated white to offwhite tablets identified with ATN and 100 engraved on one side and lip like score engraved on the other side) are supplied in bottles of 1000 tablets.

Store at controlled room temperature 20-25C (68-77F). [See USP].

Dispense in a well-closed, light-resistant containers.

Manufactured in India by Unique Pharmaceutical Laboratories
(A Div. of J. B. Chemicals & Pharmaceuticals Ltd.)
Mumbai - 400 030.

Distributed by:
PACK Pharmaceuticals, LLC
Buffalo Grove, IL 60089
(800) 521-5340

113658

January 2013

Ingredients and appearance - Product information

Atenolol tablet- Atenolol

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 16571-430
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Atenolol ( UNII: 50VV3VW0TI)( Atenolol - UNII: 50VV3VW0TI ) 25 mgin 1

Inactive Ingredients

Ingredient Name Code
Magnesium stearate ( UNII: 70097M6I30)
Cellulose, microcrystalline ( UNII: OP1R32D61U)
Povidone ( UNII: FZ989GH94E)
Sodium starch glycolate type a potato ( UNII: 5856J3G2A2)
Hypromelloses ( UNII: 3NXW29V3WO)
Titanium dioxide ( UNII: 15FIX9V2JP)
Glycerin ( UNII: PDC6A3C0OX)

Product Characteristics

Color WHITE Shape ROUND
Size 6 mm Score 1
Imprint Code ATN;25

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
ANDA ANDA077443 USA

Atenolol tablet- Atenolol

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 16571-431
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Atenolol ( UNII: 50VV3VW0TI)( Atenolol - UNII: 50VV3VW0TI ) 50 mgin 1

Inactive Ingredients

Ingredient Name Code
Magnesium stearate ( UNII: 70097M6I30)
Cellulose, microcrystalline ( UNII: OP1R32D61U)
Povidone ( UNII: FZ989GH94E)
Sodium starch glycolate type a potato ( UNII: 5856J3G2A2)
Hypromelloses ( UNII: 3NXW29V3WO)
Titanium dioxide ( UNII: 15FIX9V2JP)
Glycerin ( UNII: PDC6A3C0OX)

Product Characteristics

Color WHITE Shape ROUND
Size 8 mm Score 2
Imprint Code ATN;50

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
ANDA ANDA077443 USA

Atenolol tablet- Atenolol

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 16571-441
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Atenolol ( UNII: 50VV3VW0TI)( Atenolol - UNII: 50VV3VW0TI ) 100 mgin 1

Inactive Ingredients

Ingredient Name Code
Magnesium stearate ( UNII: 70097M6I30)
Cellulose, microcrystalline ( UNII: OP1R32D61U)
Povidone ( UNII: FZ989GH94E)
Sodium starch glycolate type a potato ( UNII: 5856J3G2A2)
Hypromelloses ( UNII: 3NXW29V3WO)
Titanium dioxide ( UNII: 15FIX9V2JP)
Glycerin ( UNII: PDC6A3C0OX)

Product Characteristics

Color WHITE Shape ROUND
Size 10 mm Score 2
Imprint Code ATN;100

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
ANDA ANDA077443 USA

Labeler - Pack Pharmaceuticals LLC( 614823875)

Establishment

Name ID/FEI Business Operations
Pack Pharmaceuticals LLC 614823875 MANUFACTURE( 16571-430, 16571-431, 16571-441)

Package label.principal display panel-25 mg package

NDC 16571-430-11

Atenolol Tablets, USP

25 mg

1000 Tablets

Pack TM
PHARMACEUTICALSR xonly

Package label.principal display panel

NDC 16571-431-11

Atenolol Tablets, USP

50 mg

1000 Tablets

Pack TM
PHARMACEUTICALSR xonly

Package label.principal display panel

NDC 16571-441-11

Atenolol
Tablets, USP

100 mg

1000 Tablets

Pack TM
PHARMACEUTICALSR xonly