Atenolol Tablets

TENORMIN® (atenolol), a synthetic, beta1-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 (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 37°C and a log partition coefficient (octanol/water) of 0.23. It is freely soluble in 1N HCl (300 mg/mL at 25°C) and less soluble in chloroform (3 mg/mL at 25°C).

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

Inactive Ingredients: Magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate.

TENORMIN Tablets

Tablets of 25 mg atenolol, NDC 0310-0107 (round, flat, uncoated white tablets identified with “T” debossed on one side and 107 debossed on the other side) are supplied in bottles of 100 tablets.

Tablets of 50 mg atenolol, NDC 0310-0105 (round, flat, uncoated white tablets identified with “TENORMIN” debossed on one side and 105 debossed on the other side, bisected) are supplied in bottles of 100 tablets.

Tablets of 100 mg atenolol, NDC 0310-0101 (round, flat, uncoated white tablets identified with “TENORMIN” debossed on one side and 101 debossed on the other side) are supplied in bottles of 100 tablets.

Store at controlled room temperature, 20-25°C (68-77°F) [see USP]. Dispense in well-closed, light-resistant containers.

Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850. Revised: Oct 2012

TENORMIN is a beta1-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, TENORMIN inhibits beta2-adrenoreceptors, chiefly located in the bronchial and vascular musculature.

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 two (2) and four (4) hours after ingestion. Unlike propranolol or metoprolol, but like nadolol, TENORMIN undergoes little or no metabolism by the liver, and the absorbed portion is eliminated primarily by renal excretion. Over 85% of an intravenous dose is excreted in urine within 24 hours compared with approximately 50% for an oral dose. TENORMIN also differs from propranolol in that only a small amount (6%-16%) is bound to proteins in the plasma. This kinetic profile results in relatively consistent plasma drug levels with about a fourfold interpatient variation.

The elimination half-life of oral TENORMIN is approximately 6 to 7 hours, and there is no alteration of the kinetic profile of the drug by chronic administration. Following intravenous administration, peak plasma levels are reached within 5 minutes. Declines from peak levels are rapid (5- to 10-fold) during the first 7 hours; thereafter, plasma levels decay with a half-life similar to that of orally administered drug. Following oral 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 TENORMIN is closely related to the glomerular filtration rate; significant accumulation occurs when the creatinine clearance falls below 35 mL/min/1.73m². (See DOSAGE AND ADMINISTRATION.)

Pharmacodynamics

In standard animal or human pharmacological tests, beta-adrenoreceptor blocking activity of TENORMIN 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 TENORMIN, 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 TENORMIN 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 beta1 selectivity of TENORMIN has been shown by its reduced ability to reverse the beta2-mediated vasodilating effect of isoproterenol as compared to equivalent beta-blocking doses of propranolol. In asthmatic patients, a dose of TENORMIN 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, TENORMIN produced a significantly smaller decrease of FEV1 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, TENORMIN increases sinus cycle length and sinus node recovery time. Conduction in the AV node is also prolonged. TENORMIN 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, TENORMIN, given as a single daily oral dose, was an effective antihypertensive agent providing 24-hour reduction of blood pressure. TENORMIN has been studied in combination with thiazide type diuretics, and the blood pressure effects of the combination are approximately additive. TENORMIN 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 TENORMIN 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 TENORMIN 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 TENORMIN (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 TENORMIN group were to receive TENORMIN I.V. Injection 5-10 mg given over 5 minutes plus TENORMIN 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 TENORMIN Tablets 100 mg once daily or TENORMIN 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 TENORMIN 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% (3.89-4.57/4.57 = -0.15). The 95% confidence limits are 1%-27%. Most of the difference was attributed to mortality in days 0-1 (TENORMIN – 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.

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.

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.

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 mmHg 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.

NDC 68382-022-01 in bottles of 100 tablets

Atenolol Tablets USP, 25 mg

Rx only

100 Tablets

ZYDUS

NDC 68382-023-01 in bottles of 100 tablets

Atenolol Tablets USP, 50 mg

Rx only

100 Tablets

ZYDUS

NDC 68382-024-01 in bottles of 100 tablets

Atenolol Tablets USP, 100 mg

Rx only

100 Tablets

ZYDUS

Take the missed dose as soon as you remember. If your next dose is less than 8 hours away, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take extra medicine to make up the missed dose.

Your pharmacist can provide more information about atenolol.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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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 (US studies) or elicited, eg, by checklist (foreign studies). The reported frequency of elicited adverse effects was higher for both TENORMIN and placebo-treated patients than when these reactions were volunteered. Where frequency of adverse effects of TENORMIN and placebo is similar, causal relationship to TENORMIN is uncertain.

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 atenololtreated 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:

In the subsequent International Study of Infarct Survival (ISIS-1) including over 16,000 patients of whom 8,037 were randomized to receive TENORMIN treatment, the dosage of intravenous and subsequent oral TENORMIN was either discontinued or reduced for the following reasons:

During postmarketing experience with TENORMIN, 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. TENORMIN, 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 TENORMIN.

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 TENORMIN. Furthermore, a number of patients who had previously demonstrated established practolol reactions were transferred to TENORMIN therapy with subsequent resolution or quiescence of the reaction.

Read the entire FDA prescribing information for Atenolol (Atenolol Tablets)