Tenormin Information
Tenormin () Description
Tenormin () ® (atenolol), a synthetic, beta-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:
CHNO
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 37ºC and a log partition coefficient (octanol/water) of 0.23. It is freely soluble in 1N HCl (300 mg/mL at 25ºC) and less soluble in chloroform (3 mg/mL at 25°C).
Tenormin () for parenteral administration is available as Tenormin () I.V. Injection containing 5 mg atenolol in 10 mL sterile, isotonic, citrate-buffered, aqueous solution. The pH of the solution is 5.5-6.5.
Inactive Ingredients: Sodium chloride for isotonicity and citric acid and sodium hydroxide to adjust pH.
Tenormin () Clinical Pharmacology
Tenormin () is a beta-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 beta-adrenoreceptors, chiefly located in the bronchial and vascular musculature.
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%) of atenolol 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/1.73m. (See .)
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 beta selectivity of Tenormin () has been shown by its reduced ability to reverse the beta-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 FEV 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 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
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
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.
Tenormin () Contraindications
Tenormin () is contraindicated in sinus bradycardia, heart block greater than first degree, cardiogenic shock, and overt cardiac failure. (See .)
Tenormin () is contraindicated in those patients with a history of hypersensitivity to atenolol or any of the drug product’s components.
Tenormin () Warnings
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 who have congestive heart failure controlled by digitalis and/or diuretics, Tenormin () should be administered cautiously. Both digitalis and atenolol slow AV conduction.
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.
PATIENTS WITH BRONCHOSPASTIC DISEASE SHOULD, IN GENERAL, NOT RECEIVE BETA BLOCKERS. Because of its relative beta
selectivity, however, Tenormin () may be used with caution in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Since beta
selectivity is not absolute, the lowest possible dose of Tenormin () should be used with therapy initiated at 50 mg and a beta
-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.
It is not advisable to withdraw beta-adrenoreceptor blocking drugs prior to surgery in the majority of patients. However, care should be taken when using anesthetic agents such as those which may depress the myocardium. Vagal dominance, if it occurs, may be corrected with atropine (1-2 mg IV).
Additionally, caution should be used when Tenormin () I.V. Injection is administered concomitantly with such agents.
Tenormin () , like other beta blockers, is a competitive inhibitor of beta-receptor agonists and its effects on the heart can be reversed by administration of such agents: eg, dobutamine or isoproterenol with caution (see section on ).
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 Tenormin () at parturition or breast-feeding may be at risk for hypoglycemia and bradycardia. Caution should be exercised when Tenormin () is administered during pregnancy or to a woman who is breast-feeding (See .)
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.
Tenormin () Precautions
Catecholamine-depleting drugs (eg, reserpine) may have an additive effect when given with beta-blocking agents. Patients treated with Tenormin () 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 Tenormin () (see ).
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, eg, indomethacin, may decrease the hypotensive effects of beta blockers.
Caution should be exercised with Tenormin () I.V. Injection when given in close proximity with drugs that may also have a depressant effect on myocardial contractility. On rare occasions, concomitant use of intravenous beta blockers and intravenous verapamil has resulted in serious adverse reactions, especially in patients with severe cardiomyopathy, congestive heart failure, or recent myocardial infarction.
Information on concurrent usage of atenolol and aspirin is limited. Data from several studies, ie, 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.
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 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), cytogenetics test (Chinese hamster) or Ames test ().
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.
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 Tenormin () 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 Tenormin () at parturition or breast-feeding may be at risk for hypoglycemia and bradycardia. Caution should be exercised when Tenormin () is administered during pregnancy or to a woman who is breast-feeding (See .)
Of the 8,037 patients with suspected acute myocardial infarction randomized to Tenormin () in the ISIS-1 trial (See ), 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
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.
Tenormin () 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 (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.
Tenormin () 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 () .
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.
Tenormin () Overdosage
Overdosage with Tenormin () 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 Tenormin () 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 Tenormin () 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. Tenormin () can be removed from the general circulation by hemodialysis. Other treatment modalities should be employed at the physician's 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 stimulant 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.
Tenormin () Dosage And Administration
In patients with definite or suspected acute myocardial infarction, treatment with Tenormin () 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 Tenormin () over 5 minutes followed by another 5 mg intravenous injection 10 minutes later. Tenormin () I.V. Injection should be administered under carefully controlled conditions including monitoring of blood pressure, heart rate, and electrocardiogram. Dilutions of Tenormin () 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), Tenormin () Tablets 50 mg should be initiated 10 minutes after the last intravenous dose followed by another 50 mg oral dose 12 hours later. Thereafter, Tenormin () can be given orally either 100 mg once daily or 50 mg twice a day for a further 6-9 days or until discharge from the hospital. If bradycardia or hypotension requiring treatment or any other untoward effects occur, Tenormin () should be discontinued. (See full prescribing information prior to initiating therapy with Tenormin () Tablets.)
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 Tenormin () Tablets 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 Tenormin () 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.
Tenormin () is an additional treatment to standard coronary care unit therapy.
Since Tenormin () is excreted via the kidneys, dosage should be adjusted in cases of severe impairment of renal function. No significant accumulation of Tenormin () occurs until creatinine clearance falls below 35 mL/min/1.73m (normal range is 100-150 mL/min/1.73m); therefore, the following maximum oral dosages are recommended for patients with renal impairment.
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.
Patients on hemodialysis should be given 50 mg after each dialysis; this should be done under hospital supervision as marked falls in blood pressure can occur.
If withdrawal of Tenormin () therapy is planned, it should be achieved gradually over a period of about two weeks. Patients should be carefully observed and advised to limit physical activity to a minimum.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Tenormin () How Supplied
Protect from light. Keep ampules in outer packaging until time of use. Store at controlled room temperature, 20-25°C (68-77°F) [see USP].
Tenormin () IV is a trademark of the AstraZeneca group of companies.
© AstraZeneca 2001, 2004
Manufactured for:
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
By: AstraZeneca LP
Wilmington, DE 19850
ASTRAZENECA
Rev 02/05 SIC 30510-01
