ATENOLOL
DESCRIPTION:
TENORMIN (atenolol), a synthetic, beta1-selective (cardioselective)
adrenoreceptor blocking agent, may be chemically described as benzeneacetamide,
4-(2'-hydroxy-3'-((1-methylethyl)amino)propoxy)-.
C14H22N2O3
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 deg C and a log
partition coefficient (octanol/water) of 0.23. It is freely soluble in 1N HCl
(300 mg/mL at 25 deg C) and less soluble in chloroform (3 mg/mL at 25 deg C).
TENORMIN is available as 25, 50 and 100 mg tablets for oral administration.
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: TENORMIN Tablets: Magnesium stearate, microcrystalline
cellulose, povidone, sodium starch glycolate. TENORMIN I.V. Injection: Sodium
chloride for isotonicity and citric acid and sodium hydroxide to adjust pH.
ACTIONS/CLINICAL PHARMACOLOGY:
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/1.73M(squared). (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.
INDICATIONS AND USAGE:
HYPERTENSION: TENORMIN is indicated in the management of hypertension. It may
be used alone or concomitantly with other antihypertensive agents, particularly
with a thiazide-type diuretic.
ANGINA PECTORIS DUE TO CORONARY ATHEROSCLEROSIS: TENORMIN is indicated for the
long-term management of patients with angina pectoris.
ACUTE MYOCARDIAL INFARCTION: TENORMIN 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 ADMINISTRATION,
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 (eg, elderly patients with
systolic blood pressure below 120 mm Hg) seemed less likely to benefit.
CONTRAINDICATIONS:
TENORMIN is contraindicated in sinus bradycardia, heart block greater than first
degree, cardiogenic shock, and overt cardiac failure. (See WARNINGS.)
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 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.
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 fully digitalized and/or be given a diuretic and the
response observed closely. If cardiac failure continues despite adequate
digitalization and diuresis, TENORMIN should be withdrawn. (SEE DOSAGE AND
ADMINISTRATION.)
CESSATION OF THERAPY WITH TENORMIN:
Patients with coronary artery disease, who
are being treated with TENORMIN, 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 TENORMIN 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
recommenced that TENORMIN be promptly
reinstituted, at least temporarily. Because
coronary artery disease is common and may
be unrecognized, it may be prudent not to
discontinue TENORMIN therapy abruptly even
in patients treated only for hypertension.
(See DOSAGE 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. When calcium channel
blockers are coadministered with beta-blockers, bradycardia and heart block can
occur and the left ventricular end diastolic pressure can rise. 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 BETA1 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 BETA1 SELECTIVITY IS NOT ABSOLUTE, THE LOWEST POSSIBLE DOSE OF
TENORMIN 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.
ANESTHESIA AND MAJOR SURGERY: 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
OVERDOSAGE).
DIABETES AND HYPOGLYCEMIA: TENORMIN 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
TENORMIN does not potentiate insulin-induced hypoglycemia and, unlike
nonselective beta blockers, does not delay recovery of blood glucose to normal
levels.
THYROTOXICOSIS: Beta-adrenergic blockade may mask certain clinical signs (eg,
tachycardia) of hyperthyroidism. Patients suspected of having thyroid disease
should be monitored closely when administering TENORMIN I.V. Injection. Abrupt
withdrawal of beta blockade might precipitate a thyroid storm; therefore,
patients suspected of developing thyrotoxicosis from whom TENORMIN therapy is to
be withdrawn should be monitored closely. (See DOSAGE AND ADMINISTRATION.)
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.
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*.
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* Based on the maximum dose of 100 mg/day in a 50kg patient.
-------------------------------------------------------------------------------------------------------------------
PRECAUTIONS:
GENERAL: Patients already on a beta blocker must be evaluated carefully before
TENORMIN is administered. Initial and subsequent TENORMIN dosages can be
adjusted downward depending on clinical observations including pulse and blood
pressure. TENORMIN may aggravate peripheral arterial circulatory disorders.
IMPAIRED RENAL FUNCTION: The drug should be used with caution in patients with
impaired renal function. (See DOSAGE AND ADMINISTRATION.)
DRUG INTERACTIONS: 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 WARNINGS.)
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.
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.
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 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.
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 dose*) 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,* respectively).
----------
*Based on the maximum dose of 100 mg/day in a 50 kg patient.
----------
USAGE IN PREGNANCY: PREGNANCY CATEGORY D: 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 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.
PEDIATRIC USE: Safety and effectiveness in pediatric patients have not been
established.
DRUG INTERACTIONS:
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 WARNINGS.)
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.
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.
(See Also PRECAUTIONS)
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.
Total--Volunteered
Volunteered and Elicited
(US Studies) ( Foreign +US Studies)
Atenolol Placebo Atenolol Placebo
(n = 164) (n = 206) (n = 399) (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 Conventional
Therapy Plus Therapy
Atenolol Alone
(n=244) (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 TENORMIN
treatment, the dosage of intravenous and subsequent oral TENORMIN was either
discontinued or reduced for the following reasons:
Reasons for Reduced Dosage
IV Atenolol Oral
Reduced Dose Partial Dose
(<5 mg)*
-------------------------------------------------------------------------------------------------------------------------------
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%)
------------------------------------------------------------------------------------------------------------------------------
* Full dosage was 10 mg and some patients received less than 10 mg but more
than 5 mg.
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 and visual disturbances. TENORMIN, like other beta blockers,
has been associated with the development of antinuclear antibodies (ANA) and
lupus syndrome.
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, Raynaud's phenomenon.
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.
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 beta2 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.
DOSAGE AND ADMINISTRATION:
HYPERTENSION: The initial dose of TENORMIN is 50mg 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 TENORMIN 100 mg given as one tablet a day.
Increasing the dosage beyond 100 mg a day is unlikely to produce any further
benefit.
TENORMIN 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 TENORMIN 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 TENORMIN 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 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.
ELDERLY PATIENTS OR PATIENTS WITH RENAL IMPAIRMENT: TENORMIN is excreted by the
kidneys; consequently dosage should be adjusted in cases of severe impairment of
renal function. Some reduction in dosage may also be appropriate for the
elderly, since decreased kidney function is a physiologic consequence of aging.
Atenolol excretion would be expected to decrease with advancing age.
No significant accumulation of TENORMIN occurs until creatinine clearance falls
below 35 mL/min/1.73 M(squared). 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:
Atenolol
Creatinine Clearance Elimination Maximum
(mL/min/1.73M(squared)) Half-Life (h) Dosage
-------------------------------------------------------------------------------------------------------------------------
15-35 16-27 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 TENORMIN: 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
TENORMIN therapy is planned, it should be achieved gradually and 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.
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