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Instruction
for medical application of the preparation of
ATENOLOL
Registration number:
Trade name of the preparation: Atenolol
International nonproprietary name : atenolol
Dosage form: tablets
Composition
1 tablet contains:
active substance - atenolol 50 milligrams or 100 milligrams;
accessory substances: maize starch, low-molecular povidone, lactose, ethanol, magnesium
stearate, talcum powder, colloidal silicon dioxide, croscarmellose sodium (primellose).
Description
Round tablets of white or white with grayish or cream tint color with facet and notch (for
the tablets of 100 milligrams dosage) or without notch (for the tablets of 50 milligrams
dosage). it Slight “marbling” is allowed.
Pharmacotherapeutic group: beta-adrenergic blocking agent selective
ATC code: С07AB03
Pharmacologic properties
Pharmacodynamics
It renders antianginal, antihypertensive and antiarrhythmic actions. I does not have membrane
stabilizing and intrinsic sympathomimetic activity. It reduces formation of cyclic adenosine
monophosphate induced by catecholamines; (cAMP) out of adenosine triphosphate (ATP), decreases intracellular current Ca +. Within first 24 hours after oral administration against the
background of lowering cardiac output the reactive rise of general peripheral vascular resistance is registered, which within 1-3 days gradually returns to initial and then gradually decreases. Hypotensive effect is associated with decrease of minute blood volume, decrease of
activity of rennin- angiotensin system, sensibility of barorecrptors and impact on central nervous system. The hypotensive action is manifested in lowering both systolic and diastolic
blood pressure, decrease of stroke and minute volume of blood.
In middle curative doses it doesnot exercise influence upon tonicity of the peripheral arteries.
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Hypotensive effect lasts 24 hours, in case of regular application it stabilizes to the end of the
second week of the treatment.
Antianginal effect is determined by reduction in requirement of myocardium in oxygen as a
result of decrease of heart rate (lengthening of a diastole and improvement of myocardium
perfusion) and contractility, as well as sensory decrement of a myocardium to impact of sympatic stimulation. It rarefies heart rate at rest and in physical activity.
By means of rise of left ventricular end diastolic pressure and increase of stretching
of muscle fibres of the ventricles it can raise oxygen requirement, especially in patients
with chronic cardiac failure.
Antiarrhythmic action is manifested in suppression of sinus tachycardia and is associated with elimination of arrhythmogen sympatic impacts on the cardiac conduction
system, deceleration of spread of activation through the sinoatrial ganglion and lengthening the refractory period. It oppresses carrying out impulses in antegrade and to a lesser
degree in retrograde direction through AV ganglion and through alternate routes of conduction.
The negative chronotropic effect is manifested in 1hour after administration,
achieves its maximum in 2-4 hours, lasts u to 24 hours. It reduces automatism of sinoatrial ganglion, rarifies heart rate, slows down AV conductibility; decrease myocardial
contractility, decrease requirement of the myocardium in oxygen. It reduces myocardium
affectivity. In application of average therapeutic doses it renders less frank impact on unstriated muscles of bronchus and on peripheral arteries than nonselective beta-adrenergic
blocking agents.
It increases survival of patients with occurred myocardial infarction (it decreases
frequency of development of ventricular arrhythmia and heart stroke).
It practically does not weaken bronchodilation action of isoproterenol.
In contrast to nonselective beta-adrenergic blocking agents it in prescription at
mean therapeutic doses renders less frank impact on organs containing beta2-adrenergic
receptors (pancreatic gland, skeletal muscle, unstriated muscles, peripheral arteries, bronchi and metra), and on carbohydrate metabolism; intensity of atherogenic action does not
differfrom the action of propranolol. It renders negative bathmotropic, chronotropic, ino-
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tropic and dromotropic effect to a lesser degree. On application in large doses (more than
100 mg/day) it renders blocking effect on both subtypes of beta-adrenergic receptors.
Pharmacokinetics
Absorption out of the gastrointestinal tract is quick, incomplete (50-60%), bioavailability
is 40-50%, time of achievement of the maximum concentration in the blood plasma is 24 hours. It poorly works way through a hematoencephalic barrier, passes in insignificant
amount through a placental barrier and in human milk. Connection with plasma protein is
6-16%. It is practically not metabolized in a liver. Half-life period is 6-9 hours
(it is increases in patients of elderly age). It is egested by kidneys by way of glomerular
filtration (85-100% in unaltered form). Malfunction of kidneys is accompanied by lengthening of the half-life period and accumulation: in creatine clearance lower than 35 milliliter/ minute/1.73 m2 the half-life period is 16-27 hours, in creatine clearance lower than
15 milliliter/minute/1.73 m2 it is more than 27 hours(reduction of dosages is necessary). It
is egested in the course of haemodialysis.
Indication to application
- arterial hypertension;
- prophylaxis heart stroke (aside from Prinzmetal's angina),
- rhythm disturbance, sinus tachycardia, prophylaxis supraventricular tachyarrhythmia,
ventricular arrhythmia.
Contra indications
Supersensitiveness to the preparation, cardiogenic shock, atrioventricular (AV) heart block of
II-III degrees, frank brachycardia (heart rate is less than 40 strokes per minute), sick sinus syndrome, sinoatrial block, sharp or chronic cardiac failure in stage of decompensation, cardiomegaly without signs of cardiac insufficiency, Prinzmetal's angina, arterial hypotension (in
case of usage in myocardial infarction, the systolic arterial tension is less than 100 millimeter
of mercury), lactation period, simultaneous administration of inhibitors of monoamine oxidase, effectiveness and safety of the preparation is not determinate for the age under 18
years.
With care: pancreatic diabetes, metabolic acidosis, hypoglycaemia, hypersensitivity reaction in anamnesis, chronical obstructive disease of the lungs (including pulmonary
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emphysema), AV blockade of the I degree, chronic cardiac failure (compensated), obliterating disease of peripheric vessels (intermittent lameness, Raynaud's syndrome), pheochromocytoma, hepatic insufficiency, chronic kidney disease, myasthenia, thyrotoxicosis, depression (including in anamnesis), psoriasis, elderly age, pregnancy.
Application by pregnancy and in the lactation period
Atenolol works way through a placental barrier and is found in the cord blood. The researches
on application of the atenolol in first trimester have not been carried out and thus, it is impossible to eliminate a possibility of its damaging action to the fetus. For treatment of arterial hypertension in the third trimester of pregnancy the preparation should be applied under careful
medical control. Application of atenolol in pregnancy can be the cause of growth disorder of
the fetus. To order atenolol to pregnant or planning pregnancy women should follow only be
done in cases where advantage for the mother exceed potential risk for the fetus, especially in
the first and second trimester of pregnancy, because beta-adrenergic blocking agents decrease
the level of placental perfusion, that can lead to antenatal fetal death or its dismaturity and
premature birth. Moreover, such adverse events as hypoglycaemia and brachycardia, can be
observed both in the fetus, and in the newborn infant.
Mode of administration and dosages
It should be prescribed per os before meal, not chewed, drunk after with small quantity of
liquid.
Arterial hypertension. The treatment should be started with 50 milligrams of atenolol
once per day. For achievement of a steady hypotensive effect it is required to be administered 1 -2 weeks. In case of insufficient evidence of hypotensive effect the dosage should
be raised to 100 milligramd in a single intake. Further increase of the dosage is not advised, because it not accompanied by strengthening of the clinical performance.
In ischemic heart disease, tachysystolic cardiac rhythm disturbance it should be oordered
50 milligram s once per day.
Senocardia. The initial dose is 50 milligrams per day. If within a week an optimal therapeutic effect has not been achieved, increase dosage to 100 milligrams per day. The patients of elderly age and patients in contravention of the kidney secretory function, correction of dosage regimen is necessary. In the presence of renal insufficiency it is recom-
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mend that the correction dosage should depend on the creatine clearance. Considerable
accumulation of atenolol does not occur in patients with renal insufficiency of value of
creatine clearance above 35 milliliters/minute/I.73m2 (the normal value is 100-150 milliliters/ minute/1. 73m2). The following maximum dose for the patients with renal insufficiency are recommended:
Creatine clearance above
milliliters/minute/I.73m2
15-35
Half-life period of
the atenolol
16-27
less than 15
More than 27
Highest dose
50 mg per day or 100 mg every
other day
50 mg per day or 100 mg once within
4 days
The patients being in haemodialysis the atenolol should be prescribed 25 or 50 milligrams per a 24-hour period right after conduction of each dyalysis, that should be conductws in stationary conditions, because decrease of arterial tension can take place.
An initial single dose for elderly patients is 25 milligrams (it can be increased under control of arterial tension, heart rate). The rise of daily dose over 100 milligrams is
not advised, because therapeutic effect does not increase, but probability of adverse
events development grows up.
Side effects
Cardiovascular system:
development (aggravation) of the symptoms of chronic
cardiac failure (water retention of ankles, feet; labored breathing), abnormality of atrioventricular conduction, anisorhythmia, brachycardia, frank decrease of arterial tension,
heartbeats, loosening myocardial contractility, postural hypotension, manifestation of angiospasm (cooling lower limb, Raynaud's syndrome), vasculitis, chest pain.
Central nervous system: paraequilibrium, impairment in ability to attention concentration, decrease in speed of reactions, drowsiness or insomnia, depression, hallucinations,
increased fatigability, headache, weakness, nightmares, unrest, confused mental state or
short-time amnesia, paresthesia in limbs (in patient with intermittent lameness and Raynaud's syndrome), muscle weakness, convulsions.
Gastrointestinal tract: dryness of the mouth, nausea, vomit, diarrhea, stomachache, astriction or diarrhea, shift in tastes.
Respiratory system: dyspnoea, bronchismus, apnoea, stuffiness in nose.
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Hematological reactions: platelet purpura, anaemia (aplastic).
Endocrine system:
decrease potency, libido decrease, hyperglycemia (in patients
with non insulin dependent diabetes mellitus), hypoglycaemia (in patients getting insulin),
hypothyroid condition.
Skin reaction: urticaria fever, dermatitis, skin itching, photoelectric sensitivity,
strengthening diaphoresis, dermahemia, aggravation of the psoriasis run, inversive alopecia.
Sense organs: paropsis, decrease of secretion of lachrymal liquid, dryness and debility lights, conjunctivitis
Impact on the fetus: antenatal growth inhibition, hypoglycaemia, brachycardia.
Laboratory factors:
agranulocytosis, leukopenia, increment in activity of "hepat-
ic" enzyme, hyperbilirubinemia, thrombocytopenia (unusual issues of blood and effusions of blood).
Others: backache, arthralgia, withdrawal symptoms (tachycardia, acceleration heart
stroke, rise of arterial tension etc.).
The frequency of adverse events grows up in increase of the preparation dosage.
Overdosage
Symptoms: frank brachycardia, AV blockade of II-III stage, increase of the symptoms of cardiac insufficiency, steep decline of arterial tension, difficulty of respiration,
bronchismus, paraequilibrium, apsychia, anisorhythmia, ventricular arrhythmia, cyanosis
of fingernails or palms, convulsions.
Treatment: gastric lavage and prescription of adsorbing medicinal preparations; in
emergence of bronchismus order inhalant or intravenous injection of beta2-adrenoceptor
agonist salbutamol.
In case of abnormality of AV conductibility, brachycardia make intravenous injection of 1-2 milligrams of atropine, epinene or set a temporary pacemaker; in case of ventricular arrhythmia use lidocaine (preparations of 1A class are not applied); in case of decrease of arterial tension the patient should be in Trendelenburg's position. If there are no
signs of pulmonary edema apply intravenous plasma-substituting solutions, in case of inefficiency inject epinephrine, dopamine, dobutamine; in case of chronic cardiac failure
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apply cardiac glycosides, diuretics, glucagon; in convulsions apply intravenous injection
of diazepam. Dyalysis can be carried out.
Interaction with other medicinal preparations
I case of simultaneous application of atenolol with insulin, hypoglycemic agent
orally, their hypoglycemizing activity activity is increased. In case of simultaneous application of antihypertensive agents of different groups or nitrates strengthening of hypotensive action takes place. Simultaneous application of atenolol and verapamil (or diltiazem) can cause mutual strengthening of cardiodepressive action. Hypotensive effect
weakens estrogens (retention of sodium) and nonsteroidal anti-inflammatory preparations,
glucocorticosteroids. In simultaneous application of atenolol and cardiac glycoside the
risk of development of brachycardia and abnormality of atrioventricular conduction is increased. In simultaneous prescription of atenolol with reserpine, methyldopa, clonidine,
verapamil emergence of frank brachycardia is possible. Simultaneous intravenous injection of verapamil and diltiazem can provoke cardiac standstill; nifedipine can result in
heavy drop of arterial tension. In simultaneous administration of atenolol with derivative
ergotamine, xanthine, its effectiveness is declining.
In case of cancellation of combined application of atenolol and clonidine the treatment with clonidine should be continued for some more days after cancellation of
atenolol.
Simultaneous application with lidocaine can lessen its egestion and raise risk of the
toxic effect of lidocaine.
Application in combination with derivatives of phenothiazines acts to raise concentration of each of the preparations in the blood serum.
Phenytoin in case of intravenous injection, medicinal preparations for general anesthesia (derivatives of hydrocarbons) raise evidence of cardiodepressive action and probability of arterial tension.
In case of simultaneous application with aminophylline and theophyllin, mutual
suppression of therapeutic effects is possible.
Simultaneous application with monoamine oxidase dissociable inhibitors is not
recommended on account of considerable strengthening of hypotensive action, interrup-
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tion in treatment between administration of the monoamine oxidase dissociable inhibitors
and atenolol should be at least 14 days.
Allergens used for immunotherapy, or extract allergens for skin testa raise risk of
emergence of severe systemic hypersensitivity reaction or anaphylaxis.
Remedies for inhalation narcosis raise risk of suppression of myocardium function
and development of arterial hypertension. Amiodarone raises risk of development of
brachycardia and suppression of AV conductibility. Cimetidine increases concentration in
blood plasma (restrains metabolism).
Iodine-containing radiopaque contrast agenst for intravenous injection raise risk of
development of anaphylactic reactions.
It extends action of nondepolarizing muscle relaxants and anticoagulant effect of
coumarins. Tricyclic and tetracyclic antidepressants, antipsychotics (neuroleptics), ethanol, opiate and hypnotic agents strengthen suppression of the central nervous system.
Non hydrogenized ergot alkaloids raise risk of development of abnormality of peripheric blood circulation.
Special instructions
The control for patients accepting atenolol should include overseeing heart rate and
arterial tension (in the beginning of the treatment daily, then once within 3 – 4 months),
glucose content in blood of the patients with pancreatic diabetes (once within 4-5
months). In elderly patients it is recommended to see after the function of the kidneys
(once within 4-5 months). The patients should be taught in methods of calculations of
heart rates and be instructed about necessity of medical consultation in case of heart rates
less than 50 strokes revolutions per minute. In thyrotoxicosis the atenolol can disguise
certain clinical features of thyrotoxicosis (for example, tachycardia). Sharp cancellation in
patients with thyrotoxicosis is contraindicated because it is capable to strengthen symptoms and signs. In case of pancreatic diabetes it can disguise tachycardia caused by hypoglycaemia. In contrast to nonselective beta-adrenergic blocking agents it practically does
not strengthen hypoglycaemia caused by insulin and does not detain restoration of glucose content in blood to normal concentration.
In patients with ischemic heart disease sharp cancellation of beta-adrenergic block-
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ing agents can induce increase of frequency or severity of anginal incursion, therefore
cancellation of the atenolol administration in the patients with ischemic heart disease
should be conducted gradually.
In comparison with nonselective beta-adrenergic blocking agents, cardioselective
beta-adrenergic blocking agents have less impact on pulmonary function, nevertheless, in
case of respiratory tract disease atenolol should be prescribed only in case of absolute indication.
In necessity of their prescription in some cases it is possible to recommend application of beta2-adrenoceptor agonists.
The patients with bronchospasmodic diseases can be prescribed with cardio selective adrenoceptor blocking agents in case of intolerance and/or inefficiency of other hypotensive medicinal preparations, but at that time strict watch for dosage should be performed. Overdosage is dangerous as it can develop bronchismus.
Special attention is required in cases if surgical intervention under narcosis is needed in patients taking atenolol. The administration of the preparation should be ceased 48
hours before the intervention.
In the capacity of anesthetic agent the preparation with possible minimal negative
inotropic effect should be selected. In case of simultaneous application atenolol and
clonidine the administration of atenolol should be ceased some day prior to clonidine for
the purpose of avoidance of the symptoms of cancellation of the latter.
It is possible to have strengthening of evidence of hypersensitivity reaction and absence of effect by common dosages of epinephrine against the background of aggravated
allergic anamnesis. Medicinal preparations decreasing reserves of catecholamines (for example, reserpine) can heighten an effect of beta-adrenergic blocking agents, therefore the
patients receiving such combinations of the medicinal preparations should be at continuous monitoring by a doctor with respect to detection of frank decrease of arterial tension
or brachycardia.
In case of appearance in the patients of elderly age of progressive brachycardia
(less than 50 strokes per minute), arterial hypotension (systolic arterial tension is below
100 millimeter of mercury), atrioventricular blockade, bronchismus, ventricular arrhyth-
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mias, heavy compromised function of liver and kidney it is necessary to lessen the dosage
or cease the treatment.
It is recommended to cease medical maintenance in development of depression
caused by administration of beta-adrenergic blocking agents.
In case of necessity of intravenous injection of verapamil it should be done in at
least 48 hours after administration of atenolol.
On application of atenolol decrease of production of lacrimal liquid is possible that
is important in patients using contact lenses.
It is impossible to abruptly interrupt the treatment because of danger of development of severe arrhythmias and myocardial infarction. The cancellation should be conducted gradually decreasing the dosage within 2 weeks and more (decrease the dosage by
25% within 3-4 days).
It should be stopped before examination of blood and urina for the content of catecholamines, normetanephrine and vanillylmandelic acid; titers of antinuclear antibodies.
In smokers the effectiveness of beta-adrenergic blocking agents is lower.
Pregnancy and the period of breast feeding
Atenolol should be prescribed to pregnant only in cases if the advantage for the
mother exceeds potential risk for the fetus. Atenolol is exuded with human milk, therefore
if the preparation is approved in the period of breast feeding, then it is better for that time
to cease breast feeding.
The impact on the ability to drive a car and operate equipment
At the time of treatment one should refrain from exercise of potentially dangerous
kinds of activity requiring elevated concentrations of attention and quickness of psychomotor actions.
Product form
Tablets of 50 milligrams, 100 milligrams.
There are 10 tablets in a contour cellular packaging.
3 or 5 contour cellular packings are put with the application data sheet in a cardboard pack.
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Storage conditions
List B. It should be stored in a place protected from light at temperature from 15 to
25° C. Keep out of reach of children.
Shelf life
2 years. Do not use after expiry date.
Pharmacy purchasing terms:
Prescription medicine.
Manufacturer/Organization accepting customer complaints:
Open Joint Stock "Kurgan Joint Stock Company of Medical Preparations and Articles "Sintez" (Sintez JSC
No. 7, Prospect Konstitutsii, city of Kurgan, Russian Federation, 640008
Tel/fax (3522) 48-16-89
e-mail: real@kurgansintez.ru ,
Web site of the manufacturing company: http://www.kurgansintez.ru
Seal of the office
issued the document:
THE RUSSIAN FEDERATION, KURGAN REGION,
THE CITY OF KURGAN, Open Joint Stock "Kurgan Joint Stock Company
of Medical Preparations and Articles "Sintez" (Sintez JSC).
Representative of the Firm
signature
V. I. Petukhov
Seal of the office
issued the document:
Institute of Pre-Clinical and Clinical Medicinal Preparations’ Expertise,
FEDERAL STATE INSTITUTION,
Federal State Institution Scientific Expert Center for Medical Goods of
Ministry of Public Health of the Russian Federation,
city of MOSCOW
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