INSTRUCTION SHEET
on Medical Application of Preparation
VEDIKARDOL®
Registration number:
Trade name of the preparation: Vedikardol®
International nonproprietary name: carvedilol
Dosage form: tablets
Composition for one tablet:
Active substance: carvedilol 6.25mg, 12.5mg, 25mg.
Auxiliary substances: cellulose microcrystalline – 44.0mg, 66.0mg, 88.0mg; calcium stearate 1.0mg, 1.5mg, 2.0mg; crospovidone – 2.0mg, 3.0mg, 4.0mg; talc – 3.0mg, 4.5mg, 6.0mg; lactose
monohydrate (milk sugar) – to tablet weight 100mg, 150mg, 200mg.
Description
White or whitish tablets of cheese-form with a bevel; mottling texture is allowed.
Pharmacotherapeutic group: alpha- and beta- adrenoreceptor blocking agent
ATC code: [C07AG02]
Pharmacological action
Pharmacodynamics
The preparation blocks alpha1-, beta1- and beta2-adrenoreceptor blocking agents; it has a vasodilating,
antianginal and antiarrhythmic action. Carvedilol represents a racemic mixture R (+) and S (-) stereoisomers; each of them has the same alpha-adrenoblocking properties. Beta-adrenoblocking action of
carvedilol has a non-selective character and it is determined by a levorotary S (-) stereoisomer. The
vasodilating effect is associated with blockade of alpha1-adrenoreceptors. Due to vasodilation the
preparation decreases general peripheral vascular resistance. It does not have its own sympathomimetic activity, but it has membrane-stabilizing properties.
Combination of vasodilatation and blocking of beta-adrenoreceptors results in the following: the preparation decreases resistance of renal vessels of patients with arterial hypertension and renal disorders,
thereat there is no significant change of the rate of glomerular filtration, renal plasma-flow or electrolyte excretion. The peripheral blood flow is maintained, so the symptom of cold hands and feet, often
observed, when beta-adrenoreceptor blocking agents rise, develops very seldom.
Cardiac rate decreases insignificantly. The preparation has the antianginal action on patients with the
ischemic heart disease. It decreases pre- and post- cardiac strain. It does not have a significant effect
on lipidic metabolism and concentration of potassium, sodium and magnesium ions in blood plasma.
The preparation affects favorably hemodynamic indices of the patients with dysfunctions of the left
ventricle of heart and/or heart insufficiencies, and it improves ejection fraction and dimensions of the
left ventricle.
Carvedilol helps decrease mortality rate and hospitalization frequency of patients; it weakens symptoms and signs and improves functioning of the left ventricle of the patients with chronic heart insufficiencies of ischemic or non-ischemic genesis. The efficacy of action of carvedilol is dose-dependent.
Pharmacokinetics
After per os administration the preparation is absorbed into the gastro-intestinal tract promptly and
almost completely. The maximum concentration in blood is reached after 1-1.5h and it comprises
5-99mcg/ml. Absolute bioavailability is 25-35 % (for S (-) stereoisomer - 15 %, for R (+) stereoisomer
- 31 %). Bonding with blood plasma proteins is 98-99 % (mainly by means of R (+) stereoisomer connected with albumins). The distribution volume is about 2l/kg.
It is metabolized in the liver (it has the effect of “initial” passage through the liver).
Metabolic reactions take place with participation of isoforms of cytochrome Р450: CYP2D6, CYP2C9,
CYP3A4, CYP2C19, CYP1A2, and CYP2E1. In the course of demethylation and hydroxylation three
active metabolites are formed that have a strong beta-adrenoblocking action. The main metabolite –
4'-hydroxiphenyl-carvedilol outperforms carvedilol as much as 13 times as for its beta-adrenoblocking
activity; thereat, its concentration in blood plasma comprises 10% of carvedilol concentration.
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The half-period of carvedilol is 6-10 hours. Plasma clearance is about 500-700ml/min. It is excreted
mainly through the intestinal tract with bile; not more than 2% is excreted by kidneys. It penetrates the
placental barrier and is egested with breast milk.
Pharmacokinetics of special groups of patients
Patients with renal dysfunctions: By long-term therapy with carvedilol the intensity of renal blood
flow is maintained and the rate of glomerular filtration does not change. The area under “concentration-time” (AUC) curve, the half-period and maximum plasma concentrations of the patients with arterial hypertensions and renal dysfunctions do not change. Renal excretion of the unchanged preparation of the patients with renal insufficiencies decreases; however, there are no significant changes of
pharmacokinetic parameters thereat.
Carvedilol is an effective preparation for patients with renovascular arterial hypertension, including
patients with chronic renal insufficiencies and patients taking renal dialysis treatment or those who had
the operation of renal transplantation. Carvedilol causes gradual fall of blood pressure both on the day
of dialysis and on dialysis-free days; thereat, its hypotensive effect is comparable to that of the patients
with a regular renal function. In the course of dialysis carvedilol is not excreted, because it cannot
penetrate dialysis membrane, probably due to strong bonds with blood plasma proteins.
Patients with hepatic dysfunctions For patients with hepatic dysfunctions its bioavailability increases
to 80 % due to lower intensity of metabolism by its “initial” passage through the liver. Consequently,
carvedilol is counter-indicative for patients with clinically manifested hepatic dysfunctions (see section
“Counter-indications”).
Old patients Old age does not affect significantly pharmacokinetics of carvedilol of the patients with
arterial hypertensions. Carvedilol tolerance of older patients with arterial hypertensions or ischemic
heart diseases does not differ very much from that of younger patients.
Patients with diabetes Carvedilol does not affect glucose concentration in blood of patients with diabetes II, when taken in either on an empty stomach or after meals, as well as the level of glycated hemoglobin (HbAl) or the dosage of hypoglycemic preparations for per os administration. Some clinical
studies showed that carvedilol does not cause decrease of glucose tolerance of patients with diabetes
II. Carvedilol improves insulin-sensitivity of the patients with arterial hypertensions, who have insulin-resistance (syndrome X), but with no concomitant diabetes. Similar findings were obtained for patients with arterial hypertension and diabetes II.
Patients with cardiac insufficiencies
Studies show that clearance of R and S stereoisomers of carvedilol of patients with heart insufficiencies is much lower than that of healthy people. These findings show that pharmacokinetics of R and S
stereoisomers of carvedilol changes significantly for patients with heart insufficiencies.
Therapeutic indications
Arterial hypertension (monotherapy or combination therapy with diuretics);
Ischemic heart disease: prevention from attacks of stable angina;
Chronic cardiac insufficiency (as part of combination therapy).
Counter-indications
High sensitivity to carvedilol and other components of the preparation; acute and chronic cardiac insufficiency at decompensation stage, requiring intravenous introduction of inotropic preparations;
atrio-ventricular (AV) blockade of degrees II or III (except for the patients with artificial pace maker);
hepatic insufficiencies, bradycardia (heart rate less than 60beat/min), sick sinus syndrome, cardiogenic
shock, bronchial asthma, severe arterial hypotension (systolic blood pressure less than 85mm of mercury), Prinzmetal's angina, severe form of chronic obstructive lungs disease, terminal stage of the
occlusive disease of periphery vessels, metabolic acidosis; current intravenous therapy with verapamil
or diltiazem due to the possibility of development of severe bradycardia (less than 40beat/min) and
arterial hypotension, pheochromocytoma (with no combination administration of alpha- adrenoreceptor blocking agents), young age (younger than18y.o., safety and efficacy of the preparation have not
been determined), lactose intolerance, lactase deficit, glucose-galactose malabsorption, breast-feeding.
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With special care
AV blockade of degree I, diabetes, hypoglycemia, thyrotoxicosis, occlusive diseases of peripheral
vessels, pheochromocytoma (by combination administration of alpha-adrenoreceptor blocking agents),
depression, myasthenia, psoriasis, chronic obstructive lungs disease, bronchial spasm in the past medical history, combination administration with inhibitors of monoaminooxydase, renal insufficiency,
severe surgical interventions and general anesthesia, pregnancy.
Administration during pregnancy and breast-feeding
Beta-adrenoreceptor blocking agents decerase placental blood flow, which can result in prenatal death
of the fetus and premature delivery; they have an unfavorable effect on the growth and development of
a fetus and can cause arterial hypotension, bradycardia and hypoglycemia of the fetus. Vedikardol®
preparation should not be administered during pregnancy, except the cases of extreme urgency, if the
potential benefit for the mother is higher than the risk for the fetus. As carvedilol is excreted with
breast milk, breast-feeding should be terminated when under therapy with Vedikardol®.
Dosages and method of administration
It is administered per os regardless of food intake and washed down with a lot of liquid.
For arterial hypertension the initial dosage is 12.5mg once a day for the first two days of therapy; then
25mg once a day with a possible gradual dose increase with the interval of at least two weeks.
When the antihypertensive effect is not sufficient, the dosage can be increased after two weeks of
therapy with the preparation. The maximum daily dosage of the preparation is 50mg once a day (the
dosage can be divided into two administrations).
Ischemic heart disease, stenocardia
The initial dosage is 12.5mg for the first two days of therapy twice a day; then 25mg twice a day. If the
antianginal effect is not sufficient, then the dose can be increased after two weeks. The maximum
recommended daily dosage of the preparation is 100mg a day, which is divided into two administrations.
For chronic heart insufficiency the dose is selected particularly (against chosen therapy with cardiac
glycosides, diuretics and inhibitors angiotensin-transforming enzyme) under careful supervision of the
doctor. The condition of the patient should be monitored for two-three hours after the first administration and after dosage increase. The recommended initial dosage is 3.125mg (it can be administered
in the dosage Ѕ of a 6.26mg tablet with a groove) for two weeks twice a day. If well tolerated the dose
is increased after the interval of at least two weeks up to 6.25mg twice a day, then up to 12.5mg twice
a day, and then to 25mg twice a day. The dose is supposed to be increased to the maximum
well-tolerated one. With the body weight less than 85kg the maximum dose is 25mg twice a day; with
the body weight more than 85kg the maximum dose is 50mg twice a day. The maximum daily dose of
the preparation for patients with severe chronic cardiac insufficiencies is 25mg twice a day regardless
of their body weight.
Before a dose increase the doctor should examine the patient to find out if there are growing symptoms
of chronic cardiac insufficiency or vasodilatation. By transitory growth of the symptoms of chronic
cardiac insufficiency or liquid detention in the body the dose of diuretics should be increased or
Vedikardol should be temporarily cancelled. Symptoms of vasodilatation can be eliminated by decrease of the dose of diuretics. If symptoms of chronic cardiac insufficiency are maintained, then the
dose of angiotensin-transforming enzyme inhibitor can be decreased (if the patient takes it in), and
then, the dose of Vedikardol® preparation can be decreased too, if necessary.
The dose of Vedikardol should not be increased until the symptoms of chronic cardiac insufficiency or
arterial hypotension stabilize.
To prevent from orthostatic hypotension patients with chronic cardiac insufficiencies should administer the preparation during meals.
If a dose is skipped, the preparation should be taken again as soon as possible, however, if it is time for
the next dose, then only one dose should be administered. Cancellation of the preparation should be
done gradually within one-two weeks.
If therapy with the preparation is discontinued for more than two weeks, then it can be resumed with
the dosage 3.125mg (it can be administered in the dosage Ѕ of a 6.26mg tablet with a groove) twice a
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day with subsequent dose increase.
Patients with a moderate degree of renal insufficiency do not require correction of Vedikardol® dosing.
Old patients do not require correction of Vedikardol dosing.
Vedikardol is counter-indicative for patients with hepatic insufficiencies.
Side effects
Classification of frequency of side effects: very frequently >1/10; frequently >1/100, <1/10; not frequently >1/1000, <1/100; rarely >1/10000, <1/1000; very rarely <1/10000, including single reports.
From the central nervous system: frequently – dizziness, headaches (especially at the beginning of
therapy or when changing doses), weakness, rarely – asthenia (including increased fatigability), depression, mood lability, sleep disorders, paresthesias.
From cardiovascular system: very frequently – ortostatic hypotension, frequently – bradycardia, AV
blockade of degrees II-III, rarely – aggravation of severity of chronic cardiac insufficiency (when doses are increased), periphery edemas (including generalized ones, perineum edemas, edemas of lower
limbs), stenocardia, significant fall of arterial blood pressure, syncopal conditions (including presyncopal ones), peripheral blood flow disorders (cold limbs, aggravation of the syndrome of remittent
lameness and Raynaud's syndrome).
From digestive system: frequently - nausea, stomachaches, diarrhea; rarely – constipation, vomiting,
very rarely – increase of activity of “hepatic” transaminases.
From respiratory system: rarely – shortness of breath and bronchial spasm (among predisposed patients), stuffiness in nose. From skin: not frequently – itching, skin rash, dermatitis and urticaria fever.
From metabolism: frequently – body weight gains, manifestations of latent diabetes, decompensation
of the existing diabetes or inhibition of the contrinsular system.
From blood-forming organs: rarely – thrombocytopenia, very rarely – leucopenia.
From urinary system: rarely – urination disorders, very rarely – renal insufficiency and renal dysfunctions of the patients with diffusive vasculitis and/or renal dysfunctions, significant renal disorders, enuresis among female patients reversible after cancellation of the preparation.
From urogenital system: not frequently – potency fall.
Laboratory indices: frequently – hypercholesteremia, hyper- or hypoglycemia.
Other reactions: frequently – eyesight impairments, tear secretion decrease and eye irritations, very
rarely – flue-like syndrome, aggravation of psoriasis, pains in limbs, rarely – dryness of the mucous
coat of the mouth, sneezing.
Overdose
Symptoms: significant fall of arterial blood pressure (accompanied by dizziness or faintness), severe
bradycardia (less than 50 beat/min); due to bronchial spasm, shortness of breath or vomiting can develop. In severe cases there can be breathing disorders, confused mental state, generalized convulsions,
cardiac insufficiencies, asequence, cardiogenic shock, heart arrest.
Treatment: symptomatic, gastric lavage and prescription of absorbents, monitoring and maintaining of
the vital functions of the body in the department of intense therapy, if required.
For heavy bradycardia intravenous introduction of m-choline-blockers is advisable (atropine
0.5-2.0mg).
If clinically overdose is presented by a significant fall of arterial blood pressure then sympathomimetics should be administered, for example, (noepinephrine (noradrenalin), epinephrine (adrenalin), dobutamine) in different dosages depending on the body weight and on response to the conducted therapy in the conditions of continuous control of circulatory dimensions.
For resistant bradycardia artificial pace maker is recommended. For bronchial spasm beta- adrenoceptor agonists are introduced as aerosol (if ineffective – then intravenously) or aminophylline is introduced intravenously. For convulsions diazepam is introduced in a slow mode.
As by heavy overdose, accompanied by shock, lengthening of the half-period of carvedilol and elimination of the preparation from the depot are possible, supporting therapy should be maintained for a
long period of time.
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Interaction with other pharmaceuticals
Carvedilol can potentiate the action of other hypotensive preparations that are administered with it at
the same time or of the preparations that have antihypertensive action (nitrates).
In combination therapy of carvedilol with digoxin the concentration of the latter increases, and AV
transmission time can increase too.
Carvedilol can potentiate the action of insulin and hypoglycemic preparations for per os administration, including urea derivatives; thereat, the symptoms of hypoglycemia (especially tachycardia) can
be hidden, so patients with diabetes are recommended regular control of glucose concentration in
blood plasma.
Inhibitors of microsomal oxidation (cimetedine) increase the antihypertensive action of carvedilol, and
inductors (phenobarbital, riphampicin) weaken it.
The preparations that increase the concentration of catecholamines (reserpine, inhibitors of monoaminooxydase) increase the risk of development of arterial hypotension and heavy bradycardia.
In combination therapy of cyclosporine with carvedilol cyclosporine concentration increases, so correction of the daily dosage of cyclosporine is recommended.
Combination therapy of clonidine with carvedilol can potentiate antihypertensive action and negative
chronotropic effect of the latter.
If combination therapy of the preparation with beta-adrenoblocking properties and clonidine is supposed to be terminated, the first preparation to be cancelled should be beta- adrenoreceptor blocking
agent, and then after a few days clonidine can be cancelled, while gradually decreasing its dosage.
General anesthetics increase the negative inotropic effect and antihypertensive action of carvedilol.
Blockers of “slow” calcium channels (varapamil, diltiazem) and antiarythmic drugs (especially of class
I) in combination therapy with carvedilol can increase the risks of disruption of atrioventricular conduction; stimulate severe arterial hypotension and cardiac insufficiency.
When on therapy with carvedilol intravenous introduction of varapamil and diltiazem is counter-indicative.
In patients with cardiac insufficiencies amiodarone decreases clearance of S(-) stereoisomer of carvedilol, suppressing CYP2C9. The average concentration of R(+) stereoisomer of carvedilol does not
change. Consequently, due to the increase of concentration of S(-) stereoisomer of carvedilol, there is
the risk of increase of the beta-adrenoblocking action.
In combination therapy of carvedilol with ergotamine one should consider the vasoconstrictive action
of the latter.
Non-steroid anti-inflammatory preparations decrease the antihypertensive action of carvedilol due to
the decrease of prostaglandine production.
Fluoxetine inhibits isoenzyme CYP2D6, which results in inhibition of carvedilol metabolism and its
cumulation. It can decrease the cardio-depressive action (including bradycardia). Fluoxetine and, especially, its metabolites are characterized by a long half-period Т1/2, so the probability of pharmaceutical action is maintained even after some days of the cancellation of fluoxetine.
As beta-adrenoblockers prevent from the broncholithing effect of bronchodilatators (agonists of beta-adrenoreceptors), careful monitoring of the patients, who administer these preparations, is required.
Special warnings
Therapy should be long-term, and it should not be terminated abruptly, especially for patients with the
ischemic heart disease, as it can result in worsening of the symptoms of the main disease. If necessary,
decrease of the dose of Vedikardol preparation should be gradual and take place within one-two
weeks.
While adjusting the dosage, patients with chronic heart insufficiencies can grow the symptoms of
chronic heart insufficiency and they can develop peripheral edemas. In such cases the dose of
Vedikardol® preparation should not be increased, and, on the contrary, the dose of diuretics should be
increased and taken in till complete stabilization of the factors of hemodynamics. Sometimes the dose
of Vedikardol® preparation should be decreased, or rarely, cancelled temporarily. It does not prevent
from a further correct selection of the dose.
Special care should be taken if Vedikardol is administered in combination with cardiac glycosides (retardation of AV conduction is possible).
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Vedikardol® can cause bradycardia; if cardiac rate gets less than 60beat/min, the preparation should
be cancelled.
Special care should be taken when prescribing Vedikardol® to patients with endocrine disorders, as
carvedilol can decrease intensity of the symptoms of thyrotoxicosis and hide symptoms of hypoglycemia, especially tachycardia (patients with diabetes should be specifically informed about it).
If Vedikardol is administered in combination with the blockers of “slow” calcium channels, derivatives of phenylalkilamine (verapamil) and benzothiazepine (diltiazem) or with antiarrhythmic drugs of
class I, then regular monitoring of the electrocardiogram and arterial blood pressure of the relevant patients is recommended.
At the beginning of therapy with Vedikardol® preparation or when the dose is increased some patients, especially older ones, can develop severe hypotension conditions, especially when changing the
position from “lying” to “standing”, which requires correction of the dose of the preparation.
When Vedikardol® preparation was prescribed to the patients with chronic heart insufficiencies and
arterial hypotension (systolic arterial pressure less than 100mm of mercury), ischemic cardiac diseases
or diffuse disorders of peripheral vessels and/or renal insufficiencies, reversible worsening of kidneys
functioning was observed. The dosage of Vedikardol® preparation is selected with regard of the functional condition of kidneys.
Patients with chronic obstructive lungs diseases, who do not administer beta2 adrenoceptor agonists
either per os or as inhalants, can be prescribed Vedikardol®, only if the benefits from its administration outweigh the potential risks. If there is predisposition of a patient to a bronchospastic syndrome,
administration of Vedikardol® preparation can result in development of dyspnoea due to the increase
of resistance of the respiratory tract. At the beginning of therapy and by dose increase such patients
should be carefully monitored; and if the initial signs of bronchial spasm develop, the dosage should
be decreased.
Also, care should be taken, when prescribing Vedikardol preparation to patients with the diseases of
peripheral vessels (including Raynaud's syndrome), as beta-adrenoreceptor blocking agents can increase symptoms of arterial insufficiency.
Special care should also be taken when prescribing Vedikardol® to patients with anamnestic indications of heavy reactions of high sensitivity or those who are taking the course of desensibilization, as
beta-adrenoreceptor blocking agents can increase sensitivity to allergic agents and severity degree of
anaphylactic reactions.
In case of a severe surgical intervention with general anesthesia, the surgeon- anesthesiologist should
be informed on prior therapy with Vedikardol® preparation.
Prior to the therapy with the preparation patients with pheochromocytoma should be prescribed alpha-adrenoreceptor blocking agents.
Patients, who wear contact lenses, should bear in mind that the preparation can cause decrease of the
secretion of lacrimal fluid.
During the course of therapy with the preparation alcoholic drinks should be avoided.
Driving and operating equipment
Special care should be taken at the beginning of therapy with vedikardol or if the dosage is increased
when driving or operating machines or engaging in some other potentially hazardous activities that
require high concentration and prompt psychomotor response.
Dosage form
6.25mg, 12.5mg and 25mg tablets;
Ten tablets are placed into blister cellular packages of polyvinylchloride film and aluminum printed
lacquered foil; one, two or three blister cellular packages and an instruction sheet should be placed into
a cardboard package.
Shelf life
3years. Do not use after expiration date.
Storage
Dry shadowed place at the temperature not higher than 25°С. Keep out of reach of children.
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Dispensing from pharmacies
Prescription medicine.
Manufacturer/organization that accepts claims:
Open Joint Stock “Kurgan Joint Stock Company of Medical Preparations and Articles “Sintez” (Sintez
Joint Stock Company);
#7, Prospect Konstitutsii, city of Kurgan, Russian Federation, 640008;
Tel. /fax: (3522)481689
Internet-site: http://www.kurgansintez.ru
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