Medokardil of the tab. of 25 mg No. 30

Pharmacological properties

Pharmacodynamics. a non-selective blocker of β-adrenoceptors with vasodilating action. it also has antioxidant and anti-proliferative properties.

Active ingredient, karvedilol, is a racemate; enantiomer differ in the effects and metabolism. S (-) an enantiomer has the activity directed to blocking α to ₁ — and β-adrenoceptors whereas R (+) the enantiomer shows the activity directed only to blocking α to ₁ - adrenoceptors. Thanks to cardionon-selective blockade of β-adrenoceptors it lowers the arterial blood pressure, ChSS and warm emission. Karvedilol reduces pressure in pulmonary arteries and the right auricle. By blockade α ₁ - adrenoceptors it causes expansion of peripheral vessels and reduces system vascular resistance. Thanks to these effects the load of a cardiac muscle decreases and development of attacks of stenocardia is prevented. At patients with heart failure it leads to increase in fraction of emission from a left ventricle and to reduction of expressiveness of symptoms of a disease. Similar effects noted at patients with dysfunction of a left ventricle. Karvedilol does not show internal sympathomimetic activity, and he, as well as propranolol, has membrane stabilizing properties. The activity of renin in blood plasma decreases, and the liquid delay in an organism occurs seldom. Influence on the ABP and ChSS is shown in 1–2 h after use.

At sick AG against the background of normal function of kidneys karvedilol is reduced by renal vascular resistance. At the same time there are no significant changes of glomerular filtration, a renal blood-groove and excretion of electrolytes. Thanks to support of a peripheral blood-groove very seldom there is a cooling of extremities characteristic of treatment with blockers of β-adrenoceptors.

Karvedilol, as a rule, does not influence the level of lipoproteids in blood plasma.

Pharmacokinetics. Karvedilol after oral introduction quickly and almost is completely soaked up. He almost completely contacts proteins of blood plasma. The volume of distribution is about 2 l/kg. Concentration in blood plasma is proportional the entered dose.

Because of considerable metabolic disintegration at the first passing through a liver (mainly by means of CYP liver enzymes 2D6 and CYP 2C9) the bioavailability of a karvedilol is about 30%. 3 active metabolites showing the β-blocking activity are formed; one of them (4’ - hydroxyphenyl derivative connection) shows by 13 times the big β-blocking activity, than karvedilol. In comparison with karvediloly the active metabolites render weak vasodilating effect. Metabolism is stereoselection therefore level R (+) the karvedilola in blood plasma by 2–3 times exceeds level S (-) of a karvedilol.

Level of active metabolites in blood plasma is about 10 times lower than that karvedilol. T _½ very much differs: 5–9 h for R (+) a karvedilola and 7–11 h for S (-) a karvedilol.

At patients of advanced age note increase in level of a karvedilol in blood plasma approximately for 50%. At patients with cirrhosis the bioavailability of a karvedilol increases by 4 times, and the C _max in blood plasma by 5 times exceeds the corresponding sizes at healthy people. At patients from the liver broken by function the bioavailability increases up to 80% because of reduced metabolic disintegration of the first passing. As karvedilol it is removed mainly with a stake, at patients with a renal failure the significant accumulation of medicament is improbable.

Existence of food in a stomach slows down absorption speed, but it does not affect its bioavailability.

Indication

Essentsialnaya ag. medicament can be used separately or in a combination with other antihypertensive medicaments (especially with thiazide diuretics). chronic stable stenocardia. chronic stable heart failure (as addition to standard therapy with diuretics, digoxin or inhibitors apf), for prevention of progressing of a disease at patients with heart failure of ii-iii of a class on classification of nyha.

Use

For delay of absorption and prevention of orthostatic effects karvedilol should be accepted at meal time to patients with heart failure. to select a dose individually. tablets should be washed down with enough liquid. treatment needs to be begun with low doses which gradually should be raised to achievement of optimum clinical effect.

should apply tablets with the corresponding content of active ingredient To the recommended dosing. After reception of the first dose and after each increase in a dose it is recommended to measure at the ABP patient in a standing position in 1 h after administration of medicament for an exception of possible hypotension.

Drug treatment should be stopped gradually by a dose decline during 1 or 2 weeks. If treatment was interrupted more than on 2 weeks, then its restoration should be begun with a low dose.

Essentsialnaya AG. The initial dose of a karvedilol makes 12.5 mg in the morning after a breakfast or on 6.25 mg 2 times a day (in the morning and in the evening). After 2 days of treatment the dose should be raised to 25 mg in the morning (1 tablet on 25 mg) or to 12.5 mg 2 times a day. In 14 days of treatment the dose can be raised to 25 mg 2 times again a day.

Maximum single dose of medicament for treatment of AG makes 25 mg, the maximum daily dose — is not higher than 50 mg.

Recommended initial dose of a karvedilol for treatment of AG at patients with heart failure makes 3.125 mg 2 times a day.

In need of use of a dose of 3.125 mg dosage forms of a karvedilol with the corresponding content of active ingredient.

Chronic stable stenocardia. The initial dose of a karvedilol makes 12.5 mg 2 times a day after a meal. In 2 days of treatment it is necessary to raise a dose to 25 mg 2 times a day.

Maximum dose of a karvedilol for treatment of chronic stenocardia makes 25 mg 2 times a day. The recommended initial dose of a karvedilol for treatment of stenocardia at patients with heart failure makes 3.125 mg 2 times a day.

Chronic stable heart failure. Karvedilol is recommended for treatment stable poorly or moderate and also heavy chronic heart failure as supportive application at use of standard drugs, such as diuretics, APF inhibitors or medicaments of a digitalis. Patients who do not transfer APF inhibitors can also take the drug. The patient can appoint karvedilol only after equilibration of doses of diuretic, APF inhibitor and a digitalis (if are applied).

individually. During the first 2–3 h after initial reception or after increase in a dose it is necessary to make careful medical observation for check of tolerance of drug. If at the patient note delay of ChSS up to the size of 55 ud. / min., that the dose of a karvedilol needs to be lowered. If there are symptoms of arterial hypotension, then at first it is necessary to consider the possibility of a dose decline of diuretic or APF inhibitor; and if these measures are insufficient, then it is necessary to lower a dose of a karvedilol.

In an initiation of treatment medicament or after increase in a dose tranzitorny strengthening of heart failure can arise. In that case it is necessary to raise a diuretic dose. Sometimes it is necessary to lower temporarily a dose of a karvedilol or even to cancel drug. After stabilization of a clinical state it is possible to resume treatment karvediloly or to raise its dose.

Initial dose makes 3.125 mg 2 times a day. If the patient well transfers this dose, then it can be raised gradually (in each 2 weeks) to achievement of an optimum dose. The following doses make 6.25 mg 2 times a day, then 12.5 mg 2 times a day and 25 mg 2 times a day under a condition if the patient well transfers previously appointed dose. The patient should accept the maximum dose which he well transfers. The maximum recommended dose makes 25 mg 2 times a day. For patients with the body weight of 85 kg the dose can be raised carefully to 50 mg 2 times a day.

Patients of advanced age. The dose is not required to be changed.

Patients with a liver failure. Drug is not recommended to be used at patients with a heavy liver failure.

Patients with a renal failure. Dose adjustment is not required for patients with systolic arterial blood pressure of 100 mm Hg.

Contraindication

Increased individual sensitivity to medicament components, heavy hypotension (systolic hell of 85 mm Hg.), unstable or dekompensirovanny heart failure; the heart failure demanding introduction of positive inotropic means and/or diuretics; heavy bradycardia (50 ud. / mines at rest), av-blockade of ii and iii of degree (except for patients with a constant pacemaker), stenocardia printsmetat, a sick sinus syndrome (including sinuatrial blockade), cardiogenic shock, obstructive respiratory diseases, oh or a bronchospasm in the anamnesis, pulmonary hypertensia, a pulmonary heart, the profound liver failure, a metabolic acidosis and a pheochromocytoma (in the absence of adequate control by means of a blocker of α-adrenoceptors).

Side effects

At use of medicaments of a karvedilol can arise the following side reactions.

Infection and invasion: bronchitis, pneumonia, infections of an upper part of airways, infections of urinary tract.

from the immune system: hypersensitivity (allergic reactions), anaphylactic reactions.

from central nervous system: a headache, dizziness, increased fatigue, a loss of consciousness (mainly in an initiation of treatment), a depression, sleep disorders, paresthesias.

from a cardiovascular system: orthostatic hypotension, bradycardia, AG, stenocardia, tachycardia, peripheral disturbances of blood circulation (pokholodeniye of extremities, a disease of peripheral vessels), the alternating lameness or a Raynaud's disease, hypostases (including generalized, peripheral, orthostatic and hypostasis of genitals and legs), a hypervolemia, orthostatic hypotension, AV blockade, progressing of heart failure.

from a respiratory system: short wind, a fluid lungs, OH (at sensitive patients), congestion of a nose.

from digestive system: nausea, diarrhea, vomiting, a constipation, an abdominal pain, dryness in a mouth, dyspepsia, periodontitis, a melena.

from skin: rash, an itching, urticaria, red flat deprive, the increased sweating, psoriasis or exacerbation of psoriasis, an allergic dieback, dermatitis, an alopecia.

from an organ of sight: disorder of vision, decrease in a slezootdeleniye (xerophthalmus), irritation of eyes.

Metabolic disturbances: increase in body weight; disturbance of control of glucose in blood (hyperglycemia, a hypoglycemia) at patients with the existing diabetes, a hypercholesterolemia.

from the musculoskeletal system: extremity pain, arthralgia, spasms.

from an urinogenital system: urination disturbance, erectile dysfunction; a renal failure at patients with diffusion disturbance of peripheral arteries, a renal failure, incontinence of urine at women, a hamaturia, an albuminuria, a glucosuria, a hyperuricemia.

Laboratory indicators: increase in level of transaminases and gamma glutamiltransferazy (GGT) in blood plasma, thrombocytopenia, a leukopenia, decrease in level of a prothrombin, anemia, a hyperpotassemia, a gipertriglitseridemiya, a hyponatremia, increase in the SF level, creatinine, urea.

Others: grippopodobny symptoms, pain, fervescence, an asthenia, are possible manifestations of latent diabetes, the expressiveness of symptoms of the existing diabetes can increase during therapy.

except for dizziness, disorders of vision and bradycardia, any of the side effects described above is not dose-dependent. Dizziness, a loss of consciousness, a headache and an asthenia usually easy and, more probably, develop in an initiation of treatment.

At patients with stagnant heart failure the deterioration in heart failure and a delay of liquid can arise at increase in a dose of a karvedilol by titration.

Special instructions

Chronic heart failure with developments of stagnation. at patients with heart failure with developments of stagnation the deterioration in heart failure or a delay of liquid at increase in a dose of a karvedilol by titration are possible. if such symptoms appear, then it is necessary to raise a dose of diuretics, and the dose of a karvedilol should not be raised, clinical stability will not be restored yet. there can sometimes be a need for a dose decline of a karvedilol or for the temporary termination of its reception. such episodes do not exclude the following successful titration of a dose of a karvedilol.

Karvedilol should be applied with care in a combination with cardiac glycosides as medicaments slow down AV conductivity.

Orthostatic hypotension. In an initiation of treatment or at increase in a dose of medicament the patients can have an orthostatic hypotension with dizziness and vertigo, sometimes also with a loss of consciousness. The greatest risk is noted at patients with heart failure, elderly people and also patients who accept other antihypertensives or diuretics. These effects can be prevented use of a low initial dose of drug, careful increase in a maintenance dose and administration of medicament after a meal. Patients need to tell about measures for avoidance of orthostatic hypotension (care when rising, at appearance of dizziness the patient should sit down or lay down).

Function of kidneys in heart failure with developments of stagnation. Reversible deterioration in function of kidneys was noted at therapy of a karvedilol at patients with chronic heart failure and the low ABP (systolic arterial blood pressure of 100 mm Hg.), ischemic heart disease and diffusion disease of vessels and/or OPN. At patients with heart failure with developments of stagnation with such risk factors it is necessary to control function of kidneys at increase in a dose of a karvedilol by titration and to stop administration of medicament or to lower a dose at increase in severity of a renal failure.

Dysfunction of a left ventricle after an acute myocardial infarction. Before treatment of a karvedilol the patient has to be clinically stable and it should accept APF inhibitor during a minimum of the previous 48 h, and the dose of APF inhibitor has to be stable during a minimum of the previous 24 h

HOBL. Drug can be used at patients with HOBL with a bronkhospastichesky component who do not take the oral or inhalation drugs, only if the potential advantage exceeds potential risk.

At patients with a tendency to a bronchospasm as a result of probable increase in resistance. The patient should be observed carefully during the beginning of reception and increase in a dose of a karvedilol by titration, the dose of a karvedilol should be lowered if during treatment any sign of a bronchospasm is revealed.

Diabetes. It is necessary to be careful at use of a karvedilol for patients with diabetes as early manifestations of a sharp hypoglycemia can be disguised or are not expressed. At patients with chronic heart failure with diabetes the use of a karvedilol can be associated with deterioration in control of level of glucose in blood therefore for patients with diabetes the regular monitoring of level of glucose in blood at the beginning of reception of a karvedilol is recommended or at increase in a dose by titration and the corresponding correction of hypoglycemic therapy.

Disease of peripheral vessels. Karvedilol it is necessary to apply with care at patients with a disease of peripheral vessels as blockers of β-adrenoceptors can accelerate or aggravate symptoms of arterial insufficiency. As karvedilol also has the α-blocking properties, this effect mostly is leveled.

Raynaud's disease. Karvedilol it is necessary to apply with care at patients with disturbances of peripheric circulation (for example a Raynaud's disease) as symptoms can become aggravated.

Thyrotoxicosis. Karvedilol can mask thyrotoxicosis symptoms.

General anesthesia. When carrying out the general anesthesia at the patients accepting blockers of β-adrenoceptors it is necessary to use medicaments which have smaller inotropic effect, or it is necessary to stop at first (gradually) treatment.

Bradycardia. Karvedilol can cause bradycardia. If the pulse rate decreases up to 55 ud. / mines less, it is necessary to lower a dose of a karvedilol.

Hypersensitivity. It is necessary to be careful at use of a karvedilol for patients with existence in the anamnesis of serious hypersensitivity reactions and patients who receive desensitization therapy as blockers of β-adrenoceptors can increase both sensitivity to allergens, and gravity of anaphylactic reactions.

Psoriasis. Patients at whom earlier against the background of treatment by blockers of β-adrenoceptors psoriasis arose or became aggravated can appoint medicament only after careful assessment of possible advantage and risk.

Simultaneous use of blockers of calcium channels or antiarrhytmic drugs. In need of co-administration of blockers of calcium channels — derivatives of a fenilalkilamin (verapamil) and a benzotiazepin (diltiazem) and also antiarrhytmic means of the I class (Amiodaronum) continuous monitoring of the ECG and the ABP is recommended.

Pheochromocytoma. At patients with a pheochromocytoma the reception of a blocker of α-adrenoceptors should be begun before use of any blocker of β-adrenoceptors. Though karvedilol also shows the pharmacological blocking activity in the relation as α-, and β-receptors, experience of use of a karvedilol at such state is absent. Therefore it is necessary to be careful at reception of a karvedilol at patients with suspicion on a pheochromocytoma.

Printsmetal's Stenocardia. Drugs with the non-selective β-blocking activity can provoke pain behind a breast at patients with Printsmetal's stenocardia. There is no clinical experience of use of a karvedilol for such patients though the α-blocking activity of a karvedilol can warn such symptoms, however it is necessary to be careful at use of a karvedilol for patients at whom suspect presence of stenocardia of Printsmetal.

Contact lenses. The persons using contact lenses have to be warned about a possibility of reduction of a slezootdeleniye.

treatment Termination. At the sharp termination of treatment karvediloly (as well as the increased sweating, tachycardia, short wind and strengthening of stenocardia can arise other blockers of β-adrenoceptors). The greatest risk is noted at patients with stenocardia who can have a heart attack. The dose needs to be reduced gradually during 1–2 weeks. If treatment was suspended more than on 2 weeks, then its updating should be carried out, since the lowest dose.

Excipients. Sucrose and lactose are a part of drug. This medicament is not recommended to be taken to patients with the following disturbances: intolerance of fructose, deficiency of lactase, galactosemia, syndrome of disturbance of absorption of glucose galactose or deficiency of sucrose-isomaltase.

Use during pregnancy and feeding by a breast. Not enough clinical data on influence of medicament during pregnancy. The potential risk for a fruit remains to unknown. Blockers of β-adrenoceptors make dangerous pharmacological impact on a fruit. They can cause hypotonia, bradycardia and a hypoglycemia in a fruit. Drug should not be used during pregnancy.

As the possibility of penetration of a karvedilol into breast milk exists, during medicament treatment it is not necessary to nurse the child.

Children. Children are not recommended to appoint medicament due to the lack of data on safety and efficiency of its use for this category of patients.

Ability to influence speed of response at control of vehicles and work with difficult mechanisms. Did not conduct researches on influence of a karvedilol on ability of patients to run vehicles or to work with mechanisms. Considering possibility of side reactions (for example dizziness, increased fatigue), the speed of reactions of the patient can be broken that, in particular, concerns an initiation of treatment, increase in a dose, medicament change therefore it is recommended to refrain for the specified periods from control of vehicles or works with other mechanisms.

Interaction

Digoksin. concentration of digoxin increase approximately by 15% at simultaneous use of digoxin and a karvedilol. as digoxin, and karvedilol slow down av-conductivity. the increased monitoring of level of digoxin at the beginning is recommended, at dose adjustment or the termination of reception of a karvedilol.

Insulin or oral hypoglycemic means. Drugs with the β-blocking properties can enhance effect of decrease in level of glucose in blood of insulin and oral hypoglycemic means. Manifestations of a hypoglycemia can be disguised or weakened (especially tachycardia). Therefore regular monitoring of level of glucose in blood is recommended to patients who accept insulin or oral hypoglycemic means.

Stimulators and inhibitors of metabolism in a liver. Rifampicin reduces concentration of a karvedilol in blood plasma approximately by 70%. Cimetidinum increases AUC approximately by 30%, but does not cause any changes With _max . Special attention can be required by those who accept stimulators of oxidases of the mixed function, for example, rifampicin as the level of a karvedilol in blood plasma can be reduced, or the level of inhibitors of oxidases of the mixed function can be increased. However, despite rather insignificant influence of Cimetidinum on the level of a karvedilol, exists the probability of any clinically important interaction is minimum.

Drugs reducing the level of catecholamines. The patients taking the medicaments with the β-blocking properties and medicaments which can reduce the level of catecholamines (for example reserpine, guanetedin, Methyldopum, guanfatsin and MAO inhibitors, except for MAO-B inhibitors) should be controlled carefully concerning manifestations of hypotension and/or heavy bradycardia.

Cyclosporine. Moderate increase in average minimum concentration of cyclosporine after an initiation of treatment karvediloly patients with transplantation of a kidney with chronic vascular rejection is revealed. Approximately at 30% of patients the dose of cyclosporine should have been lowered for maintenance of concentration of cyclosporine in the therapeutic range, at the same time as dose adjustment was not required for others. On average at these patients the dose of cyclosporine was reduced approximately by 20%. Careful control of concentration of cyclosporine after the beginning of therapy karvediloly because of broad individual variability of the clinical answer at patients is recommended.

Verapamil, diltiazem or other antiarrhytmic drugs. In a combination with karvediloly increase in risk of disturbance of AV conductivity is possible. Noted separate cases of disturbance of conductivity (seldom — with hemodynamic disturbance) when karvedilol and diltiazem was applied at the same time. As well as at intake of other medicaments with the β-blocking properties (if karvedilol it is appointed orally together with blockers of calcium channels (verapamil or diltiazem)), it is recommended to carry out the ECG and monitoring of the ABP. It is not necessary to administer these medicaments in / century. It is necessary to carry out careful monitoring of a condition of the patient at simultaneous use of a karvedilol and Amiodaronum (orally) or antiarrhytmic medicaments I of a class. Soon after an initiation of treatment by blockers of β-adrenoceptors it was reported about development of bradycardia, cardiac arrest, fibrillation of ventricles in the patients who are at the same time accepting Amiodaronum. There is a risk of developing heart failure in case of carrying out accompanying in/in therapy by antiarrhytmic medicaments of the classes Ia or Ic.

Klonidin. The accompanying reception of a clonidine and medicaments with the β-blocking properties can enhance effects of decrease in the ABP and ChSS. At completion of the accompanying treatment by medicaments with the β-blocking properties and a clonidine at first it is necessary to stop reception of a blocker of β-adrenoceptors. Then, in several days, it is possible to stop therapy by a clonidine by a gradual dose decline.

Antihypertensive drugs. As well as with the β-blocking action, karvedilol the effect of other medicaments administered at the same time with antihypertensive properties can strengthen other medicaments (for example antagonists α ₁ - adrenoceptors) or can lead to hypotension according to the profile of side effects.

Anesthetics. It is necessary to be careful during anesthesia because of synergy negative inotropic and hypertensive effects of a karvedilol and anesthetics.

Overdose

Symptoms: sharp arterial hypotension (systolic hell of ≤80 mm Hg.), bradycardia (50 ud. / mines), heart failure, cardiogenic shock, breath dysfunction (bronchospasm), circulatory unefficiency, vomiting, spasms, cardiac arrest, confusion of consciousness, generalized spasms. increase in expressiveness of side reactions is possible.

Treatment: during the first hours — to cause vomiting and to wash out a stomach, further — control and correction of the vital indicators in intensive care unit.

Maintenance therapy: in the profound bradycardia — atropine of 0.5-2 mg in/in; for maintenance of warm activity — a glucagon of 1-5 mg (the maximum dose — 10 mg) in/in struyno, then 2–5 mg/h in the form of long infusions and/or adrenomimetik (ortsiprenalin, izoprenalin) 0.5-1 mg in / century. In need of positive inotropic effect it is necessary to resolve an issue of administration of FDE inhibitors. At prevalence of peripheral vasodilating action to appoint Norepinephrinum in repeated doses on 5–10 mkg or in the form of infusion of 5 mkg/min. with titration according to the ABP indicator. To apply to stopping of a bronchospasm β ₂ - adrenomimetik in the form of aerosol or, in case of inefficiency — in/in; or Aminophyllinum in/in in the form of a slow injection or infusion. In spasms — diazepam or clonazepam in/in slowly. In hard cases of intoxication at cardiogenic shock to continue maintenance therapy before stabilization of a condition of the patient, considering T _½ a karvedilola. In bradycardia, resistant to treatment, the use of a pacemaker is shown.

Storage conditions

At a temperature not above 25 °C.