Karvedilol

General characteristics. Structure:

Each tablet of 12,5 mg contains Active agent - карведилол 12,5 mg.

Excipients: lactoses monohydrate (sugar milk) - 64,0 mg, cellulose microcrystallic - 15,0 mg, starch corn - 2,0 mg, krospovidon- 2,0 mg, povidone (polyvinylpirrolidone) - 3,5 mg of magnesium stearate - 1,0 mg.

Each tablet of 25 mg contains Active agent - карведилол 25,0 mg.

Excipients: lactoses monohydrate (sugar milk)-128,0 mg, cellulose microcrystallic - 30,0 mg, starch corn - 4,0 mg, кросповидон - 4,0 mg, povidone (polyvinylpirrolidone) - 7,0 mg, magnesium stearate - 2,0 mg.

Pharmacological properties:

Pharmacodynamics. Blocks alfa1-, beta1-and beta2-adrenoceptors. Has vazodilatiruyushchy, anti-anginal and antiarrhytmic effect. Karvedilol represents racemic mix R (+) and S (-) of stereoisomers, each of which possesses identical and - adrenoceptor blocking and antioxidant properties. Beta and adrenoceptor blocking action of a karvedilol has non-selective character and is caused by left-handed S (-) stereoisomer. Drug has no own sympathomimetic activity, has membrane stabilizing properties.
The Vazodilatiruyushchy effect is connected mainly with blockade alfa1 - adrenoceptors. Thanks to a vazodilatation the general peripheric resistance of vessels (GPRV) decreases.
The combination of a vazodilatation and blockade of beta adrenoceptors results in the following effects: at patients with arterial hypertension the lowering of arterial pressure (ABP) is not followed by increase in OPSS, the peripheral blood stream does not decrease (unlike beta adrenoblockers). The Heart Rate (HR) decreases slightly. At patients with coronary heart disease has anti-anginal effect. Reduces before - and an afterload by heart. Does not exert the expressed impact on lipidic exchange and the maintenance of potassium ions, sodium and magnesium in a blood plasma. At patients with dysfunctions of a left ventricle and/or heart failure favorably influences hemodynamic indicators and improves fraction of emission and the sizes of a left ventricle. Has antioxidant effect, eliminating free oxygen radicals.
Karvedilol reduces rate of mortality and reduces the frequency of hospitalization, reduces symptomatology and improves function of a left ventricle at patients with chronic heart failure of ischemic and not ischemic genesis. Effects of a karvedilol are dozozavisimy.

Pharmacokinetics. Karvedilol is quickly soaked up from digestive tract. Has high lipophilicity. The maximum concentration in blood is reached in 1-1,5 hours. The elimination half-life makes 6-10 hours. Contacts proteins of a blood plasma for 95-99%. Bioavailability of drug of 24-28%. Meal does not influence bioavailability. It is metabolized in a liver with formation of a number of active metabolites - 60-75% of the absorbed drug are metabolized at first "passing" through a liver. Metabolites possess antioxidant and adrenoceptor blocking action. An elimination half-life - 6-10 h. Removal happens, mainly, to bile and a stake. At a renal failure pharmacokinetic parameters of a karvedilol significantly do not change. At patients with an abnormal liver function system bioavailability of a karvedilol increases due to decrease in metabolism at first "passing" through a liver. At serious violations of function of a liver карведилол it is contraindicated. Karvedilol gets through a placental barrier.

Indications to use:

- arterial hypertension (in monotherapy or in a combination with other anti-hypertensive means, for example, blockers of "slow" calcium channels);
- coronary heart disease (including at patients with unstable stenocardia and bezbolevy ischemia of a myocardium);
- chronic heart failure (as a part of a combination therapy).

Route of administration and doses:

Inside, washing down with enough liquid. Arterial hypertension
The initial dose makes 12,5 mg of 1 times a day in the first two days of treatment. Then on 25 mg of 1 times a day. Perhaps gradual increase in a dose with an interval not less than 2 weeks. At insufficiency of anti-hypertensive effect in 2 weeks of therapy the dose can be increased twice. The maximum recommended daily dose of drug makes 50 mg of 1 times a day (perhaps divided into 2 receptions). Coronary heart disease, stenocardia the Initial dose makes 12,5 mg 2 times a day in the first two days of treatment. Then on 25 mg 2 times a day. At insufficiency of anti-anginal effect in 2 weeks of therapy the dose can be increased twice. The maximum recommended daily dose of drug makes 100 mg the day divided into 2 receptions. Chronic heart failure the Dose is selected individually, under careful observation of the doctor. The recommended initial dose makes 3,125 mg (possibly drug use karvedi-lol in a dose of 6,25 mg from risky) 2 times a day within 2 weeks. At good tolerance the dose is increased with an interval by not less than 2 weeks to 6,25 mg (1/2 tablets on 12,5 mg) 2 times a day, then to 12,5 mg 2 times a day, then - to 25 mg 2 times a day. The dose should be increased to maximum which is well transferred by the patient. At body weight less than 85 kg - the maximum dose makes 25 mg 2 times a day, weighing more than 85 kg - 50 mg 2 times a day. If treatment is interrupted more than for 2 weeks, then its resuming there begin with a dose 3,125 mg (possibly drug use карведилол in a dose of 6,25 mg from risky) 2 times a day, with the subsequent increase in a dose.
With moderate and heavy degree of a renal failure, dose adjustment of Karvedilol it is not required from patients.
Karvedilol is contraindicated to patients with clinical manifestations of abnormal liver functions.

Features of use:

Therapy has to be carried out is long and should not stop sharply, especially at patients with coronary heart disease as it can lead to deterioration in a current of a basic disease. In case of need the dose decline of drug has to be gradual, within 1-2 weeks.
At patients with chronic heart failure during selection of a dose of Karvedilol it can be noted increase of symptoms of chronic heart failure or a delay of liquid. At emergence of such symptoms it is necessary to increase a dose of diuretics and not to raise Karvedilol's dose to stabilization of indicators of a hemodynamics. Sometimes there is a need to reduce Karvedilol's dose or, in rare instances, temporarily to cancel drug. Similar cases do not interfere with further correct selection of a dose of Karvedilol.
Karvedilol with care apply in a combination with cardiac glycosides (perhaps excessive delay of atrioventricular conductivity). Karvedilol can cause bradycardia, at ChSS urezheniya less than 55 уд. / a min. dose of drug Karvedilol need to be lowered.
With care appoint Karvedilol a sick diabetes mellitus as it can mask or weaken hypoglycemia symptoms (especially tachycardia). At patients with chronic heart failure and a diabetes mellitus drug use Karvedilol can be followed by disturbances of glycemic control. Care is necessary at Karvedilol's appointment for patients with diseases of peripheral vessels (including with Reynaud's syndrome) as beta adrenoblockers can strengthen symptoms of arterial insufficiency.
As well as other beta adrenoblockers Karvedilol can reduce expressiveness of symptoms of a thyrotoxicosis. It is necessary to be careful at Karvedilol's appointment to patients with anamnestic instructions on heavy hypersensitivity reactions or taking desensitization course as beta adrenoblockers can increase sensitivity to allergens and severity of anaphylactic reactions. At the beginning of therapy by Karvedilol or at increase in a dose of drug at patients, especially advanced age, excess decrease in the ABP can be noted preferential upon transition from situation "lying" in a standing position. Drug dose adjustment is necessary. Regular ECG control and the ABP indicators is recommended at co-administration of Karvedilol and blockers of "slow" calcium channels like verapamil and diltiazem, and also - with antiarrhytmic means.
Non-selective beta adrenoblockers can provoke emergence of pains in patients with Printsmetal's stenocardia though alpha and adrenoceptor blocking properties can prevent similar symptomatology, it is necessary to appoint Karvedilol in such cases with care. At Karvedilol's appointment the patient with chronic heart failure and arterial hypotension (systolic the ABP less than 100 mm hg), coronary heart disease and diffusion changes of vessels and / or a renal failure noted reversible deterioration in function of kidneys. Karvedilol's dose is selected depending on a functional condition of kidneys. To the patients with a chronic obstructive pulmonary disease (including a bronkhospastichesky syndrome) who are not receiving inside or it is inhalation beta2-adrenostimulyator, Karvedilol appoint only if advantages of its use exceed potential risk. With initially predisposition to a bronkhospastichesky syndrome at Karvedilol's reception as a result of increase in resistance of respiratory tracts an asthma can develop. At the beginning of therapy and at increase in a dose of Karvedilol of these patients it is necessary to observe carefully, reducing a drug dose at emergence of initial signs of a bronchospasm. In case of carrying out surgical intervention with use of the general anesthesia it is necessary to warn the anesthesiologist about the previous therapy by Karvedilol.
During treatment to avoid alcohol intake. Patients with a pheochromocytoma prior to therapy of any beta adrenoblocker need to appoint alpha adrenoblocker.
The patients carrying contact lenses should consider that drug can cause reduction of a slezootdeleniye.

INFLUENCE ON ABILITY TO DRIVING OF VEHICLES AND WORK WITH CARS AND MECHANISMS
Considering potentially possible side effects of Karvedilol, patients whose work demands bystry psychomotor reaction, especially at the beginning of therapy, and also at a concomitant use of alcohol should appoint drug with care.

Side effects:

- From the central nervous system: very often - dizziness, a headache (as a rule, not strong and arising in an initiation of treatment), weakness, increased fatigue, a depression, paresthesias, sleep disorders, an adynamy, lability of mood.
- From cardiovascular system: often - bradycardia, orthostatic hypotension, an atrioventricular block of degree, progressing of heart failure (during increase in doses), hypostases (including generalized, hypostases of the lower extremities, a hypervolemia, a liquid delay), stenocardia, the expressed decrease in the ABP, syncopal states (including presinkopalny), it is rare - disturbances of peripheric circulation (a cold snap of extremities, an aggravation of a syndrome of the "alternating" lameness and Reynaud's syndrome).
From a digestive tract: dryness of a mucous membrane of an oral cavity, nausea, diarrhea or lock, vomiting, abdominal pain.
- Laboratory indicators: increase in activity "hepatic" transaminazalaninaminotransferaza (ALT), aspartate aminotransferase (ACT) and gammaglutamiltransferaza, thrombocytopenia and leukopenia.
- From system of a hemopoiesis: seldom - thrombocytopenia, a leukopenia.
- From a metabolism: increase in body weight, hypercholesterolemia; patients with the available diabetes mellitus have a hyperglycemia or a hypoglycemia, disturbances of glycemic control.
- From integuments: skin reactions (skin rash, dermatitis, small tortoiseshell and skin itch), separate cases of allergic reactions.
- From respiratory system: often - an asthma and a bronchospasm (at predisposed patients), it is rare - a nose congestion.
- Other: the vision disorder, reduction of a slezootdeleniye and irritation of eyes, a grippopodobny syndrome, sneezing, is rare - disturbance of an urination, a renal failure and a renal failure at patients with a diffusion vasculitis and/or a renal failure; very seldom - an aggravation of a course of psoriasis, extremity pain, infrequently - decrease in a potentiality; exceptional cases of an incontience of urine at women are registered; existence at drug of beta and adrenoceptor blocking properties does not exclude a possibility of manifestation latentno of the proceeding diabetes mellitus, a decompensation of already available diabetes mellitus or oppression of kontrinsulyarny system.

Interaction with other medicines:

Karvedilol can exponentiate action of other at the same time accepted anti-hypertensive means or drugs which render hypotensive effect (nitrates).
At combined use of a karvedilol and diltiazem, Amiodaronum and other antiarrhytmic means disturbances of conductivity of cordial impulses and disturbance of indicators of a hemodynamics can develop. At a concomitant use of a karvedilol and digoxin concentration of the last increases and time of atrioventricular carrying out can increase. Karvedilol can exponentiate effect of insulin and hypoglycemic means for intake, at the same time hypoglycemia symptoms (especially tachycardia) can mask therefore at patients with a diabetes mellitus regular control of concentration of glucose in blood is recommended.
Inhibitors of a microsomal oxidation strengthen (Cimetidinum), and inductors (phenobarbital, rifampicin) weaken hypotensive effect of a karvedilol. The drugs reducing the maintenance of katekholamii (Reserpinum, monoaminooxidase inhibitors) increase risk of development of arterial hypotension and the expressed bradycardia.
At simultaneous use of cyclosporine concentration of the last increases (correction of a daily dose of cyclosporine is recommended).
Co-administration of a clonidine can exponentiate an anti-hypertensive and urezhayushchy cordial rhythm effects of a karvedilol. If is planned to stop a combination therapy drug with beta and adrenoceptor blocking properties and a clonidine, the first should cancel beta adrenoblocker, and in several days it is possible to cancel a clonidine, gradually reducing its dose.
The general anesthetics strengthen negative inotropic and hypotensive effect of a karvedilol.

Contraindications:

Hypersensitivity to a karvedilol or other components of drug, the acute and chronic heart failure in a decompensation stage demanding intravenous administration of inotropic means; clinically significant abnormal liver function; an atrioventricular block of the II-III degree (except for patients with an artificial pacemaker of heart, the expressed bradycardia (ChSS less than 50 beats/min), a sick sinus syndrome (including a sinoauricular block), the expressed arterial hypotension (the systolic arterial pressure (AP) less than 85 mm of mercury.), cardiogenic shock, a bronchospasm and bronchial asthma (in the anamnesis), age up to 18 years (efficiency and safety are not established), a lactose intolerance, deficit of lactase, glyukozo-galaktozny malabsorption (drug contains lactose).

WITH CARE
Chronic obstructive pulmonary disease, Printsmetal's stenocardia, thyrotoxicosis, occlusal diseases of peripheral vessels, pheochromocytoma, psoriasis, renal failure, atrioventricular block of the I degree, extensive surgical interventions and general anesthesia, diabetes mellitus, hypoglycemia, depression, myasthenia.

USE AT PREGNANCY AND IN THE PERIOD OF THE LACTATION
Beta adrenoblockers reduce a placental blood stream that can lead to pre-natal death of a fruit and premature births. Besides, the fruit and newborns can have undesirable reactions (in particular, a hypoglycemia and bradycardia, complications from heart and lungs).
There is no sufficient experience of use of Karvedilol for pregnant women. Karvedilol is contraindicated to use at pregnancy, except for cases when possible advantages of its use for mother, exceed potential risk for a fruit.
Data on penetration of a karvedilol into breast milk are absent therefore if Karvedilol's reception is necessary in the period of a lactation, then breastfeeding needs to be stopped.

Overdose:

Symptoms: the expressed decrease in the ABP, bradycardia, heart failure, cardiogenic shock, a cardiac standstill; breath disturbances, a bronchospasm, vomiting, confusion of consciousness and generalized spasms are possible.
Treatment: it is necessary to carry out monitoring and correction of the vital indicators, if necessary - in intensive care unit. It is possible to use the following events:
a) to lay the patient on a back (with the raised legs);
b) at the expressed bradycardia - atropine on 0,5-2 mg intravenously;
c) for maintenance of cardiovascular activity - a glucagon on 1-10 mg intravenously struyno, then on 2-5 mg
in an hour in the form of long infusion;
d) sympathomimetics (Dobutaminum, Epinephrinum (adrenaline))
in various doses, depending on the body weight and the response to the carried-out therapy.
If in a clinical picture of overdose arterial hypotension prevails, enter Norepinephrinum (noradrenaline); it is appointed in the conditions of continuous control of indicators of blood circulation. At bradycardia, resistant to treatment, use of an artificial pacemaker is shown. At a bronchospasm enter beta-adrenergic agonists in the form of an aerosol (at inefficiency - intravenously) or Aminophyllinum intravenously.
At spasms intravenously slowly enter diazepam. As at heavy overdose with symptomatology of shock lengthening of an elimination half-life of a karvedilol and removal of drug from depot is possible, it is necessary to continue a maintenance therapy rather long time.

Storage conditions:

To store in the dry, protected from light place at a temperature not above 25 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets on 12,5 mg and 25 mg.
On 10, 30 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished.
On 10, 20, 30, 40, 50 or 100 tablets in banks polymeric for medicines.
To one bank or 1, 2, 3, 4, 5 or 10 blister strip packagings together with the application instruction place in cardboard packaging (pack) from a cardboard.