Karvedilol-Mick

General characteristics. Structure:

Active ingredient: 6,25 mg, 12,5 mg or 25 mg of a karvedilol.

Excipients: calcium stearate, potato starch, lactose.

Structure of a cover of the capsule: glycerin pharmaceutical, glycerin, нипагин, нипазол, sodium lauryl sulfate, the water purified titanium dioxide, dye red charming E-129.

The cardiological drug having anti-anginal, hypotensive, antioxidant, vasodilating and anti-proliferative action.

Pharmacological properties:

Pharmacodynamics. Pharmacological action – anti-anginal, hypotensive, antioxidant, vasodilating, anti-proliferative. Karvedilol has β-1-adrenoblokiruyushchy, and also antioxidant properties. It reduces an afterload on heart thanks to an arteriolar vazodilatation and slows down neurohumoral konstriktorny activation of vessels and heart. Karvedilol has the prolonged anti-hypertensive effect. To it it is inherent as well anti-anginal effect. It has no internal sympathomimetic activity. Karvedilol slows down proliferation and migration of smooth muscle cells, apparently, affecting specific mitogenetic receptors. Perhaps, Karvedilol is capable to prevent development of an atheroma. Does not exert the expressed impact on lipidic exchange and the maintenance of K+, Na + and Mg2 + in plasma. Karvedilol and several his metabolites possess antioxidant svoysta as can slow down oxidation of noradrenaline with the subsequent formation of toxic intermediate connections, including reactive free radicals of oxygen, in a myocardium. Thereby Karvedilol has cardioprotective effect. Thanks to antioxidant activity Karvedilol also blocks an expression of several genes, in particular ICAM-1 (an intracellular molecule-1 of adhesion), whose product – protein ICAM-1 – is the key adhesive molecule responsible for an attachment of neutrophils to endothelial and smooth muscle cells. The gene of ICAM-1 is involved in injury of a myocardium and remodeling of heart, and Karvedilol, inhibiting an expression of this gene, suppresses thereby infiltration of neutrophils in an ischemic myocardium. Karvedilol slows down activation of the factors of a transcription induced by free radicals, prevents release by neutrophils of oxygen radicals and considerably inhibits apoptosis (the programmed death of cells), perhaps, thanks to multiple mechanisms, including removal of oxygen radicals, neurohumoral antagonism and modulation of a transcription of a gene.

At an arterial hypertension decrease in the ABP is not followed by increase in OPSS and change of a renal blood-groove, characteristic of beta adrenoblockers. Long anti-anginal action at an ischemic heart disease is connected with reduction before - and afterloads. At patients with a systolic form of congestive heart failure increases tolerance to exercise stresses, reduces ChSS, OPSS, raises fraction of emission of a left ventricle, cardiac index, reduces pressure of jamming of pulmonary capillaries. Reduces risk of death of patients with dekompensirovanny heart failure (by 65%) and the frequency of hospitalization (for 38%). At moderate chronic heart failure reduces risk of death by 28%. Efficiency is more expressed at patients with tachycardia (ChSS> of 82 blows/min.) and low fraction of emission (23%). The therapeutic effect is shown also at an ischemic etiology of chronic heart failure and at patients with a dilatatsionny cardiomyopathy.

At treatment by Karvedilol in a dose of 25 mg once a day within 12 months almost all patients from soft/moderate AG needed hydrochlorothiazide diuretic accession (25 mg once a day) for achievement and maintenance of the diastolic ABP less than 90 mm of mercury.

Pharmacokinetics. At intake it is quickly and well absorbed from a GIT, is exposed to intensive presistemny metabolism. Absolute bioavailability makes 25-35% (for S (-) - an enantiomer of 15%, for R (+)-enantiomera 31%). The maximum concentration of a karvedilol in a blood plasma after reception in a dose of 25 mg averages 5-99 mkg/ml on average in 1,46 h (0,68-3,10 h). Linkng of a karvedilol with proteins of plasma makes 98-99% (generally for account R (+)-enantiomera, connected with albumine), the specific volume of distribution of 1,5-2,0 l/kg. Metabolism of a karvedilol proceeds with demethylation and oxidation of an aromatic ring with the subsequent glyukuronization or sulphation. Not synthetic reactions of metabolism proceed with the participation of isoforms of P450 CYP2D6 cytochrome (provides 4'i 5’ - a hydroxylation of a phenolic ring), CYP2C9 (provides O-demethylation of S (-) - an enantiomer), minor metabolizing isoforms are CYP3A4, CYP2C19, CYP1A2, CYP2E1. In the course of demethylation and a hydroxylation 3 active metabolites having β-adrenoceptor blocking activity are formed. The main metabolite-4 '-hydroxyphenyl-karvedilol by 13 times surpasses initial connection in the β-blocking activity, at the same time its level in a blood plasma makes 10% of the level of a karvedilol. The period of semi-elimination of a karvedilol makes from 4 to 7 hours (considerable fluctuations in connection with genetic polymorphism of CYP2D6 and increase in the period of semi-elimination at persons with a defective isoform of enzyme are possible till 10 o'clock). It Eliminirutsya preferential with bile, in urine no more than 2% of the entered karvedilol are allocated. The general clearance of a karvedilol makes 0,52 л/ч×кг.

Indications to use:

Indications to use Karvedilola-Mick are:
- arterial hypertension – in the form of monotherapy and in a combination with other anti-hypertensive means;
- angina of exertion;
- chronic heart failure of the II-III class on NYHA, in a combination with diuretics, digoxin or APF inhibitors.

Route of administration and doses:

Inside, with enough liquid. The dose is selected individually.
Arterial hypertension: the recommended dose during the first 2 days of treatment – 6,25 - 12,5 mg once a day in the morning (1-2 capsules). The recommended maintenance dose – 25 mg of a karvedilol.

At insufficient clinical effect, but not earlier than the 14th day of treatment, the dose can be increased to maximum – 50 mg a day. The maximum single dose – 25 mg, a daily dose should not exceed 50 mg.

Angina of exertion: the recommended initial dose – on 12,5 mg 2 times a day (in the morning and in the evening) within 2 first days. The recommended maintenance dose – 25 mg 2 times a day. At insufficient clinical effect, but not earlier than the 14th day of treatment, it is possible to increase a dose to maximum – on 50 mg 2 times a day. At insufficient efficiency and good tolerance in 2 weeks the dose of a karvedilol can be still increased. The maximum daily dose at stenocardia makes 100 mg divided into two receptions. To patients 70 years are aged more senior the daily dose of a karvedilol should not exceed 50 mg (on 25 mg 2 times a day).

Chronic heart failure: the dose should be selected individually, during increase in a dose to carry out careful monitoring. It is necessary to watch a condition of the patient during 2-3 h after the first reception or after the first increased dose.

The recommended initial dose makes 6,25 mg of 1 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 2 times a day, then to 12,5 mg 2 times a day, then - to 25 mg 2 times a day.

Gradually sick appoint the most tolerable dose – on 25 mg 2 times a day for patients with body weight to 85 kg, and on 50 mg twice a day for patients with body weight more than 85 kg.

Patients with heart failure for the purpose of prevention of orthostatic hypotension are recommended to accept drug during food.

At the admission of a dose drug should be used as soon as possible, however if time of reception of the following dose comes, then accept only it, without doubling. Drug withdrawal needs to be made gradually during 1-2 weeks (especially at patients with stenocardia).

If drug was not accepted more than 2 weeks, treatment needs to be resumed, since the smallest doses (6,25 mg 1 or 2 times a day).

Features of use:

With care appoint drug at a bronkhospastichesky syndrome, chronic bronchitis, emphysema of lungs, Printsmetal's stenocardia, a diabetes mellitus, a hypoglycemia, a hyperthyroidism, diseases of peripheral vessels, AV to blockade of the I degree, unstable stenocardia, at treatment alfa1-adrenoblockers or alfa2-adrenomimetika, at combined use of MAO inhibitors, a pheochromocytoma (only stabilized by purpose of alpha adrenoblockers), depressions, a myasthenia, psoriasis, a renal failure.

Patients with heavy heart failure (it is more than III degrees of NYHA), with the broken electrolytic balance, with the lowered ABP level (less than 100 mm hg) or at advanced age have to is under fixed medical observation during 2 h after reception of the first dose or after reception of the first increased dose, in connection with risk of development of sudden falling of the ABP, orthostatic hypotension and a syncope. Danger of these complications can be reduced at purpose of drug in small initial doses and its reception during food.

Drug is not recommended for use to patients with the low ABP.

At patients with heart failure, if at them initial the GARDEN less than 100 mm of mercury. or there are associated diseases – coronary heart disease, defeat of peripheral vessels or a renal failure, the thicket should check a condition of an urinary system since treatment can influence function of kidneys (usually temporarily). If oppression of function of kidneys is observed, the dose of drug has to be lowered or treatment has to be stopped.

As well as other beta adrenoblockers, карведилол can mask symptoms of a hypoglycemia and it is adverse to influence carbohydrate metabolism. According to it treatment karvediloly patients with a diabetes mellitus requires special attention and more frequent measurement of content of sugar in blood.

Treatment karvediloly can mask symptoms of hyperfunction of a thyroid gland. At sudden drug withdrawal strengthening of a thyrotoxicosis is probable and thyrocardiac crisis is possible.

Treatment karvediloly patients with the established pheochromocytoma should not be begun before the corresponding therapeutic blockade an alpha - adrenoceptors.

Treatment karvediloly patients with psoriasis demands assessment advantage/risk since it карведилол can strengthen a disease or provoke emergence of symptoms.      

Use of a karvedilol can reduce sensitivity of allergy tests.
Against the background of use of a karvedilol with care it is necessary to carry out the general anesthesia with use of drugs with negative inotropic effect (ether, cyclopropane, trichloroethylene). Before extensive surgical interventions gradual drug withdrawal is recommended.

It is necessary to be careful at use of drug in case of the expressed metabolic acidosis.

The patients using contact lenses should be warned that карведилол reduces products of the lacrimal liquid.

During use of drug it is necessary to avoid alcohol intake.

It is necessary to stop treatment gradually, reducing a dose.

During use of drug it is necessary to abstain from occupations potentially dangerous types of activity requiring special attention and speed of psychomotor reactions.

Side effects:

In the recommended doses drug usually well is transferred.

From TsNS and peripheral nervous system: a headache, dizziness, syncopal states, muscular weakness (is more often in an initiation of treatment), sleep disorders, a depression, paresthesias.

From cardiovascular system: bradycardia, orthostatic hypotension, stenocardia attacks, AV blockade; seldom – disturbances of peripheric circulation (cold extremities), the "alternating" lameness, progressing of heart failure, the expressed decrease in the ABP, peripheral hypostases.

From a respiratory organs: asthma, bronchospasm; seldom - a nose congestion.
From the alimentary system: dryness in a mouth, nausea, abdominal pains, diarrhea; seldom - a lock, vomiting, increase in activity of hepatic transaminases.

From system of a hemopoiesis: thrombocytopenia, leukopenia.

From skin: allergic dieback, small tortoiseshell, itch, exacerbation of psoriasis rashes; very seldom – anaphylactoid reactions.

Others: seldom - grippopodobny effect, extremity pains, reduction of a slezootdeleniye, irritation of eyes, frustration of an urination, a renal failure.

Interaction with other medicines:

At combined use of a karvedilol with the means exhausting stocks of catecholamines (Reserpinum, MAO inhibitors) heavy bradycardia and arterial hypotension is possible.

Blockers of calcium channels (verapamil, diltiazem) and antiarrhythmic means (especially the I class) against the background of reception of a karvedilol can provoke the expressed arterial hypotension and heart failure. In/in administration of these drugs together with reception of a karvedilol contraindicated.

With alpha and beta-adrenergic agonists developing of the hypertensia expressed to reflex bradycardia and an asystolia and also reduction of beta and adrenoceptor blocking action of a karvedilol is possible.

Clonidine and карведилол can increase ability to reduce each other the ABP and ChSS. At combined use cancellation has to be made gradually: at first it is excluded карведилол, then, in several days, reception of a clonidine can be gradually stopped.

At simultaneous use of a karvedilol with digoxin AV conductivity is slowed down.

Insulin and hypoglycemic means for intake increase hypotensive action of a karvedilol and mask hypoglycemia symptoms.

Nitrates and antihypertensives (a clonidine, гуанетидин, alpha Methyldopa, гуанфацин, etc.) strengthen hypotensive action of a karvedilol and reduce ChSS.

Anesthetics increase negative inotropic effect and hypotensive effect of a karvedilol.

The means influencing TsNS (hypnotic drugs, tranquilizers, tricyclic antidepressants and alcohol) and карведилол mutually strengthen effects of each other.

NPVS reduce hypotensive action of a karvedilol owing to decrease in products of prostaglandins.

At combined use of a karvedilol with ergotamine it is necessary to take vasoconstrictive effect of ergotamine into account.

Xanthine derivatives (Aminophyllinum, theophylline) reduce beta and adrenoceptor blocking action of a karvedilol.

As карведилол is exposed to oxidizing metabolism, its pharmacokinetics can change at induction or oppression of fermental system of P450 cytochrome therefore it is necessary to consider influence:
- rifampicin (there are 70% decrease in concentration of a karvedilol in blood serum);
- barbiturates (reduce action of a karvedilol);
- CYP2D6 isoenzyme inhibitors (quinidine, fluoxetine, пароксетин, пропафенон; it is possible to assume increase in concentration of R (+) an enantiomer of a karvedilol);
- Cimetidinum (increases bioavailability of a karvedilol by 30%).
Karvedilol detains cyclosporine metabolism, increases concentration of digoxin in a blood plasma.

Contraindications:

- chronic obstructive diseases of lungs, bronchial asthma;
- liver failure;
- the expressed bradycardia (ChSS is less than 50 beats per minute);
- conductivity disturbances (syndrome of weakness of a sinus node; sinuatrial blockade, AV blockade of II and III degrees), except for patients with an artificial pacemaker;
- heart failure in a decompensation stage (the IV class on NYHA);
- cardiogenic shock;
- arterial hypotension (with the ABP it is less than 85 mm of mercury.);
- bronchial asthma;
- metabolic acidosis;
- pregnancy and lactation;
- children's and teenage age up to 18 years (safety and efficiency of use are not established);
- hypersensitivity to drug.

Overdose:

Symptoms: the expressed arterial hypotension, bradycardia, breath disturbance (including a bronchospasm), heart failure; in hard cases - cardiogenic shock, disturbances of conductivity up to a cardiac standstill, consciousness disturbance, up to a coma, generalized spasms.

Treatment: within several hours after administration of drug the gastric lavage or purpose of vomitives is shown. If the patient in consciousness, it is necessary to put it on a back with slightly raised legs and the hung head, the unconscious patient should be laid sideways.

The beta and adrenoceptor blocking effect is eliminated in/in introduction of an ortsiprenalin or izoprenalin in a dose of 0.5-1 mg and/or a glucagon in a dose of 1-5 mg (the maximum dose of 10 mg).

At the expressed hypotension parenteral administration of liquid and administration of adrenaline in a dose of 5-10 mkg is shown (or it in/in infusion with a speed of 5 mkg/min.).

For stopping of the expressed bradycardia appoint atropine in/in in a dose of 0.5-2 mg; at heart failure - a glucagon of 1-10 mg in/in quickly for 30 with then continuous infusion at the rate of 2-5 mg/h is carried out.

If peripheral vasodilating action prevails (warm extremities, in addition to considerable hypotension), it is necessary to appoint noradrenaline in repeated introductions on 5-10 mkg or in a view in/in infusion with a speed of 5 mkg/min.

For stopping of a bronchospasm appoint beta-adrenergic agonists (in the form of an aerosol or in/in) or Aminophyllinum in / century.

If spasms develop, it is recommended slow in/in administration of diazepam or clonazepam.

In hard cases when shock symptoms dominate, treatment has to continue until the condition of the patient, taking into account T1/2 of a karvedilol (6-10 h) is stabilized.

Storage conditions:

Drug should be stored in the place protected from moisture and light at a temperature from 15 °C to 25 °C. A period of validity - 2 years.

Issue conditions:

According to the recipe

Packaging:

On 10 capsules in blister strip packagings, on 3 strip packagings in a cardboard box.