Karvedilol

General characteristics. Structure:

Active ingredient: 6,25 mg, 12,5 mg or 25 mg of a karvedilol in 1 tablet.

Excipients: lactoses моногидрад, starch corn, cellulose microcrystallic, magnesium stearate, talc, silicon dioxide colloid.

Pharmacological properties:

Pharmacodynamics. Blocks alfa1-, beta1-and beta2-adrenoceptors, has vazodilatiruyushchy, anti-anginal and antiarrhytmic effect. The Vazodilatiruyushchy effect is connected mainly with blockade of alfa1-adrenoceptors. Thanks to a vazodilatation reduces the general peripheric resistance of vessels (GPRV). Has no own sympathomimetic activity (SMA), has membrane stabilizing properties.

Represents racemic mix R (+) and S (-) of stereoisomers, each of which has identical alpha and adrenoceptor blocking and antioxidant properties.

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 the coronary heart disease (CHD) has anti-anginal effect. Reduces before - and post-load of heart. Does not exert the expressed impact on lipidic exchange and the maintenance of potassium ions (K+), sodium (Na+) and magnesium (Mg2+) in a blood plasma.

At patients with dysfunctions of the left ventricle (LV) and/or the heart failure (HF) favorably influences hemodynamic indicators and improves fraction of emission and the LZh sizes.

Karvedilol reduces rate of mortality and reduces number of hospitalization, improves symptomatology and improves function of a left ventricle at patients with the chronic heart failure (CHF) of ischemic and not ischemic genesis, effects of a karvedilol are dozozavisimy.

Pharmacokinetics. Absorption. After intake quickly and almost it is completely soaked up in the digestive tract (DT). The maximum concentration (Cmax) in a blood plasma is reached approximately in 1,5 h. Bioavailability – 25% (for S (-) stereoisomer - 15%, for R (+) - stereoisomer - 31%).

Distribution. Communication with proteins of a blood plasma about 95%. Distribution volume - about 2 l/kg. Gets through a placental barrier, it is allocated with breast milk.

Metabolism. It is metabolized in a liver (has effect of "primary passing" through a liver). Metabolism of a karvedilol as a result of oxidation is the stereoselection. R (+) stereoisomer is metabolized generally by means of isoenzymes of CYP2D6 and CYP1A2, and S (-) a stereozomer – generally by means of CYP2D6 isoenzyme. Isoenzymes of CYP3A4, CYP2E1 and CYP1C19 belong to other isoenzymes of P450 participating in metabolism of a karvedilol. The maximum concentration of R (+) stereoisomer in a blood plasma exceeds that for S approximately twice (-) of a stereozomer.

R (+) stereoisomer is metabolized, mainly, by a hydroxylation. At "slow" metabolizator of an isoenzyme of CYP2D6 increase in plasma concentration of a karvedilol, first of all, of R (+) stereoisomer is possible that is expressed in increase in alpha and adrenoceptor blocking activity of a karvedilol.

As a result of demethylation and a hydroxylation of a phenolic ring 3 metabolites (their concentration 10 times lower, than concentration of initial substance) with beta and adrenoceptor blocking activity are formed (at 4-gidroksi-
it is about 13 times stronger than a phenolic metabolite, than at the karvedilol). 3 active metabolites have less expressed vazodilatiruyushchy properties, than карведилол. 2 gidroksikarbozolny metabolites of a karvedilol are extremely powerful antioxidants, and their activity in this respect at 30-80 times exceeds that at a karvedilol.

Removal. An elimination half-life (T1/2) – 4-7 h (considerable fluctuations in connection with genetic polymorphism of CYP2D6 and increase in an elimination half-life at persons with a defective isoform of enzyme are possible till 10 o'clock). Plasma clearance - 590 ml/min. It is removed generally with bile through intestines, in urine no more than 2% of the entered karvedilol are allocated.

Pharmacokinetics at special groups of patients. At elderly patients concentration of a karvedilol in a blood plasma is about 50% higher, than at young patients.

At patients with an abnormal liver function bioavailability can increase up to 80%.

At a renal failure pharmacokinetic parameters of a karvedilol significantly do not change.

At heart failure R pharmacokinetics (+) and S (-) of stereoisomers of a karvedilol considerably changes (the clearance decreases).

Patients with a diabetes mellitus have 2 types and arterial hypertension карведилол does not influence concentration of glucose in blood, level of glikozirovanny hemoglobin (HbA1) or a dose of hypoglycemic means; does not cause decrease in tolerance to glucose.

Indications to use:

Arterial hypertension (in monotherapy or in a combination with other anti-hypertensive means, for example, blockers of "slow" calcium channels or diuretics); stenocardia (including at patients with unstable stenocardia and bezbolevy ischemia of a myocardium); HSN (stable and symptomatic easy, moderate and heavy HSN of ischemic and not ischemic genesis as a part of a combination therapy with APF inhibitors and diuretics, with or without cardiac glycosides).

Route of administration and doses:

Inside, washing down with enough liquid. At arterial hypertension - an initial dose of 12,5 mg once a day in the first 2 days, then on 25 mg once a day, with possible gradual increase in a dose with an interval not less than 2 weeks. The maximum recommended daily dose of drug makes 50 mg once a day (possibly division into two receptions).

At stenocardia - an initial dose of 12,5 mg once a day in the first 2 days, then on 25 mg 2 times a day (as much as possible - to 100 mg divided into 2 receptions).

At HSN (against the background of the picked-up therapy - begin with cardiac glycosides, diuretics and inhibitors of an angiotensin-converting enzyme (APF) with 3,125 mg (1/2 tablets of 6,25 mg (the tablet has to risk)) 2 times a day within 2 weeks, then (at good tolerance) this dose 2 times a day increase up to 6,25 mg, then - to 12,5 – 25 mg 2 times a day (at the body weight of the patient less than 85 kg - the maximum dose makes 25 mg 2 times a day, at the body weight of the patient more than 85 kg - 50 mg 2 times a day).

Before each increase in a dose it is necessary to consult with the doctor for avoidance of increase of symptoms of HSN or a vazodilatation.

At increase of symptoms HSN or a delay of liquid in an organism should increase a dose of diuretics, or to reduce a dose of a karvedilol or to temporarily cancel it.

If treatment by Karvedilol is interrupted more than for 1 week, then his appointment is resumed in a smaller dose, and then increased according to the stated above recommendations. If treatment is interrupted more than for 2 weeks, then its resuming there begin with a dose 3,125 mg (1/2 tablets of 6,25 mg (the tablet has to risk)) 2 times a day, with the subsequent increase in a dose.

At a vazodilatation it is necessary to reduce a dose of diuretics. If symptoms remain, it is possible to lower an APF inhibitor dose (if the patient accepts it), and then, if necessary – a dose of a karvedilol. The dose of a karvedilol should not be increased before stabilization of symptoms of the amplifying heart failure or arterial hypotension.

Dosing at special groups of patients. For patients with a moderate and heavy renal failure, and also patients of advanced age dose adjustment of a karvedilol is not required.

For patients with clinical manifestations of an abnormal liver function карведилол it is contraindicated.

Features of use:

Use at pregnancy and during breastfeeding. Karvedilol is contraindicated to use at pregnancy and during breastfeeding. Beta-blockers reduce a placental blood stream that can lead to pre-natal death of a fruit and premature births. The fruit and the newborn can have undesirable reactions (in particular a hypoglycemia and bradycardia, complications from heart and lungs). Researches on animals did not reveal teratogenic effect at a karvedilol. The potential risk for the person is unknown. At animals карведилол and its metabolites get into breast milk. Data on penetration of a karvedilol into breast milk of the person are absent. If administration of drug of KARVEDILOL is necessary during breastfeeding, then breastfeeding needs to be stopped.

It is necessary to appoint with care to patients whose work demands bystry psychomotor reaction (in operating time with machines and mechanisms, at control of vehicles), to the patients using contact lenses (reduction of a slezootdeleniye).

Cancellation has to be carried out gradually (in avoidance of development of a syndrome of "cancellation"), within several days (especially at patients with an ischemic heart disease).

At storage on light discoloration of tablets is possible.

Can mask symptoms of a thyrotoxicosis, a hypoglycemia.

Clinical experience of use of a karvedilol in pediatric practice is absent.

In case of need carrying out surgical intervention using the general anesthesia it is necessary to warn the anesthesiologist about the previous therapy karvediloly, because of a possibility of summation of negative effects of drug KARVEDILOL and means for the general anesthesia.

When progressing SN against the background of treatment it is recommended to increase a dose of diuretics, at a renal failure the dose is regulated depending on a functional condition of kidneys.

During treatment alcohol intake is excluded.

To patients with HOBL which is not receiving inhalation drugs or drugs for intake (antiasthmatic means), KARVEDILOL is appointed only if possible advantages of its use exceed potential risk.

With care drug appoint to patients with a diabetes mellitus as it can mask or weaken hypoglycemia symptoms (especially tachycardia). At patients with HSN and a diabetes mellitus use of KARVEDILOLA can be followed by fluctuations of a glycemia.

As well as other beta adrenoblockers, KARVEDILOL can reduce expressiveness of symptoms of a thyrotoxicosis. To patients with anamnestic instructions on emergence or an exacerbation of psoriasis at use of beta adrenoblockers, it is possible to appoint drug KARVEDILOL after the careful analysis of possible advantage and risk.

Patients with a pheochromocytoma prior to use of any beta adrenoblocker need to appoint alpha adrenoblocker. Though KARVEDILOL has both beta, and alpha and adrenoceptor blocking properties, there is no experience of its use for such patients therefore with care patients should appoint with suspicion to a pheochromocytoma.

Non-selective beta adrenoblockers can provoke emergence of pains in patients with Printsmetal's stenocardia. Though its alpha and adrenoceptor blocking properties can prevent similar symptomatology, it is necessary to appoint KARVEDILOL in such cases with care.

It is necessary to be careful at patients with a depression, a metabolic acidosis and a malignant myasthenia (myasthenia gravis). Care is necessary at the drug KARVEDILOL use for patients with diseases of peripheral vessels (including with Reynaud's syndrome) as beta adrenoblockers can strengthen symptoms of arterial insufficiency.

KARVEDILOL with care is applied in a combination with cardiac glycosides at patients with AV blockade of the I degree because of a possibility of excessive delay of AV of conductivity.

At patients with a renal failure at use of a karvedilol reversible deterioration in function of kidneys was noted. The dose of drug should be selected depending on a functional condition of kidneys.

There is no sufficient experience of use of drug KARVEDILOL for pregnant women. Therefore it is contraindicated to use at pregnancy.

Influence on ability of control of motor transport and work with mechanisms. It must be kept in mind that in an initiation of treatment and at increase in a dose KARVEDILOLA AD can excessively decrease, causing dizziness. Therefore during treatment patients should abstain from occupations potentially dangerous types of activity requiring special attention and speed of psychomotor reactions.

Side effects:

For the description of frequency of undesirable reactions the following gradation of frequency of development of undesirable reactions was used: very often –> 10%, are frequent –> 1% and <10%, is not frequent –> 0,1% and <1%, is rare –> 0,01% and <0,1%, is very rare – <0,01%, including separate messages.

From a nervous system: very often – dizziness, a headache, a loss of consciousness, a myasthenia (is more often in an initiation of treatment), is frequent – sleep disorders, a depression, paresthesia.

From cardiovascular system (CCC): often – bradycardia, orthostatic hypotension, stenocardia, AV blockade, the expressed decrease in the ABP, a hypervolemia; infrequently – occlusal disturbances of peripheric circulation, progressing of SN, syncopal and presinkopalny states; seldom - the "alternating" lameness.

From the alimentary system: often – nausea, diarrhea or a lock, an abdominal pain, vomiting, it is rare – dryness of a mucous membrane of an oral cavity, is very rare – increase in activity of "hepatic" transaminases.

From a metabolism: often – a hypercholesterolemia, a hyperglycemia or a hypoglycemia at patients with already available diabetes mellitus.

From bodies of a hemopoiesis: often – anemia, it is rare – thrombocytopenia, is very rare – a leukopenia.

From respiratory system: often - a fluid lungs, pneumonia, bronchitis, upper respiratory tract infections, it is rare - a nose congestion.

From an urinary system: often – hypostases, infections of urinary tract, it is rare – heavy renal failures.

Allergic reactions: not often – skin allergic reactions (a dieback, urticaria, a skin itch, rashes), it is very rare – an exacerbation of psoriasis rashes, sneezing, a nose congestion, a bronchospasm (at predisposed patients).

Others: often – a grippopodobny syndrome, extremity pains, reduction of a slezootdeleniye, irritation of eyes; increase in body weight; not often – disturbance of a potentiality; a vision disorder (it is frequent at patients with chronic heart failure); seldom – an urine incontience at women, reversible after drug withdrawal, an alopecia.

Interaction with other medicines:

Pharmacokinetic interaction: карведилол is both substrate, and inhibitor of a glycoprotein P, at its simultaneous use with the drugs transported by a glycoprotein P, bioavailability of the last can increase. Besides, bioavailability of a karvedilol can change under the influence of inductors or inhibitors of a glycoprotein of River.

Inhibitors and the inductors CYP2D6 and CYP2C9 can stereoselektivno change system and/or presistemny metabolism of a karvedilol, leading to increase or decrease in concentration of R (+) and S (-) of stereoisomers of a karvedilol in a blood plasma.

Some examples of the similar interactions observed at patients or at healthy volunteers are listed below, however this list is not full.

Digoxin: at simultaneous use of a karvedilol and digoxin of concentration of digoxin increase approximately by 15%. At the beginning of therapy karvediloly, at selection of its dose or drug withdrawal, regular control of concentration of digoxin in a blood plasma is recommended.

Cyclosporine: карведилол increases concentration of cyclosporine in a blood plasma at its oral administration. Maintenance of concentration of cyclosporine in the therapeutic range, requires reduction of a dose of cyclosporine on average for 10-20%. Due to the expressed individual fluctuations of concentration of cyclosporine careful monitoring of its concentration after the beginning of therapy karvediloly and, if necessary, the corresponding correction of a daily dose of cyclosporine is recommended. At intravenous administration (in/in) cyclosporine of any interaction with karvediloly it is not expected.

Rifampicin, phenobarbital: rifampicin, phenobarbital accelerate metabolism and reduce plasma concentration of a karvedilol, leading to decrease in its anti-hypertensive effect.

Amiodaronum: upatsiyent with heart failure Amiodaronum reduced clearance of S (-) of stereoisomer of a karvedilol, suppressing CYP2C9. Average concentration of R (+) stereoisomer of a karvedilol did not change. Therefore, in connection with increase in concentration of S (-) in stereoisomer of a karvedilol the risk of increase in beta and adrenoceptor blocking action is possible.

CYP2D6 isoenzyme inhibitors: use of inhibitors of an isoenzyme of CYP2D6, including quinidine, fluoxetine, a paroksetin, propafenon, can lead to the stereoselection suppression of metabolism of a karvedilol (possibly increase in concentration of R (+) stereoisomer).

Pharmakodinamichesky interaction. Insulin or hypoglycemic means for intake: drugs with beta and adrenoceptor blocking properties can strengthen hypoglycemic effect of insulin or hypoglycemic means for intake. Hypoglycemia symptoms, especially tachycardia, can mask or weaken. Regular control of content of glucose in blood is recommended to the patients receiving insulin or hypoglycemic means for intake.

The drugs reducing the maintenance of catecholamines: the patients accepting at the same time drugs with beta and adrenoceptor blocking properties and the drugs reducing the maintenance of catecholamines (for example, Reserpinum and monoamine oxidase inhibitors (MAO)), have to be under careful observation in connection with risk of development of arterial hypotension and/or the expressed bradycardia.

Digoxin. The combination therapy beta adrenoblockers and digoxin can lead to additional delay of AV conductivity.

Verapamil, diltiazem, Amiodaronum or other antiarrhytmic means: their simultaneous use with karvediloly can increase risk of disturbance of AV conductivity.

At simultaneous use of a karvedilol and diltiazem separate cases of disturbances of cordial conductivity were noted (seldom – with disturbances of indicators of a hemodynamics). Use of a karvedilol together with blockers "slow" кальциев channels (for example, verapamil or diltiazem) is recommended to be carried out under control of an ECG and the ABP.

Clonidine: simultaneous use of a clonidine with beta adrenoblockers can exponentiate hypotensive and bradikardichesky effect. If is planned to stop a combination therapy drug beta adrenoblocker and a clonidine, the first should cancel beta adrenoblocker, and in several days it is possible to cancel a clonidine, gradually reducing its dose.

Antihypertensives: as well as with beta and adrenoceptor blocking activity, карведилол action of other at the same time accepted antihypertensives (for example, alpha adrenoblockers) or drugs which cause arterial hypotension as side effect can strengthen other drugs.

Means for the general anesthesia: it is necessary to make careful observation of the main vital signs of an organism when carrying out the general anesthesia in connection with a possibility of synergistic negative inotropic action of a karvedilol and means for the general anesthesia.

Non-steroidal anti-inflammatory drugs (NPVP): simultaneous use of NPVP and beta adrenoblockers reduces anti-hypertensive effect of a karvedilol.

Bronchodilators (agonists of beta adrenoceptors): as not cardioselective beta adrenoblockers interfere with broncholitic effect of the bronchodilators which are stimulators of β-adrenoceptors, careful observation of the patients receiving these drugs is necessary.

Inhibitors of a microsomal oxidation (Cimetidinum), diuretics and APF inhibitors strengthen anti-hypertensive effect of a karvedilol.

Contraindications:

Hypersensitivity to a karvedilol and to any other component of drug, the acute and dekompensirovanny HSN demanding intravenous administration of inotropic drugs, atrioventricular (AV) blockade of the II-III Art. (without artificial pacemaker), the expressed bradycardia (ChSS less than 50 beats/min), the sick sinus syndrome (SSS), cardiogenic shock, a heavy liver failure, bronchial asthma or a bronchospasm (in the anamnesis), heavy arterial hypotension (systolic the ABP is less than 85 mm hg), the breastfeeding period, age up to 18 years (safety and efficiency of use are not established), a lactose intolerance, deficit of lactase, a syndrome of glyukozo-galaktozny malabsorption (drug contains lactose), a pheochromocytoma without simultaneous use of alpha adrenoblockers.

With care. The Chronic Obstructive Pulmonary Disease (COPD), Printsmetal's stenocardia, AV blockade of the I degree, a diabetes mellitus, a hypoglycemia, a thyrotoxicosis, occlusal diseases of peripheral vessels, suspicion on a pheochromocytoma, a depression, a myasthenia, psoriasis, extensive surgical interventions, the general anesthesia, a diabetes mellitus, a renal failure, pregnancy.

Overdose:

Symptoms: vomiting, confusion of consciousness, the expressed decrease in the ABP (systolic the ABP of 80 mm hg below), bradycardia (less than 50 beats/min), disturbance of respiratory function (including a bronchospasm), SN, cardiogenic shock, a cardiac standstill, generalized spasms.

Treatment: cardiotonics, control of CCC, functions of respiratory system and kidneys. The hemodialysis is not effective.

Storage conditions:

To store in the dry, protected from light place at a temperature not above 25 °C. To store in the places unavailable to children. A period of validity - 2 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets on 6,25 mg, 12,5 mg, 25 mg. On 7 tablets in a blister strip packaging. 2, 3, 4 blister strip packagings together with the application instruction are placed in a pack from a cardboard. On 10 tablets in a blister strip packaging. 1, 2, 3, 4, 5 blister strip packagings together with the application instruction are placed in a pack from a cardboard.