Karvedilol Sandoz of the tab. of 12.5 mg No. 30

Pharmacological properties

Pharmacodynamics. karvedilol is a blocker of adrenoceptors which has numerous effects. it blocks α1-, β1 — and β2-адренорецепторы. protective influence of a karvedilol on bodies is confirmed. karvedilol is powerful antioxidant and removes reactive radicals of oxygen (absorption function). karvedilol represents racemic mix. both enantiomer (r [+] and s [–]) have the identical α-blocking and antioxidant properties. karvedilol has anti-proliferative impact on cells of unstriated muscles of vessels. clinical trials in which measured various markers during long-term treatment karvediloly showed decrease in an oxidizing stress at patients. the β-blocking effect is not selection relatively β1 — and β2-адренорецепторов and s (–) to an enantiomer is attributed.

Karvedilol does not show own sympathomimetic activity (VSMA). As well as propranolol, it has membrane stabilizing properties. Karvedilol oppresses renin-angiotensin-aldosteronovuyu a system by β-blockade, reducing renin release. Therefore deduction of water is an unusual occurrence.

Karvedilol reduces peripheric vascular resistance by blockade α ₁ - adrenoceptors. Karvedilol lowers the arterial blood pressure whose increase is caused by Phenylephrinum, agonist α ₁ - an adrenoceptor, but not the increase caused by angiotensin II.

Karvedilol has no undesirable impact on a lipidic profile. The normal ratio of lipoproteins of high density and lipoproteins of the low density (LPVP/LPNP) does not change.

Clinical performance

AG. Karvedilol leads to decrease in the ABP at patients with AG thanks to a combination of β-blockade and α ₁ - the mediated vazodilatation. Decrease in the ABP is not connected with the accompanying increase in the general peripheric resistance which is observed at use of clean blockers of β-adrenoceptors. ChSS decreases a little. Renal perfusion and function of kidneys remain. It was established that during treatment karvediloly the stroke output of heart remains whereas OPSS decreases. Karvedilol does not influence blood supply of separate bodies and vessels, such as kidneys, skeletal muscles, forearms, legs, skin, brain or carotids. Cold extremities and early fatigue at physical activity are observed seldom. Long-term antihypertensive effects of a karvedilol were proved in several controlled double blind researches.

an ischemic heart disease. At patients with an ischemic heart disease karvedilol possesses anti-ischemic (increase in the general time under loading, time under loading before appearance of a depression of a segment of ST of 1 mm and also time before appearance of stenocardia) and anti-anginal properties which remain during long therapy. Researches of acute hemodynamic effects showed what karvedilol considerably reduces the need of a myocardium for oxygen and activity of sympathetic nervous system. Besides, decrease preloading (pulmonary pressure and pressure in pulmonary capillaries) and an afterload of ventricles (OPSS).

Subjective indicators. Karvedilol did not affect the quality of life connected with health (primary final point in one research) which was measured by means of the standard questionnaire. However in the majority of researches the considerable improvement of the general state by assessment of both patients, and the researcher was observed.

Renal failure. The metaanalysis of placebo - controlled clinical trials with a large number of patients (4000) with a slight and moderate chronic renal failure testified in favor of treatment karvediloly patients with dysfunction of a left ventricle with symptomatic heart failure or without it in terms of decrease in the general mortality and also frequency of development of heart failure.

Pharmacokinetics. Absorption. After oral administration of capsules of 25 mg at healthy faces karvedilol it is quickly absorbed, and the C _max in blood plasma which is reached approximately in 1.5 h (T _max ), it is equal to 21 mg/l. There is a linear dependence between _{values C of max} and a dose.

After oral administration karvedilol is exposed to considerable metabolism of the first passing therefore the absolute bioavailability at healthy people is about 25%. Karvedilol represents racemic mix, and S-(–)-enantiomery as it appeared, are metabolized quicker, than R-(+)-enantiomery. what provides absolute oral bioavailability of 15% in comparison with 31% for R-(+)-enantiomerov. The C _max R-karvedilola in plasma exceeds that S-karvedilola approximately twice. The researches in vitro showed what karvedilol is substrate of the conveyor of outflow of the R-glycoprotein. The R-glycoprotein role concerning availability of a karvedilol was also confirmed at healthy faces of in Vivo.

Distribution. High-lipophilic Karvedilol Sandoz, and his linking with proteins of blood plasma makes about 95%. Its volume of distribution (Vd _SS ) fluctuates from 1.5 to 2 l/kg.

Biotransformation. At all studied animal species and at people Karvedilol Sandoz is almost completely metabolized in a liver by oxidation and conjugation to several metabolites. Demethylation and hydroxylation on a phenolic ring lead to receiving three active metabolites with the β-blocking activity. At animals a metabolite the 4th -hydroxyphenol has by 13 times more powerful β-blocking activity, than karvedilol. In comparison with karvediloly the specified three active metabolites show weak vazodilatiruyushchy effect. The _{value C of max} active metabolites in 1 h reached the following values: Sq.m — 3.9 ng/ml, M4 — 4.1 ng/ml, M5 — 3.3 ng/ml (about 20% of value of a karvedilol, the C _max — 49 ng/ml).

Besides, 2 hydroxycarbacindery metabolites are very strong antioxidants which activity is 30-80 times more powerful than activity of a karvedilol.

Pharmacokinetic researches at people showed that oxidizing metabolism of a karvedilol is stereoselection. Results of the research in vitro demonstrate that various isoenzymes of P450 cytochrome, including CYP 2D6, CYP 3A4, CYP 2E1, CYP 2C9 and CYP 1A2, can be involved in processes of oxidation and hydroxylation.

Research at healthy faces and patients was shown that R-enantiomery are metabolized mainly under the influence of CYP 2D6, and S-enantiomer — mainly under the influence of CYP 2D6 and CYP 2C9.

Genetic polymorphism. Results of a research of clinical pharmacokinetics at people showed that CYP 2D6 plays an important role in metabolism of R- and S-karvedilola. Thus, at slow metabolizator of CYP 2D6 concentration of R- and S-karvedilola in blood plasma increases. The value of a genotype of CYP 2D6 for pharmacokinetics of R- and S-karvedilola was also supported in a population research of pharmacokinetics while other researches did not confirm this observation. It indicates that the genetic polymorphism of CYP 2D6 can have the limited clinical importance.

Removal. After oral administration of T _½ Karvedilola Sandoz makes about 6-10 h. After a single dose of 50 mg of a karvedilol about 60% of a dose cosecrete with bile in the form of metabolites and is removed for 11 days with a stake. After single oral administration only about 16% are removed with urine in the form of a karvedilol. Less than 2% of not changed substance are removed with urine. Later in/in infusion of 12.5 mg at healthy volunteers the clearance of a karvedilol is about 600 ml/min., and T _½ — about 2.5 h. At all persons T _½ capsules of 50 mg made about 6.5 h that corresponds to the valid period of semi-absorption of the capsule. After oral administration the general clearance of S-karvedilola approximately twice exceeds value of clearance R-karvedilola.

Pharmacokinetics at special groups of patients

Patients with a renal failure. Long-term therapy karvediloly does not influence an autoregulyation of renal perfusion or glomerular filtration.

At patients with AG with a renal failure noted significant changes of T _½ and the C _max in blood plasma. At patients with a renal failure the AUC value increases by 40–50%, and the renal clearance of initial substance decreases. However changes of pharmacokinetic indicators are insignificant.

Several open researches showed that karvedilol is an effective remedy at patients from renal AG. The same concerns also patients with chronic kidney disease, patients on dialysis and the patients who transferred transplantation of a kidney. After oral administration of 10 mg of a karvedilol of the C _max in blood plasma it is reached in 5 h both in days of dialysis, and in days without dialysis. Substance is not defined by 24 h in plasma.

to gradual decrease in the ABP both in days of dialysis, and in days and without dialysis. The hypotensive effect is comparable with observed at patients with normal function of kidneys. Karvedilol is not brought at dialysis as it does not pass through a dialysis membrane, perhaps, because of very high extent of linking with proteins of blood plasma.

Knowledge gained in a comparative research at patients on a hemodialysis shows that karvedilol exceeds diltiazem in terms of efficiency in silent ischemia.

Patients with an abnormal liver function. Showed pharmacokinetic researches at patients with cirrhosis that AUC of a karvedilol at patients with an abnormal liver function increases by 6.8 times in comparison with the same indicator at healthy faces.

Therefore, karvedilol it is contraindicated to use for patients with clinically obvious abnormal liver function (see CONTRAINDICATIONS and USE, undressed Special instructions for selection of a dose).

Patients with heart failure. In a research of 24 patients of the Japanese nationality with heart failure the clearance of R- and S-of a karvedilol was much lower, than estimated earlier at healthy people. These results indicate that heart failure has significant effect on pharmacokinetics of R- and S-karvedilola.

Patients of advanced age. The pharmacokinetics Karvedilola Sandoz depends on age of patients. Concentration of a karvedilol in blood plasma of patients of advanced age is 50% higher, than at young patients. Patients of advanced age have C _max and AUC can increase. In such cases the dose adjustment is necessary.

Age had no significant effect on pharmacokinetics of a karvedilol at patients with AG. In a research at patients of advanced age with AG the difference in a profile of undesirable effects in comparison with young patients is not revealed. The further research which patients of advanced age with an ischemic heart disease entered did not reveal any distinctions for young patients in terms of messages about the undesirable phenomena. Therefore patients of advanced age do not need correction of an initial dose.

Patients of children's age. Showed researches at children and teenagers that the clearance corrected on body weight at children and teenagers is much higher, than at adults.

Indication

Essentsialnaya ag of easy and average degree.

• Prevention of heart attacks in chronic stenocardia.

• Treatment of stable heart failure from easy to heavy degree (class II—IV on classification of NYHA) ischemic or cardiomyopathic origin in complex therapy with standard treatment (diuretics, digoxin, APF inhibitors).

Use

Essentsialnaya ag. adults. the initial dose makes 12.5 mg of 1 times a day during the first 2 days. after that treatment using a dose of 25 mg of 1 times a day is recommended. if effect insufficient, a daily dose it is possible to raise gradually to 50 mg for 1 or 2 receptions a day (with an interval, at least, each 2 weeks). the maximum dose at ag makes 50 mg.

Patients of advanced age. An initial dose — 12.5 mg of 1 times a day. For some patients of this dose it is enough for appropriate control of the ABP. If effect insufficient, a dose it is possible to raise gradually a maximum to 50 mg for 1 or 2 receptions a day.

Stenocardia. The initial dose makes 12.5 mg twice a day during the first 2 days. After that treatment using a dose of 25 mg twice a day is recommended. If effect insufficient, a dose it is possible to raise gradually a maximum to 100 mg for 2 receptions (with an interval, at least, each 2 weeks).

Patients of advanced age. Usually it is not necessary to exceed a dose of 25 mg twice a day.

Treatment of stable heart failure from easy to heavy degree (class II—IV on classification of NYHA). It is necessary to select a dose individually and to carefully control a condition of the patient during a titration phase.

Dose of a digitalis, diuretics and APF inhibitors should be stabilized prior to the Karvedilol Sandoz medicament treatment.

Recommended dose in an initiation of treatment makes 3.125 mg twice a day for 2 weeks. If this dose is well transferred, it can be raised gradually (with an interval, at least, each 2 weeks) to 6.25 mg twice a day, and then — to 12.5 mg twice a day (2 times on 1 tablet Karvedilola Sandoz of 12.5 mg) and at last — to 25 mg twice a day (2 times on 1 tablet Karvedilola Sandoz of 25 mg). The dose needs to be titrated to the maximum dose which is well transferred by the patient.

Maximum recommended dose makes 25 mg twice a day at patients with body weight to 85 kg and 50 mg twice a day at patients with body weight more than 85 kg.

Before increase in a dose the doctor has to examine the patient for the purpose of identification of symptoms of exacerbation of heart failure, a vazodilatation (falling of the ABP, dizziness) or bradycardia. Temporary exacerbations of heart failure or at appearance of hypostases it is necessary to treat with the accompanying use of the raised doses of diuretics. Nevertheless the dose decline of the medicament Karvedilol Sandoz or the temporary termination of treatment can be required. If Karvedilol Sandoz was cancelled for more than 2 weeks, therapy has to be resumed using a dose of 3.125 mg with gradual increase (with an interval, at least, each 2 weeks) as it is described above. Vazodilatation symptoms at first should be eliminated with a dose decline of diuretics. If symptoms remain, the dose of APF inhibitors should be lowered with the subsequent dose decline Karvedilola Sandoz. Under such circumstances it is impossible to raise a dose Karvedilola Sandoz to disappearance of symptoms of exacerbation of heart failure and a vazodilatation.

Special instructions for selection of a dose. Patients with chronic heart failure and a renal failure. The necessary dose has to be defined separately for each patient. According to indicators of pharmacokinetics of the medicament Karvedilol Sandoz Karvedilola Sandoz is not required to patients with heart failure and a moderate and heavy renal failure of dose adjustment (see Pharmacokinetics).

Patients with an abnormal liver function. At clinical manifestations of an abnormal liver function the use of the medicament Karvedilol Sandoz is contraindicated (also see Pharmacokinetics and CONTRAINDICATIONS).

Route of administration. It is necessary to swallow of tablets, washing down with enough liquid.

it is not obligatory for p to take the Pill together with food. However patients with heart failure have to take a pill with food to slow down absorption and to reduce the frequency of development of orthostatic effects. The Karvedilol Sandoz medicament treatment usually is long. As well as in a case with other blockers of β-adrenoceptors, cancellation of a karvedilol should not be cutting, and happen by a dose decline for several days (for example a dose decline half to 3-day intervals). It is especially important for patients from the accompanying ischemic heart disease.

Children. Safety and efficiency of the medicament Karvedilol Sandoz at patients aged up to 18 years did not investigate. Use of the medicament Karvedilola Sandoz for children is not recommended.

Contraindication

Hypersensitivity to acting or to other excipients as a part of drug; dekompensirovanny chronic heart failure of the class ii-1v on nyha at patients, it is required to whom auxiliary in/in inotropic treatment; hobl; oh (2 lethal outcomes at patients with the asthmatic status after use of a single dose were registered)

;

• allergic rhinitis

;

• laryngeal edema;
• pulmonary heart;
• dysfunction of sinus node (including sinuatrial blockade);
• heavy hypotension (systolic arterial blood pressure of 85 mm Hg.);
• AV blockade of II and III degree;
• heavy bradycardia (less than 45-50 ud. / mines at rest);
• cardiogenic shock;
• heart attack with complications;
• an abnormal liver function with clinical manifestations;
• metabolic acidosis;
• accompanying use of MAO inhibitors (except MAO-B inhibitors);
• slow metabolism of debrisoquine and Mephenytoinum;
• feeding by a breast.

Side effects

Frequency of emergence of side reactions does not depend on a dose, except for dizziness, a disorder of vision and bradycardia.

thus: very often — ≥1/10; often — from ≥1/100 to 1/10: infrequently — from ≥1/1000 to 1/100; seldom — from ≥1/10 000 to 1/1000; very seldom — 1/10,000.

Disturbance of blood and lymphatic system: often — anemia, it is rare — thrombocytopenia; very seldom — a leukopenia.

from a cardiovascular system: very often — heart failure; often — bradycardia, hypostasis, a hypervolemia, a liquid delay; infrequently — AV blockade, stenocardia.

from an organ of sight: often — a disorder of vision, reduced dacryagogue (dryness in eyes), irritation of eyes.

from a digestive tract: often — nausea, diarrhea, vomiting, dyspepsia, an abdominal pain; infrequently — a constipation; seldom — dryness in a mouth.

General disturbances: very often — an asthenia (fatigue); often — hypostasis, pain.

from digestive system: very seldom — increase in the AlAT, AsAT level and gamma glutamiltransferazy (GGT).

from the immune system: very seldom — hypersensitivity (allergic reactions).

Infection and invasion: often — pneumonia, bronchitis, upper respiratory tract infections, infections of urinary tract.

from a metabolism and food: often — increase in body weight, a hypercholesterolemia, disturbance of control of glucose in blood (hyperglycemia, a hypoglycemia) at patients with the available diabetes.

from musculoskeletal and connective tissue: often — extremity pain.

from nervous system: very often — dizziness, a headache; often — a syncope, a preunconscious state; infrequently — paresthesias.

Psychiatric disorders: often — a depression, suppressed mood; infrequently — sleep disorders, nightmares, hallucinations, a loss of consciousness; very seldom — psychosis.

from kidneys and urinary tract: often — a liver failure and deviations of function of kidneys at patients with a diffusion vascular disease and/or a renal failure; seldom — urination disturbance; very seldom — incontinence of urine at women.

from a reproductive system and a mammary gland: infrequently — erectile dysfunction.

from a respiratory system, a thorax and mediastinum: often — short wind, a fluid lungs, OH at predisposed patients; seldom — congestion of a nose.

from skin and hypodermic fabrics: infrequently — skin reactions (for example allergic rash, dermatitis, a small tortoiseshell, an itching, psoriasis and lishayny damages of skin); very seldom — skin reactions (for example a multiformny erythema, Stephens's syndrome — Johnson, a toxic epidermal necrolysis).

from vessels: very often — arterial hypotension; often — orthostatic hypotension, disturbance of peripheric circulation (cold extremities, diseases of peripheral vessels, exacerbation of the alternating lameness and Reynaud's syndrome), AG.

Description of separate side reactions. Dizziness, a faint, a headache and an asthenia, as a rule, have easy temper and more often arise 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 doses of a karvedilol (see. Special INSTRUCTIONS).

Heart failure was the widespread undesirable phenomenon at the patients receiving placebo and karvedilol (14.5 and 15.4% respectively), at patients with dysfunction of a left ventricle after an acute myocardial infarction.

during therapy karvediloly at patients with chronic heart failure with the low ABP, an ischemic heart disease and a diffusion vascular disease and/or background heart failure (see. Special INSTRUCTIONS).

Besides, observed the following:

• increase in number of complaints at patients with the alternating lameness or Reynaud's syndrome;

• deterioration in the diagnosed heart failure in some cases;

• small damage of a liver (isolated cases) (see. Special INSTRUCTIONS);

• skin defeats similar to defeats in red flat herpes;

• initiation or exacerbation of psoriasis;

• because of possible increase in resistance of airways the patients with tendency to bronkhospastichesky reactions can have difficulties with breath or attacks OH (see. Special INSTRUCTIONS).

Post-registration experience. Throughout the period of post-registration use of a karvedilol the side reactions given below were registered. As messages about these reactions arrive from groups of patients whose number is unknown, it is not always possible to estimate authentically their frequency and/or to define a causal relationship with medicine influence.

from a metabolism and food. Thanks to the β-blocking properties, medicament can cause appearance of latent diabetes, deterioration in manifestations of the existing diabetes and disturbance of control of level of glucose in blood (see. Special INSTRUCTIONS). Disturbance of regulation of level of glucose in blood was observed (hypoglycemia).

Disturbance from side of skin and hypodermic fabrics. Alopecia. Heavy undesirable skin reactions, such as toxic epidermal necrolysis and Stephens's syndrome — Johnson (see. Special INSTRUCTIONS).

Disturbance from side of kidneys and urinary tract. It was in some cases reported about incontinence of urine at women. The symptom disappears after medicament withdrawal.

Special instructions

Should use with care medicament at the following states:

• children's age;

• labile or secondary AG;

• unstable stenocardia;

• total block of a leg of a ventriculonector;

• an end-stage of perfusion of peripheral arteries (for example Reynaud's syndrome) as blockers of β-adrenoceptors can cause emergence or aggravation of symptoms of arterial insufficiency;

• myocardial infarction postponed recently;

• a tendency to decrease in the ABP at change of situation (ortostaz);

• patients who receive the accompanying certain hypotensive medicaments (blockers α ₁ - receptors)

.

Hypersensitivity. At use of blockers of β-adrenoceptors there is a risk of increase in sensitivity to allergens and frequencies of emergence of serious reactions of hypersensitivity (for example disturbance of cardiovascular regulation, a bronchospasm, an asthma, shock) at patients with serious reactions of hypersensitivity in the anamnesis and the patients receiving the desensibilizing therapy. Therefore in such cases it is recommended to use medicament with care.

Heavy skin reactions (SCAR). During treatment karvediloly very exceptional cases of heavy skin undesirable reactions, such as toxic epidermal necrolysis and Stephens's syndrome — Johnson were registered (see. Side EFFECTS), Karvedilol it is not necessary to apply at patients with heavy skin reactions which can be connected with karvediloly.

Psoriasis. Patients with psoriasis in the anamnesis should appoint blockers of β-adrenoceptors, including Karvedilol Sandoz, only after careful assessment of a ratio advantage/risk.

Withdrawal. At patients from AG and the accompanying ischemic heart disease demanding cancellation of use of the medicament Karvedilol Sandoz it is necessary to reduce a dose gradually. It concerns also all other blockers of β-adrenoceptors.

Bradycardia. In clinical trials at 2% of patients from AG and 9% of patients with heart failure the bradycardia was observed. If ChSS 55 ud. / mines, the dose should be lowered. Arterial hypotension was registered at 9.7% and a loss of consciousness — at 3.4% of patients with heart failure, and the corresponding indicators at the patients receiving placebo made 3.6 and 2.5% respectively. The risk of emergence of such effects was the highest in the first 30 days of treatment. This period corresponds to a titration phase (see USE).

At patients of advanced age high the ABP can decrease after the first administration of medicament Karvedilol Sandoz.

Hyperthyroidism. Thanks to the β-blocking activity karvedilol can mask hyperthyroidism symptoms, such as tachycardia. At sudden medicament withdrawal strengthening of a hyperthyroidism and development of hyper thyroid crisis is possible.

Diabetes. Especially careful monitoring is necessary for patients with diabetes as the Karvedilol Sandoz medicament treatment can influence glucose level in blood. Patients with diabetes should be informed that Karvedilol Sandoz can increase insulin resistance and mask or reduce expressiveness of symptoms of a hypoglycemia, especially tachycardia. Non-selective blockers of β-adrenoceptors can aggravate the hypoglycemia induced by insulin and delay normalization of level of glucose in blood serum. It is regularly necessary to check glucose level in blood and in case of need to adjust doses of insulin or oral antidiabetic drugs.

At patients with heart failure and the accompanying diabetes to aggravation of a hyperglycemia which demands strengthening of hypoglycemic therapy. It is recommended to watch closely glucose level in blood at use of the medicament Karvedilol Sandoz, to adjust doses or if it is necessary, to stop administration of drug.

At patients with AG and the accompanying diabetes from which insulin use is not required karvedilol did not influence glucose level in blood on an empty stomach and after a meal and also on glikozilirovanny hemoglobin A ₁ . Also dose adjustment of antidiabetic medicaments was not required.

At patients with diabetes which insulin was not required karvedilol had no significant impact on test results on tolerance to glucose. At patients with AG without diabetes with reduced insulin reaction (metabolic syndrome) karvedilol improved insulin reaction a little. The same was observed at patients with AG and diabetes for which insulin was not required.

Contact lenses. The patients using contact lenses have to be informed on possible reduction of dacryagogue.

Heart failure. During a phase of titration of the medicament Karvedilol Sandoz at patients with heart failure cases of increase in expressiveness of symptoms of heart failure, appearance of hypostases were registered. If there are such symptoms, the dose of diuretics should be raised whereas the dose of the medicament Karvedilol Sandoz has to remain invariable before stabilization of a condition of the patient. The temporary dose decline of the medicament Karvedilol Sandoz or the termination of treatment can be required (see USE).

to Patients with dekompensirovanny heart failure which already receive a digitalis (for example digoxin) diuretics and/or APF inhibitors, it is necessary to appoint with care Karvedilol Sandoz as a digitalis and Karvedilol Sandoz can slow down AV conductivity, and Karvedilol Sandoz can increase digitalis level (see INTERACTIONS).

Function of kidneys in heart failure. During treatment karvediloly at patients with dekompensirovanny heart failure and the low ABP (systolic arterial blood pressure of 100 mm Hg.), the ischemic heart disease or other vascular disorders and/or a renal failure observed reversible deterioration in function of kidneys. After cancellation of use of means the indicators of function of kidneys returned to initial levels. During a phase of titration it is necessary to control a condition of function of kidneys at patients with heart failure with risk factors. If deterioration is observed, it is necessary to lower a dose or to stop treatment.

Pheochromocytoma. Patients with a pheochromocytoma should appoint Karvedilol Sandoz only on condition of sufficient blockade of α-receptors. Though Karvedilol Sandoz combines these two pharmacological properties, still there is no corresponding experience. Therefore it is necessary to apply with care Karvedilol Sandoz at patients a pheochromocytoma.

Printsmetal's Stenocardia. Drugs with the non-selective β-blocking activity can provoke a stethalgia at patients with Printsmetal's stenocardia. Clinical experience of use of a karvedilol for such patients is absent though the α-blocking activity of a karvedilol can prevent development of such symptoms. However it is necessary to apply with care Karvedilol Sandoz at patients with suspicion on presence of stenocardia of Printsmetal.

HOBL. Blockers of β-adrenoceptors can strengthen bronchial obstruction therefore patients with a chronic disease of lungs are not recommended to use these drugs. Karvedilol Sandoz, nevertheless, patients can appoint with care with a mild disease of lungs in case of inefficiency of other drugs. When prescribing the medicament Karvedilol Sandoz it is necessary to use a minimal effective dose with care to reduce inhibition of endogenous and exogenous β-antagonists. Because of increase in resistance of airways there can be a breath difficulty.

for participation in clinical trials if they did not need oral and inhalation medicaments for treatment of this disease. It is necessary to adhere to strictly recommended dose which has to be reduced at emergence of the first suspicion on a bronchospasm during a titration phase (see INTERACTIONS).

Abnormal liver function. During treatment karvediloly the small damage of cells of a liver was sometimes observed. In controlled researches at patients with AG the frequency of developing of an abnormal liver function, the registered side reaction, was 1.1% (13 of 1142 people) at the patients receiving karvedilol and the patients receiving placebo have 0.9% (4 of 462 people). One patient receiving karvedilol in placebo - a controlled research, was excluded because of liver dysfunction.

In controlled researches at patients with chronic heart failure the frequency of an abnormal liver function, the registered side effect, was 5.0% (38 of 765 people) at the patients receiving karvedilol and the patients receiving placebo have 4.6% (20 of 437 people).

3 patients, receiving treatment karvediloly (0.4%), and 2 patients receiving placebo treatment (0.5%) excluded from placebo - controlled researches owing to liver dysfunction.

It was established that injury of a liver is reversible and arises in the form of insignificant clinical a symptom