Velcardio, tablets 12.5mg 30 pcs

Pharmacotherapeutic group: Alpha- and beta-adrenoblocker

ATX code: C07AG02

Pharmacological properties

Pharmacodynamics

Carvedilol is an α-, β1- and β2-adrenoreceptor blocker with vasodilatory, anti-anginal and antiarrhythmic effects. Carvedilol is a racemic mixture of R(+)- and S(-)-stereoisomers, each with the same α-adrenoblocking and antioxidant properties. The β-adrenoblocking effects of carvedilol are non-selective and are due to the left-handed S(-)-stereoisomer.

Carvedilol has no sympathomimetic activity of its own and has membrane stabilizing properties. Its vasodilatory effect is mainly due to blockade of α1-adrenoreceptors. Due to vasodilatation, total peripheral vascular resistance (TPRR) decreases.

By blocking β-adrenoceptors, it reduces the activity of renin-angiotensin-aldosterone system (RAAS), reducing the release of renin, so fluid retention, typical of selective α-adrenoblockers, occurs rarely.

Carvedilol has no significant effect on lipid profile, maintaining a normal ratio of high and low density lipoproteins (HDL/LDL).

Efficacy

In patients with arterial hypertension, carvedilol reduces blood pressure (BP) due to the combined blockade of β- and α1-adrenoreceptors. BP reduction is not accompanied by a simultaneous increase in total peripheral vascular resistance, which is observed with non-selective β-adrenoblockers. Heart rate (HR) decreases slightly. Renal blood flow and renal function are preserved in patients with arterial hypertension. It has been shown that carvedilol does not change the blood stroke volume and reduces the RPS; it does not impair the blood supply to organs and the peripheral blood flow, including in the skeletal muscles, forearms, lower extremities, skin, brain and carotid artery. Cooling of the extremities and increased fatigue during physical activity are rarely noted. The antihypertensive effect of carvedilol in arterial hypertension persists for a long time.

Renal dysfunction

Carvedilol is an effective treatment for patients with renovascular arterial hypertension, including patients with chronic renal insufficiency, as well as in patients on hemodialysis or who have undergone a kidney transplant. Carvedilol causes gradual reduction of BP on both dialysis and non-dialysis days, and its antihypertensive effect is comparable with that of patients with normal renal function.

Based on results obtained in comparative studies in patients on hemodialysis, it has been concluded that carvedilol is more effective and has better tolerability compared to slow calcium channel blockers (CCBs).

Carvedilol reduces morbidity and mortality among patients with cardiomyopathy on dialysis. A meta-analysis of placebo-controlled studies involving a significant number of patients (>4000) with chronic kidney disease confirmed that treating patients with left ventricular dysfunction with or without heart failure symptoms with carvedilol reduces mortality and heart failure events.

Ischemic heart disease

In patients with ischemic heart disease, carvedilol has antiischemic and antianginal effects (increased total exercise time, time to ST-segment depression of 1 mm, and time to angina attack) that persist with long-term therapy. Carvedilol significantly reduces myocardial oxygen demand and sympathoadrenal activity. It also reduces preload (pulmonary artery occlusion pressure and pulmonary capillary pressure) and postload (PPS).

Chronic Heart Failure

Carvedilolol reduces mortality and hospitalization rates, reduces symptoms, and improves left ventricular function in patients with chronic heart failure of ischemic and non-ischemic genesis. The effects of carvedilol are dose-dependent.

Pharmacokinetics

Intake

After oral administration, carvedilol is rapidly absorbed from the gastrointestinal tract. Carvedilolol is a substrate of glycoprotein P (Pgp) carrier protein, which acts as a pump in intestinal lumen. Glycoprotein P plays a major role in the bioavailability of certain drugs. Maximum plasma concentration (Cmax) is reached approximately 1 hour after oral administration. When taken orally, carvedilol undergoes presystemic metabolism, as a result of which its absolute bioavailability in healthy male volunteers is about 25-30% for R-form and 15% for S-form. The maximum plasma concentration of the R-stereoisomer is approximately 2 times higher than that of the S-stereoisomer. Bioavailability is not influenced by food intake.

Distribution

Carvedilol has high lipophilicity. About 98-99% of carvedilol is bound to plasma proteins. Its volume of distribution is approximately 2 l/kg.

Metabolism

Carvedilol undergoes biotransformation in the liver by oxidation and conjugation to form a number of metabolites. 60-75% of absorbed carvedilol is metabolized by “primary passage” through the liver. The existence of intestinal-hepatic circulation of the initial substance has been shown.

The metabolism of carvedilol by oxidation is stereoselective. The R-stereoisomer is metabolized primarily by the CYP2D6 and CYP1A2 isoenzymes, while the S-stereoisomer is metabolized primarily by the CYP2D9 isoenzyme and, to a lesser extent, by the CYP2D6 isoenzyme. Other cytochrome P450 isoenzymes involved in the metabolism of carvedilol include the CYP3A4, CYP2E1 and CYP2C19 isoenzymes.

The R-stereoisomer is metabolized mainly by hydroxylation. In patients with low activity of CYP2D6 isoenzyme there may be an increase in plasma concentration of carvedilol, primarily of R-stereoisomer, which is expressed by increased α-adrenoblocking activity of carvedilol.

Demethylation and hydroxylation of the phenolic ring results in 3 metabolites (their concentrations are 10 times lower than those of the parent substance) with β-adrenoblocking activity (the 4′-hydroxyphenol metabolite has about 13 times stronger activity than carvedilol itself). The three active metabolites have less pronounced vasodilatory properties than does carvedilol. Two of the hydroxycarbazole metabolites of carvedilol are extremely potent antioxidants, and their activity in this respect is 30-80 times greater than that of carvedilol.

After a single oral dose of 50 mg, about 60% of carvedilol is secreted with the bile and excreted in the intestine in the form of metabolites within 11 days. About 16% is excreted by the kidneys as carvedilol or its metabolites. Renal excretion of unchanged carvedilol is less than 2%. Plasma clearance of carvedilol reaches about 500-700 ml/min, the elimination half-life (T1/2) is about 2.5 hours. After oral administration, the total clearance of the S-stereoisomer of carvedilol was approximately 2 times greater than that of the R-stereoisomer.

Pharmacokinetics in special patient groups Patients with impaired renal function

With long-term therapy with carvedilol, the intensity of renal blood flow is maintained and glomerular filtration rate does not change.

In patients with arterial hypertension and impaired renal function the area under the curve “concentration-time” (AUC), T1/2 and Cmax do not change. Renal excretion of unchanged carvedilol decreases in patients with renal impairment, but changes in pharmacokinetic parameters are insignificant.

Carvedilol is effective for treatment of patients with renovascular hypertension, including patients with chronic renal failure, as well as patients on hemodialysis or undergoing kidney transplantation. Carvedilol causes gradual decrease of BP both on the day of hemodialysis and on days without hemodialysis, and its antihypertensive effect is comparable with that of patients with normal renal function.

Carvedilol is not excreted during hemodialysis because it does not pass through the dialysis membrane, probably due to its strong binding to plasma proteins. Patients with impaired liver function

In patients with cirrhosis, the systemic bioavailability of carvedilol increases by 80% due to reduced metabolism during “primary passage” through the liver. Therefore, carvedilol is contraindicated in patients with severe hepatic impairment (see section “Contraindications”).

Patients with Chronic Heart Failure (CHF)

The clearance of the R- and S-stereoisomer of carvedilol was significantly lower in patients with CHF compared with previously observed clearance in healthy volunteers. These results suggest that the pharmacokinetics of the R- and S-stereoisomers of carvedilol are significantly altered in heart failure.

Elderly and elderly patients

Age has no statistically significant effect on the pharmacokinetics of Carvedilol in patients with arterial hypertension. According to data from clinical studies, tolerability of carvedilol in patients with arterial hypertension or coronary heart disease of elderly and senile patients does not differ from that in younger patients.

Children

Data on the pharmacokinetics of carvedilol in patients less than 18 years of age are currently limited.

Patients with Diabetes Mellitus

In patients with type 2 diabetes mellitus and arterial hypertension, carvedilol has no effect on fasting or post-meal blood glucose concentrations, glycosylated hemoglobin levels (HbA1), or oral hypoglycemic agents doses. In some clinical trials, it has been shown that in patients with type 2 diabetes mellitus, carvedilol does not cause a decrease in glucose tolerance. In patients with arterial hypertension with insulin resistance (syndrome X), but without concomitant diabetes mellitus, carvedilol improves insulin sensitivity. Similar results were obtained in patients with arterial hypertension and type 2 diabetes.

Indications

– Arterial hypertension (in monotherapy or in combination with other antihypertensive drugs, for example, blockers of “slow” calcium channels or diuretics).

– Coronary heart disease (including in patients with unstable angina and silent myocardial ischemia).

– Chronic heart failure. Treatment of stable and symptomatic mild, moderate and severe chronic heart failure (II-IV functional class according to the NYHA classification) of ischemic or non-ischemic origin in combination with angiotensin-converting enzyme (ACE) inhibitors and diuretics, with or without cardiac glycosides (standard therapy), in the absence of contraindications.

Pharmacological effect

Pharmacotherapeutic group: Alpha and beta blocker

ATX code: C07AG02

Pharmacological properties

Pharmacodynamics

Carvedilol is a blocker of α-, β1- and β2-adrenergic receptors, has a vasodilating, antianginal and antiarrhythmic effect. Carvedilol is a racemic mixture of R(+)- and S(-)-stereoisomers, each of which has the same α-adrenergic blocking and antioxidant properties. The β-adrenergic blocking effect of carvedilol is non-selective and is due to the levorotatory S(-)-stereoisomer.

Carvedilol does not have its own sympathomimetic activity and has membrane-stabilizing properties. The vasodilating effect is associated mainly with the blockade of α1-adrenergic receptors. Thanks to vasodilation, total peripheral vascular resistance (TPVR) decreases.

By blocking β-adrenergic receptors, it reduces the activity of the renin-angiotensin-aldosterone system (RAAS), reducing the release of renin, so fluid retention, characteristic of selective α-blockers, rarely occurs.

Carvedilol does not have a pronounced effect on the lipid profile, maintaining a normal ratio of high and low density lipoproteins (HDL/LDL).

Efficiency

Arterial hypertension

In patients with arterial hypertension, carvedilol reduces blood pressure (BP) due to the combined blockade of β- and α1-adrenergic receptors. The decrease in blood pressure is not accompanied by a simultaneous increase in total peripheral vascular resistance, which is observed when taking non-selective beta-blockers. The heart rate (HR) decreases slightly. Renal blood flow and renal function are preserved in patients with hypertension. It has been shown that carvedilol does not change stroke volume and reduces peripheral vascular resistance; does not interfere with the blood supply to organs and peripheral blood flow, including in skeletal muscles, forearms, lower extremities, skin, brain and carotid artery. Coldness of the extremities and increased fatigue during physical activity are rare. The antihypertensive effect of carvedilol in arterial hypertension persists for a long time.

Renal dysfunction

Carvedilol is an effective treatment for patients with renovascular hypertension, including patients with chronic renal failure, as well as in patients on hemodialysis or who have undergone a kidney transplant. Carvedilol causes a gradual decrease in blood pressure both on the day of dialysis and on non-dialysis days, and its antihypertensive effect is comparable to that in patients with normal renal function.

Based on the results obtained in comparative studies in patients on hemodialysis, it was concluded that carvedilol is more effective and has better tolerability compared to slow calcium channel blockers (SCBs).

Carvedilol reduces morbidity and mortality among patients with cardiomyopathy on dialysis. A meta-analysis of placebo-controlled trials including a large number of patients (>4000) with chronic kidney disease confirmed that treatment with carvedilol in patients with left ventricular dysfunction with or without symptomatic heart failure reduces mortality and heart failure-related events.

Coronary heart disease

In patients with coronary heart disease, carvedilol has anti-ischemic and antianginal effects (increasing the total duration of physical activity, the time until the development of ST segment depression with a depth of 1 mm and the time until the onset of an angina attack), which persists with long-term therapy. Carvedilol significantly reduces myocardial oxygen demand and the activity of the sympathoadrenal system. It also reduces preload (pulmonary artery wedge pressure and pulmonary capillary pressure) and afterload (OPSS).

Chronic heart failure

Carvedilol reduces mortality and hospitalization, reduces symptoms and improves left ventricular function in patients with chronic heart failure of ischemic and non-ischemic origin. The effects of carvedilol are dose-dependent.

Pharmacokinetics

Suction

After oral administration, carvedilol is rapidly absorbed from the gastrointestinal tract. Carvedilol is a substrate of the P glycoprotein (Pgp) transport protein, which acts as a pump in the intestinal lumen. Glycoprotein P plays a major role in the bioavailability of certain drugs. The maximum concentration in blood plasma (Cmax) is achieved approximately 1 hour after oral administration. When taken orally, carvedilol undergoes first-pass metabolism, as a result of which its absolute bioavailability in healthy male volunteers is about 25-30% for the R-form and 15% for the S-form. The maximum concentration of the R-stereoisomer in blood plasma is approximately 2 times higher than that for the S-stereoisomer. Food intake does not affect bioavailability.

Distribution

Carvedilol is highly lipophilic. About 98-99% of carvedilol is bound to plasma proteins. Its volume of distribution is approximately 2 l/kg.

Metabolism

Carvedilol undergoes biotransformation in the liver through oxidation and conjugation to form a number of metabolites. 60-75% of absorbed carvedilol is metabolized during the first pass through the liver. The existence of enterohepatic circulation of the starting substance has been demonstrated.

The metabolism of carvedilol by oxidation is stereoselective. The R-stereoisomer is metabolized mainly by the CYP2D6 and CYP1A2 isoenzymes, and the S-stereoisomer is metabolized mainly by the CYP2D9 isoenzyme and, to a lesser extent, by the CYP2D6 isoenzyme. Other cytochrome P450 isoenzymes involved in the metabolism of carvedilol include CYP3A4, CYP2E1 and CYP2C19.

The R-stereoisomer is metabolized primarily by hydroxylation. In patients with low activity of the CYP2D6 isoenzyme, an increase in the plasma concentration of carvedilol, primarily the R-stereoisomer, is possible, which is reflected in an increase in the α-adrenergic blocking activity of carvedilol.

As a result of demethylation and hydroxylation of the phenolic ring, 3 metabolites are formed (their concentrations are 10 times lower than the concentration of the parent substance) with β-adrenergic blocking activity (for the 4′-hydroxyphenolic metabolite it is approximately 13 times stronger than that of carvedilol itself). The three active metabolites have less pronounced vasodilating properties than carvedilol. Two of the hydroxycarbazole metabolites of carvedilol are extremely potent antioxidants, with activity 30 to 80 times greater than that of carvedilol.

Removal

After a single oral dose of 50 mg, about 60% of carvedilol is secreted into the bile and excreted through the intestines within 11 days in the form of metabolites. About 16% is excreted by the kidneys in the form of carvedilol or its metabolites. Renal excretion of unchanged carvedilol is less than 2%. Plasma clearance of carvedilol reaches approximately 500-700 ml/min, the half-life (T1/2) is about 2.5 hours. After oral administration, the total clearance of the S-stereoisomer of carvedilol was approximately 2 times greater than the R-stereoisomer.

Pharmacokinetics in special groups of patients Patients with impaired renal function

With long-term therapy with carvedilol, the intensity of renal blood flow is maintained, and the glomerular filtration rate does not change.

In patients with arterial hypertension and impaired renal function, the area under the concentration-time curve (AUC), T1/2 and Cmax do not change. Renal excretion of unchanged carvedilol in patients with renal failure is reduced, but changes in pharmacokinetic parameters are insignificant.

Carvedilol is an effective treatment for patients with renovascular hypertension, including patients with chronic renal failure, as well as patients on hemodialysis or who have undergone a kidney transplant. Carvedilol causes a gradual decrease in blood pressure both on the day of hemodialysis and on days without hemodialysis, and its antihypertensive effect is comparable to that in patients with normal renal function.

During hemodialysis, carvedilol is not excreted because it does not pass through the dialysis membrane, probably due to the fact that it is strongly bound to plasma proteins. Patients with liver dysfunction

In patients with liver cirrhosis, the systemic bioavailability of carvedilol increases by 80% due to a decrease in the severity of first-pass metabolism through the liver. Therefore, carvedilol is contraindicated in patients with severe hepatic impairment (see section “Contraindications”).

Patients with chronic heart failure (CHF)

In patients with CHF, the clearance of R- and S-stereoisomers of carvedilol was significantly lower compared to previously observed clearance in healthy volunteers. These results indicate that the pharmacokinetics of the R- and S-stereoisomers of carvedilol are significantly altered in heart failure.

Elderly and senile patients

Age does not have a statistically significant effect on the pharmacokinetics of carvedilol in patients with arterial hypertension. According to clinical studies, the tolerability of carvedilol in elderly and senile patients with arterial hypertension or coronary heart disease does not differ from that in younger patients.

Children

Data on the pharmacokinetics of carvedilol in patients under 18 years of age are currently limited.

Patients with diabetes

In patients with type 2 diabetes mellitus and arterial hypertension, carvedilol does not affect fasting and postprandial blood glucose concentrations, glycosylated hemoglobin (HbA1) levels, or the dose of oral hypoglycemic agents. Some clinical studies have shown that carvedilol does not cause a decrease in glucose tolerance in patients with type 2 diabetes mellitus. In hypertensive patients with insulin resistance (syndrome X) but without concomitant diabetes mellitus, carvedilol improves insulin sensitivity. Similar results were obtained in patients with arterial hypertension and type 2 diabetes mellitus.

Special instructions

Chronic heart failure

In patients with chronic heart failure, during the period of drug dose selection, an increase in symptoms of chronic heart failure or fluid retention may be observed. If such symptoms occur, it is necessary to increase the dose of diuretics and not increase the dose of the drug until hemodynamic parameters stabilize. Sometimes it may be necessary to reduce the dose of the drug or, in rare cases, temporarily discontinue the drug. Such episodes do not prevent further correct selection of the dose of the drug. The drug is used with caution in combination with cardiac glycosides (excessive slowing of atrioventricular conduction is possible).

At the beginning of drug therapy or when the dose is increased in patients, especially the elderly, an excessive decrease in blood pressure may be observed, mainly when moving from the “lying” to the “standing” position. A dose adjustment of the drug is necessary. Kidney function in chronic heart failure

When prescribing the drug to patients with chronic heart failure and low blood pressure (systolic blood pressure less than 100 mm Hg), coronary heart disease and diffuse vascular changes and/or renal failure, a reversible deterioration in renal function was observed. The dose of the drug is selected depending on the functional state of the kidneys. It is recommended to monitor renal function in patients with chronic renal failure, arterial hypotension and chronic heart failure.

COPD

In patients with COPD, including bronchospastic syndrome, who are not receiving oral or inhaled antiasthmatic drugs, carvedilol is prescribed only if the possible benefits of its use outweigh the potential risks. If there is an initial predisposition to bronchospastic syndrome, shortness of breath may develop when taking the drug as a result of increased airway resistance. At the beginning of treatment and as the dose of the drug increases, these patients should be carefully monitored, reducing the dose of the drug when initial signs of bronchospasm appear.

Diabetes mellitus

The drug is prescribed with caution to patients with diabetes mellitus, as it may mask or weaken the symptoms of hypoglycemia (especially tachycardia). In patients with chronic heart failure and diabetes mellitus, the use of the drug may be accompanied by disturbances in glycemic control. However, numerous studies have shown that β-blockers with vasodilating properties (such as carvedilol) have a more beneficial effect on glucose concentrations and lipid profiles.

Carvedilol has a modest positive effect on insulin sensitivity and may also improve some symptoms of metabolic syndrome.

Peripheral vascular diseases

Caution is necessary when prescribing the drug to patients with peripheral vascular diseases, including Raynaud’s syndrome, since β-blockers may increase the symptoms of arterial insufficiency.

Thyrotoxicosis

Like other β-blockers, carvedilol may reduce the severity of symptoms of thyrotoxicosis.

General anesthesia and major surgery

Caution is required in patients undergoing surgery under general anesthesia due to the potential for additive adverse effects of carvedilol and general anesthetic agents.

Bradycardia

Carvedilol may cause bradycardia. If the heart rate drops below 55 beats/min, the dose of the drug should be reduced.

Increased sensitivity

Caution should be exercised when prescribing the drug to patients with a history of severe hypersensitivity reactions or undergoing desensitization, since β-blockers may increase sensitivity to allergens and the severity of anaphylactic reactions.

Severe skin reactions

In rare cases, carvedilol can cause the development of serious skin reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome (see section “Side effects”, subsection “Post-marketing observations”). If severe skin reactions develop, the drug should be completely stopped.

Psoriasis

In patients with anamnestic indications of the onset or exacerbation of psoriasis when using β-blockers, carvedilol can be prescribed only after a thorough analysis of the possible benefits and risks.

Interaction with other drugs

There are a number of important pharmacokinetic and pharmacodynamic interactions with other drugs (including digoxin, cyclosporine, rifampicin, antiarrhythmic drugs and general anesthesia drugs) (see section

“Interaction with other drugs”, subsection “Pharmacokinetic interaction”).

Simultaneous use of BMCC

In patients simultaneously taking BMCCs such as verapamil or diltiazem, as well as other antiarrhythmic drugs, it is necessary to regularly monitor ECG and blood pressure.

As with other drugs with beta-blocking properties, the use of carvedilol together with NBMCAs such as verapamil or diltiazem, amiodarone or other antiarrhythmic drugs is recommended under ECG and blood pressure monitoring. Pheochromocytoma

Patients with pheochromocytoma should be given an α-blocker before starting any β-blocker. Although carvedilol has both β- and α-blocking properties, there is no experience with its use in these patients and should be used with caution in patients with suspected pheochromocytoma.

Prinzmetal’s angina

Non-selective beta-blockers may cause pain in patients with Prinzmetal’s angina. There is no experience in prescribing carvedilol to these patients. Although its α-adrenergic blocking properties may prevent such symptoms, carvedilol should be used with caution in such cases.

Contact lenses

Patients who wear contact lenses should be aware of the possibility of reducing the amount of tear fluid.

Withdrawal syndrome

Treatment with carvedilol is long-term. It should not be stopped abruptly; it is necessary to gradually reduce the dose of the drug at intervals of 1-2 weeks. This is especially important in patients with coronary heart disease.

If it is necessary to perform surgery using general anesthesia, it is necessary to warn the anesthesiologist about previous therapy with carvedilol.

During the treatment period, alcohol consumption is excluded.

Handling of unused and expired medicines The release of medicines into the environment should be kept to a minimum. Disposal of the drug through wastewater or household waste is not allowed. Where possible, special systems should be used to dispose of medications.

Impact on the ability to drive vehicles and machinery Care must be taken when driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions, due to the possibility of developing dizziness.

Active ingredient

Carvedilol

Composition

For one tablet:

Pregnancy

Animal studies have shown reproductive toxicity. The potential risk to humans is unknown.

β-blockers reduce placental blood flow, which can lead to intrauterine fetal death and premature birth. In addition, the fetus and newborn may experience adverse reactions, in particular hypoglycemia and bradycardia, complications from the heart and lungs.

There is no sufficient experience with the use of carvedilol in pregnant women. The drug is contraindicated during pregnancy unless absolutely necessary and the potential benefit to the mother outweighs the risk to the fetus.

Carvedilol and its metabolites pass into breast milk, therefore, if taking the drug is necessary during lactation, breastfeeding should be discontinued.

Contraindications

– hypersensitivity to carvedilol or any component of the drug;

– acute and chronic heart failure in the stage of decompensation, requiring intravenous administration of inotropic agents;

– severe liver failure;

– atrioventricular block II and III degrees (except for patients with a pacemaker);

– severe bradycardia (heart rate less than 50 beats/min);

– sick sinus syndrome (including sinoauricular block);

– severe arterial hypotension (systolic blood pressure less than 85 mm Hg);

– cardiogenic shock;

– anamnestic indications of bronchospasm and bronchial asthma;

– pheochromocytoma (without simultaneous use of α-blockers);

– lactose intolerance, lactase deficiency, glucose-galactose malabsorption;

– severe obliterating diseases of peripheral vessels (intermittent claudication, Raynaud’s syndrome);

– period of breastfeeding;

– age under 18 years (efficacy and safety have not been established).

With caution

The drug is used with caution in patients with a burdened allergic history, chronic obstructive pulmonary disease (COPD), depression, myasthenia gravis, hypoglycemia, first degree atrioventricular block, thyrotoxicosis, during extensive surgical interventions and general anesthesia, Prinzmetal angina, diabetes mellitus, obliterating diseases of peripheral vessels of mild or moderate severity, if there is a suspicion of pheochromocytoma, renal failure, psoriasis.

Side Effects

According to the World Health Organization (WHO), adverse reactions (ARs) are classified according to their frequency as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (< 1/10000); frequency unknown - based on available data, it was not possible to determine the frequency of occurrence.

The incidence of some undesirable effects, such as dizziness, hypotension, bradycardia and visual disturbances, is proportional to the dose size. These undesirable effects develop more often in patients with CHF. If serious undesirable effects develop, treatment with the drug should be discontinued.

Infectious and parasitic diseases: often – pneumonia, bronchitis, upper respiratory tract infections, urinary tract infections.

Disorders of the blood and lymphatic system: often – anemia; rarely – thrombocytopenia; very rarely – leukopenia.

Immune system disorders: very rarely – hypersensitivity reactions (allergic reactions).

Endocrine system disorders: often – in patients with existing diabetes mellitus – hyperglycemia or hypoglycemia, impaired glycemic control.

The presence of β-adrenergic blocking properties of the drug does not exclude the possibility of manifestation of latent diabetes mellitus, decompensation of existing diabetes mellitus, or inhibition of the contrainsular system.

Metabolic and nutritional disorders: often – weight gain, hypercholesterolemia.

Mental disorders: often – depression, depressed mood; infrequently – sleep disturbances. Nervous system disorders: often – dizziness, headache (usually mild and occurring more often at the beginning of treatment), asthenia (including increased fatigue); rarely – paresthesia, loss of consciousness.

Visual disturbances: often – blurred vision, eye irritation, decreased tear production (pay attention when using contact lenses).

Heart disorders: very often – heart failure; often – bradycardia, hypervolemia, fluid retention; infrequently – atrioventricular block, angina pectoris.

Vascular disorders: very often – marked decrease in blood pressure; often – orthostatic hypotension, impaired peripheral circulation (cold extremities, peripheral vascular disease, exacerbation of the syndrome

“intermittent” claudication and Raynaud’s syndrome), increased blood pressure. Disorders of the respiratory system, chest and mediastinal organs: often – shortness of breath, pulmonary edema, bronchospasm in predisposed patients; rarely – nasal congestion; very rarely – sneezing.

Gastrointestinal disorders: often – nausea, diarrhea, vomiting, dyspeptic disorders, abdominal pain; infrequently – constipation; rarely – dryness of the oral mucosa.

Disorders of the skin and subcutaneous tissues: uncommon – skin reactions (including skin rash, dermatitis, urticaria, itching, skin lesions such as psoriasis and lichen planus); very rarely – exacerbation of psoriasis, alopecia.

Musculoskeletal and connective tissue disorders: often – pain in the extremities; rarely – myasthenia gravis, pain in the spine.

Renal and urinary tract disorders: often – renal failure and impaired renal function in patients with diffuse vasculitis and/or impaired renal function; rarely – urinary disorders.

Disorders of the genital organs and mammary gland: infrequently – decreased potency. General disorders and disorders at the injection site: very often – asthenia (general weakness); often – swelling, pain; very rarely – “flushes” of blood to the skin of the face, flu-like syndrome.

Laboratory and instrumental data: very rarely – increased activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gammaglobulin transferase.

Description of individual HP

The incidence of HP is not dose-dependent, with the exception of dizziness, visual disturbances and bradycardia. Dizziness, syncope, headache and asthenia are usually mild and occur more often at the beginning of treatment. In patients with chronic heart failure, during the period of increasing the dose, aggravation of symptoms of heart failure and fluid retention are possible (see section “Special Instructions”).

Heart failure was a very common HP in both patients receiving carvedilol (15.4%) and placebo (14.5%).

During carvedilol therapy, a reversible deterioration in renal function was observed in patients with chronic heart failure and low blood pressure, coronary heart disease and diffuse vascular changes and/or renal failure (see section “Special Instructions”).

Post-marketing observations

Disorders of the skin and subcutaneous tissues: possible development of alopecia; serious skin adverse reactions (toxic epidermal necrolysis, Stevens-Johnson syndrome).

Renal and urinary tract disorders: rare cases of urinary incontinence in women have been reported, reversible after discontinuation of the drug.

Interaction

Pharmacokinetic interaction

Effect of carvedilol on the pharmacokinetics of other drugs

Since carvedilol is both a substrate and an inhibitor of Pgp, the bioavailability of the latter may be increased when administered concomitantly with drugs transported by Pgp. In addition, the bioavailability of carvedilol may be altered by Pgp inducers or inhibitors.

Digoxin

In studies in healthy volunteers and patients with heart failure, there was a 20% increase in digoxin exposure. However, a more pronounced effect was observed in men. Thus, it is recommended to monitor digoxin concentrations at the time of initiation of therapy, dose selection and discontinuation of carvedilol therapy (see section “Special Instructions”). However, carvedilol does not affect the pharmacokinetics of intravenously administered digoxin.

Cyclosporine

In two studies, increased plasma concentrations of cyclosporine were observed when carvedilol was administered to kidney and heart transplant patients receiving oral cyclosporine. It turned out that carvedilol increases the exposure of cyclosporine in the blood plasma when taken orally by an average of 10-20%. To maintain cyclosporine plasma concentrations within the therapeutic range, a cyclosporine dose reduction of an average of 10-20% was required. The mechanism of this interaction is unknown, but inhibition of Pgp activity in the intestine by carvedilol cannot be ruled out. Due to pronounced individual fluctuations in the concentration of cyclosporine in the blood plasma, careful monitoring of its concentration is recommended after starting carvedilol therapy and, if necessary, appropriate adjustment of the daily dose of cyclosporine. In the case of intravenous administration of cyclosporine, no interaction with carvedilol is expected.

Effect of other drugs on the pharmacokinetics of carvedilol

Inhibitors and inducers of the CYP2D6 and CYP2C9 isoenzymes can stereoselectively alter the systemic and/or presystemic metabolism of carvedilol, leading to an increase or decrease in the concentrations of R- and S-stereoisomers of carvedilol in blood plasma. Some examples of such interactions observed in patients or healthy volunteers are listed below, but this list is not complete.

Rifampicin

In a study of 12 healthy volunteers, concomitant administration of rifampicin reduced carvedilol exposure to approximately 60% and a decreased effect of carvedilol on systolic blood pressure was observed. The mechanism of this interaction is unknown, but most likely it is due to the induction of Pgp by rifampicin in the intestine. Close monitoring of β-blocking activity is recommended in patients receiving carvedilol in combination with rifampicin.

Amiodarone

In vitro studies with human liver microsomes showed that amiodarone and desethylamiodarone inhibited the oxidation of the R- and S-stereoisomer of carvedilol. Compared with patients receiving carvedilol monotherapy, in patients with heart failure receiving carvedilol concomitantly with amiodarone, the concentrations of the R- and S-stereoisomers of carvedilol immediately before taking the next dose increased by 2.2 times. The effect of the S-stereoisomer of carvedilol is due to desethylamiodarone, a metabolite of amiodarone, which is a potent inhibitor of the CYP2C9 isoenzyme. It is recommended to monitor beta-blocking activity in patients receiving carvedilol concomitantly with amiodarone.

Fluoxetine and paroxetine

In a randomized, crossover design study in 10 patients with heart failure, coadministration of fluoxetine (a CYP2D6 inhibitor) resulted in stereoselective inhibition of carvedilol metabolism, resulting in a 77% increase in mean AUC for R(+) and a non-statistical increase in mean AUC for S(-) of 35% compared with patients receiving placebo. However, there were no differences in side effects, blood pressure, or heart rate between the two groups. The effect of a single oral dose of paroxetine (a potent inhibitor of the CYP2D6 isoenzyme) on the pharmacokinetics of carvedilol was studied in 12 healthy volunteers. Despite the significant reduction in exposure to R- and S-stereoisomers of carvedilol, it was not clinically significant.

Pharmacodynamic interaction

Insulin or oral hypoglycemic agents

Drugs with β-adrenergic blocking properties may enhance the hypoglycemic effect of insulin or oral hypoglycemic agents. Symptoms of hypoglycemia, especially tachycardia, may be masked or weakened. For patients receiving insulin or oral hypoglycemic agents, regular monitoring of blood glucose concentrations is recommended.

Drugs that reduce catecholamine levels

Patients taking drugs with beta-blocking properties and drugs that reduce the concentration of catecholamines (for example, reserpine and monoamine oxidase inhibitors) simultaneously should be carefully monitored due to the risk of developing arterial hypotension and/or severe bradycardia.

Digoxin

Combination therapy with drugs with β-adrenergic blocking properties and digoxin may lead to additional slowing of atrioventricular conduction.

Non-dihydropyridine BMCCs (NBMCs), amiodarone or other antiarrhythmic drugs Concomitant use with carvedilol may increase the risk of atrioventricular conduction disturbances. With the simultaneous use of carvedilol and diltiazem, isolated cases of conduction disturbances were observed (rarely with disturbances in hemodynamic parameters). As with other drugs with beta-blocking properties, the use of carvedilol concomitantly with NBMCBs such as verapamil or diltiazem, amiodarone or other antiarrhythmic drugs is recommended under electrocardiogram (ECG) and blood pressure monitoring.

Clonidine

Concomitant use of clonidine with drugs with β-adrenergic blocking properties may potentiate the antihypertensive and bradycardic effect. If it is planned to discontinue combination therapy with a drug with β-blocking properties and clonidine, the β-blocker should be discontinued first, and after a few days clonidine can be discontinued, gradually reducing its dose.

Antihypertensive drugs

Like other drugs with β-blocking activity, carvedilol may potentiate the effects of other concomitantly administered antihypertensive drugs (eg, α-blockers) or drugs that cause hypotension as an adverse reaction.

General anesthesia products

Vital signs should be closely monitored during general anesthesia due to the possibility of a synergistic negative inotropic effect between carvedilol and general anesthesia agents.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Concomitant use of NSAIDs and beta-blockers may lead to increased blood pressure and decreased blood pressure control.

Bronchodilators (beta-adrenergic agonists)

Because non-cardioselective beta-blockers interfere with the bronchodilator effect of bronchodilators that are beta-adrenergic stimulants, careful monitoring of patients receiving these drugs is necessary.

Overdose

Symptoms: marked decrease in blood pressure, bradycardia, heart failure, cardiogenic shock, cardiac arrest; Possible respiratory disturbances, bronchospasm, vomiting, confusion and generalized convulsions.

Patients should be monitored for the occurrence of these symptoms and signs and managed according to generally accepted therapy for beta-blocker overdose (eg, atropine, phosphodiesterase inhibitors such as beta-sympathomimetics) and as determined by the prescribing physician.

Since in case of severe overdose with symptoms of shock, the half-life of carvedilol may be prolonged and carvedilol may be removed from the depot, it is necessary to continue maintenance therapy for a sufficiently long time. The duration of maintenance/detoxification therapy depends on the severity of the overdose and should be continued until the patient’s clinical condition has stabilized.

Hemodialysis is not effective.

For severe bradycardia, atropine 0.5-2 mg is used intravenously. To maintain cardiovascular activity, it is possible to use glucagon 1-10 mg intravenously in a bolus, then 2-5 mg per hour as a long-term infusion. For treatment-resistant bradycardia, installation of a temporary pacemaker is indicated. For bronchospasm, beta-agonists are used in the form of an aerosol (if ineffective – intravenously) or aminophylline intravenously. For seizures, slow intravenous administration of diazepam is recommended.

Storage conditions

In a place protected from light at a temperature not exceeding 25 ° C. Keep out of the reach of children.

Shelf life

3 years.

Do not use after expiration date.

Manufacturer

Velfarm LLC, Russia