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 hypotensive agents, such as “slow” calcium channel blockers or diuretics).

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

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

Active ingredient

How to take, the dosage

Ingestion with plenty of fluid.

Hypertension

The recommended starting dose is 12.5 mg once daily for the first 2 days of therapy, then 25 mg once daily. If necessary, the dose may be further increased at intervals of at least 2 weeks, up to a maximum recommended dose of 50 mg once daily (or divided into 2 doses).

Ischemic Heart Disease

The recommended starting dose is 12.5 mg twice daily for the first 2 days, then 25 mg twice daily. If subsequently inadequate, the dose may be increased at intervals of at least 2 weeks, up to a maximum daily dose of 100 mg divided into 2 doses.

Chronic heart failure

The dose is adjusted individually, and close monitoring by a physician is necessary. In patients receiving cardiac glycosides, diuretics, and ACE inhibitors, their doses should be adjusted before treatment with carvedilol.

The recommended starting dose is 3.125 mg (1/2 tablet of 6.25 mg) 2 times daily for 2 weeks. If tolerated well, the dose is increased at intervals of at least 2 weeks to 6.25 mg twice a day, then to 12.5 mg twice a day, then to 25 mg twice a day. The dose should be increased to the maximum dose that is well tolerated by the patient. The recommended maximum dose is 25 mg 2 times daily for all patients with severe chronic heart failure and for patients with mild to moderate chronic heart failure with a patient body weight less than 85 kg. In patients with mild to moderate chronic heart failure and a body weight greater than 85 kg, the recommended maximum dose is 50 mg twice daily.

Before each dose increase, a physician should be seen to detect a possible increase in symptoms of chronic heart failure or vasodilation. If there is a transient increase in symptoms of chronic heart failure or fluid retention, the dose of diuretics should be increased, although sometimes the dose of carvedilol must be reduced or temporarily withdrawn.

The symptoms of vasodilation can be resolved by reducing the dose of diuretics. If symptoms persist, the dose of ACE inhibitor (if the patient is taking it) may be reduced and then, if necessary, the dose of carvedilol may be reduced. In such a situation, the dose of carvedilol should not be increased until symptoms of worsening chronic heart failure or arterial hypotension have improved.

If treatment with the drug is interrupted for more than 1 week, it should be resumed at a lower dose and then increased according to the recommendations above.

If treatment with the drug is interrupted for more than 2 weeks, it should be restarted at a dose of 3.125 mg (1/2 tablet of 6.25 mg) twice daily, then the dose should be adjusted according to the above recommendations.

Dosing in Special Patient Groups

Disorders of Renal Function

Current pharmacokinetic data in patients with varying degrees of renal impairment (including renal failure) suggest that patients with moderate to severe renal impairment do not require dosage adjustment (see The section “Pharmacokinetics”, subsection “Pharmacokinetics in Special Patient Groups”).

Hepatic impairment

Carvedilol is contraindicated in patients with clinical manifestations of hepatic impairment (see section “Contraindications”).

Children

The safety and effectiveness of Carvedilol in children and adolescents (<18 years) have not been established (see section “Pharmacokinetics”, subsection “Pharmacokinetics in special patient groups”).

Elderly patients

There is no data on the need for dose adjustment.

Interaction

Pharmacokinetic interaction

The effect of carvedilol on the pharmacokinetics of other drugs

As carvedilol is both a substrate and a Pgp inhibitor, its bioavailability with Pgp-transported drugs may be increased when taken simultaneously. 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, a 20% increase in digoxin exposure was observed. A more pronounced effect was observed in men. Thus, it is recommended to monitor digoxin concentrations at the start of therapy, dose adjustment and withdrawal of therapy with carvedilol (see section “Cautions”). However, carvedilol has no effect on the pharmacokinetics of intravenous digoxin.

Cyclosporine

In two studies, increased plasma concentrations of cyclosporine were observed with carvedilol in kidney and heart transplant patients who received oral cyclosporine. Carvedilolol was found to increase the plasma exposure of cyclosporine by an average of 10-20% when administered orally. In order to maintain cyclosporine plasma concentrations in the therapeutic range, it was necessary to reduce the dose of cyclosporine by an average of 10-20%. The mechanism of this interaction is unknown, but inhibition of intestinal Pgp activity by carvedilol cannot be excluded. Due to the pronounced individual fluctuations of cyclosporine plasma concentrations, it is recommended to monitor carefully its concentration after the start of therapy with carvedilol and, if necessary, to adjust the daily dose of cyclosporine accordingly. In case of intravenous administration of cyclosporine, no interaction with carvedilol is expected.

The effects of other drugs on the pharmacokinetics of carvedilol

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

Rifampicin

In a study involving 12 healthy volunteers, concomitant administration of rifampicin reduced carvedilol exposure by approximately 60% and had the effect of reducing the effect of carvedilol on systolic BP. The mechanism of this interaction is unknown, but is likely due to the induction of Pgp by rifampicin in the gut. Close monitoring of β-adrenoblocking activity in patients receiving carvedilol in combination with rifampicin is recommended.

Amiodarone

In vitro studies with human liver microsomes have shown that amiodarone and desethylamiodarone inhibited oxidation of the R- and S-stereoisomer of carvedilol. Compared with patients receiving carvedilol monotherapy, patients with heart failure receiving carvedilol concomitantly with amiodarone had a 2.2-fold increase in the R- and S-stereoisomer concentration of carvedilol immediately before the next dose. 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 that β-adrenoblocking activity be monitored in patients receiving carvedilol concomitantly with amiodarone.

Fluoxetine and paroxetine

. In a randomized crossover study in 10 patients with heart failure, concomitant administration of fluoxetine (a CYP2D6 isoenzyme inhibitor) resulted in stereoselective inhibition of carvedilol metabolism-a 77% increase in mean AUC for R (+) and a 35% nonstatic increase in mean AUC for S (-) compared with the group of patients receiving placebo. However, no difference in adverse events, BP or HR was observed between the two groups. The effect of single oral paroxetine (a potent CYP2D6 isoenzyme inhibitor) on the pharmacokinetics of carvedilol was studied in 12 healthy volunteers. Although there was a significant decrease in exposure to the R- and S-stereoisomers of carvedilol, there was no clinical significance.

Pharmacodynamic interaction

Insulin or oral hypoglycemic agents

Drugs with β-adrenoblocking properties may increase the hypoglycemic effects of insulin or oral hypoglycemic agents. Symptoms of hypoglycemia, especially tachycardia, may be masked or weakened. Patients receiving insulin or oral hypoglycemic agents are recommended to have regular monitoring of blood glucose concentration.

Catecholamine-lowering drugs

. Patients taking concomitant agents with β-adrenoblocking properties and catecholamine-lowering agents (e.g., reserpine and monoamine oxidase inhibitors) should be closely monitored due to the risk of developing arterial hypotension and/or marked bradycardia.

Digoxin

Combined therapy of agents with β-adrenoblocking properties and digoxin may lead to additional slowing of atrioventricular conduction.

Non-dihydropyridine NSAIDs (NSAIDs), amiodarone or other antiarrhythmic agents Concurrent use of carvedilol may increase the risk of atrioventricular conduction disturbances. When concomitant use of carvedilol and diltiazem, some cases of conduction abnormalities (rarely with abnormal hemodynamic parameters) have been reported. As with other drugs with β-adrenoblocking properties, concomitant use of carvedilol with NSAIDs such as verapamil or diltiazem, amiodarone or other antiarrhythmic drugs is recommended under control of electrocardiogram (ECG) and BP.

Clonidine

The concomitant use of clonidine with drugs with β-adrenoblocking properties may potentiate antihypertensive and bradycardic effects. If combined therapy with a β-adreno-blocker and clonidine is planned to be discontinued, the β-adreno-blocker should be discontinued first, and clonidine may be discontinued a few days later, gradually reducing its dose.

Hypotensive agents

Like other drugs with β-adrenoblocking activity, carvedilol may increase the effect of other concomitantly taken hypotensive agents (e.g., α-adrenoblockers) or drugs that cause arterial hypotension as an adverse reaction.

General anesthesia agents

The basic vital signs of general anesthesia should be closely monitored during general anesthesia due to the possibility of synergistic negative inotropic effects of carvedilol and general anesthesia agents.

Non-steroidal anti-inflammatory drugs (NSAIDs)

The simultaneous use of NSAIDs and β-adrenoblockers may increase BP and decrease BP control.

Bronchodilators (β-adrenoreceptor agonists)

Because noncardioselective β-adrenoblockers interfere with the bronchodilator effect of β-adrenoreceptor stimulators, close monitoring of patients receiving these drugs is necessary.

Special Instructions

Chronic Heart Failure

In patients with chronic heart failure, an increase in symptoms of chronic heart failure or fluid retention may be noted during the drug dosage adjustment period. If these symptoms occur, the dose of diuretics should be increased and the drug dose should not be increased until hemodynamic parameters have stabilized. Sometimes it may be necessary to reduce the dose of the drug or, in rare cases, temporarily withdraw the drug. Such episodes do not prevent further correct dosing of the drug. The drug should be used with caution in combination with cardiac glycosides (excessive slowing of atrioventricular conduction is possible).

At the beginning of therapy with the drug or when increasing the dose, especially in elderly patients, an excessive decrease of blood pressure mainly during the transition from “lying” position to “standing” position may be noted. Correction of the drug dose is required. Renal function in chronic heart failure

When prescribing the drug in patients with chronic heart failure and low BP (systolic BP less than 100 mmHg), coronary heart disease and diffuse vascular changes and/or renal insufficiency reversible deterioration of renal function has been noted. The dose of the drug is adjusted depending on the functional state of the kidneys. It is recommended to monitor renal function in patients with chronic renal insufficiency, arterial hypotension and chronic heart failure.

Patients with COPD, including those with bronchospastic syndrome, who are not receiving oral or inhaled antiasthmatic agents, carvedilol is prescribed only if the possible benefits of its use exceed the potential risk. In the presence of initial predisposition to bronchospastic syndrome when taking the drug, dyspnea may develop as a result of increased airway resistance. These patients should be closely monitored at the start of administration and when increasing the dose of the drug, reducing the dose of the drug when the initial signs of bronchospasm appear.

Diabetes mellitus

The drug is prescribed with caution in patients with diabetes mellitus because it may mask or attenuate the symptoms of hypoglycemia (especially tachycardia). In patients with chronic heart failure and diabetes mellitus, use of the drug may be accompanied by impaired glycemic control. However, numerous studies have shown that β-adrenoblockers with vasodilator properties (such as carvedilol), have a more favorable effect on glucose concentration and lipid profile.

Carvedilol has a moderate beneficial effect on insulin sensitivity and may also alleviate some manifestations of metabolic syndrome.

Peripheral vascular disease

Caution is necessary when prescribing the drug in patients with peripheral vascular disease, including Raynaud’s syndrome, because the β-adrenoblockers may increase the symptoms of arterial insufficiency.

Thyrotoxicosis

Like other β-adrenoblockers, carvedilol may decrease the severity of thyrotoxicosis symptoms.

General anesthesia and major surgical procedures

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

Bradycardia

Carvedilol can cause bradycardia. If the HR is less than 55 bpm, the drug dose should be reduced.

Persons with a history of severe hypersensitivity reactions or who are undergoing desensitization should be cautious when prescribing the drug, because β-adrenoblockers may increase allergen sensitivity and the severity of anaphylactic reactions.

Serious skin reactions

In rare cases, carvedilol may cause serious skin reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome (see section “Adverse effects”, subsection “Postmarketing observations”). If severe skin reactions develop, the drug should be discontinued completely.

Patients with a history of psoriasis or exacerbation with β-adrenoblockers should only be prescribed Carvedilol after a thorough benefit-risk analysis.

Interactions 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

“Interaction with other medicinal products”, subsection “Pharmacokinetic interaction”).

Concomitant use of DMARDs

Patients taking concomitant use of verapamil or diltiazem-type DMARDs or other antiarrhythmic agents should have their ECG and BP monitored regularly.

As with other drugs with β-adrenoblocking properties, the use of carvedilol together with NSAIDs such as verapamil or diltiazem, amiodarone or other antiarrhythmic drugs is recommended under ECG and BP monitoring. Pheochromocytoma

Patients with pheochromocytoma should be prescribed an α-adrenoblocker before starting any β-adrenoblocker. Although carvedilol has both β- and α-adrenoblocking properties, there is no experience with its use in these patients, so it should be prescribed with caution in patients with suspected pheochromocytoma.

Prinzmetal angina

Nonselective β-adrenoblockers may cause pain in patients with Prinzmetal angina. There is no experience with prescribing carvedilol in these patients. Although its α-adrenoblocking properties may prevent these symptoms, caution should be exercised when prescribing carvedilol in these cases.

Contact lenses

Patients who use contact lenses should be aware of the possibility of decreased tear fluid.

The “withdrawal” syndrome

The treatment with carvedilol is long term. It should not be stopped abruptly; the dose of the drug should be gradually reduced at 1-2 week intervals. This is especially important in patients with coronary artery disease.

If it is necessary to perform a surgical intervention using general anesthesia, the anesthesiologist should be warned about the previous therapy with carvedilol.

The use of alcohol should be avoided during treatment.

The disposal of unused and expired medication should be kept to a minimum. Do not dispose of the medication with wastewater or with household waste. If possible, special systems should be used to dispose of medications.

Impact on the ability to drive vehicles and mechanisms Caution should be exercised when driving motor vehicles and engaging in potentially hazardous activities requiring increased concentration and speed of psychomotor reactions due to the possibility of developing dizziness.

Synopsis

Contraindications

– hypersensitivity to carvedilol or any component of the drug;

– acute and chronic decompensated heart failure requiring intravenous administration of inotropic agents;

– severe hepatic insufficiency;

– Stage II or III atrioventricular block (except for pacemaker patients);

– Severe bradycardia (heart rate less than 50 bpm);

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– sinus node weakness syndrome (including sinoauricular blockade);

– severe arterial hypotension (systolic BP less than 85 mm Hg. Hg.);

– cardiogenic shock;

– anamnestic evidence of bronchospasm and bronchial asthma;

– pheochromocytoma (without concomitant use of α-adrenoblockers);

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

– severe peripheral vascular obliterative disease (intermittent claudication, Raynaud’s syndrome);

– breastfeeding period;

– age less than 18 years (effectiveness and safety are not established).

With caution

. The drug is used with caution in patients with a history of allergy, chronic obstructive pulmonary disease (COPD), depression, myasthenia gravis, hypoglycemia, atrioventricular block of degree I, thyrotoxicosis, In major surgical interventions and general anesthesia, Prinzmetal angina, diabetes, peripheral vascular obliterating diseases of mild to moderate severity, with suspected pheochromocytoma, renal failure, psoriasis.

Side effects

According to the World Health Organization (WHO), adverse reactions (ARs) are classified according to their frequency of development as follows: Very common (≥1/10), common (≥1/100 to < 1/10), infrequent (≥1/1000 to < 1/100), rare (≥1/10000 to < 1/1000), very rare (< 1/10000); frequency unknown – the incidence could not be determined from available data.

The frequency of some adverse effects, such as dizziness, arterial hypotension, bradycardia, and visual disturbance, is proportional to dose size. These adverse effects occur more frequently 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 blood and lymphatic system: often – anemia; rarely – thrombocytopenia; very rarely – leukopenia.

Intrinsic system disorders: very rare – hypersensitivity reactions (allergic reactions).

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

The presence of β-adrenoblocking properties of the drug does not exclude the possibility of manifestation of latent diabetes mellitus, decompensation of existing diabetes mellitus or suppression of the counterinsulatory system.

Disorders of metabolism and nutrition: often – weight gain, hypercholesterolemia.

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

Visual disorders: often – visual disturbances, eye irritation, decreased tear production (pay attention if using contact lenses).

Cardiac disorders: very common – heart failure; common – bradycardia, hypervolemia, fluid retention; infrequent – atrioventricular block, angina pectoris.

Vascular disorders: very common – marked decrease of blood pressure; common – orthostatic hypotension, peripheral circulation disorders (cold extremities, peripheral vascular disease, worsening of

Intermittent claudication syndrome and Raynaud’s syndrome), increased arterial pressure. Respiratory, thoracic and mediastinal disorders: frequently – dyspnea, pulmonary edema, bronchospasm in susceptible patients; rarely – nasal congestion; very rarely – sneezing.

Gastrointestinal disorders: frequently – nausea, diarrhea, vomiting, dyspeptic disorders, abdominal pain; infrequently – constipation; rarely – dry mouth.

Skin and subcutaneous tissue disorders: infrequent skin reactions (including skin rash, dermatitis, urticaria, pruritus, skin lesions similar to psoriasis and alopecia); very rare – exacerbation of psoriasis, alopecia.

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

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

Gender and mammary gland disorders: infrequent – decreased potency. General disorders and disorders at the place of administration: very often – asthenia (general weakness); often – edema, pain syndrome; very rare – “rushes” 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 (ACT), and gamma globulin transferase.

Description of individual HP

The incidence of HP is not dose-dependent, except for phenomena of dizziness, visual disturbances, and bradycardia. Dizziness, syncope, headache and asthenia are usually mild and occur more frequently at the beginning of treatment. In patients with chronic heart failure during dose increase, worsening of heart failure symptoms and fluid retention are possible (see sect. Cautionary Note).

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

In therapy with carvedilol, reversible impairment of renal function has been observed in patients with chronic heart failure and low blood pressure, coronary heart disease and diffuse vascular changes and/or renal insufficiency (see section “Special Precautions”).

Postmarketing observations

Skin and subcutaneous tissue disorders: possible development of alopecia; serious skin adverse reactions (toxic epidermal necrolysis, Stevens-Johnson syndrome).

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

Overdose

Symptoms: marked BP decrease, bradycardia, heart failure, cardiogenic shock, cardiac arrest; respiratory disorders, bronchospasm, vomiting, confusion and generalized convulsions are possible.

Patients should be monitored for these signs and symptoms and these should be managed according to the accepted therapy for overdose with β-adrenoblockers (e.g., atropine, phosphodiesterase inhibitors such as β-sympathomimetics) and as determined by the treating physician.

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

Hemodialysis is not effective.

In case of marked bradycardia, atropine 0.5-2 mg intravenously is used. To maintain cardiovascular activity, glucagon may be used 1-10 mg intravenously by trickle, then 2-5 mg per hour as a prolonged infusion. In treatment-resistant bradycardia a temporary pacemaker is indicated. For bronchospasm, beta-adrenomimetics in aerosol form (intravenously if ineffective) or intravenous aminophylline are used. Slow intravenous administration of diazepam is recommended for seizures.

Pregnancy use

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

The β-adrenoblockers decrease placental blood flow, which can lead to intrauterine fetal death and premature birth. In addition, adverse reactions, such as hypoglycemia and bradycardia, heart and lung complications may occur in the fetus and the newborn.

There is no sufficient experience of using carvedilol in pregnant women. The drug is contraindicated during pregnancy, unless absolutely necessary, if the potential benefit to the mother exceeds the risk to the fetus.

Carvedilol and its metabolites penetrate into breast milk, so breastfeeding should be stopped if the drug is needed during lactation.

Similarities