Vedicardol^® (Tablets) Instructions for Use

Marketing Authorization Holder

Sintez PJSC (Russia)

ATC Code

C07AG02 (Carvedilol)

Active Substance

Carvedilol

Dosage Forms

	Vedicardol®	Tablets 6.25 mg: 30 pcs.
		Tablets 12.5 mg: 30 pcs.
		Tablets 25 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, flat-cylindrical, with a bevel, marbling is allowed.

Excipients: microcrystalline cellulose – 44 mg, calcium stearate – 1 mg, crospovidone – 2 mg, talc – 3 mg, lactose monohydrate – up to 100 mg.

10 pcs. – blister packs (3) – cardboard packs.

Tablets white or almost white, flat-cylindrical, with a bevel, marbling is allowed.

Excipients: microcrystalline cellulose – 66 mg, calcium stearate – 1.5 mg, crospovidone – 3 mg, talc – 4.5 mg, lactose monohydrate – up to 150 mg.

10 pcs. – blister packs (3) – cardboard packs.

Tablets white or almost white, flat-cylindrical, with a bevel, marbling is allowed.

Excipients: microcrystalline cellulose – 88 mg, calcium stearate – 2 mg, crospovidone – 4 mg, talc – 6 mg, lactose monohydrate – up to 200 mg.

10 pcs. – blister packs (3) – cardboard packs.

Clinical-Pharmacological Group

Beta₁-, beta₂-adrenoblocker. Alpha₁-adrenoblocker

Pharmacotherapeutic Group

Alpha- and beta-adrenergic blocker

Pharmacological Action

Alpha- and beta-adrenoblocker.

It blocks α₁-, β₁-, and β₂-adrenoreceptors, has vasodilating, antianginal, and antiarrhythmic effects. Carvedilol is a racemic mixture of R(+) and S(-)-stereoisomers, each of which has the same alpha-adrenoblocking properties. The beta-adrenoblocking action of carvedilol is non-selective and is due to the levorotatory S(-)-stereoisomer. The vasodilating effect is mainly associated with the blockade of α₁-adrenoreceptors. Due to vasodilation, it reduces total peripheral vascular resistance. It has no intrinsic sympathomimetic activity and has membrane-stabilizing properties.

The combination of vasodilation and beta-adrenoreceptor blockade leads to the following effects: in patients with arterial hypertension and kidney diseases, Carvedilol reduces renal vascular resistance, without significant changes in glomerular filtration rate, renal plasma flow, or electrolyte excretion. Peripheral blood flow is preserved, so cold hands and feet, often noted when taking beta-adrenoblockers, rarely develops.

The drug slightly reduces heart rate. In patients with coronary artery disease, it has an antianginal effect. It reduces pre- and afterload on the heart. It does not have a significant effect on lipid metabolism and the content of potassium, sodium, and magnesium ions in blood plasma.

In patients with left ventricular dysfunction and/or heart failure, it has a favorable effect on hemodynamic parameters and improves ejection fraction and left ventricular dimensions.

Carvedilol reduces mortality and decreases the frequency of hospitalizations, 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

Absorption

After oral administration, it is rapidly and almost completely absorbed in the gastrointestinal tract. C_max in blood is reached in 1-1.5 hours and is 5-99 µg/ml. Absolute bioavailability is 25-35% (for the S(-)-stereoisomer – 15%, for the R(+)-stereoisomer – 31%).

Distribution

Binding to plasma proteins – 98-99% (mainly due to the R(+)-stereoisomer bound to albumin). V_d – about 2 L/kg.

Metabolism

It is metabolized in the liver (has a first-pass effect through the liver).

Metabolic reactions occur with the participation of cytochrome P450 isoforms: CYP2D6, CYP2C9, CYP3A4, CYP2C19, CYP1A2, CYP2E1. Three active metabolites are formed during demethylation and hydroxylation, which have a pronounced beta-adrenoblocking effect. The main metabolite is 4′-hydroxyphenyl-Carvedilol, which is 13 times more potent than Carvedilol in beta-adrenoblocking activity, while its concentration in blood plasma is 10% of the concentration of carvedilol.

Elimination

T_1/2 of carvedilol – 6-10 hours. Plasma clearance – about 500-700 ml/min. It is excreted mainly through the intestines with bile, no more than 2% is excreted by the kidneys. It crosses the placental barrier and is excreted in breast milk.

Pharmacokinetics in special patient groups

Patients with impaired renal function

During long-term therapy with carvedilol, the intensity of renal blood flow is preserved, and the glomerular filtration rate does not change. In patients with arterial hypertension and impaired renal function, AUC, T_1/2, and plasma C_max do not change. Renal excretion of the unchanged drug in patients with renal failure decreases, but changes in pharmacokinetic parameters are insignificant.

Carvedilol is an effective treatment for patients with renovascular arterial hypertension, including patients with chronic renal failure, as well as patients on hemodialysis or after kidney transplantation. Carvedilol causes a gradual decrease in blood pressure both on the day of dialysis and on days without dialysis, and its hypotensive effect is comparable to that in patients with normal renal function. During dialysis, Carvedilol is not removed 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 impaired liver function, bioavailability increases to 80% due to reduced first-pass metabolism through the liver. Therefore, Carvedilol is contraindicated in patients with clinically manifest liver dysfunction.

Elderly and senile patients

Age does not significantly affect the pharmacokinetics of carvedilol in patients with arterial hypertension. The tolerability of carvedilol in elderly or senile patients with arterial hypertension or coronary artery disease does not differ from that in younger patients.

Patients with diabetes mellitus

In patients with type 2 diabetes mellitus and arterial hypertension, Carvedilol does not affect fasting and postprandial blood glucose levels, glycated hemoglobin (HbA1) levels, or the dose of oral hypoglycemic drugs. Some clinical studies have shown that in patients with type 2 diabetes mellitus, Carvedilol does not cause a decrease in glucose tolerance. In patients with arterial hypertension who had 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.

Patients with heart failure

Studies show that in patients with heart failure, the clearance of R(+) and S(-)-stereoisomers of carvedilol is significantly lower compared to the clearance in healthy volunteers. These results indicate that the pharmacokinetics of R(+) and S(-)-stereoisomers of carvedilol are significantly altered in heart failure.

Indications

• Arterial hypertension (in monotherapy and in combination with diuretics);
• Coronary artery disease: prevention of attacks of stable angina pectoris;
• Chronic heart failure (as part of combination therapy).

ICD codes

Dosage Regimen

Orally, regardless of meals, with a sufficient amount of liquid.

For arterial hypertension, the initial dose is 12.5 mg once a day for the first 2 days of treatment, then – 25 mg once a day, with a possible gradual increase in dose at intervals of at least 2 weeks. If the antihypertensive effect is insufficient after 2 weeks of therapy, the dose may be increased. The maximum recommended daily dose of the drug is 50 mg once a day (this dose can be divided into 2 doses per day).

For coronary artery disease, angina pectoris, the initial dose is 12.5 mg twice a day for the first 2 days of therapy, then – 25 mg twice a day. If the antianginal effect is insufficient after 2 weeks of therapy, the dose may be increased. The maximum recommended daily dose of the drug is 100 mg/day, divided into 2 doses.

For chronic heart failure, the dose is selected individually (against the background of selected therapy with cardiac glycosides, diuretics, and ACE inhibitors), under careful medical supervision. The patient’s condition should be monitored for 2-3 hours after the first dose or after the first increased dose. The recommended initial dose is 3.125 mg (it is possible to use carvedilol in another dose – 1/2 tab. of 6.25 mg with a score) twice a day for 2 weeks. If well tolerated, 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 that is well tolerated by the patient. For body weight less than 85 kg – the maximum dose is 25 mg twice a day, for body weight more than 85 kg – 50 mg twice a day. The maximum dose of the drug in patients with severe chronic heart failure is 25 mg twice a day, regardless of their body weight.

Before each dose increase, the doctor should examine the patient to identify worsening symptoms of chronic heart failure or vasodilation. With transient worsening of chronic heart failure symptoms or fluid retention, the dose of diuretics should be increased or Vedicardol^® should be temporarily discontinued. Symptoms of vasodilation can be eliminated by reducing the dose of diuretics. If symptoms of chronic heart failure persist, the dose of the ACE inhibitor (if the patient is taking it) can be reduced, and then, if necessary, the dose of the drug Vedicardol^®. The dose of the drug Vedicardol^® should not be increased until the symptoms of chronic heart failure or arterial hypotension stabilize.

For patients with chronic heart failure, to prevent orthostatic hypotension, it is recommended to take the drug with meals.

If a dose is missed, the drug should be taken as soon as possible, but if it is almost time for the next dose, only that dose should be taken, without doubling. Discontinuation of the drug should be gradual over 1-2 weeks.

If treatment is interrupted for more than 2 weeks, its resumption should start with a dose of 3.125 mg (it is possible to use carvedilol in another dose – 1/2 tab. of 6.25 mg with a score) twice a day, followed by a dose increase.

In patients with moderate renal impairment, no dose adjustment of the drug Vedicardol^® is required.

For elderly patients, no dose adjustment of the drug Vedicardol^® is required.

Vedicardol^® is contraindicated in patients with hepatic insufficiency.

Adverse Reactions

Classification of the frequency of adverse effects: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10 000, <1/1000); very rare (<1/10 000), including isolated reports.

From the central nervous system common – dizziness, headache (especially at the beginning of treatment or when changing doses), weakness; rare – asthenia (including increased fatigue), depression, mood lability, sleep disorders, paresthesia.

From the cardiovascular system very common – orthostatic hypotension; common – bradycardia, AV block II-III degree; rare – exacerbation of chronic heart failure (during dose increase), peripheral edema (including generalized, perineal edema, lower extremities), angina pectoris, pronounced decrease in blood pressure, syncope (including presyncope), peripheral circulation disorders (cold extremities, exacerbation of intermittent claudication and Raynaud’s syndrome).

From the digestive system common – nausea, abdominal pain, diarrhea; rare – constipation, vomiting; very rare – increased activity of liver transaminases.

From the respiratory system rare – dyspnea and bronchospasm (in predisposed patients), nasal congestion.

From the skin uncommon – skin itching, rash, dermatitis and urticaria.

From metabolism common – weight gain, manifestation of latent diabetes mellitus, decompensation of pre-existing diabetes mellitus or suppression of the counter-regulatory system.

From the hematopoietic system rare – thrombocytopenia; very rare – leukopenia.

From the urinary system rare – urination disorder; very rare – renal failure and impaired renal function in patients with diffuse vasculitis and/or impaired renal function, severe renal impairment, urinary incontinence in women, reversible after drug withdrawal.

From the reproductive system: uncommon – decreased potency.

Laboratory parameters common – hypercholesterolemia, hyper- or hypoglycemia.

Other common – visual impairment, decreased tear production and eye irritation; very rare – flu-like syndrome, exacerbation of psoriasis, limb pain; rare – dry mouth, sneezing.

Contraindications

• Acute heart failure;
• Chronic heart failure in the stage of decompensation, requiring intravenous administration of inotropic agents;
• AV block II and III degree (except for patients with an artificial pacemaker);
• Bradycardia (less than 60 beats/min);
• Sick sinus syndrome;
• Severe arterial hypotension (systolic blood pressure less than 85 mm Hg);
• Cardiogenic shock;
• Prinzmetal’s angina;
• Hepatic insufficiency;
• Severe form of chronic obstructive pulmonary disease;
• Bronchial asthma;
• Terminal stage of occlusive peripheral vascular diseases;
• Metabolic acidosis;
• Patients receiving intravenous therapy with verapamil or diltiazem, due to the possibility of developing severe bradycardia (less than 40 beats/min) and arterial hypotension;
• Pheochromocytoma (without simultaneous use of alpha-adrenoblockers);
• Age under 18 years (safety and efficacy of use have not been established);
• Lactose intolerance, lactase deficiency, glucose/galactose malabsorption syndrome;
• Breastfeeding period;
• Hypersensitivity to carvedilol and other components of the drug.

With caution: AV block I degree, diabetes mellitus, hypoglycemia, thyrotoxicosis, occlusive peripheral vascular diseases, pheochromocytoma (with simultaneous use of alpha-adrenoblockers), depression, myasthenia, psoriasis, chronic obstructive pulmonary disease, history of bronchospasm, simultaneous use with MAO inhibitors, renal failure, extensive surgical interventions and general anesthesia, pregnancy.

Use in Pregnancy and Lactation

Beta-adrenoblockers reduce placental blood flow, which can lead to intrauterine fetal death and premature birth, have an adverse effect on embryonic development, and can cause arterial hypotension, bradycardia, and hypoglycemia in the fetus. The drug Vedicardol^® should not be used during pregnancy, except in cases of extreme necessity, if the potential benefit to the mother justifies the risk to the fetus.

Since Carvedilol is excreted in breast milk, breastfeeding must be discontinued during therapy with the drug Vedicardol^®.

Use in Hepatic Impairment

In patients with impaired liver function, the systemic bioavailability of carvedilol increases due to reduced first-pass metabolism through the liver. In severe liver dysfunction, Carvedilol is contraindicated.

Use in Renal Impairment

In case of impaired renal function, the pharmacokinetic parameters of carvedilol do not change significantly. Use with caution in renal failure.

Pediatric Use

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

Geriatric Use

At the beginning of therapy with Vedicardol^® or when increasing the dose of the drug in patients, especially the elderly, excessive lowering of blood pressure may be noted, mainly when standing up. Dose adjustment of the drug is necessary.

Special Precautions

Therapy should be long-term and should not be abruptly discontinued, especially in patients with coronary artery disease, as this may lead to worsening of the underlying disease. If necessary, reducing the dose of the drug Vedicardol^® should be gradual, over 1-2 weeks.

In patients with chronic heart failure, when selecting the dose, worsening of chronic heart failure symptoms and the appearance of peripheral edema are possible. In this case, the dose of the drug Vedicardol^® should not be further increased, but the dose of diuretics should be increased until hemodynamic parameters stabilize. Sometimes it becomes necessary to reduce the dose of the drug Vedicardol^® or, in rare cases, temporarily discontinue it, which does not prevent further correct dose selection.

Vedicardol^® should be used with caution in combination with cardiac glycosides (excessive slowing of AV conduction is possible).

Vedicardol^® may cause bradycardia; if the heart rate decreases to less than 60 beats per minute, the dose must be reduced or the drug discontinued.

Vedicardol^® should be used with caution in patients with endocrine disorders, since Carvedilol may reduce the severity of symptoms of thyrotoxicosis and mask the symptoms of hypoglycemia, especially tachycardia (patients with diabetes mellitus should be warned about this).

Regular monitoring of ECG and blood pressure is recommended when Vedicardol^® is prescribed concomitantly with slow calcium channel blockers, phenylalkylamine derivatives (verapamil) and benzodiazepine derivatives (diltiazem), as well as with class I antiarrhythmic drugs.

At the beginning of therapy with Vedicardol^® or when increasing the dose, especially in elderly patients, an excessive decrease in blood pressure may be observed, mainly when moving from a lying to a standing position, which requires dose adjustment of the drug.

When prescribing Vedicardol^® to patients with chronic heart failure and arterial hypotension (systolic blood pressure less than 100 mm Hg), coronary artery disease and diffuse peripheral vascular diseases and/or renal failure, a reversible deterioration of renal function was observed. The dose of Vedicardol^® should be selected depending on the functional state of the kidneys.

Vedicardol^® is prescribed to patients with COPD who are not receiving beta₂-adrenomimetics orally or by inhalation only if the benefits of its use outweigh the potential risk. In patients with a predisposition to bronchospastic syndrome, taking Vedicardol^® may lead to the development of dyspnea due to increased airway resistance. These patients should be closely monitored at the beginning of therapy and when increasing the dose, reducing the drug dose at the first signs of bronchospasm.

Caution is necessary when prescribing Vedicardol^® to patients with peripheral vascular diseases (including Raynaud’s syndrome), since beta-blockers may increase the symptoms of arterial insufficiency.

Caution is necessary when prescribing Vedicardol^® to patients with a history of severe hypersensitivity reactions or those undergoing a course of desensitization, since beta-blockers may increase sensitivity to allergens and the severity of anaphylactic reactions.

In case of surgery using general anesthesia, the surgeon-anesthesiologist should be informed about previous therapy with Vedicardol^®.

Patients with pheochromocytoma must be prescribed alpha-blockers before starting therapy.

Patients wearing contact lenses should take into account that the drug may cause a decrease in the secretion of tear fluid.

Alcohol consumption should be avoided during treatment.

Effect on the ability to drive vehicles and machinery

Caution should be exercised when driving vehicles, operating machinery, and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions at the beginning of therapy and when increasing the dose of Vedicardol^®.

Overdose

Symptoms: pronounced decrease in blood pressure (accompanied by dizziness or fainting), pronounced bradycardia (less than 50 beats/min), dyspnea may occur due to bronchospasm, vomiting. In severe cases, respiratory distress, confusion, generalized convulsions, heart failure, conduction disorders, cardiogenic shock, cardiac arrest are possible.

Treatment: symptomatic, gastric lavage and administration of adsorbents, monitoring and maintenance of vital body functions, if necessary – in the intensive care unit.

In case of pronounced bradycardia, intravenous administration of m-cholinoblockers (atropine 0.5-2 mg) is advisable.

If a pronounced decrease in blood pressure predominates in the clinical picture of overdose, sympathomimetics (norepinephrine, epinephrine, dobutamine) are administered in various doses, depending on body weight and response to the therapy, under continuous monitoring of circulatory parameters.

In case of bradycardia resistant to treatment, the use of an artificial pacemaker is indicated.

In case of bronchospasm, beta-adrenomimetics are administered in aerosol form (if ineffective – intravenously) or aminophylline intravenously.

In case of convulsions, diazepam is administered intravenously slowly.

Since in severe overdose with shock symptoms, a prolongation of the T_1/2 of carvedilol and release of the drug from depots is possible, supportive therapy should be continued for a sufficiently long time.

Drug Interactions

Carvedilol may potentiate the effect of other concurrently taken antihypertensive agents or drugs that have an antihypertensive effect (nitrates).

When carvedilol and digoxin are taken concomitantly, the concentration of the latter increases, and AV conduction time may increase.

Carvedilol may potentiate the effect of insulin and oral hypoglycemic agents, including sulfonylurea derivatives, while the symptoms of hypoglycemia (especially tachycardia) may be masked, so regular monitoring of plasma glucose concentration is recommended in patients with diabetes mellitus.

Inhibitors of microsomal oxidation (cimetidine) enhance, while inducers (phenobarbital, rifampicin) weaken the antihypertensive effect of carvedilol.

Drugs that increase the content of catecholamines (reserpine, MAO inhibitors) increase the risk of arterial hypotension and pronounced bradycardia.

When cyclosporine is used concomitantly with carvedilol, the concentration of cyclosporine increases, so adjustment of the daily dose of cyclosporine is recommended.

Concomitant use of clonidine may potentiate the antihypertensive effect and negative chronotropic effect of carvedilol. If it is planned to discontinue combined therapy with a drug with beta-adrenergic blocking properties and clonidine, the beta-blocker should be discontinued first, and clonidine can be discontinued a few days later by gradually reducing its dose.

General anesthetics enhance the negative inotropic effect and antihypertensive action of carvedilol.

Slow calcium channel blockers (verapamil, diltiazem) and antiarrhythmic drugs (especially class I) against the background of carvedilol intake may increase the risk of AV conduction impairment, provoke pronounced arterial hypotension and heart failure. Intravenous administration of verapamil and diltiazem simultaneously with carvedilol intake is contraindicated.

In patients with heart failure, amiodarone reduces the clearance of the S(-)-stereoisomer of carvedilol by inhibiting CYP2C9. The average concentration of the R(+)-stereoisomer of carvedilol does not change. Consequently, due to the increase in the concentration of the S(-)-stereoisomer of carvedilol, there is a risk of increased beta-adrenergic blocking action.

When carvedilol is used concomitantly with ergotamine, the vasoconstrictive effect of ergotamine should be taken into account.

NSAIDs reduce the antihypertensive effect of carvedilol due to decreased production of prostaglandins.

Fluoxetine inhibits the isoenzyme CYP2D6, which leads to inhibition of carvedilol metabolism and its accumulation. This may enhance the cardiodepressive effect (including bradycardia). Fluoxetine and, mainly, its metabolites are characterized by a long T_1/2, so the likelihood of drug interaction persists even several days after discontinuation of fluoxetine.

Since beta-blockers prevent the bronchodilatory effect of bronchodilators (β-adrenergic receptor agonists), patients receiving these drugs should be monitored.

Storage Conditions

The drug should be stored out of the reach of children, in a dry, light-protected place at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.