Carvedilol-Akrikhin (Tablets) Instructions for Use

Marketing Authorization Holder

Akrikhin Chemical and Pharmaceutical Plant, JSC (Russia)

Contact Information

AKRIKHIN JSC (Russia)

ATC Code

C07AG02 (Carvedilol)

Active Substance

Carvedilol (Rec.INN registered by WHO)

Dosage Forms

	Carvedilol-Akrikhin	Tablets 6.25 mg: 30 pcs.
		Tablets 12.5 mg: 30 pcs.
		Tablets 25 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Tablets are round, flat-cylindrical, with a bevel and a score, from white to white with a creamy tint, slight marbling is allowed.

Excipients: Ludipress LCE (lactose monohydrate – 94.7-98.3%, povidone – 3-4%) – 81.95 mg, sodium carboxymethyl starch – 0.9 mg, magnesium stearate – 0.9 mg.

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

Tablets are square with rounded corners, biconvex, with a cross-shaped notch on one side and an engraving “AL1” on the other, from white to white with a creamy tint, slight marbling is allowed.

Excipients: Ludipress LCE (lactose monohydrate – 94.7-98.3%, povidone – 3-4%) – 95.3 mg, sodium carboxymethyl starch – 1.1 mg, magnesium stearate – 1.1 mg.

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

Tablets are oval, biconvex, with a partial notch on both sides and an engraving “AL2” on one side, from white to white with a creamy tint, slight marbling is allowed.

Excipients: Ludipress LCE (lactose monohydrate – 94.7-98.3%, povidone – 3-4%) – 190.6 mg, sodium carboxymethyl starch – 2.2 mg, magnesium stearate – 2.2 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

Carvedilol is a blocker of α₁-, β₁-, and β₂-adrenergic receptors, has an organoprotective effect, is an antioxidant that eliminates free oxygen radicals, and has an antiproliferative effect on vascular smooth muscle cells. Carvedilol is a racemic mixture of R(+) and S(-) stereoisomers, each of which has the same alpha-adrenergic blocking and antioxidant properties. The beta-adrenergic blocking action of carvedilol is non-selective and is due to the levorotatory S(-) stereoisomer.

Carvedilol has no intrinsic sympathomimetic activity and, like propranolol, has membrane-stabilizing properties. By blocking β-adrenergic receptors, it reduces the activity of the renin-angiotensin-aldosterone system by reducing renin release, so fluid retention (characteristic of selective alpha-blockers) rarely occurs.

By selectively blocking α₁-adrenergic receptors, Carvedilol reduces total peripheral vascular resistance.

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

In patients with arterial hypertension, Carvedilol reduces blood pressure due to combined blockade of α₁– and β-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. Heart rate decreases slightly. Renal blood flow and renal function in patients with arterial hypertension are preserved. It has been shown that Carvedilol does not change stroke volume and reduces total peripheral vascular resistance; it does not impair blood supply to organs and peripheral blood flow, including in skeletal muscles, forearms, lower extremities, skin, brain, and carotid artery. Cold extremities and increased fatigue during physical exertion are rarely noted. The hypotensive effect of carvedilol in arterial hypertension persists for a long time.

In patients with coronary artery disease, Carvedilol has an anti-ischemic and antianginal effect (increasing the total duration of physical exertion, time to development of ST segment depression of 1 mm and time to onset of angina attack), which persists during 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 (total peripheral vascular resistance). Carvedilol reduces the mortality rate and reduces 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, Carvedilol is rapidly absorbed. Carvedilol is a substrate of the transport protein that acts as a pump in the intestinal lumen, glycoprotein P. C_max in blood plasma is reached in approximately 1 hour. The absolute bioavailability of carvedilol is approximately 25%.

Distribution

Carvedilol is highly lipophilic. About 98-99% of carvedilol is bound to plasma proteins. Its V_d is approximately 2 L/kg. Carvedilol undergoes biotransformation in the liver by oxidation and conjugation to form a number of metabolites. 60-75% of the absorbed drug is metabolized during the “first pass” through the liver. The existence of enterohepatic circulation of the parent substance has been shown.

Metabolism

The metabolism of carvedilol by oxidation is stereoselective. The R stereoisomer is metabolized mainly by CYP2D6 and CYP1A2, and the S stereoisomer is metabolized mainly by CYP2D9 and to a lesser extent by CYP2D6. Other P450 isoenzymes involved in the metabolism of carvedilol include CYP3A4, CYP2E1 and CYP2C19. The C_max of the R stereoisomer in plasma is approximately 2 times higher than that of the S stereoisomer.

The R stereoisomer is metabolized mainly by hydroxylation. In slow CYP2D6 metabolizers, an increase in the plasma concentration of carvedilol, primarily the R stereoisomer, is possible, which is expressed in an increase in the alpha-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 beta-adrenergic blocking activity (the 4′-hydroxyphenolic metabolite is approximately 13 times more potent than carvedilol itself). The 3 active metabolites have less pronounced vasodilating properties than Carvedilol. 2 of the hydroxycarbonyl metabolites of carvedilol are extremely powerful antioxidants, and their activity in this regard is 30-80 times greater than that of carvedilol.

Elimination

The T_1/2 of carvedilol is about 6 hours, plasma clearance is about 500-700 ml/min. Elimination occurs mainly through the intestines, the main route of elimination is with bile. A small part of the dose is excreted by the kidneys in the form of various metabolites.

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 C_max do not change. Renal excretion of the unchanged drug in patients with renal failure decreases, but the changes in pharmacokinetic parameters are insignificant.

Patients with impaired liver function

In patients with liver cirrhosis, the systemic bioavailability of the drug increases by 80% due to a decrease in the severity of metabolism during the “first pass” through the liver. Therefore, Carvedilol is contraindicated in patients with clinically manifest liver dysfunction.

Patients with heart failure

In some studies, in patients suffering from heart failure, the clearance of R and S stereoisomers of carvedilol was significantly lower compared to the clearance previously observed in healthy volunteers. These results indicate that the pharmacokinetics of 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.

Children

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

Patients with diabetes mellitus

In patients with type 2 diabetes mellitus and arterial hypertension, Carvedilol does not affect fasting and postprandial blood glucose concentrations, the level of glycosylated hemoglobin (HbA₁), or the dose of oral hypoglycemic agents. 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.

Indications

• Arterial hypertension: essential hypertension (in monotherapy or in combination with other antihypertensive drugs, for example, slow calcium channel blockers or diuretics);
• Coronary artery 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 (functional classes II-IV according to the New York Heart Association /NYHA/) of ischemic or non-ischemic origin in combination with ACE inhibitors and diuretics, with or without cardiac glycosides (standard therapy), in the absence of contraindications.

ICD codes

Dosage Regimen

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

Essential hypertension

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

Coronary artery disease

The recommended initial dose is 12.5 mg twice a day for the first 2 days, then 25 mg twice a day. If necessary, the dose can subsequently be increased at intervals of at least 2 weeks, up to the highest daily dose of 100 mg, divided into 2 doses.

Chronic heart failure

The dose is selected individually, careful medical supervision is necessary. In patients receiving cardiac glycosides, diuretics and ACE inhibitors, their doses should be adjusted before starting treatment with Akridilol^®.

The recommended initial dose is 3.125 mg (1/2 tab. of 6.25 mg) 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 dose that is well tolerated by the patient. The recommended maximum dose is 25 mg twice a day for all patients with severe chronic heart failure and for patients with mild and moderate chronic heart failure withpatient body weight less than 85 kg. In patients with mild and moderate chronic heart failure andbody weight over 85 kg – the recommended maximum dose is 50 mg twice a day.

Before each dose increase, the physician should examine the patient to identify possible worsening of symptoms of chronic heart failure or vasodilation. With transient worsening of symptoms of chronic heart failure or fluid retention, the dose of diuretics should be increased, although sometimes it is necessary to reduce the dose of Akridilol^® or temporarily cancel it.

Symptoms of vasodilation can be eliminated by reducing the dose of diuretics. If symptoms persist, the dose of the ACE inhibitor (if the patient is taking it) can be reduced, and then, if necessary, the dose of Akridilol^®. In this situation, the dose of Akridilol^® should not be increased until the symptoms of worsening chronic heart failure or arterial hypotension improve.

If treatment with Akridilol^® is interrupted for more than 1 week, then its administration is resumed at a lower dose and then increased in accordance with the above recommendations. If treatment with Akridilol^® is interrupted for more than 2 weeks, then its administration should be resumed at a dose of 3.125 mg (1/2 tab. of 6.25 mg) twice a day, then the dose is selected in accordance with the above recommendations.

Dosing in special patient groups

Existing data on pharmacokinetics in patients with varying degrees of renal impairment (including renal failure) suggest that patients with moderate and severe renal failure do not require dose adjustment of Akridilol^®.

Akridilol is contraindicated in patients with clinical manifestations of impaired liver function.

There are no data that would dictate the need for dose adjustment in elderly patients.

Adverse Reactions

Adverse reactions occurring with a frequency of < 10% are considered very common. Adverse reactions occurring with a frequency from < 1% to <10 % are considered common. Adverse reactions occurring with a frequency from < 0.1% to <1 % are considered uncommon. Adverse reactions occurring with a frequency from < 0.01% to < 0.1% are considered rare. Adverse reactions occurring with a frequency of < 0.01%, including individual reports, are considered very rare. The frequency of adverse reactions, with the exception of dizziness, visual impairment and bradycardia, does not depend on the dose of the drug.

Adverse reactions in patients with chronic heart failure

From the central nervous system very common – dizziness, headache (usually mild and occurring more often at the beginning of treatment); asthenia (including increased fatigue), depression.

From the cardiovascular system common – bradycardia, postural hypotension, pronounced decrease in blood pressure, edema (including generalized, peripheral, dependent on body position, perineal edema, lower limb edema, hypervolemia, fluid retention); uncommon – syncope (including presyncope), AV block and heart failure during dose increase.

From the gastrointestinal tract common – nausea, diarrhea, vomiting.

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

From the metabolism common – weight gain, hypercholesterolemia; in patients with pre-existing diabetes mellitus – hyperglycemia or hypoglycemia, impaired glycemic control.

Other common – visual impairment; rare – renal failure and impaired renal function in patients with diffuse vasculitis and/or impaired renal function.

Adverse reactions in patients with arterial hypertension and coronary artery disease

The nature of side effects from the cardiovascular system in the treatment of arterial hypertension and long-term therapy of coronary artery disease is similar to that in chronic heart failure, but their frequency is somewhat lower.

From the central nervous system: common – dizziness, headache and general weakness, usually mild and occurring, in particular, at the beginning of treatment; uncommon – mood lability, sleep disorders, paresthesia.

From the cardiovascular system common – bradycardia, postural hypotension, syncope (uncommon), especially at the beginning of therapy; uncommon – peripheral circulation disorders (cold extremities, exacerbation of intermittent claudication syndrome and Raynaud’s syndrome), AV block, angina (chest pain), development or worsening of symptoms of heart failure and peripheral edema.

From the respiratory system common – bronchospasm and shortness of breath in predisposed patients; rare – nasal congestion.

From the gastrointestinal tract common – dyspeptic disorders (including nausea, abdominal pain, diarrhea); uncommon – constipation, vomiting.

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

Laboratory parameters very rare – increased activity of liver transaminases (ALT, AST and GGT), thrombocytopenia and leukopenia.

Other common – limb pain, decreased tear production and eye irritation; uncommon – decreased potency, visual impairment; rare – dry mouth and urination disorders; very rare – exacerbation of psoriasis, sneezing, flu-like syndrome. Isolated cases of allergic reactions.

Contraindications

• Acute and chronic heart failure in the stage of decompensation, requiring intravenous administration of inotropic agents;
• Clinically significant liver dysfunction;
• Age under 18 years (the efficacy and safety of the drug Akridilol^® have not been established);
• AV block of II and III degree (except for patients with an artificial pacemaker);
• Severe bradycardia (heart rate less than 50 beats/min);
• Sick sinus syndrome (including sinoatrial block);
• severe arterial hypotension (systolic BP less than 85 mm Hg);
• cardiogenic shock;
• History of bronchospasm and bronchial asthma;
• lactose intolerance, lactase deficiency, glucose-galactose malabsorption;
• hypersensitivity to carvedilol or any component of the drug.

Use with caution in: COPD, depression, myasthenia, hypoglycemia, first-degree AV block, thyrotoxicosis, during major surgical interventions and general anesthesia, Prinzmetal’s angina, diabetes mellitus, occlusive peripheral vascular diseases, suspected pheochromocytoma, renal failure, psoriasis.

Use in Pregnancy and Lactation

Beta-blockers reduce placental blood flow, which can lead to intrauterine fetal death and premature birth. In addition, adverse reactions may occur in the fetus and newborn (in particular, hypoglycemia and bradycardia, cardiac and pulmonary complications).

Animal studies did not reveal a teratogenic effect of carvedilol.

There is insufficient experience with the use of the drug Acridilol^® in pregnant women. Carvedilol is contraindicated during pregnancy, except in cases where the potential benefits of its use to the mother outweigh the potential risk to the fetus.

In animals, Carvedilol and its metabolites pass into breast milk. There are no data on the passage of carvedilol into human breast milk; therefore, if it is necessary to take the drug during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

The drug is contraindicated in severe hepatic insufficiency.

Use in Renal Impairment

It is recommended to monitor renal function in patients with chronic renal failure.

Pediatric Use

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

Geriatric Use

There are no data that would necessitate dose adjustment in elderly patients.

Special Precautions

Chronic heart failure

In patients with chronic heart failure, during the dose titration period of Acridilol^®, an increase in the 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 Acridilol^® until hemodynamic parameters stabilize.

Sometimes it may be necessary to reduce the dose of Acridilol^® or, in rare cases, to temporarily discontinue the drug. Such episodes do not preclude further proper dose titration of Acridilol^®.

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

Renal function in chronic heart failure

When prescribing Acridilol^® to patients with chronic heart failure and low BP (systolic BP less than 100 mm Hg), coronary artery disease and diffuse vascular changes and/or renal failure, reversible deterioration of renal function was observed. The dose of the drug should be titrated depending on the functional state of the kidneys.

COPD

Acridilol^® should be prescribed to patients with COPD (including bronchospastic syndrome) who are not receiving oral or inhaled anti-asthmatic drugs only if the potential benefits of its use outweigh the potential risk. In the presence of an initial predisposition to bronchospastic syndrome, taking Acridilol^® may lead to the development of dyspnea due to increased airway resistance. At the start of treatment and when increasing the dose of Acridilol^®, these patients should be carefully monitored, reducing the dose of the drug at the first signs of bronchospasm.

Diabetes mellitus

The drug should be prescribed with caution to patients with diabetes mellitus, as it may mask or attenuate the symptoms of hypoglycemia (especially tachycardia). In patients with chronic heart failure and diabetes mellitus, the use of Acridilol^® may be accompanied by impaired glycemic control.

Peripheral vascular diseases

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

Thyrotoxicosis

Like other beta-blockers, Acridilol^® may reduce the severity of symptoms of thyrotoxicosis.

General anesthesia and major surgical interventions

Caution is required in patients undergoing surgery under general anesthesia due to the possibility of summation of the negative effects of Acridilol^® and general anesthetics.

Bradycardia

Acridilol^® may cause bradycardia; if the heart rate decreases to less than 55 beats/min, the dose of the drug should be reduced.

Hypersensitivity

Caution should be exercised when prescribing Acridilol^® to patients with a history of severe hypersensitivity reactions or undergoing a course of desensitization, as beta-blockers may increase sensitivity to allergens and the severity of anaphylactic reactions.

Psoriasis

In patients with a history of the onset or exacerbation of psoriasis when using beta-blockers, Acridilol^® should be prescribed only after careful analysis of the potential benefit and risk.

Concomitant use of slow calcium channel blockers (CCBs)

In patients simultaneously taking CCBs of the verapamil or diltiazem type, as well as other antiarrhythmic drugs, regular monitoring of ECG and BP is necessary.

Pheochromocytoma

In patients with pheochromocytoma, an alpha-blocker must be prescribed before starting any beta-blocker. Although Acridilol^® has both beta- and alpha-blocking properties, there is no experience with its use in such patients, so it should be prescribed with caution to patients with suspected pheochromocytoma.

Prinzmetal’s angina

Non-selective beta-blockers may provoke pain in patients with Prinzmetal’s angina. There is no experience with prescribing Acridilol^® to these patients. Although its alpha-blocking properties may prevent such symptoms, Carvedilol should be prescribed in such cases with caution.

Contact lenses

Patients using contact lenses should be aware of the possibility of reduced tear fluid production.

Withdrawal syndrome

Treatment with Acridilol^® is long-term. It should not be discontinued abruptly; the dose of the drug should be gradually reduced at weekly intervals. This is especially important in patients with coronary artery disease.

If it is necessary to perform surgery using general anesthesia, the anesthesiologist must be informed of the prior therapy with Acridilol^®.

Alcohol consumption is excluded during treatment.

Effect on ability to drive vehicles and operate machinery

During treatment, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms pronounced decrease in BP, bradycardia, heart failure, cardiogenic shock, cardiac arrest; respiratory disturbances, bronchospasm, vomiting, confusion, and generalized seizures are possible.

Treatment in addition to general measures, it is necessary to monitor and correct vital signs, if necessary – in the intensive care unit. The following measures can be used

• Place the patient in a supine position (with legs elevated);
• In case of severe bradycardia – atropine 0.5-2 mg IV;
• To maintain cardiovascular activity – glucagon 1-10 mg IV bolus, then 2-5 mg per hour as a prolonged infusion;
• Sympathomimetics (dobutamine, isoprenaline, orciprenaline or epinephrine (adrenaline) in various doses, depending on body weight and response to treatment.

If arterial hypotension dominates the clinical picture of overdose, norepinephrine (noradrenaline) is administered; it is prescribed under conditions of continuous monitoring of circulatory parameters. In case of bradycardia resistant to treatment, the use of an artificial pacemaker is indicated. For bronchospasm, beta-adrenergic agonists are administered by aerosol (if ineffective – IV) or aminophylline IV. For seizures, diazepam or clonazepam is administered IV slowly.

Since in severe overdose with shock symptoms, a prolongation of the half-life of carvedilol and the release of the drug from depots is possible, it is necessary to continue supportive therapy for a sufficiently long time. The duration of supportive/detoxification therapy depends on the severity of the overdose and should be continued until the patient’s clinical condition stabilizes.

Drug Interactions

Pharmacokinetic interaction

Since Carvedilol is both a substrate and an inhibitor of P-glycoprotein, its simultaneous administration with drugs transported by P-glycoprotein may increase the bioavailability of the latter. In addition, the bioavailability of carvedilol may be altered by inducers or inhibitors of P-glycoprotein. Inhibitors and inducers of CYP2D6 and CYP2C9 may stereoselectively alter the systemic and/or presystemic metabolism of carvedilol, leading to an increase or decrease in the plasma concentrations of the R and S stereoisomers of carvedilol. Some examples of such interactions observed in patients or in healthy volunteers are listed below, but this list is not exhaustive.

Digoxin

With simultaneous administration of carvedilol and digoxin, digoxin concentrations increase by approximately 15%. At the start of carvedilol therapy, during its dose titration, or upon drug withdrawal, regular monitoring of digoxin plasma concentration is recommended.

Cyclosporine

In two studies, when carvedilol was prescribed to patients who had undergone kidney and heart transplantation and were receiving oral cyclosporine, an increase in cyclosporine concentration was observed. It turned out that due to inhibition of P-glycoprotein activity in the intestine, Carvedilol increases the absorption of cyclosporine when taken orally. To maintain cyclosporine concentrations within the therapeutic range, a reduction in the cyclosporine dose by an average of 10-20% was required. Due to significant individual fluctuations in cyclosporine concentration, careful monitoring of its concentration is recommended after starting carvedilol therapy and, if necessary, appropriate adjustment of the daily dose of cyclosporine. In case of intravenous administration of cyclosporine, no interaction with carvedilol is expected.

Rifampicin

In a study involving healthy volunteers, rifampicin reduced the plasma concentrations of carvedilol, most likely by inducing P-glycoprotein, leading to reduced intestinal absorption of carvedilol and a decrease in its antihypertensive effect.

Amiodarone

In patients with heart failure, amiodarone reduced the clearance of the S stereoisomer of carvedilol by suppressing CYP2C9. The mean concentration of the R stereoisomer of carvedilol did not change. Consequently, due to the increased concentration of the S stereoisomer of carvedilol, there is a risk of increased beta-blocking action.

Fluoxetine

In a randomized crossover study in patients with heart failure, simultaneous administration of fluoxetine (a CYP2D6 inhibitor) led to stereoselective suppression of carvedilol metabolism – an increase in the mean AUC for R (+) by 77%. However, no difference in adverse effects, BP, or heart rate was observed between the two groups.

Pharmacodynamic interaction

Insulin or oral hypoglycemic agents

Drugs with beta-blocking properties may enhance the hypoglycemic effect of insulin or oral hypoglycemic agents. Symptoms of hypoglycemia, especially tachycardia, may be masked or attenuated. Patients receiving insulin or oral hypoglycemic agents are advised to have regular blood glucose monitoring.

Drugs that reduce catecholamine levels

Patients taking drugs with beta-blocking properties and drugs that reduce catecholamine levels (e.g., reserpine and MAO inhibitors) simultaneously should be closely monitored due to the risk of arterial hypotension and/or severe bradycardia.

Digoxin

Combination therapy with drugs with beta-blocking properties and digoxin may lead to additional slowing of atrioventricular conduction. Verapamil, diltiazem, amiodarone or other antiarrhythmic drugs Simultaneous administration with carvedilol may increase the risk of impaired AV conduction.

Clonidine

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

Slow calcium channel blockers (CCBs)

When carvedilol and diltiazem were prescribed simultaneously, isolated cases of conduction disturbances (rarely – with hemodynamic impairment) were observed. As with other drugs with beta-blocking properties, the administration of carvedilol together with CCBs of the verapamil or diltiazem type is recommended under ECG and BP monitoring.

Antihypertensive agents

Like other drugs with beta-blocking activity, Carvedilol may enhance the effect of other concurrently taken antihypertensive agents (e.g., alpha₁-blockers) or drugs that cause arterial hypotension as a side effect.

General anesthetics

Careful monitoring of vital signs should be carried out during general anesthesia due to the possibility of a synergistic negative inotropic effect of carvedilol and general anesthetics.

NSAIDs

Concomitant use of NSAIDs and beta-blockers may lead to increased BP and reduced BP control.

Bronchodilators (β-adrenergic receptor agonists)

Since non-cardioselective beta-blockers prevent the bronchodilatory effect of bronchodilators that are β-adrenergic receptor stimulants, careful monitoring of patients receiving these drugs is necessary.

Storage Conditions

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

Shelf Life

Shelf life – 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.