Dilatrend^® (Tablets) Instructions for Use

Marketing Authorization Holder

Cheplapharm Arzneimittel, GmbH (Germany)

Manufactured By

Delpharm Milano, S.r.l. (Italy)

Packaging and Quality Control Release

DELPHARM MILANO, S.r.l. (Italy)

Or

F.Hoffmann-La Roche, Ltd (Switzerland)

ATC Code

C07AG02 (Carvedilol)

Active Substance

Carvedilol (Rec.INN registered by WHO)

Dosage Forms

	Dilatrend®	Tablets 6.25 mg: 10, 30, 50 or 100 pcs.
		Tablets 12.5 mg: 10, 30, 50 or 100 pcs.
		Tablets 25 mg: 10, 30, 50 or 100 pcs.

Dosage Form, Packaging, and Composition

Tablets light brown, round, marbled, with a score on both sides and marked “BM H3”.

Excipients: lactose, sucrose, povidone K25, crospovidone, colloidal anhydrous silica, yellow iron oxide (E172), red iron oxide (E172), magnesium stearate.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (5) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.

Tablets from white to pale yellowish-beige, round, slightly marbled, with a score on both sides and marked “BM D5”.

Excipients: lactose, sucrose, povidone K25, crospovidone, colloidal anhydrous silica, yellow iron oxide (E172), red iron oxide (E172), magnesium stearate.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (5) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.

Tablets yellow, round, slightly marbled, with a score on both sides and marked “BM F1”.

Excipients: lactose, sucrose, povidone K25, crospovidone, colloidal anhydrous silica, yellow iron oxide (E172), red iron oxide (E172), magnesium stearate.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (5) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.

Clinical-Pharmacological Group

Beta₁-, beta₂-adrenoblocker. Alpha₁-adrenoblocker

Pharmacotherapeutic Group

Alpha- and beta-adrenergic blocker

Pharmacological Action

The instructions for medical use of the drug were introduced by Order of the Federal Service for Surveillance in Healthcare and Social Development dated October 21, 2005 No. 56.

Carvedilol is a blocker of α₁-, β₁-, and β₂-adrenergic receptors, has an organoprotective effect, is a powerful 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 beta-adrenergic receptors, it reduces the activity of the renin-angiotensin-aldosterone system by reducing the release of renin, 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 and low density lipoproteins (HDL/LDL).

Efficacy

Arterial hypertension. In patients with arterial hypertension, Carvedilol lowers blood pressure (BP) due to combined blockade of β- and α₁-adrenergic receptors. The decrease in BP is not accompanied by a simultaneous increase in total peripheral vascular resistance, which is observed when taking non-selective beta-blockers. Heart rate decreases somewhat. 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 to 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.

Coronary artery disease. In patients with coronary artery disease, Carvedilol has anti-ischemic and antianginal effects (increasing the total duration of physical exertion, time to development of ST segment depression of 1 mm depth, and time to onset of angina attack), which persist 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).

Chronic heart failure. Carvedilol reduces mortality in patients with chronic heart failure of any stage and functional class and is well tolerated by them (COPERNICUS, COMET studies). Carvedilol significantly reduces the need for hospitalization for cardiovascular reasons, increases ejection fraction and reduces symptoms 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. Maximum plasma concentration (C_max) 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 volume of distribution is approximately 2 L/kg.

Metabolism

Carvedilol undergoes biotransformation in the liver 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.

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 weaker vasodilating properties than Carvedilol. Two 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 half-life of carvedilol is about 6 hours, plasma clearance is about 500-700 ml/min. Elimination occurs mainly with feces, the main route of elimination is through bile. A small part of the dose is excreted through 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 glomerular filtration does not change.

In patients with arterial hypertension and renal failure, the area under the concentration-time curve, half-life, and maximum plasma concentrations do not change. Renal excretion of the unchanged drug in patients with renal failure is reduced; however, changes in pharmacokinetic parameters are moderate.

Carvedilol is an effective drug for the treatment of patients with renal hypertension, including patients with chronic renal failure, as well as patients on hemodialysis or after kidney transplantation. Carvedilol causes a gradual decrease in BP 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 strong binding to plasma proteins.

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 extent of first-pass metabolism. Therefore, Carvedilol is contraindicated in patients with clinically manifest liver dysfunction (see “Contraindications”). Elderly and senile patients. Age does not affect the pharmacokinetics and tolerability of carvedilol in patients with arterial hypertension. Children. Data on the pharmacokinetics of the drug in patients under 18 years of age are currently limited.

Patients with diabetes mellitus. In patients with type 2 (non-insulin-dependent) diabetes mellitus and arterial hypertension, Carvedilol did not affect fasting and postprandial blood glucose levels, glycosylated hemoglobin (HbA1) levels, or the dose of hypoglycemic drugs. Some clinical studies have shown that in patients with non-insulin-dependent diabetes mellitus, Carvedilol does not cause changes in glucose tolerance test parameters. In patients with arterial hypertension without diabetes mellitus who had insulin resistance (syndrome X), Carvedilol improves insulin sensitivity. Similar results were obtained in patients with arterial hypertension and type 2 diabetes mellitus (non-insulin-dependent).

Indications

• Arterial hypertension. Essential arterial hypertension (as monotherapy or combination therapy with other antihypertensive agents, e.g., slow calcium channel blockers or diuretics).
• Coronary artery disease (including in patients with unstable angina and silent myocardial ischemia).
• Chronic heart failure. Treatment of mild, moderate and severe chronic heart failure of ischemic or non-ischemic origin (to reduce the number of complications – hospitalization for cardiovascular reasons, and mortality, as well as to improve well-being and slow the progression of the disease), when used in combination with ACE inhibitors, diuretics and, sometimes, digitalis preparations (standard therapy).

Dilatrend^® can be prescribed both as an addition to standard therapy and to patients who are not receiving digitalis preparations, vasodilators, or nitrates.

ICD codes

Dosage Regimen

Orally, with a sufficient amount of liquid.

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

Coronary artery disease. The recommended initial dose is 12.5 mg twice a day for the first 2 days, after that – 25 mg twice a day. If necessary, the dose can be increased subsequently 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 digitalis preparations, diuretics and ACE inhibitors, their doses should be stabilized before starting treatment with Dilatrend^®.

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

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

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

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 Dilatrend^®. In this situation, the dose of Dilatrend^® should not be increased until the symptoms of worsening heart failure or arterial hypotension stabilize.

Doses for special patient groups

Renal impairment. Existing pharmacokinetic data in patients with varying degrees of renal impairment (including renal failure) suggest that no dose adjustment of Dilatrend^® is required in patients with moderate and severe renal failure.

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

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 cases, are considered very rare.

Adverse reactions in patients with chronic heart failure

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

Cardiovascular system. common – bradycardia, postural hypotension, pronounced decrease in BP, edema (including generalized, peripheral, position-dependent, perineal edema, lower extremity edema, hypervolemia, fluid retention). Uncommon – syncope (including presyncope), atrioventricular block and heart failure during dose increase.

Gastrointestinal tract common- nausea, diarrhea, vomiting.

Hematopoietic system: rare – thrombocytopenia. Very rare – leukopenia.

Metabolic disorders common – weight gain, hypercholesterolemia; in patients with pre-existing diabetes mellitus – hyperglycemia or hypoglycemia, decompensation of carbohydrate metabolism.

Other common – visual disturbances. 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 the side effects of Dilatrend^® on the cardiovascular system in the treatment of arterial hypertension and long-term therapy of coronary artery disease is similar to that in heart failure, but their frequency is somewhat lower.

Central nervous system common – dizziness, headache and general weakness, usually mild and occurring, in particular, at the beginning of treatment. Uncommon – depressed mood, sleep disorders, paresthesia.

Cardiovascular system: common: bradycardia, postural hypotension, syncope, 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), symptoms of heart failure and peripheral edema.

Respiratory organs common – bronchospasm and shortness of breath in predisposed patients; rare – nasal congestion.

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

Skin uncommon – skin reactions (allergic rash, dermatitis, urticaria and itching).

Laboratory parameters: very rare – increased activity of “liver” transaminases – ALT (ALT), AST (AST) and gamma-glutamyltransferase, 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 – skin allergic reactions (exanthema, urticaria, itching, rash), exacerbation of psoriatic rashes, sneezing, nasal congestion, bronchospasm, shortness of breath (in predisposed patients), flu-like syndrome.

The presence of beta-adrenergic blocking properties in the drug does not exclude the possibility of manifestation of latent diabetes mellitus, decompensation of pre-existing diabetes mellitus, or suppression of the counter-regulatory hormonal system.

Contraindications

• Hypersensitivity to carvedilol or any component of the drug;
• Acute and decompensated chronic heart failure requiring intravenous inotropic therapy;
• Clinically significant liver dysfunction;
• Age under 18 years (efficacy and safety of Dilatrend^® have not been established);
• Pregnancy;
• Second- and third-degree AV block (except in patients with a pacemaker), severe bradycardia (less than 50 beats/min);
• Sick sinus syndrome;
• Severe arterial hypotension (systolic BP less than 85 mm Hg);
• Cardiogenic shock;
• History of bronchospasm and bronchial asthma.

Use with caution in patients with chronic obstructive pulmonary disease (COPD), depression, myasthenia gravis, hypoglycemia, first-degree AV block, thyrotoxicosis, during major surgical interventions and general anesthesia, Prinzmetal’s angina, diabetes mellitus, occlusive peripheral vascular disease, 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 have not revealed teratogenicity.

There is insufficient experience with the use of Dilatrend^® in pregnant women. Carvedilol is contraindicated during pregnancy, except in cases where the potential benefits outweigh the possible risk to the woman and fetus.

In animals, Carvedilol and its metabolites pass into breast milk. There are no data on the excretion of the drug into human milk, therefore it should not be used during lactation.

Use in Hepatic Impairment

Contraindicated in clinically significant liver dysfunction.

Use in Renal Impairment

Use with caution in renal failure.

Pediatric Use

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

Geriatric Use

There are no data that would necessitate dose adjustment.

Special Precautions

Chronic heart failure. In patients with chronic heart failure, an increase in heart failure symptoms or fluid retention may be observed during the dose titration period of Dilatrend^®. If such symptoms occur, it is necessary to increase the dose of diuretics and not increase the dose of Dilatrend^® until the patient’s condition stabilizes. Sometimes it is necessary to reduce the dose of Dilatrend^® or, in rare cases, temporarily discontinue the drug. Such episodes do not preclude further proper dose titration of Dilatrend^®. Dilatrend^® should be used with caution in combination with cardiac glycosides (excessive slowing of AV conduction is possible).

Renal function in chronic heart failure. Administration of Dilatrend^® 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 has been associated with reversible deterioration of renal function. The drug dose should be adjusted depending on renal function.

Chronic obstructive pulmonary disease (COPD) . Dilatrend^® should be prescribed to patients with chronic obstructive pulmonary diseases (including those with bronchospastic syndrome) who are not receiving oral or inhaled anti-asthmatic drugs only if the potential benefits outweigh the potential risk. In patients with a pre-existing tendency to bronchospastic syndrome, respiratory distress syndrome may develop due to increased airway resistance when taking Dilatrend^®. These patients should be closely monitored at the start of treatment and when increasing the dose of Dilatrend^®, reducing the dose if early signs of bronchospasm appear.

Diabetes mellitus . The drug should be prescribed with caution to patients with diabetes mellitus, as it may mask or attenuate symptoms of hypoglycemia (especially tachycardia). In patients with heart failure and diabetes mellitus, the use of Dilatrend^® may be accompanied by decompensation of carbohydrate metabolism.

Peripheral vascular disease . Caution is necessary when prescribing Dilatrend^® to patients with peripheral vascular disease (including Raynaud’s syndrome), as beta-blockers may exacerbate symptoms of arterial insufficiency.

Thyrotoxicosis . Like other beta-blockers, Dilatrend^® 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 possibility of summation of the negative effects of Dilatrend^® and anesthetics.

Bradycardia. Dilatrend^® may cause bradycardia; if the heart rate decreases below 55 beats per minute, the dose of Dilatrend^® should be reduced.

Hypersensitivity . Caution should be exercised when prescribing Dilatrend^® to persons 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 onset or exacerbation of psoriasis when using beta-blockers, Dilatrend^® can be prescribed only after careful analysis of the potential benefit and risk.

Concomitant use of “slow” calcium channel blockers . In patients simultaneously taking “slow” calcium channel blockers such as verapamil or diltiazem, as well as other antiarrhythmic drugs, regular monitoring of ECG and BP is necessary.

Pheochromocytoma. Patients with pheochromocytoma must be prescribed an alpha-blocker before starting any beta-blocker. Although Dilatrend^® has both beta- and alpha-adrenergic 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 Dilatrend^® to these patients. Although its alpha-adrenergic blocking properties may prevent such symptoms, Carvedilol should be prescribed with caution in such cases.

Contact lenses. Persons using contact lenses should be aware of the possibility of decreased tear fluid production.

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

Exposure to light may cause a change in the color of the tablets.

If surgery under general anesthesia is necessary, the anesthesiologist must be informed of prior therapy with Dilatrend^®.

Consumption of ethanol is excluded during treatment.

Effect on ability to drive vehicles and operate machinery. Studies on the effect of Dilatrend^® on the ability to drive vehicles or operate machinery have not been conducted. Due to individual reactions to the drug (e.g., dizziness, general weakness), this ability may be impaired (especially at the beginning of treatment, when changing the dosage, and in case of simultaneous alcohol intake). It should be prescribed with caution to patients whose work requires quick 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, monitoring and correction of vital signs is necessary, if required – in the intensive care unit. The following measures can be used

A) place the patient in a supine position (with legs elevated)

B) in case of severe bradycardia – atropine 0.5-2 mg IV;

C) to maintain cardiovascular function – glucagon 1-10 mg IV bolus, then 2-5 mg per hour as a prolonged infusion;

D) sympathomimetics (dobutamine, isoprenaline, orciprenaline or epinephrine (adrenaline) in various doses, depending on body weight and therapeutic effectiveness. If administration of drugs with positive inotropic action is necessary, phosphodiesterase inhibitors are prescribed. 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 a pacemaker is indicated.

In case of bronchospasm, beta-adrenergic agonists are administered by aerosol (if ineffective – IV) or aminophylline IV.

In case of seizures, diazepam or clonazepam is administered IV slowly.

Since in severe overdose with shock symptoms, a prolongation of the half-life of carvedilol and release of the drug from depots is possible, supportive therapy should be continued 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 condition stabilizes.

Drug Interactions

Digoxin. With simultaneous administration of carvedilol and digoxin, digoxin concentrations increase by approximately 15%. Both digoxin and Carvedilol slow atrioventricular conduction. At the start of carvedilol therapy, during its dose titration or withdrawal, regular monitoring of plasma digoxin concentration is recommended.

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

Inducers or inhibitors of hepatic metabolism . Rifampicin reduces plasma concentrations of carvedilol by approximately 70%. Cimetidine increases the area under the concentration-time curve by approximately 30%, but does not change C_max. Caution may be required in patients receiving inducers of polyfunctional oxidases, e.g., rifampicin (decreased plasma concentrations of carvedilol), as well as inhibitors of polyfunctional oxidases, e.g., cimetidine (increased plasma concentrations of carvedilol). However, given the relatively minor effect of cimetidine on carvedilol concentration, the likelihood of any clinically significant interactions is minimal.

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

Cyclosporine . When carvedilol was prescribed to patients who had undergone kidney transplantation and developed chronic vascular rejection of the transplant, a moderate increase in mean trough cyclosporine concentrations was observed. To maintain cyclosporine concentrations within the therapeutic range, the cyclosporine dose had to be reduced in approximately 30% of patients (by an average of 20%), while the remaining patients did not require dose adjustment. Due to significant individual fluctuations in the required daily dose of cyclosporine, careful monitoring of cyclosporine concentration is recommended after initiation of carvedilol therapy and, if necessary, appropriate adjustment of the daily cyclosporine dose.

Verapamil, diltiazem and other antiarrhythmic drugs (propranolol, amiodarone) . Simultaneous administration with carvedilol may increase the risk of impaired atrioventricular conduction.

Clonidine . Simultaneous administration of clonidine with drugs with beta-blocking properties may potentiate the antihypertensive and heart rate-lowering effects. 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 after a few days clonidine can be discontinued by gradually reducing its dose.

“Slow” calcium channel blockers . Isolated cases of conduction disturbances (rarely with hemodynamic impairment) have been reported with simultaneous administration of carvedilol and diltiazem. As with other drugs with beta-adrenergic blocking properties, administration of carvedilol together with “slow” calcium channel blockers such as verapamil or diltiazem is recommended under ECG and BP monitoring.

Like other drugs with beta-adrenergic blocking activity, Carvedilol may enhance the effect of other simultaneously taken antihypertensive agents (e.g., α₁-blockers) or drugs that have a hypotensive effect as a side effect.

It prevents the increase in BP caused by administration of the α₁-adrenergic receptor agonist – phenylephrine, but does not affect the increase in BP caused by angiotensin II.

Special attention should be paid during general anesthesia to the possibility of a synergistic negative inotropic effect of carvedilol and some anesthetics.

Storage Conditions

Prescription drug. Store at a temperature not exceeding 25°C (77°F), in a light-protected place. Keep out of reach of children.

Since exposure to light may change the color of the tablets, it is recommended to store them in closed packaging.

Shelf Life

The shelf life of the 6.25 mg tablet is 3 years, the 12.5 mg tablet is 4 years, the 25 mg tablet is 5 years.

The drug should not be used after the expiration date stated on the packaging.

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.