Dilatrand, tablets 12.5 mg, 30 pcs.

Pharmgroup:

The alpha- and beta-adrenoblocker.

Pharmic action:

Carvedilol is an α1-, β1,- and β2-adrenoreceptor blocker, has an organoprotective effect, is an antioxidant that eliminates free oxygen radicals, has an antiproliferative effect against smooth muscle cells of the vascular walls. Carvedilol is a racemic mixture of R(+) and S(-) stereoisomers, each with the same α-adrenoblocking and antioxidant properties. The beta-adrenoblocking effects of carvedilol are non-selective and are due to the left-handed S(-) stereoisomer.

Carvedilol has no intrinsic sympathomimetic activity and, like propranololol, has membrane-stabilizing properties. By blocking beta-adrenoceptors it reduces activity of renin-angiotensin-aldosterone system, decreasing release of renin, therefore fluid retention (characteristic for selective alpha-adrenoblockers) occurs rarely.
By selectively blocking α1-adrenoceptors, carvedilolol reduces total peripheral vascular resistance.

Carvedilol has no adverse 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) by 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 beta-adrenoblockers. Heart rate (HR) decreases slightly. Renal blood flow and renal function in patients with arterial hypertension are preserved. It has been shown that carvedilol does not change the blood stroke volume and reduces the total peripheral vascular resistance; 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. Hypotensive effect of carvedilol in arterial hypertension is prolonged.
Ischemic heart disease

In patients with ischemic heart disease, carvedilol has antiischemic and antianginal effects (increase of total duration of exercise, time to ST-segment depression of 1 mm and time to angina attack) maintained during 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 (total peripheral vascular resistance).

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

Carvedilol is rapidly absorbed after oral administration. Carvedilolol is a substrate of the carrier protein that acts as a pump in the intestinal lumen, glycoprotein P. Glycoprotein P plays a major role in the bioavailability of certain drugs. Maximum plasma concentration (Cmax) is reached after about 1 hour. The absolute bioavailability of Carvedilol is approximately 25%.

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 the absorbed drug is metabolized during “first 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 CYP2D6 and CYP1A2, while the S stereoisomer is metabolized primarily by CYP2D9 and to a lesser extent by CYP2D6. Other P450 isoenzymes involved in the metabolism of carvedilol include CYP3A4, CYP2E1 and CYP2C19. The maximum plasma concentration of the R stereoisomer is approximately 2 times higher than that of the S stereoisomer.

The R stereoisomer is metabolized mainly by hydroxylation. Slow CYP2D6 metabolizers may have increased plasma concentrations of carvedilol, primarily the R stereoisomer, which is reflected in increased alpha-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 beta-adrenoblocking activity (the 4′-hydroxyphenol metabolite has about 13 times stronger activity than carvedilol itself). The 3 active metabolites have less pronounced vasodilatory properties than does carvedilol. 2 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.

The elimination half-life of carvedilolol is about 6 hours and plasma clearance is about 500-700 ml/min. Excretion is mainly through the intestine, the main excretion route is with the bile. A small part of the dose is excreted by the kidneys as various metabolites.

Pharmacokinetics in special groups of patients

Patients with impaired renal function

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

In patients with arterial hypertension and renal dysfunction the area under “concentration-time” curve (AUC), half-life and maximal plasma concentrations are not changed. Renal excretion of unchanged drug in patients with renal insufficiency decreases, but changes of pharmacokinetic parameters are insignificant.
Carvedilol is effective for treatment of patients with renovascular arterial hypertension, including patients with chronic renal insufficiency, as well as patients on hemodialysis or after renal transplantation. Carvedilol causes gradual reduction of BP both on the day of dialysis and days without dialysis, and its hypotensive effect is comparable with that in patients with normal renal function. Carvedilol is not excreted during dialysis because it does not pass through the dialysis membrane, probably due to its strong binding to plasma proteins.

Based on results from comparative studies in patients on hemodialysis, it has been concluded that carvedilol is more effective with better tolerability compared to slow calcium channel blockers.

Patients with impaired liver function

In patients with cirrhosis, the systemic bioavailability of the drug is increased by 80% due to a decrease in the severity of metabolism during “first passage” through the liver. Therefore, carvedilol is contraindicated in patients with clinically manifest liver dysfunction (see section “Contraindications”).

Patients with heart failure

In a study of 24 patients with heart failure, the clearance of the R and S stereoisomers of carvedilol was significantly lower compared to the previously observed clearance in healthy volunteers. These results suggest that the pharmacokinetics of the R and S stereoisomers of carvedilolol 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 elderly and elderly patients with arterial hypertension or coronary heart disease does not differ from that in younger patients.

Children

There are currently limited data on the pharmacokinetics of the drug in patients under 18 years of age.

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 who have 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. Dilatrend is indicated mainly in essential hypertension (as monotherapy or combined therapy with other antihypertensive drugs, e.g., slow calcium channel blockers or diuretics).

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

Chronic heart failure. Dilatrend is indicated for the treatment of clinically manifest mild, moderate and severe chronic heart failure of ischemic or non-ischemic genesis, to reduce complications (hospitalizations for cardiovascular causes) and mortality and to improve well-being and slow disease progression when used in combination with ACE inhibitors, diuretics and, sometimes, digitalis drugs (standard therapy).

Dilatrand may be prescribed as an adjunct to standard therapy and in patients who are not receiving digitalis, vasodilators, or nitrates.

Active ingredient

Composition

1 tablet contains carvedilol – 12.5 mg.

How to take, the dosage

The drug is taken orally with plenty of fluid.

The treatment with Dilatrand is prolonged. It should not be stopped abruptly; the dose of the drug should be gradually reduced at weekly intervals. This is especially important in patients with coronary heart disease.

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

Ischemic heart disease. The recommended starting dose is 12.5 mg twice daily for the first 2 days, 25 mg twice daily thereafter. If necessary, the dose may be subsequently increased at intervals of at least two weeks, reaching the highest daily dose of 100 mg divided into two doses.

Chronic heart failure. The dose should be adjusted individually, under close medical supervision In patients receiving foxglove drugs, diuretics and ACE inhibitors, their doses should be stabilized before starting treatment with Dilatrand.

The recommended starting dose is 3.125 mg twice daily for two weeks. If tolerated well, the dose is increased at intervals of at least two weeks, to 6.25 mg twice daily, then to 12.5 mg twice daily, then to 25 mg twice daily. The dose should be increased to a maximum that is well tolerated by the patient. The recommended maximum dose is 25 mg twice daily for all patients with severe chronic heart failure and for patients with mild to moderate chronic heart failure with body weight less than 85 kg. In patients with mild to moderate chronic heart failure and body weight over 85 kg – the recommended maximum dose is 50 mg twice daily. Before each dose increase, the physician should examine the patient for possible increase in symptoms of heart failure or vasodilation. If there is a transient increase in heart failure symptoms or fluid retention, the dose of diuretics should be increased, although sometimes the dose of Dilatrand must be reduced or temporarily discontinued.

If treatment with Dilatrand is interrupted for more than 1 week, its prescription is resumed at a lower dose and then increased according to the above recommendations. If treatment with Dilatrand is interrupted for more than 2 weeks, it should be restarted at a dose of 3.125 mg twice daily, then the dose should be adjusted according to the above recommendations.

The symptoms of vasodilatation can be resolved by reducing the dose of diuretics. If symptoms persist, the dose of the ACE inhibitor (if the patient is taking it) may be reduced, and then, if necessary, the dose of Dilatrand In this situation, the dose of Dilatrand should not be increased until the symptoms of increasing heart failure or arterial hypotension have stabilized. Doses in special patient groups.

Interaction

Digoxin. Concomitant administration of carvedilol and digoxin increases digoxin concentrations by approximately 15%. Regular monitoring of plasma digoxin concentrations is recommended at the beginning of therapy with carvedilol, when adjusting the dose or cancelling the drug.

Insulin or oral antidiabetic drugs. Drugs with beta-adrenoblocking properties may enhance the antidiabetic effect of insulin or oral antidiabetic drugs. Symptoms of hypoglycemia, especially tachycardia, may be masked or weakened. Patients receiving insulin or oral antidiabetic drugs are recommended to have regular blood glucose monitoring.

Hepatic metabolism inducers or inhibitors. Rifampicin reduces plasma concentrations of Carvedilol by approximately 70%.
Drugs that reduce catecholamines. Patients taking concomitant drugs with beta-adrenoblocking properties and catecholamine-lowering drugs (such as reserpine and monoamine oxidase inhibitors) should be closely monitored due to the risk of arterial hypotension and/or marked bradycardia.
Cyclosporine. Administration of carvedilol in patients undergoing renal transplantation, who developed chronic vascular rejection of transplant was observed a moderate increase in mean minimum concentrations of cyclosporine To keep cyclosporine concentrations in therapeutic range, in approximately 30% of patients the dose of cyclosporine had to be reduced (by 20% on average), the remaining patients did not need dose adjustment. Due to pronounced individual fluctuations of the required daily dose of cyclosporine it is recommended to carefully monitor cyclosporine concentration after the start of carvedilol therapy and, if necessary, appropriate correction of daily dose of cyclosporine.

Verapamil. diltiazem and other antiarrhythmic agents (propranololol, amiodarone). Concomitant use with carvedilol may increase the risk of atrioventricular conduction disorders.

Clonidine. Concomitant administration of clonidine with drugs with beta-blocking properties may potentiate antihypertensive and cardiac arrhythmia-reducing effects. If combined therapy with a beta-adreno-blocker and clonidine is planned to be discontinued, the beta-adreno-blocker should be withdrawn first and the clonidine may be withdrawn after a few days, gradually reducing its dose.

Slow calcium channel blockers. When concomitant administration of carvedilol and diltiazem, there have been isolated cases of conduction abnormalities (rarely with abnormal hemodynamic parameters). As with other drugs with beta-adrenoblocking properties, administration of carvedilol together with “slow” calcium channel blockers such as verapamil or diltiazem is recommended under ECG and blood pressure monitoring.

As with other drugs with beta-adrenoblocking activity, carvedilol may increase the effect of other concomitant antihypertensive agents (e.g., B-adrenoblockers) or drugs that have a hypotensive effect as a side effect.

Particular attention should be paid in general anesthesia to the possibility of synergistic negative inotropic effects of carvedilol and some anesthetics.

Special Instructions

Cronic Heart Failure

In patients with chronic heart failure, an increase in symptoms of chronic heart failure or fluid retention may be noted while adjusting the dose of Dilatrand®. If such symptoms occur, it is necessary to increase the dose of diuretics and not to increase the dose of the drug Dilatrand® until hemodynamic parameters are stabilized. Sometimes it is necessary to reduce the dose of Dilatrand® or, in rare cases, temporarily discontinue the drug. Such episodes do not prevent further proper dosing of Dilatrand®.

Dilatrand® is used with caution in combination with cardiac glycosides (excessive slowing of AV conduction is possible).

Renal function in chronic heart failure

When Dilatrend® was administered to patients with chronic heart failure and low blood pressure (systolic BP less than 100 mm Hg), coronary heart disease and diffuse vascular changes and/or renal failure, a reversible deterioration of renal function was observed. The dose of the drug is adjusted depending on the functional state of the kidneys.

Patients with COPD (including bronchospastic syndrome) who do not receive oral or inhaled antiasthmatic agents, Dilatrand® is administered only if possible benefits of its use exceed the potential risk. In the presence of initial predisposition to bronchospastic syndrome when taking Dilatrand® due to the increase of airway resistance, dyspnea may develop. At the beginning of use and when increasing the dose of Dilatrand® these patients should be carefully monitored, reducing the dose of the drug when the initial signs of bronchospasm appear.

Diabetes mellitus

The drug is prescribed with caution in diabetic patients because it may mask or attenuate the symptoms of hypoglycemia (especially tachycardia). In patients with chronic heart failure and diabetes mellitus the use of Dilatrand® may be accompanied by impaired glycemic control.

Peripheral vascular disease

Perhaps caution should be exercised when using Dilatrand® in patients with peripheral vascular disease (including Raynaud’s syndrome) because beta-adrenoblockers may increase the symptoms of arterial insufficiency.

Thyrotoxicosis

Like other beta-adrenoblockers, Dilatrand® may decrease the severity of symptoms of thyrotoxicosis.

General anesthesia and major surgical interventions

Caution is required in patients who are undergoing surgery under general anesthesia because of the possibility of summation of the negative effects of Dilatrend® and general anesthesia agents.

Bradycardia

Dilatrand® may cause bradycardia; if heart rate falls below 55 bpm the dose of Dilatrand® should be decreased.

We should use caution when prescribing Dilatrand® in patients with a history of severe hypersensitivity reactions or undergoing desensitization therapy, since beta-adrenoblockers may increase sensitivity to allergens and the severity of anaphylactic reactions.

Persons with a history of psoriasis occurrence or exacerbation when using beta-adrenoblockers, Dilatrand® should be prescribed only after a careful analysis of the possible benefits and risks.

Concomitant use of “slow” calcium channel blockers (CMBs)

In patients simultaneously taking CMBs such as verapamil or diltiazem as well as other antiarrhythmic agents, ECG and BP should be monitored regularly.

Pheochromocytoma

Pheochromocytoma patients should be prescribed an alpha-adrenoblocker before starting any beta-adrenoblocker. Although Dilatrand® has both beta- and alpha-adrenoblocking properties, there is no experience with its use in such patients, so it should be prescribed with caution in patients with suspected pheochromocytoma.

Prinzmetal angina

Nonselective beta-adrenoblockers may provoke pain in patients with Prinzmetal angina. There is no experience with Dilatrand® in these patients. Although its alpha-adrenoblocking properties may prevent this symptomatology, caution should be exercised when prescribing carvedilol in these cases.

Contact lenses

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

The “withdrawal” syndrome

The treatment with Dilatrand® is prolonged. It should not be stopped abruptly; the dose of the drug should be gradually reduced at weekly intervals. This is especially important in patients with coronary heart disease.

If there is a need for surgical intervention with general anesthesia it is necessary to warn the anesthesiologist about the previous therapy with dilatrend®.

At the time of treatment the use of alcohol is excluded.

Impact on driving and operating machinery

With regard to the potential side effects of Dilatrand® , caution should be exercised when prescribing it in patients whose work requires rapid psychomotor reaction, especially at the start of treatment, and when alcohol is taken concomitantly.

Contraindications

Hypersensitivity to carvedilol or any component of the drug, acute heart failure, clinically significant liver dysfunction, breast-feeding period.

Like other beta-adrenoblockers, Dilatrand should not be prescribed in patients with atrioventricular block of II and III degree (if no permanent pacemaker is installed), significant bradycardia (less than 50 bpm), sinus node weakness syndrome, significant arterial hypotension (systolic blood pressure less than 85 mm Hg), cardiogenic syndrome. st), cardiogenic shock, anamnestic signs of bronchospasm and bronchial asthma. The drug is used with caution in pulmonary emphysema, depression, myasthenia gravis, pregnancy.

Side effects

Adverse events in patients treated for arterial hypertension and ischemic heart disease
The nature of adverse events of Dilatrand in the treatment of arterial hypertension and long-term therapy of ischemic heart disease is similar to that in heart failure, but their frequency is somewhat lower.

The following adverse events have been reported in clinical studies in patients with arterial hypertension and coronary heart disease.

Central nervous system. Frequent: dizziness, headache and general weakness, usually mild and occurring particularly at the beginning of treatment. Infrequent: decreased mood, sleep disturbances, paresthesias.

The cardiovascular system. Frequent: bradycardia, postural hypotension, syncope, especially at the beginning of therapy. Infrequent: peripheral circulatory disorders (cold extremities, worsening of “intermittent” claudication and Raynaud’s syndrome), atrioventricular blockade angina pectoris (chest pain), symptoms of heart failure and peripheral edema.

Respiratory organs. Frequent: bronchospasm and dyspnea in predisposed patients. Rare: nasal congestion.

Gastrointestinal tract. Frequent: dyspeptic disorders (including nausea, abdominal pain, diarrhea). Infrequent: constipation, vomiting.
Skin. Infrequent: skin reactions (allergic rash, dermatitis, urticaria and itching).

Laboratory indicators. Occasional cases of increased activity of “liver” transaminases – alanine aminotransferase (ALT), aspartate aminotransferase (ACT) and gamma-glutamyltransferase, thrombocytopenia and leukopenia.

Other. Frequent: pain in the extremities, decreased lacrimation and eye irritation. Infrequent: decreased potency, visual impairment. Rare: dry mouth and urinary disorders.

Some cases of skin allergic reactions (exanthema, urticaria, itching, rashes), exacerbation of psoriatic rashes, sneezing, nasal congestion, bronchospasm, shortness of breath (in predisposed patients). Occasional cases of flu-like syndrome.

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

Overdose

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

Treatment: in addition to general measures, monitoring and correction of vital signs should be carried out, if necessary – in the intensive care unit. The following measures can be used:

a) lay the patient on his back
b) in case of marked bradycardia – atropine 0.5-2 mg intravenously;
c) to maintain cardiovascular activity – glucagon by 1-10 mg intravenous stream, then by 2-5 mg per hour as a long infusion;
d) sympathomimetics (dobutamine, isoprenaline, orciprenaline or adrenaline) in different doses, depending on body weight and therapeutic efficiency. If it is necessary to administer drugs with positive inotropic action, phosphodiesterase inhibitors are prescribed. If arterial hypotension dominates the clinical picture of overdose, norepinephrine shall be administered; it shall be administered with continuous monitoring of circulatory parameters.

In treatment-resistant bradycardia, an artificial pacemaker is indicated.

In case of bronchospasm, beta-adrenomimetics in the form of aerosol (intravenously if ineffective) or intravenous aminophylline are administered. In convulsions, diazepam or clonazepam should be given slowly intravenously. Since in severe overdose with shock symptoms the half-life of carvedilol may be prolonged and the drug may be eliminated from the depot, maintenance therapy should be continued for a sufficiently long time. Duration of maintenance/detoxification therapy depends on the severity of overdose, it should be continued until the patient’s condition stabilizes.

Similarities