Carvedilol-Acrichin tablets 25 mg, tablets

Carvedilol is a blocker of α₁-, β₁,- and β₂-adrenoreceptors, 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 alpha-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 β-adrenoreceptors, it reduces the activity of renin-angiotensin-aldosterone system, reducing the release of renin, so fluid retention (characteristic of selective alpha-adrenoblockers) is rare.

By selectively blocking α₁-adrenoreceptors, carvedilol reduces HRP.

Carvedilol has no adverse effect on lipid profile, maintaining a normal ratio of high and low density lipoproteins (HDL/LDL).

In patients with arterial hypertension, carvedilol reduces BP by combined blockade of α₁– and β-adrenoreceptors. BP reduction is not accompanied by a simultaneous increase in PPS, which is observed with nonselective beta-adrenoblockers. 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 decreases the FFR; it does not disturb the blood supply of 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 rare. The hypotensive effect of carvedilol in arterial hypertension persists for a long time.

In patients with CHD, carvedilolol 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 (PPS). Carvedilol 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.

Indications

– arterial hypertension: essential hypertension (in monotherapy or in combination with other antihypertensive agents, such as slow calcium channel blockers or diuretics);

– CHD (including patients with unstable angina and myocardial ischemia);

– Chronic heart failure: treatment of stable and symptomatic mild, moderate and severe chronic heart failure (New York Heart Association /NYHA/ functional classes II-IV) of ischemic or nonischemic genesis in combination with ACE inhibitors and diuretics, with or without cardiac glycosides (standard therapy), in the absence of contraindications.

Active ingredient

Composition

1 tablet – carvedilol 25 mg.

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.

How to take, the dosage

Overly, regardless of meals, with plenty of fluid.

Essential hypertension

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

Chronic heart failure

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

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

Before each dose increase, the physician should examine the patient for a possible increase in symptoms of chronic heart failure or vasodilation. If there is a transient increase in symptoms of chronic heart failure or fluid retention, the dose of diuretics should be increased, although sometimes the dose of Accridilol® must be reduced or temporarily discontinued.

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

If treatment with Accridilolol® is interrupted for more than 1 week, its administration is resumed at a lower dose and then increased according to the above recommendations. If treatment with Acridylol®® is interrupted for more than 2 weeks, it should be restarted at a dose of 3.125 mg (1/2 tablet of 6.25 mg) 2 times daily, then the dose should be adjusted according to the above recommendations.

Dosing in Special Patient Groups

The current pharmacokinetic data in patients with various degrees of renal impairment (including renal failure) suggest that no dosage adjustment is necessary in patients with moderate to severe renal impairment®.

Acridilol® is contraindicated in patients with clinical manifestations of hepatic impairment.

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

Interaction

Pharmacokinetic interaction

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

Digoxin

The 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 discontinuing the drug.

Cyclosporine

In two studies, increased concentrations of cyclosporine were observed with carvedilol in patients who underwent kidney and heart transplantation and received oral cyclosporine. It appeared that due to inhibition of glycoprotein P activity in the intestine, carvedilol increases absorption of cyclosporine when administered orally. In order to maintain cyclosporine concentrations in the therapeutic range, it was necessary to reduce the dose of cyclosporine by an average of 10-20%. Due to the marked individual fluctuations of cyclosporine concentrations, it is recommended to monitor carefully its concentration after the start of carvedilol therapy and, if necessary, to adjust daily dose of cyclosporine accordingly. In case of intravenous administration of cyclosporine, no interaction with carvedilol is expected.

Rifampicin

In a study with healthy volunteers, rifampicin decreased plasma concentrations of carvedilol, most likely by induction of glycoprotein P, leading to decreased intestinal absorption of carvedilol and decreased its antihypertensive effect.

Amiodarone

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

Fluoxetine

In a randomized cross-over study in patients with heart failure, concomitant administration of fluoxetine (a CYP2D6 inhibitor) resulted in stereoselective inhibition of carvedilol metabolism – a 77% increase in the mean AUC for R (+). However, no difference in adverse events, BP or HR was observed between the two groups.

Pharmacodynamic interaction

Insulin or oral hypoglycemic agents

The drugs with beta-adrenoblocking properties may increase the hypoglycemic effect of insulin or oral hypoglycemic agents. Symptoms of hypoglycemia, especially tachycardia, may be masked or weakened. Patients receiving insulin or oral hypoglycemic agents are recommended to monitor blood glucose regularly.

Catecholamine-lowering agents

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

Digoxin

The combined therapy of agents with beta-adrenoblocking properties and digoxin may lead to additional slowing of atrioventricular conduction. Verapamil, diltiazem, amiodarone or other antiarrhythmic agents Concurrent use with carvedilol may increase the risk of AV conduction disturbances.

Clonidine

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

Slow calcium channel blockers (SCBs)

In concomitant administration of carvedilol and diltiazem there have been occasional cases of abnormal conduction (rarely with abnormal hemodynamic parameters). As with other drugs with beta-adreno-blocker properties, administration of carvedilol with BMCCs like verapamil or diltiazem is recommended under ECG and BP monitoring.

Antihypertensives

Like other drugs with beta-adrenoblocking activity, carvedilol may potentiate the effects of other concomitant antihypertensive agents (e.g., alpha1-adrenoblockers) or drugs that cause arterial hypotension as a side effect.

General anesthesia agents

The basic vital signs of general anesthesia should be monitored closely during general anesthesia because of the possible synergistic negative inotropic effect of carvedilol and general anesthesia agents.

NSAIDs

The co-administration of NSAIDs and beta-adrenoblockers may increase BP and decrease BP control.

Bronchodilators (β-adrenoreceptor agonists)

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

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 the dose of Akridilolol® is being adjusted. If such symptoms occur, the dose of diuretics should be increased and the dose of Accridilol® should not be increased until hemodynamic parameters are stabilized.

Sometimes it may be necessary to decrease the dose of Accridilol® or, in rare cases, temporarily discontinue the drug. Such episodes do not prevent further proper dosing of Accridilol®®.

Acridilolol® is used with caution in combination with cardiac glycosides (excessive slowing of AV conduction may occur).

Renal function in chronic heart failure

Acridilol ® is indicated in patients with chronic heart failure and low BP (systolic BP less than 100 mm Hg).st), CHD and diffuse vascular changes and/or renal insufficiency reversible worsening of renal function was noted. The dose of the drug is adjusted depending on the functional state of the kidneys.

Patients with COPD (including bronchospastic syndrome) who are not receiving oral or inhaled antiasthmatic agents, Akridilol® is indicated only if the possible benefits of its use exceed the potential risk. If there is an initial predisposition to bronchospastic syndrome, dyspnea may develop when taking Akridilol® as a result of increased airway resistance. These patients should be closely monitored at the beginning of administration and when the dose of the drug Akridilol® is increased, reducing the dose of the drug when the initial signs of bronchospasm appear.

Diabetes mellitus

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

Peripheral vascular disease

Acridilolol® should be used with caution in patients with peripheral vascular disease (including Raynaud’s syndrome) because beta-adrenoblockers may increase symptoms of arterial insufficiency.

Thyrotoxicosis

As with other beta-adrenoblockers, Akridilol® 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 that the adverse effects of Ackrodilol® and general anesthesia agents may add up.

Bradycardia

Acridilol® may cause bradycardia; if the heart rate is less than 55 bpm, the dose of the drug should be reduced.

Hypersensitivity

Acridilol® should be used with caution when prescribingpatients with a history of severe hypersensitivity reactions or who are undergoing desensitization, 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-adrenal blockers, Akridilol® should be prescribed only after a careful analysis of the possible benefits and risks.

Concomitant use of slow calcium channel blockers (CMBs)

In patients concomitantly 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 Acridylol® 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 cause pain in patients with Prinzmetal angina. There is no experience with Akridilolol® prescription in these patients. Although its alpha-adrenoblocking properties may prevent these symptoms, 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 Akridilol® is long-term. 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 CHD.

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

The use of alcohol should be avoided during treatment.

Impact on driving and operating machinery

At the time of treatment, care must be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased concentration and quick psychomotor reactions.

Contraindications

– acute and chronic decompensated heart failure requiring IV inotropic agents;

– clinically significant impairment of liver function;

–

– Under 18 years of age (the efficacy and safety of Acridylol®

– degree II or III AV blockade (except for patients with pacemaker);

– severe bradycardia (HR less than 50 bpm)./min);

– SSRI (including sinoatrial block);

– Severe arterial hypotension (systolic BP less than 85 mmHg.);

– cardiogenic shock;

– anamnestic evidence of bronchospasm and bronchial asthma;

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

– Hypersensitivity to carvedilol or any component of the drug.

With caution: in COPD, depression, myasthenia gravis, hypoglycemia, AV blockade of degree I, thyrotoxicosis, major surgical interventions and general anesthesia, Prinzmetal angina, diabetes, peripheral vascular occlusive disease, suspected pheochromocytoma, renal failure, psoriasis.

Side effects

Unwanted reactions occurring with a frequency of < 10% are considered to be very common. Unwanted reactions occurring with a frequency of < 1% to <10% are considered to be frequent. Unwanted reactions, occurring with a frequency of < 0.1% to <1%, are classified as infrequent. Unwanted reactions, occurring with a frequency of < 0.01% to < 0.1%, are classified as rare. Unwanted reactions occurring with a frequency of < 0.01%, including individual reports, are regarded as very rare. The incidence of adverse reactions, with the exception of dizziness, visual disturbances and bradycardia, is independent of the dose of the drug.

Unwanted reactions in patients with chronic heart failure

CNS disorders: very common – dizziness, headache (usually mild and occurring more frequently at the beginning of treatment); asthenia (including increased fatigue), depression.

Cardiovascular system: often – bradycardia, postural hypotension, significant BP decrease, edema (including generalized peripheral edema). generalized, peripheral, position-dependent edema, perineal edema, edema of lower extremities, hypervolemia, fluid retention); infrequent – syncopal states (including presyncopal), AV-blockade and heart failure during dose increase.

Gastrointestinal disorders: frequently – nausea, diarrhea, vomiting.

The hematopoietic system: rare – thrombocytopenia; very rare – leukopenia.

Metabolism: often – weight gain, hypercholesterolemia; in patients with preexisting diabetes – hyperglycemia or hypoglycemia, disorders of glycemic control.

Others: often – visual disturbances; rarely – renal failure and impaired renal function in patients with diffuse vasculitis and/or impaired renal function.

Unwanted reactions in patients with arterial hypertension and CHF

The nature of adverse cardiovascular events during treatment of arterial hypertension and long-term therapy of CHF is similar to that of chronic heart failure, but their frequency is somewhat lower.

CNS disorders: frequently – dizziness, headache and general weakness, usually mild and occurring especially at the beginning of treatment; infrequently – mood lability, sleep disturbances, paresthesias.

Cardiovascular system disorders: frequent – bradycardia, postural hypotension, syncopal states (infrequent), especially at the beginning of therapy; infrequent – peripheral circulatory disorders (coldness of extremities, worsening of intermittent claudication syndrome and Raynaud syndrome), AV-blockade, angina (chest pain), development or exacerbation of symptoms of heart failure and peripheral edema.

Respiratory system disorders: often – bronchospasm and dyspnea in predisposed patients; rarely – nasal congestion.

Gastrointestinal system disorders: frequently – dyspeptic disorders (including nausea, abdominal pain, diarrhea); rarely – constipation, vomiting.

Skin disorders: infrequent – skin reactions (skin rash, dermatitis, urticaria and itching).

Laboratory measures: very rarely – increase of liver transaminases activity (ALT, ACT and GGT) thrombocytopenia and leukopenia.

Others: often – pain in extremities, decreased tear production and eye irritation; infrequent – decreased potency, visual impairment; rare – dry mouth and urinary disorders; very rare – exacerbation of psoriasis, sneezing, flu-like syndrome. Individual cases of allergic reactions.

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, if necessary, in the intensive care unit should be carried out. The following measures can be used:

– lay the patient on his back (with elevated legs);

– in case of marked bradycardia – atropine 0.5-2 mg w/v;

– to maintain cardiovascular activity – glucagon 1-10 mg w/v in a stream, then 2-5 mg per hour as a prolonged infusion;

– sympathomimetics (dobutamine, isoprenaline, orciprenaline or epinephrine (adrenaline)) in different doses, depending on body weight and response to treatment.

If arterial hypotension dominates the clinical picture of overdose, norepinephrine (noradrenaline) is administered; it is administered with continuous monitoring of circulatory parameters. In treatment-resistant bradycardia an artificial pacemaker is indicated. In bronchospasm, beta-adrenomimetics are administered in aerosol form (if ineffective, intravenously) or aminophylline intravenously. In convulsions, diazepam or clonazepam are administered slowly by IV.

Since in severe overdose with symptoms of shock, the half-life of carvedilol and withdrawal of the drug from the depot may be prolonged, maintenance therapy should be continued for quite a long time. Duration of maintenance/detoxification therapy depends on the severity of overdose, it should be continued until the clinical condition of the patient is stabilized.

Pregnancy use

Similarities