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Composition:


active ingredients: carvedilol;


1 film-coated tablet contains 6.25 mg or 12.5 mg or 25 mg of carvedilol;


excipients: lactose, monohydrate; colloidal anhydrous silicon dioxide; crospovidone; povidone; sucrose; magnesium stearate; macrogol 400; polysorbate 80; Titanium Dioxide (E 171); hypromellose.


Dosage form. Film-coated tablets.


Basic physical and chemical properties:


6.25 mg tablets: white to almost white oval-shaped film-coated tablets marked "F 57" on one side and a deep fault line on the other side;


12.5 mg tablets: white to almost white oval-shaped film-coated tablets marked "F 58" on one side and a deep fault line on the other side;


25 mg tablets: white to off-white oval-shaped film-coated tablets marked "F 59" on one side and a deep fault line on the other side.


Pharmacotherapeutic group. A - and b-adrenergic blockers.


ATX code C07A G02.


Pharmacological properties.


Pharmacodynamics.


Carvedilol is a non-selective b-blocker with antioxidant properties. Its minor vasodilating effect is mainly manifested through selective blockade of A1 receptors. Due to vasodilation, carvedilol slightly reduces peripheral vascular resistance. In addition, it inhibits the activity of the renin-angiotensin-aldosterone system by blocking beta-adrenergic receptors. Carvedilol does not have its own sympathomimetic activity and, like propranolol, exhibits membrane-stabilizing properties. Carvedilol is a diostereoisomeric racemate. Blocking of adrenergic receptors β1 and β2 occurs mainly due to the enantiomer S(-). Carvedilol is a powerful antioxidant and free radical scavenger.


Carvedilol improves ejection fraction and left ventricular size in patients with left ventricular dysfunction. Carvedilol has virtually no adverse effect on the composition of serum lipids or electrolytes.


Pharmacokinetics.


Absolute bioavailability is approximately 25%. The peak concentration in the blood serum is reached after about 1 hour. The ratio between dose and serum concentration is linear. Food intake does not affect bioavailability, although it increases the time to reach the maximum concentration in blood plasma. Carvedilol is a highly lipophilic compound. Approximately 98-99% of carvedilol binds to plasma proteins. Its volume of distribution is approximately 2 l/kg, and it is higher in patients with cirrhosis of the liver. The effect of presystemic metabolism when taken orally is approximately 60-75 %.


The elimination half-life of carvedilol is 6-10 hours. Plasma clearance is approximately 590 mL / min. Excretion occurs mainly with bile and feces. A small part of the dose is excreted by the kidneys in the form of various metabolites. Carvedilol is metabolized in the liver, mainly by oxidation of the aromatic ring and glucuronidation. Demethylation and hydroxylation in the phenol ring lead to the formation of three active metabolites that affect beta-receptors. 4-hydroxyphenol is a metabolite as a beta-blocker 13 times more active than carvedilol. Compared to carvedilol, these three metabolites have a weak vasodilating effect. In humans, their concentrations are 10 times lower than those of carvedilol. Two of the hydroxycarbosol metabolites of carvedilol are exceptionally powerful antioxidants, and their activity in this regard is 30-80 times higher than that of carvedilol.


Clinical characteristics.


Indications.


* Essential hypertension.


* Chronic stable angina pectoris.


* Moderate to severe chronic stable heart failure as adjunctive therapy.


Contraindications.


Hypersensitivity to carvedilol or other components of the drug; decompensated heart failure (Class IV according to the NYHA classification, requiring intravenous administration of positive inotropic drugs and/or diuretics); chronic obstructive pulmonary disease with bronchial obstruction, bronchial asthma; clinically significant liver dysfunction; atrioventricular block II and III degrees (except when a permanent pacemaker is installed); severe bradycardia (


Interactions with other drugs and other types of interactions.


Antiarrhythmic drugs


When carvedilol, as well as other beta-blockers, are co-administered with calcium antagonists such as verapamil or diltiazem, as well as antiarrhythmic drugs, including amiodarone, due to the risk of atrioventricular conduction disorders and the risk of heart failure (synergistic effect), ECG and blood pressure should be carefully monitored. During treatment with carvedilol, these drugs should not be administered intravenously.


Cimetidine should be administered with caution, as the effect of carvedilol may increase.


Concomitant administration of reserpine, guanethidine, methyldopa, guanfacine, and monoamine oxidase inhibitors (with the exception of Mao – B inhibitors) may lead to an additional decrease in heart rate.


Dihydropyridine


The use of dihydropyridines and carvedilol should be carried out under close medical supervision, as there are reports of heart failure and severe hypotension.


Nitrates


Concomitant use with carvedilol leads to an increase in the hypotensive effect.


Cardiac glycosides


Taking carvedilol and digoxin may increase the time of atrioventricular conduction. In addition, the equilibrium minimum concentration of digoxin in patients with arterial hypertension increases by approximately 16% and digitoxin – by 13 %. It is recommended to monitor the concentration of digoxin in blood plasma at the beginning, at the end or adjustment of carvedilol therapy.


Other antihypertensive agents


Carvedilol may potentiate the action of antihypertensive agents that are prescribed simultaneously with it (for example, α1-receptor antagonists), and drugs with an antihypertensive additional effect, such as barbiturates, phenothiazines, tricyclic antidepressants, sleeping pills, tranquilizers, vasodilators and ethanol.


Cyclosporine


The level of cyclosporine in blood plasma increases with the simultaneous use of carvedilol. It is recommended to carefully monitor cyclosporine concentrations.


Antidiabetic medications, including insulin


Carvedilol may increase the reduction of blood sugar levels. Symptoms of hypoglycemia can be masked. Therefore, it is necessary to regularly monitor the level of glucose in patients with diabetes mellitus.


Clonidine


If carvedilol and clonidine are discontinued, the drug should be discontinued several days before the gradual withdrawal of clonidine.


Anesthetics


Caution is recommended when using anesthesia due to the synergistic, inotropic and hypotensive effects of carvedilol and certain anesthetics.


Nonsteroidal anti-inflammatory drugs, estrogens and corticosteroids


The antihypertensive effect of carvedilol decreases due to water and sodium retention.


Drugs that stimulate and inhibit cytochrome P450 enzymes


Patients receiving drugs that stimulate (e.g. rifampicin and barbiturates) or inhibit (e.g. cimetidine, ketoconazole, fluoxetine, haloperidol, verapamil, erythromycin) cytochrome P450 enzymes should be carefully monitored during concomitant treatment with carvedilol, because the concentration of carvedilol in the blood serum may decrease with the first of the above drugs and increase with Enzyme Inhibitors.


Sympathomimetics with α-mimetic and β-mimetic effects


Risk of developing arterial hypertension and severe bradycardia.


Ergotamine


Vasoconstriction increases.


Muscle relaxants


Carvedilol enhances the effect of muscle relaxants.


Xanthine derivatives


It should be used with caution with xanthine derivatives (aminophylline, theophylline) due to a decrease in the beta-blocking effect.

Application features.


Temporary worsening of heart failure symptoms may occur at the beginning of treatment or with an increase in the dose, especially in patients with severe heart failure and/or those taking high doses of diuretics. Although this usually does not require discontinuation of treatment, the dose should not be increased. The patient should be monitored by a cardiologist for at least 2 hours after taking the initial dose or increasing the dose. Before each dose increase, it is necessary to conduct an examination for possible worsening of heart failure or symptoms of excessive vasodilation (renal function, body weight, blood pressure, pulse and rhythm). Worsening of heart failure or fluid retention is treated by increasing the dose of the diuretic, and the dose of carvedilol should not be increased or decreased until the patient's clinical condition stabilizes. If bradycardia occurs or atrioventricular conduction is prolonged, sometimes it is necessary to reduce the dose of carvedilol or temporarily stop treatment. Even in these cases, titration of carvedilol doses can be successfully performed.


Renal function, platelets, and glucose should be monitored regularly when titrating the dose. However, at the end of titration, the frequency of control can be reduced.


Kidney failure


In patients with heart failure and low blood pressure (systolic pressure below 100 mm Hg). renal function may temporarily deteriorate during treatment with carvedilol.


This is especially true for patients who have disorders such as coronary heart disease, atherosclerosis, and/or pre-existing renal dysfunction. Renal function should be carefully monitored during dose titration in such patients. If renal function is significantly impaired, the dose of carvedilol should be reduced or treatment should be discontinued.


Moderate liver dysfunction


Dose selection may be required.


Patients with chronic obstructive pulmonary disease who do not receive oral or inhaled medications should only be prescribed carvedilol when the possible benefits of its use outweigh the potential risk. If there is a tendency to bronchospasm as a result of increased airway resistance when taking carvedilol, respiratory distress syndrome may develop. At the beginning of administration and with an increase in the dose of carvedilol, the condition of these patients should be carefully monitored, reducing the dose of the drug with the appearance of initial signs of bronchospasm.


With caution, the drug is prescribed to patients with diabetes mellitus, since it can mask the symptoms of hypoglycemia. At the beginning of carvedilol therapy or when changing its dose, frequent self – monitoring of glycemia is recommended and, if necessary, dose adjustment of hypoglycemic drugs.


Carvedilol may reduce the severity of thyrotoxicosis symptoms and may hide or reduce the symptoms of increased thyroid activity.


Carvedilol may cause bradycardia. If the pulse rate decreases to less than 55 beats per minute and there are symptoms associated with bradycardia, the dose of carvedilol should be reduced. People who use contact lenses should be informed about the possible reduction in tear production.


Caution should be exercised when prescribing carvedilol to patients suffering from allergic reactions and those undergoing desensitization, as beta-blockers can increase sensitivity to allergens and increase anaphylactic reactions. Caution should be exercised when prescribing beta-blockers to patients with psoriasis, as skin reactions may increase.


Caution should be exercised when prescribing carvedilol to patients with peripheral vascular diseases, as beta-blockers may increase the symptoms of arterial insufficiency and Raynaud's syndrome.


Patients with poor debrisoquine metabolism should be closely monitored by a doctor at the beginning of treatment.


Caution should be exercised when prescribing carvedilol to patients with labile and secondary arterial hypertension, since the experience of its use in these categories of patients is insufficient.


Patients with pheochromocytoma should be prescribed an alpha-blocker before using any beta-blockers. Although carvedilol has both beta-and Alpha-blocking properties, there is no experience of its use in such patients, so it is necessary to prescribe this drug to patients with suspected pheochromocytoma with caution.


Due to the negative Dromotropic effect, carvedilol Aurobindo should be used with caution in patients with first-degree AV block of the heart.


beta-blockers reduce the risk of arrhythmias during anesthesia, but the risk of hypotension may increase. Therefore, caution should be exercised when using anesthetics such as Ether, cyclopropane, trichloroethylene, which inhibit myocardial function. As with other beta-blockers, treatment with carvedilol should not be discontinued abruptly or suddenly due to the risk of withdrawal symptoms. Treatment with carvedilol should be discontinued gradually over two weeks, that is, by reducing the Daily Dose by half every three days. If necessary, you can simultaneously start replacement therapy to prevent exacerbation of the disease.


Elderly patients


Elderly patients may be more sensitive to the effects of carvedilol and therefore should be monitored by a doctor.


The drug contains lactose and sucrose. Patients with hereditary problems of sensitivity to galactose and fructose, lactase deficiency, sugar-isomaltase or glucose-galactose malabsorption, which occur rarely, should not take this medicine.


The drug should be used with extreme caution in the following conditions: blockage of the Right bundle branch, acute carditis, impaired heart valve function and hemodynamic disorders, bradycardia, left ventricular failure against the background of acute myocardial infarction. Patients with low blood pressure (less than 100 mm Hg).ST.) or the elderly (over 70 years of age) should be under close medical supervision for 2 hours after taking the first dose or after taking the first increased dose.


Use during pregnancy or lactation.


Clinical experience with the use of carvedilol during pregnancy is limited. When using carvedilol, the fetus or newborn may develop distress syndrome (bradycardia, hypotension, respiratory depression, hypoglycemia and hypothermia). Therefore, the use of carvedilol during pregnancy is contraindicated. It is not known whether carvedilol penetrates into breast milk. Since carvedilol may have harmful effects on infants, treatment with carvedilol should be discontinued during breast-feeding.


Ability to influence the reaction rate when driving vehicles or other mechanisms.


An individual response to the drug can change the ability to respond, that is, reduce the ability to actively participate in traffic, driving a car, and working with other mechanisms. This is especially true when starting treatment and changing the dosage. Treatment with carvedilol requires regular medical supervision.


Dosage and administration.


The drug should be taken orally, regardless of food intake, with a sufficient amount of liquid. However, patients with heart failure are advised to take carvedilol with a meal to prolong absorption and reduce the risk of orthostatic hypotension.


The dose should be adjusted individually, depending on the prescriptions and effectiveness of treatment. In any case, treatment should begin with the minimum effective doses. 1 hour after applying the recommended initial dose or after changing the dose, it is recommended to measure blood pressure to prevent the risk of hypotension. Stop treatment gradually, reducing the dose over 1-2 weeks. If carvedilol therapy is interrupted for more than 2 weeks, treatment should be resumed from the recommended initial dose and gradually increased according to the dosage recommendations of the drug.


Essential hypertension


Carvedilol can be used both in monotherapy and in combination with other antihypertensive drugs, especially diuretics. The drug is recommended to be used 1 time a day.


The maximum single dose should not exceed 25 mg, the recommended maximum daily dose is 50 mg.


The recommended starting dose in the first 2 days of treatment is 12.5 mg once a day. Then continue treatment at a dose of 25 mg twice a day. In the future, if necessary, the dose can be gradually increased at intervals of 2 weeks.


The recommended maximum daily dose is 100 mg, which should be divided into two doses.


Elderly patients. The recommended starting dose is 12.5 mg once a day and may be sufficient for further treatment. However, if the therapeutic effect of this dose is insufficient, it can be gradually increased at intervals of 2 weeks or more.


Chronic stable angina pectoris

The recommended mode of use is twice a day.


Adults. The recommended starting dose for the first 2 days is 12.5 mg twice daily. Then the treatment is continued at a dose of 25 mg twice a day. In the future, if necessary, the dose can be gradually increased at intervals of 2 weeks or more to the recommended maximum daily dose of 100 mg, divided into two doses.


Elderly patients. The recommended starting dose for the first 2 days is 12.5 mg twice daily. Treatment should then be continued at a dose of 25 mg twice daily, which is the recommended maximum daily dose.


Chronic heart failure


Carvedilol is used for moderate to severe heart failure as an adjunct therapy to conventional basic therapy with diuretics, ACE inhibitors, digitalis and/or vasodilators. Patients ' condition should be clinically stable (no changes in NYHA class, no hospitalization for heart failure), and Baseline therapy should be constant for at least the last 4 weeks prior to starting treatment. Additionally, patients should have a reduced left ventricular ejection fraction, heart rate >50 beats/min, and systolic blood pressure >85 mm Hg.art.


The initial dose for 2 weeks is 3,125 mg twice daily. If tolerated, the dose can be slowly increased at intervals of at least 2 weeks to a dose of 6.25 mg twice a day, then to 12.5 mg twice a day and eventually to 25 mg twice a day. The dose should be increased to the maximum level that is well tolerated by the patient.


The recommended maximum dose is 25 mg twice daily for patients weighing up to 85 kg and 50 mg of carvedilol twice daily for patients weighing more than 85 kg, provided that heart failure is not severe. Increasing the dose to 50 mg twice a day should be carried out carefully, under careful medical supervision.


At the beginning of treatment or with an increase in the dose, especially in patients with severe heart failure and/or those taking high-dose diuretics, there may be a temporary deterioration in the symptoms of heart failure. This is usually not a reason to cancel treatment, but the dose should not be increased. The patient should be monitored by a general practitioner/cardiologist for 2 hours after starting treatment or increasing the dose. Before each dose increase, it is necessary to assess possible signs of complications of heart failure or symptoms that indicate excessive vasodilation (for example, check kidney function, body weight, blood pressure, heart rate and rhythm). Complications of heart failure or fluid retention are treated with an increased dose of diuretics, and the dose of carvedilol should not be increased until the patient's condition stabilizes. If bradycardia occurs or in the case of prolongation of atrioventricular conduction, first of all, it is necessary to monitor the level of digoxin. Sometimes it may be necessary to reduce the dose of carvedilol or temporarily stop treatment. Often, even in such cases, treatment can be successfully continued by titrating the dose of carvedilol. During dose titration, renal function, platelet and glucose levels should be regularly monitored (in the case of insulin-dependent and/or non-insulin-dependent diabetes mellitus). However, after dose titration is completed, the frequency of studies may be reduced.


If carvedilol was discontinued less than 2 weeks ago, further treatment should be started with a dose of 3.125 mg twice daily and gradually increased according to the above recommendations.


Impaired renal function. The dosage should be set individually for each patient. However, according to pharmacokinetic parameters, it is unlikely that patients with impaired renal function will need to adjust the dose.


Moderate liver function disorders. You may need to adjust the dose.


Elderly patients. Elderly patients may be more sensitive to the effects of carvedilol and therefore need more careful monitoring.


If the patient is taking beta-blockers, and especially in the presence of coronary heart disease, carvedilol should be discontinued gradually.


Children.

The drug is not used in children.


Overdose.


Symptoms: severe hypotension, bradycardia, heart failure, cardiogenic shock, cardiac arrest; possible respiratory disorders, bronchospasm, vomiting, confusion, generalized seizures.


Treatment: patients should be monitored for the above signs and symptoms and treated with a doctor's view of the best option in accordance with standard practice in working with patients with an overdose of beta-blockers (for example, atropine, transvenous stimulation, glucagon, phosphodiesterase inhibitors such as amrinone or milrinone, beta-sympathomimetics).


Gastric lavage and artificially induced vomiting are effective in the first few hours after an overdose.


In case of severe overdose with shock symptoms, maintenance therapy should be continued for quite a long time, since it is possible to wait for the Half-Life of carvedilol to lengthen and redistribute it from the deep compartment. Supportive measures should be continued until the patient's condition stabilizes.


Adverse reactions.


Adverse reactions are more likely to occur at the beginning of treatment.


From the central nervous system and psyche: dizziness, headache, increased fatigue, fainting, dyskinesia, paresthesia, hypesthesia, vertigo, sleep disorders, depression.


From the side of the visual organs: visual impairment, decreased lacrimation, eye irritation, dry eyes.


From the gastrointestinal tract: nausea, diarrhea, vomiting, constipation, abdominal pain, Melena.


From the cardiovascular system: bradycardia, orthostatic reactions, AV block, angina attacks, worsening of heart failure, increased heart rate, orthostatic hypotension, arterial hypertension, leg edema, convulsions, hypotension.


From the skin and subcutaneous tissue: allergic exanthema, pruritus, urticaria, reactions that resemble lichen planus, the appearance of psoriatic plaques or exacerbation of the psoriatic process, increased sweating, alopecia, periodontitis, allergic reactions, anaphylactic reactions; dermatitis, increased sweating, alopecia, hyperemia, rashes.


From the side of metabolism and digestion: hyperglycemia (in patients with diabetes mellitus), peripheral edema, hypervolemia, fluid retention, hypercholesterolemia, glucosuria, hyperkalemia, hypertriglyceridemia, hyponatremia, anorexia/weight loss.


From the hematopoietic and lymphatic system: peripheral blood flow disorders, thrombocytopenia, leukopenia, anemia.


From the urinary system: deterioration of renal function, impaired urination, renal failure, hematuria, albuminuria, urinary incontinence in women, hyperuricemia, urinary tract infection.


Laboratory parameters: increased transaminase activity in blood serum, increased levels of alkaline phosphatase, creatinine, urea, decreased levels of prothrombin.


Musculoskeletal disorders: muscle atrophy, joint pain, pain in the extremities.


From the respiratory system: runny nose, pulmonary edema, bronchospasm, bronchitis, pneumonia, asthma, dry mouth, nasal congestion. In patients with a tendency to bronchial asthma, asthmatic shortness of breath and suffocation attacks were observed.


Immune system disorders: flu-like symptoms, fever, upper respiratory tract infections; hypersensitivity reactions, including angioedema; Stevens-Johnson syndrome; toxic epidermal necrolysis, erythema multiforme.


From the reproductive system: genital edema, impotence.


Common disorders: weight gain (at the beginning of treatment), infections, intermittent claudication, or Raynaud's disease.


Reactions in the form of acute hepatic insufficiency and impaired hepatic function were rare in patients with generalized atherosclerosis.


In patients with diabetes mellitus, carvedilol can cause latent diabetes mellitus. When treated with carvedilol, a moderate violation of the glucose balance may occur, but this is rare.

Tags: Carvedilol