Pharmacological properties
Pharmacodynamics. Non-selective β-adrenergic blocker with vasodilator action. It also has antioxidant and antiproliferative properties.
The active ingredient, carvedilol, is a racemate; the enantiomers differ in their effects and metabolism. The S (-) enantiomer has activity directed at blocking both α 1 - and β-blockers, while the R (+) enantiomer exhibits activity directed at blocking only α 1 -adrenoceptors. Due to cardioselective blockade of β-blockers, it reduces blood pressure, heart rate and cardiac output. Carvedilol reduces pressure in the pulmonary arteries and right atrium. By blocking α 1 -adrenoceptors, it causes peripheral vasodilation and reduces systemic vascular resistance. Due to these effects, the load on the heart muscle is reduced and the development of angina attacks is prevented. In patients with heart failure, this leads to an increase in the ejection fraction from the left ventricle and a decrease in the severity of the symptoms of the disease. Similar effects have been observed in patients with left ventricular dysfunction. Carvedilol does not exhibit intrinsic sympathomimetic activity and, like propranolol, has membrane-stabilizing properties. Plasma renin activity is reduced and fluid retention is rare. Effects on blood pressure and heart rate are evident 1-2 hours after administration.
In patients with hypertension and normal renal function, carvedilol reduces renal vascular resistance. There are no significant changes in filtration, renal blood flow, or electrolyte excretion. Due to the maintenance of peripheral blood flow, cooling of the extremities, which is characteristic of treatment with β-adrenergic blockers, is very rare.
Carvedilol generally does not affect plasma lipoprotein levels.
Pharmacokinetics. Carvedilol is rapidly and almost completely absorbed after oral administration. It is almost completely bound to plasma proteins. The volume of distribution is about 2 l/kg. The plasma concentration is proportional to the administered dose.
Due to extensive first-pass metabolism (mainly by the hepatic enzymes CYP 2D6 and CYP 2C9), the bioavailability of carvedilol is approximately 30%. Three active metabolites are formed that exhibit β-blocking activity; one of them (the 4'-hydroxyphenyl derivative) exhibits 13 times greater β-blocking activity than carvedilol. Compared with carvedilol, the active metabolites have a weak vasodilator effect. Metabolism is stereoselective, so the plasma level of R (+) carvedilol is 2-3 times higher than the level of S (-) carvedilol.
The plasma levels of active metabolites are approximately 10 times lower than that of carvedilol. The half-lives are very different: 5-9 hours for R (+) carvedilol and 7-11 hours for S (-) carvedilol.
Elderly patients have an increase in plasma carvedilol levels by approximately 50%. In patients with cirrhosis of the liver, the bioavailability of carvedilol is increased by 4 times, and C max in plasma is 5 times higher than in healthy subjects. In patients with impaired liver function, the bioavailability increases to 80% due to reduced first-pass metabolism. Since carvedilol is excreted mainly in the feces, significant accumulation of the drug is unlikely in patients with impaired renal function.
The presence of food in the stomach slows down the rate of absorption, but this does not affect its bioavailability.
Indication
Essential ag. The drug can be used alone or in combination with other antihypertensive drugs (especially with thiazide diuretics). Chronic stable angina. Chronic stable heart failure (as an adjunct to standard therapy with diuretics, digoxin or ACE inhibitors), to prevent disease progression in patients with heart failure II-III class according to the NYHA classification.
Application
To slow down absorption and prevent orthostatic effects, carvedilol should be taken with food in patients with heart failure. The dose should be selected individually. The tablets should be washed down with sufficient fluid. Treatment should be started with low doses, which should be gradually increased until the optimal clinical effect is achieved.
For the recommended dosage, tablets with the appropriate active substance content should be used. After taking the first dose and after each dose increase, it is recommended to measure the patient's blood pressure in a standing position 1 hour after taking the drug to exclude possible hypotension.
Treatment with the drug should be discontinued gradually by reducing the dose over 1 or 2 weeks. If treatment has been interrupted for more than 2 weeks, then its resumption should be started at a low dose.
Essential hypertension. The initial dose of carvedilol is 12.5 mg in the morning after breakfast or 6.25 mg 2 times a day (morning and evening). After 2 days of treatment, the dose should be increased to 25 mg in the morning (1 tablet of 25 mg) or to 12.5 mg 2 times a day. After 14 days of treatment, the dose can be increased again to 25 mg 2 times a day.
The maximum single dose of the drug for the treatment of hypertension is 25 mg, the maximum daily dose is not higher than 50 mg.
The recommended initial dose of carvedilol for the treatment of hypertension in patients with heart failure is 3.125 mg twice daily.
Chronic stable angina. The initial dose of carvedilol is 12.5 mg 2 times a day after meals. After 2 days of treatment, the dose should be increased to 25 mg 2 times a day.
The maximum dose of carvedilol for the treatment of chronic angina is 25 mg twice daily. The recommended initial dose of carvedilol for the treatment of angina in patients with heart failure is 3.125 mg twice daily.
Chronic stable heart failure. Carvedilol is recommended for the treatment of stable mild to moderate and severe chronic heart failure as an adjunct to standard therapy such as diuretics, ACE inhibitors or digitalis. The drug can also be used in patients who are intolerant to ACE inhibitors. Carvedilol should only be administered to the patient after titration of the diuretic, ACE inhibitor and digitalis (if applicable).
The dose should be selected individually. During the first 2-3 hours after the initial intake or after increasing the dose, careful medical supervision is necessary to check the tolerability of the drug. If the patient has a slowing of the heart rate to 55 beats / min, the carvedilol dose should be reduced. If symptoms of hypotension appear, then first of all, you should consider reducing the dose of the diuretic or ACE inhibitor; and if these measures are insufficient, then the carvedilol dose should be reduced.
At the beginning of treatment with the drug or after increasing the dose, a transient increase in heart failure may occur. In this case, it is necessary to increase the dose of the diuretic. Sometimes it is necessary to temporarily reduce the dose of carvedilol or even cancel the drug. After stabilization of the clinical condition, carvedilol treatment can be resumed or its dose increased.
The initial dose is 3.125 mg twice daily. If the patient tolerates this dose well, it can be gradually increased (every 2 weeks) until the optimal dose is reached. Subsequent doses are 6.25 mg twice daily, then 12.5 mg twice daily and 25 mg twice daily, provided that the patient tolerates the previously prescribed dose well. The patient should take the maximum dose that he tolerates well. The maximum recommended dose is 25 mg twice daily. For patients weighing 85 kg, the dose can be carefully increased to 50 mg twice daily.
Elderly patients: No dose adjustment is required.
Patients with hepatic impairment. The drug is not recommended for use in patients with severe hepatic impairment.
Patients with renal impairment: No dose adjustment is required for patients with systolic blood pressure <100 mmHg.
Contraindication
Increased individual sensitivity to the components of the drug, severe hypotension (systolic blood pressure 85 mm Hg), unstable or decompensated heart failure; heart failure requiring the administration of positive inotropic agents and / or diuretics; severe bradycardia (50 beats / min at rest), AV block II and III degree (except for patients with a permanent pacemaker), Prinzmetal's angina, sick sinus syndrome (including sinoatrial block), cardiogenic shock, obstructive airway diseases, BA or bronchospasm in history, pulmonary hypertension, cor pulmonale, severe hepatic failure, metabolic acidosis and pheochromocytoma (in the absence of adequate control with α-blockers).
Side effects
The following adverse reactions may occur when using carvedilol preparations.
Infections and infestations: bronchitis, pneumonia, upper respiratory tract infections, urinary tract infections.
On the part of the immune system: hypersensitivity (allergic reactions), anaphylactic reactions.
From the side of the central nervous system: headache, dizziness, increased fatigue, loss of consciousness (mainly at the beginning of treatment), depression, sleep disturbances, paresthesia.
From the cardiovascular system: orthostatic hypotension, bradycardia, hypertension, angina pectoris, tachycardia, peripheral circulatory disorders (cold extremities, peripheral vascular disease), claudication or Raynaud's disease, edema (including generalized, peripheral, orthostatic and edema of the genitals and legs), hypervolemia, orthostatic hypotension, AV block, progression of heart failure.
On the part of the respiratory system: shortness of breath, pulmonary edema, bronchial asthma (in sensitive patients), nasal congestion.
On the part of the digestive system: nausea, diarrhea, vomiting, constipation, abdominal pain, dry mouth, dyspepsia, periodontitis, melena.
Skin: rash, itching, urticaria, lichen planus, increased sweating, psoriasis or exacerbation of psoriasis, allergic exanthema, dermatitis, alopecia.
On the part of the organ of vision: visual impairment, decreased tear production (dry eyes), eye irritation.
Metabolic disorders: weight gain; impaired blood glucose control (hyperglycemia, hypoglycemia) in patients with pre-existing diabetes mellitus, hypercholesterolemia.
Musculoskeletal system: pain in the extremities, arthralgia, cramps.
Laboratory indicators: increased levels of transaminases and gamma-glutamyltransferase (GGT) in blood plasma, thrombocytopenia, leukopenia, decreased prothrombin levels, anemia, hyperkalemia, hypertriglyceridemia, hyponatremia, increased levels of ALP, creatinine, and urea.
Others: flu-like symptoms, pain, fever, asthenia, possible manifestations of latent diabetes, symptoms of existing diabetes may increase during therapy.
With the exception of dizziness, visual disturbances and bradycardia, none of the side effects described above are dose-related. Dizziness, fainting, headache and asthenia are usually mild and are most likely to occur at the beginning of treatment.
In patients with congestive heart failure, worsening of heart failure and fluid retention may occur when the carvedilol dose is increased by titration.
Special instructions
Chronic congestive heart failure. In patients with congestive heart failure, worsening of heart failure or fluid retention may occur when the carvedilol dose is increased by titration. If such symptoms occur, the diuretic dose should be increased, and the carvedilol dose should not be increased until clinical stability is restored. Occasionally, it may be necessary to reduce the carvedilol dose or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of the carvedilol dose.
Carvedilol should be used with caution in combination with cardiac glycosides, as the drugs slow AV conduction.
Orthostatic hypotension. At the beginning of treatment or when the dose of the drug is increased, patients may experience orthostatic hypotension with dizziness and vertigo, sometimes also with loss of consciousness. The greatest risk is observed in patients with heart failure, the elderly, as well as patients taking other antihypertensive drugs or diuretics. These effects can be prevented by using a low initial dose of the drug, carefully increasing the maintenance dose and taking the drug after a meal. Patients should be told about measures to prevent orthostatic hypotension (caution when standing up, if dizziness occurs, the patient should sit or lie down).
Renal function in congestive heart failure. Reversible deterioration of renal function has been observed during treatment with carvedilol in patients with chronic heart failure and low blood pressure (systolic blood pressure 100 mm Hg), ischemic heart disease and diffuse vascular disease and/or acute renal failure. In patients with congestive heart failure with such risk factors, renal function should be monitored when the carvedilol dose is increased by titration and the drug should be discontinued or the dose reduced if renal failure becomes more severe.
Left ventricular dysfunction after acute myocardial infarction. Before treatment with carvedilol, the patient should be clinically stable and should have been taking an ACE inhibitor for at least the previous 48 hours, and the dose of the ACE inhibitor should have been stable for at least the previous 24 hours.
COPD. The drug can be used in patients with COPD with a bronchospastic component who are not taking oral or inhaled medications only if the potential benefit outweighs the potential risk.
In patients with a tendency to bronchospasm, respiratory arrest is possible as a result of a possible increase in resistance. The patient should be carefully observed during initiation and titration of carvedilol, and the carvedilol dose should be reduced if any sign of bronchospasm is detected during treatment.
Diabetes mellitus. Caution should be exercised when using carvedilol in patients with diabetes mellitus, since early signs of acute hypoglycemia may be masked or not expressed. In patients with chronic heart failure with diabetes mellitus, the use of carvedilol may be associated with worsening of blood glucose control, therefore, regular monitoring of blood glucose levels is recommended for patients with diabetes mellitus when starting carvedilol or when increasing the dose by titration and appropriate correction of hypoglycemic therapy.
Peripheral vascular disease: Carvedilol should be used with caution in patients with peripheral vascular disease, as β-blockers may precipitate or exacerbate symptoms of arterial insufficiency. Since carvedilol also has α-blocking properties, this effect is largely counteracted.
Raynaud's disease: Carvedilol should be used with caution in patients with peripheral circulatory disorders (e.g. Raynaud's disease) as symptoms may be exacerbated.
Thyrotoxicosis: Carvedilol may mask the symptoms of thyrotoxicosis.
General anesthesia. When performing general anesthesia in patients taking β-adrenergic blockers, it is necessary to use drugs that have a less inotropic effect, or it is necessary to first stop (gradually) the treatment.
Hypersensitivity: Caution should be exercised when using carvedilol in patients with a history of serious hypersensitivity reactions and in patients receiving desensitization therapy, since β-blockers may increase both sensitivity to allergens and the severity of anaphylactic reactions.
Psoriasis. Patients who have previously developed or worsened psoriasis while receiving β-adrenergic blockers should be prescribed the drug only after careful assessment of the potential benefits and risks.
Concomitant use of calcium channel blockers or antiarrhythmic drugs. If necessary, simultaneous administration of calcium channel blockers - phenylalkylamine derivatives (verapamil) and benzothiazepine (diltiazem), as well as class I antiarrhythmic drugs (amiodarone), constant monitoring of ECG and blood pressure is recommended.
Pheochromocytoma. In patients with pheochromocytoma, α-adrenergic blocking agents should be initiated before any β-adrenergic blocking agents are used. Although carvedilol exhibits pharmacological blocking activity at both α- and β-receptors, there is no experience with carvedilol in this condition. Therefore, caution should be exercised when using carvedilol in patients suspected of having pheochromocytoma.
Prinzmetal's angina. Drugs with non-selective β-blocking properties may precipitate chest pain in patients with Prinzmetal's angina. There is no clinical experience with carvedilol in such patients, although the α-blocking activity of carvedilol may prevent such symptoms, but caution should be exercised when using carvedilol in patients suspected of having Prinzmetal's angina.
Contact lenses: Contact lens wearers should be warned about the possibility of decreased tear production.
Discontinuation of treatment. Abrupt discontinuation of carvedilol (as with other β-blockers) may result in increased sweating, tachycardia, dyspnea, and worsening of angina pectoris. The greatest risk is seen in patients with angina pectoris, who may experience a heart attack. The dose should be reduced gradually over 1-2 weeks. If treatment has been discontinued for more than 2 weeks, it should be restarted at the lowest dose.
Excipients. The drug contains sucrose and lactose. This drug is not recommended for patients with the following disorders: fructose intolerance, lactase deficiency, galactosemia, glucose-galactose malabsorption syndrome or sucrose-isomaltase deficiency.
Use during pregnancy and breastfeeding. There is insufficient clinical data on the effects of the drug during pregnancy. The potential risk to the fetus remains unknown. β-adrenergic blockers have a dangerous pharmacological effect on the fetus. They can cause hypotension, bradycardia and hypoglycemia in the fetus. The drug should not be used during pregnancy.
Since there is a possibility of carvedilol passing into breast milk, you should not breastfeed your baby during treatment with the drug.
Children. The drug is not recommended for use in children due to the lack of data on the safety and efficacy of its use in this category of patients.
Ability to influence the speed of reaction when driving vehicles or working with complex mechanisms. No studies have been conducted on the effect of carvedilol on the ability of patients to drive vehicles or work with complex mechanisms. Given the possibility of adverse reactions (for example, dizziness, increased fatigue), the patient's reaction speed may be impaired, which, in particular, applies to the start of treatment, increasing the dose, changing the drug, therefore it is recommended to refrain from driving vehicles or working with other mechanisms for the specified periods.
Interactions
Digoxin. Digoxin concentrations are increased by approximately 15% when digoxin and carvedilol are coadministered. Both digoxin and carvedilol slow AV conduction. Increased monitoring of digoxin levels is recommended when initiating, adjusting the dose, or discontinuing carvedilol.
Insulin or oral hypoglycemic agents. Drugs with β-blocking properties may enhance the blood glucose-lowering effect of insulin and oral hypoglycemic agents. Symptoms of hypoglycemia may be masked or attenuated (especially tachycardia). Therefore, regular monitoring of blood glucose levels is recommended in patients taking insulin or oral hypoglycemic agents.
Catecholamine-Depleting Drugs: Patients taking drugs with β-blocking properties and drugs that may deplete catecholamine levels (e.g. reserpine, guanethidine, methyldopa, guanfacine and MAO inhibitors, except MAO-B inhibitors) should be closely monitored for hypotension and/or severe bradycardia.
Cyclosporine. A modest increase in mean trough cyclosporine concentrations has been observed after initiation of carvedilol therapy in renal transplant patients with chronic vascular rejection. Approximately 30% of patients required a reduction in cyclosporine dose to maintain cyclosporine concentrations within the therapeutic range, while the remainder did not require dose adjustment. On average, the cyclosporine dose was reduced by approximately 20% in these patients. Close monitoring of cyclosporine concentrations is recommended after initiation of carvedilol therapy due to the wide individual variability in clinical response among patients.
Verapamil, diltiazem or other antiarrhythmic drugs. In combination with carvedilol, there may be an increased risk of AV conduction disturbances. Isolated cases of conduction disturbances (rarely with hemodynamic disturbances) have been reported when carvedilol and diltiazem were used concomitantly. As with other drugs with β-blocking properties (if carvedilol is administered orally together with calcium channel blockers (verapamil or diltiazem)), ECG and blood pressure monitoring are recommended. These drugs should not be administered intravenously. Careful monitoring of the patient's condition is necessary when carvedilol is administered concomitantly with amiodarone (oral) or class I antiarrhythmic drugs. Bradycardia, cardiac arrest, and ventricular fibrillation have been reported shortly after initiation of treatment with β-adrenergic blockers in patients receiving amiodarone. There is a risk of developing heart failure in the event of concomitant intravenous therapy with class Ia or Isa antiarrhythmic drugs.
Colindians. Concomitant administration of clonidine and drugs with β-blocking properties may enhance the effects of lowering blood pressure and heart rate. When concomitant treatment with drugs with β-blocking properties and clonidine is terminated, the β-adrenergic blocker should first be discontinued. Then, after a few days, clonidine therapy can be discontinued by gradually reducing the dose.
Antihypertensive drugs: Like other drugs with β-blocking activity, carvedilol may enhance the effect of other concomitantly administered drugs with antihypertensive properties (e.g. α1-adrenoceptor antagonists) or may lead to hypotension, consistent with its side effect profile.
Anesthetics: Caution should be exercised during anesthesia due to the synergistic negative inotropic and hypertensive effects of carvedilol and anesthetics.
Overdose
Symptoms: severe arterial hypotension (systolic blood pressure ≤80 mm Hg), bradycardia (50 beats / min), heart failure, cardiogenic shock, respiratory failure (bronchospasm), circulatory failure, vomiting, convulsions, cardiac arrest, confusion, generalized convulsions. Possible increase in adverse reactions.
Treatment: in the first hours - induce vomiting and wash the stomach, then - monitor and correct vital signs in the intensive care unit.
Supportive therapy: with severe bradycardia - atropine 0.5-2 mg IV; to support cardiac activity - glucagon 1-5 mg (maximum dose - 10 mg) IV jet, then 2-5 mg / h in the form of long-term infusions and / or adrenomimetics (orciprenaline, isoprenaline) 0.5-1 mg IV. If a positive inotropic effect is necessary, the issue of administering phosphodiesterase inhibitors should be resolved. If the peripheral vasodilator effect prevails, prescribe noradrenaline in repeated doses of 5-10 μg or as an infusion of 5 μg / min with titration according to the blood pressure. To relieve bronchospasm, use β 2-adrenomimetics in the form of an aerosol or, in case of ineffectiveness - IV; or aminophylline IV in the form of a slow injection or infusion. For convulsions - diazepam or clonazepam i/v slowly. In severe cases of intoxication with cardiogenic shock, continue supportive therapy until the patient's condition stabilizes, taking into account T ½ of carvedilol. For bradycardia resistant to treatment, the use of a pacemaker is indicated.
Storage conditions
At a temperature not exceeding 25 °C.
