Description
Pharmacological action
Has a combined nonselective beta-blocking, alpha1-blocking and antioxidant effect. The vasodilating effect is associated, mainly with alpha1 receptor blockade.
Thanks to vasodilation, it reduces the overall peripheral vascular resistance. It has no internal sympathomimetic activity and, like propranolol, has a membrane stabilizing effect.
A powerful antioxidant that eliminates free oxygen radicals. The combination of vasodilators and beta-blockers has the following effect: the combination of the vasodilating effect and beta-blocking properties of carvedilol leads to the fact that in patients with arterial hypertension, a decrease in blood pressure (BP) is not accompanied by a simultaneous increase in the total peripheral resistance, which is noted when taking beta-blockers . The heart rate slightly decreases, renal blood flow and kidney function are maintained. Since peripheral blood flow is maintained, cooling of the extremities is very rare, unlike patients who are treated with beta-blockers. The antihypertensive effect develops quickly – 2-3 hours after a single dose – and lasts for 24 hours. With prolonged treatment, the maximum effect is observed after 3-4 weeks.
In patients with coronary heart diseaseand carvedilol has anti-ischemic and antianginal effects. Reduces pre- and afterload on the heart. It does not have a pronounced effect on lipid metabolism and the content of potassium, sodium and magnesium ions in blood plasma.
In patients with impaired left ventricular function and / or circulatory failure, carvedilol has a beneficial effect on hemodynamic parameters: it increases the ejection function of the left ventricle and reduces its size.
Carvedilol has a beneficial effect on the hemodynamics of the heart and the ejection fraction of the left ventricle in both dilated cardiomyopathy and ischemic heart failure. With heart failure, end-systolic and end-diastolic volume decreases, as well as peripheral and pulmonary vascular resistance.
The ejection fraction and cardiac index do not change with normal heart function.
In case of dysfunction of the left ventricle, the alpha1-adrenergic blocking effect of carvedilol leads to the expansion of arterial and, to a lesser extent, venous vessels.
It has been established that with additional administration against the background of cardiac glycosides, angiotensin converting enzyme inhibitors and diuretics, carvedilol reduces the mortality rate, slows the progression of the disease and improves the general condition of the patient, regardless of the severity of the disease. The effect of carvedilol is more pronounced in patients with tachycardia (heart rate more than 82 beats / min) and a low ejection fraction (less than 23%). During treatment with carvedilol, the ratio of HDL / LDL cholesterol (high density lipoproteins / low density lipoproteins) does not change.
Indications
Arterial hypertension (in monotherapy or when used simultaneously with other antihypertensive drugs, for example, slow calcium channel blockers or diuretics)
coronary heart disease (including in patients with unstable angina pectoris and painless myocardial ischemia) failure (treatment of stable and symptomatic mild, moderate and severe chronic heart failure in combination with angiotensin converting enzyme inhibitors (ACE) and diuretics, with or without cardiac glycosides, in the absence of contraindications).
Contraindications
Hypersensitivity to the active substance and other components of the drug
acute and chronic heart failure in the decompensation stage, requiring intravenous administration of inotropic agents
sinus node weakness syndrome, collapse
bronchospasm and bronchial asthma (history)
severe hepatic impairment
metabolic acidosis
untreated pheochromocytoma (without the simultaneous use of alpha adenoblockers)
severe peripheral arterial circulatory disorders pulmonary obstructive pulmonary disease
pregnancy
lactation
age up to 18 years (efficacy and safety not established)
intolerance l actoses, lactase deficiency, glucose-galactose malabsorption.
Caution
should be used in patients with diabetes mellitus, hypoglycemia, thyrotoxicosis, chronic obstructive pulmonary disease (COPD), Prinzmetal angina, pheochromocytoma (with the simultaneous use of alpha-adrenergic blocking agents, see Special Instructions ), peripheral vascular occlusion diseases, grade I atrioventricular block, chronic heart failure with reduced myocardial contractility, left ventricular dysfunction after acute myocardial infarction, psoriasis, , depression, myasthenia, during general anesthesia, burdened with an allergic history (see section “Special instructions”), in the treatment of alpha-adrenoble with okator and alpha-adrenergic agonists, with simultaneous use with cardiac glycosides, diuretics and / or monoamine oxidase inhibitors (MAOs), slow calcium channel blockers (verapamil, diltiazem).
Use in pregnancy and lactation
There have been no controlled clinical trials in pregnant women taking carvedilol. Animal studies have revealed the presence of reproductive toxicity, the potential risk to humans is unknown. Beta-blockers reduce placental blood flow, which can lead to fetal death or premature birth. In addition, the fetus and newborns may develop hypoglycemia, bradycardia, and the risk of developing complications from the heart and lungs increases. The drug Carvedilol is contraindicated for use during pregnancy, unless the benefit to the mother outweighs the potential risk to the fetus. Animal studies have not revealed teratogenicity.
It is not known whether carvedilol passes into breast milk, however, most beta-blockers of the lipophilic structure to varying degrees penetrate into breast milk.
If you need to use the drug Carvedilol during lactation, breastfeeding should be discontinued.
Special instructions
In patients with chronic heart failure, symptoms of heart failure may be exacerbated or fluid retention may occur during titration of a dose of carvedilol. If such symptoms are observed, it is recommended to increase the dose of diuretics and suspend the increase in the dose of carvedilol until the patient’s condition stabilizes. Sometimes it may be necessary to reduce the dose of carvedilol or, in rare cases, its temporary withdrawal. Such episodes do not exclude the possibility of subsequent successful titration of a dose of carvedilol. Reversible impairment of renal function was observed during treatment with Carvedilol in patients with chronic heart failure and low blood pressure (systolic blood pressure. Dysfunction of the left ventricle after acute
myocardial infarction. Patients must be clinically stable and take ACE inhibitors for at least 48 h, and the dose of an ACE inhibitor should be stable for at least the last 24 hours
Carvedilol should be used with caution in patients with chronic obstructive pulmonary disease (COPD) with a bronchospastic component who do not receive bronchodilators (by mouth or by inhalation), and only when the potential benefit outweighs the potential risk.
In patients with a predisposition to bronchospasm, while taking Carvedilol, a possible increase in airway resistance may result in respiratory distress syndrome. Patients should be carefully observed at the beginning of therapy and during titration of the dose of the drug. The dose should be reduced if bronchospasm occurs during treatment.
Caution should be exercised when using the drug in patients with diabetes mellitus, since the early signs and symptoms of acute hypoglycemia may be masked or weakened. The use of the drug in patients with chronic heart failure with diabetes may be accompanied by poor control of blood glucose concentration.
Carvedilol should be used with caution in patients with peripheral vascular disease (for example, Raynaud’s syndrome), since beta-blockers can provoke or aggravate the symptoms of arterial insufficiency.
Carvedilol may mask the symptoms of thyrotoxicosis.
Carvedilol may cause bradycardia. If the patient ² ¢s heart rate drops below 55 beats per minute, the dose of carvedilol should be reduced or the drug should be discontinued.
Caution should be exercised when using Carvedilol in patients with a history of serious hypersensitivity reactions and when undergoing desensitizing therapy, since beta-blockers can increase sensitivity to allergens and aggravate the symptoms of anaphylactic reactions.
Patients with a history of psoriasis associated with the use of beta-blockers should take Carvedilol only after considering the risk / benefit ratio.
Careful monitoring of ECG and blood pressure is necessary in patients with concomitant therapy with nondihydropyridine blockers of “slow” calcium channels (eg, verapamil, diltiazem) or other antiarrhythmic drugs.
In patients with pheochromocytoma, an alpha-blocker should be prescribed before joining beta-blocker therapy (starting carvedilol therapy). Although carvedilol is both an alpha and beta blocker, there is no experience with its use in such patients. Therefore, caution should be exercised when using the drug in patients with suspected pheochromocytoma.
The use of non-selective beta-blockers can cause chest pain in patients with Prinzmetal angina pectoris. There is no clinical experience with carvedilol in such patients, although the alpha-adrenergic blocking property of the drug can prevent these symptoms.
Patients using contact lenses should be warned that the drug reduces lacrimation.
During treatment, alcohol intake should be excluded.
Discontinuation of the drug should be done gradually (within 1-2 weeks) in order to avoid the development of the “withdrawal” syndrome, especially in patients with coronary heart disease.
Effect on the ability to drive vehicles,
mechanisms During treatment with Carvedilol, caution should be exercised (risk of dizziness, headache, visual impairment) when driving vehicles and performing other potentially dangerous activities that require increased concentration and speed of psychomotor reactions.
Composition
Active ingredient: carvedilol 6.25 mg
Excipients 0.20 oxide yellow mg lactose monohydrate 61.8 mg microcrystalline cellulose 21.25 mg crospovidone 5.0 mg povidone K30 4.0 mg silicon colloidal dioxide 0.5 mg magnesium stearate 1.0 mg.
Dosage and administration
Carvedilol is taken orally with plenty of fluids.
Carvedilol is excreted mainly through the gastrointestinal tract, therefore, with impaired renal function, cumulation of the drug is not observed.
Arterial hypertension:
Initial dose – 12.5 mg / day once (in the morning after breakfast) for the first 2 days, then 25 mg once a day. If necessary, after 14 days the dose may be increased.
The maximum dose is 50 mg per day once or in 2 divided doses (morning and evening).
In elderly patients, in some cases, a dose of 12.5 mg may be effective.
Angina pectoris:
Initial dose – 12.5 mg 2 times a day for the first 2 days, then 25 mg twice (morning and evening) per day. If necessary, after 7-14 days, the daily dose can be increased to a maximum of 100 mg / day, divided into 2 doses.
In the elderly, the maximum daily dose is 50 mg, divided into 2 doses.
Chronic heart failure:
The dose is selected individually by careful monitoring. You should monitor the condition of the patient during the first 2-3 hours after the first dose or after the first increased dose. The dose and prescription of other drugs, such as digoxin, diuretics and ACE inhibitors should be fixed before the appointment of Carvedilol.
Carvedilol should be taken with meals (to reduce the risk of orthostatic hypotension).
Recommended starting dose of 3.125 mg twice daily for 14 days. With good tolerability of the drug and the need to increase the dosage, the drug is prescribed at a dose of 6.25 mg twice a day, then up to 25 mg twice a day. Patients are prescribed the maximum tolerated dose. The maximum recommended dose is 25 mg twice a day for patients with body weight up to 85 kg and 50 mg twice a day for patients with body weight more than 85 kg.
At the beginning of treatment and before each dose increase, the patient’s condition should be monitored, as the course of heart failure may worsen.
Fluid retention may develop, and due to the presence of a vasodilating effect, arterial hypotension and lethargy. With fluid retention, the dose of diuretics should be increased, in addition, a temporary reduction in the dose of Carvedilol may be required. Sometimes temporary suspension of treatment is required.
Side effects
According to the World Health Organization (WHO), unwanted effects are classified according to their frequency of development as follows: very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, <1/100), rarely (> 1/10000, <1/1000) and very rarely (<1/10000), the frequency is unknown - according to the available data, it was not possible to establish the frequency of occurrence. Infectious and parasitic diseases often: bronchitis, pneumonia, upper respiratory tract infections, urinary tract infections. Disorders of the blood and lymphatic system often: anemia rare: thrombocytopenia very rare: leukopenia. Immune disorders of the system are very rare: allergic reactions. Metabolic and nutritional disorders often: weight gain, hypercholesterolemia, in patients with diabetes mellitus – hyperglycemia or hypoglycemia, latent diabetes mellitus. Disturbances from the nervous system very often: dizziness, headache (usually mild and occurring more often at the beginning of treatment) often: depression, depressed mood, syncope, presyncopal conditions infrequently: loss of consciousness, sleep disturbances, paresthesia. Visual disturbances often: visual impairment, decreased lacrimation, eye irritation. Disorders from the cardiovascular system very often: development or worsening of symptoms of heart failure, marked decrease in blood pressure often: bradycardia, orthostatic hypotension, edema (including generalized, peripheral, body-dependent, perineal edema, edema of the lower extremities , hypervolemia, fluid retention), impaired peripheral circulation (cold extremities, exacerbation of the syndrome of “intermittent” claudication, Raynaud’s syndrome), increased blood pressure infrequently: atrioventriculum naya block, angina, chest pain. Disorders of the respiratory system, chest and mediastinal organs often: shortness of breath, pulmonary edema, bronchospasm (in predisposed patients) rare: nasal congestion. Disorders of the gastrointestinal tract often: dyspeptic disorders (including nausea, diarrhea, vomiting, abdominal pain) infrequent: constipation rare: dry mucous membrane of the oral cavity very rare: increased activity of the liver transaminase (alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase). Renal and urinary tract disorders often: impaired urination, impaired renal function in patients with diffuse vasculitis and / or impaired renal function very rarely: urinary incontinence in women. Genital and breast disorders infrequently: erectile dysfunction. Disorders of the musculoskeletal and connective tissue often: pain in the limbs. Disorders of the skin and subcutaneous tissue infrequently: skin reactions (urticaria, dermatitis, skin itching, skin rash, the appearance of skin lesions such as psoriasis and lichen planus), alopecia very rarely: toxic epidermal necrolysis (Lyell’s syndrome), polymorphic erythema, including malignant exudative erythema (Stevens-Johnson syndrome). Common disorders and disorders at the injection site of very often: asthenia (including increased fatigue), general weakness often: pain frequency unknown: sneezing, flu-like syndrome. Description of individual adverse events The frequency of occurrence of adverse reactions is not dose-dependent, with the exception of dizziness, visual impairment and bradycardia. Dizziness, syncope, headache and asthenia, as a rule, occur in a mild form and more often occur at the beginning of treatment. In patients with chronic heart failure during an increase in dose, symptoms of heart failure and fluid retention may be exacerbated (see Special Instructions). Drug interaction Pharmacokinetic interaction Carvedilol is a substrate and also an inhibitor of P-glycoprotein, so the bioavailability of drugs that bind to P-glycoprotein can be increased when used simultaneously with carvedilol. In addition, the bioavailability of carvedilol may be altered while being used with inducers or inhibitors of P-glycoprotein. Inhibitors and inducers of the isoenzyme CYP2D6 and CYP2C9 can selectively alter the systemic and / or presystemic metabolism of carvedilol, which leads to an increase or decrease in the plasma concentration of R (+) and S (-) stereoisomers of carvedilol. Digoxin The concentration of digoxin increases by approximately 15% when used with carvedilol. Since both drugs slow down AV conduction, it is recommended to control the concentration of digoxin in blood plasma at the beginning / cancellation of treatment and when adjusting the dose of carvedilol. Rifampicin Rifampicin reduces the plasma concentration of carvedilol by approximately 70%, probably due to the induction of P-glycoprotein, which leads to a decrease in the absorption of carvedilol in the intestine. Cyclosporin In some studies, when cyclosporin was administered orally, its plasma concentration increased after treatment with carvedilol was initiated. It is recommended that the plasma concentration of cyclosporin be carefully monitored after initiation of carvedilol therapy, since its fluctuations are possible over a wide range. If necessary, the dose adjustment of cyclosporin should be addressed. Amiodarone In patients with heart failure, amiodarone reduces the clearance of the S (-) stereoisomer of carvedilol, probably by inhibiting the CYP2C9 isoenzyme. The average plasma concentrations of the R (+) stereoisomer of carvedilol did not change. Therefore, there is a potential risk of increased AV blockade of beta-adrenergic receptors caused by an increase in the plasma concentration of the S (-) stereoisomer of carvedilol. Fluoxetine The simultaneous use of fluoxetine, a potent inhibitor of the CYP2D6 isoenzyme, led to a stereoselective inhibition of carvedilol metabolism with an increase of 77% on average of the plasma concentration of R (+) stereoisomer carvedilol. However, the clinical significance of this is unknown. Pharmacodynamic interaction Insulin or hypoglycemic agents for oral administration Carvedilol enhances the action of insulin and hypoglycemic agents for oral administration (while masking or reducing the severity of symptoms of hypoglycemia, reducing the breakdown of liver glycogen to glucose). In patients taking insulin or hypoglycemic agents by mouth, plasma glucose concentration should be regularly monitored. Catecholamine-depleting agents (reserpine, monoamine oxidase inhibitors) can cause severe bradycardia and hypotension. When combined with antiarrhythmic drugs (especially class I) and non-dihydropyridine blockers of slow calcium channels (verapamil, diltiazem), the risk of AV conduction disorders increases, and also increases the risk of severe arterial hypotension and heart failure (ECG and blood pressure monitoring is recommended). Intravenous administration of these drugs while taking carvedilol is contraindicated. Clonidine The simultaneous use of clonidine with beta-blockers can reduce blood pressure and heart rate. In the case of the simultaneous administration of clonidine and beta-blocker, in order to avoid the development of “withdrawal syndrome”, beta-blocker should first be canceled. Then, clonidine therapy can also be discontinued after a few days with a gradual dose reduction. Other antihypertensive drugs Inhibitors of microsomal oxidation (cimetidine), diuretics (including thiazide ones), vasodilators and angiotensin converting enzyme (ACE) inhibitors enhance the antihypertensive effect of carvedilol and can lead to a sharp drop in blood pressure. General anesthetics enhance the negative inotropic and hypotensive effects. Nonsteroidal anti-inflammatory drugs (NSAIDs) The simultaneous use of NSAIDs and beta-blockers can lead to increased blood pressure. Beta-adrenergic agonists (bronchodilators) Cardiac-selective beta-adrenergic blockers reduce the bronchodilatory effect of beta-adrenergic agonists, therefore careful monitoring of patients is recommended. Overdose Symptoms: vomiting, impaired consciousness, marked decrease in blood pressure (systolic pressure Treatment: within the first two hours, induce vomiting and rinse the stomach. Overdose requires intensive treatment. The patient should be in a raised position (Trendelenburg position). Antidote β-adrenergic blocking action is orciprenaline or isoprenaline 0.5-1 mg intravenously and / or glucagon in a dose of 1-5 mg (maximum dose 10 mg). Severe hypotension is treated with parenteral administration of fluid and repeated administration of adrenaline at a dose of 5-10 mg (or its intravenous infusion at a rate of 5 μg / min). With severe bradycardia, atropine is administered intravenously at a dose of 0.5-2 mg. If the peripheral vasodilating effect prevails (warm limbs, in addition to significant arterial hypotension), it is necessary to prescribe norepinephrine in repeated doses of 5-10 μg or in the form of infusion – 5 μg / min. For the relief of bronchospasm, beta-blockers are prescribed (in the form of an aerosol or intravenous) or aminophylline intravenously. If convulsions develop, slow administration of diazepam or clonazepam is recommended. In case of severe intoxication, when shock symptoms dominate, symptomatic therapy should continue until the patient’s condition stabilizes, taking into account the half-life of carvedilol 6-10 hours. In conditions of resuscitation, monitor the performance of vital organs. Active ingredient Carvedilol lekarstvennaja form tablets
