Instructions for use Corvazan film-coated tablets 25 mg No. 30
Composition
active ingredient: carvedilol;
1 tablet contains carvedilol in terms of 100% substance 12.5 mg or 25 mg;
excipients: microcrystalline cellulose; povidone; lactose monohydrate; potato starch; talc; calcium stearate; coating mixture "Opadry II Pink"*.
* The coating mixture "Opadry II Pink" contains triacetin; hypromellose; lactose monohydrate; titanium dioxide (E 171), polyethylene glycol, iron oxide yellow (E 172); iron oxide black (E 172); erythrosine (E 127); indigo carmine (E 132).
Dosage form
Film-coated tablets.
Main physicochemical properties: round tablets, coated with a pink film coating, with a biconvex surface, with two perpendicularly intersecting lines on one side of the tablet (for a dosage of 12.5 mg) or round tablets, coated with a pink film coating, with a biconvex surface, with a line and the inscription "KMP" on both sides of the line on one side of the tablet (for a dosage of 25 mg).
Pharmacotherapeutic group
Alpha- and beta-adrenergic blockers. Carvedilol.
ATX code C07A G02.
Pharmacological properties
Pharmacodynamics
Carvedilol is a vasodilator, non-selective beta-blocker with antioxidant properties. The vasodilator effect is mainly due to selective blockade of alpha-1-adrenoreceptors. Carvedilol reduces peripheral vascular resistance by vasodilation and inhibition of the renin-angiotensin-aldosterone system activity as a result of blockade of beta-adrenoreceptors. Plasma renin activity is reduced, so fluid retention in the body is observed only in isolated cases.
Carvedilol has no sympathomimetic activity of its own and, like propranolol, exhibits membrane-stabilizing properties.
Carvedilol is a racemic mixture of two stereoisomers. Both stereoisomers have been shown to have alpha-adrenergic blocking properties in laboratory animal models. The beta-adrenergic blocking effects are not selective for beta-1 and beta-2 adrenoceptors and are associated with the levorotatory stereoisomer of carvedilol.
Carvedilol acts as a powerful antioxidant, reducing the number of active oxygen radicals.
Clinical data indicate that the vasodilator and beta-adrenergic blocking properties of carvedilol lead to the development of the following effects.
In patients with arterial hypertension, the decrease in blood pressure is not accompanied by a simultaneous increase in total peripheral vascular resistance, which is observed with the use of true beta-blockers. Heart rate (HR) decreases slightly. Renal perfusion and renal function remain unchanged. Since peripheral blood circulation is also not changed, a feeling of coldness in the extremities (which is often observed with the use of true beta-blockers) is rarely observed.
In patients with coronary heart disease, carvedilol exhibits anti-ischemic and antianginal effects that are maintained with long-term use of the drug. Carvedilol reduces pre- and afterload on the heart.
In patients with impaired left ventricular function or chronic heart failure, the drug has a beneficial effect on hemodynamic parameters and improves left ventricular ejection fraction.
During treatment with carvedilol, the ratio of high-density lipoproteins to low-density lipoproteins (HDL/LDL) remains normal. Electrolyte balance is not disturbed.
Pharmacokinetics
In men, the absolute bioavailability of carvedilol is approximately 25%. Peak serum concentrations are reached approximately 1 hour after oral administration. The relationship between dose and serum concentration is linear. Food intake does not affect bioavailability and peak serum concentrations, but increases the time to peak plasma concentrations. Carvedilol is a highly lipophilic compound: plasma protein binding is approximately 98-99%. The volume of distribution is approximately 2 l/kg, but is greater in patients with cirrhosis. Animal data suggest enterohepatic circulation of the parent compound.
Carvedilol is extensively metabolized to a number of metabolites, which are excreted mainly in the bile. Carvedilol is metabolized primarily in the liver, primarily by conjugation with glucuronic acid. Demethylation and hydroxylation of the phenolic ring lead to the formation of three active metabolites that have beta-adrenergic blocking activity. According to preclinical data, the 4-hydroxyphenolic metabolite is almost 13 times more active as a beta-adrenergic blocker than carvedilol. Compared with carvedilol, these three active metabolites have a weak vasodilator effect. In humans, their concentrations are 10 times lower than those of the parent compound. In addition, the two hydroxycarbazole metabolites of carvedilol are exceptionally potent antioxidants, with antioxidant activity 30-80 times greater than that of carvedilol.
Age does not affect the pharmacokinetics of the drug: in elderly patients, plasma levels of carvedilol are approximately 50% higher compared to those in young patients. There is evidence that the bioavailability of carvedilol in patients with liver cirrhosis is 4 times higher, and the maximum plasma concentration is 5 times higher than in healthy individuals.
There is evidence that in patients with arterial hypertension who have moderate (creatinine clearance 20-30 ml/min) or severe renal insufficiency (creatinine clearance < 20 ml/min), an increase in plasma concentrations of carvedilol by 40-55% is observed compared with that in patients with arterial hypertension whose renal function is within normal limits.
Indication
Essential hypertension.
Chronic stable angina.
Chronic heart failure (adjunctive treatment).
Contraindication
Hypersensitivity to the active substance or to any of the excipients of the drug;
decompensated heart failure;
NYHA class IV heart failure requiring intravenous inotropic agents;
atrioventricular block of the 2nd and 3rd degree (except in cases where a permanent pacemaker is installed);
concomitant intravenous administration of verapamil, diltiazem or other antiarrhythmic drugs (especially class I antiarrhythmic drugs);
severe bradycardia (heart rate <50 beats/min);
severe arterial hypotension (systolic pressure below 85 mm Hg);
heart attack with complications;
cardiogenic shock;
sick sinus syndrome (including sinoatrial block);
decompensated heart failure requiring intravenous administration of positive inotropic agents and/or diuretics;
pulmonary heart, pulmonary hypertension;
bronchial asthma or obstructive airway diseases accompanied by bronchospasm;
allergic rhinitis;
swelling of the glottis;
pheochromocytoma (unless adequately controlled with alpha-blockers);
Prinzmetal's angina;
severe liver dysfunction;
clinically manifest liver failure;
use of slow metabolizers such as debrisoquine and mephenytoin;
concomitant use of MAO inhibitors (except MAO-B inhibitors);
galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption;
metabolic acidosis;
pregnancy or breastfeeding;
childhood.
Interaction with other medicinal products and other types of interactions
Some antiarrhythmics, narcotics, antihypertensives, drugs for the treatment of angina, other β-blockers (e.g. in the form of eye drops), drugs that reduce the level of catecholamines (e.g. monoamine oxidase inhibitors, reserpine) and cardiac glycosides may enhance the effects of carvedilol. Therefore, the dose of these drugs and the drug Corvazan® should be selected with caution.
Pharmacokinetic interactions.
Inducers or inhibitors of P-glycoprotein, CYP2D6, CYP2D9.
Carvedilol is an inhibitor of P-glycoprotein, therefore the bioavailability of drugs transported by P-glycoprotein may increase when co-administered with carvedilol.
Inhibitors, as well as inducers of CYP2D6 and CYP2D9, can stereoselectively alter the systemic or presystemic metabolism of carvedilol, increasing or decreasing the plasma concentrations of R- and S-carvedilol.
Fluoxetine.
In studies of patients with heart failure, concomitant use of fluoxetine, a potent CYP2D6 inhibitor, resulted in stereoselective inhibition of carvedilol metabolism with a 77% increase in AUC of the R (+) enantiomer.
β-agonist bronchodilators.
Non-cardioselective β-blockers antagonize the effects of β-agonist bronchodilators, so such patients require close monitoring.
Antiarrhythmic drugs.
Careful monitoring of the patient's condition is necessary when carvedilol is used concomitantly with amiodarone (oral) or class I antiarrhythmic drugs. Bradycardia, cardiac arrest, ventricular fibrillation have been reported shortly after the start of treatment with β-blockers in patients receiving concomitant amiodarone. There is a risk of heart failure in the case of concomitant intravenous therapy with class Ia or Ia antiarrhythmic drugs.
Pharmacodynamic interactions.
Dihydropyridines.
When dihydropyridines and carvedilol are used concomitantly, careful patient monitoring should be ensured, as cases of heart failure and severe arterial hypotension have been reported.
Nitrates.
Enhances the hypotensive effect.
NSAIDs, estrogens, and corticosteroids.
The antihypertensive effect of carvedilol is weakened when used concomitantly with drugs that retain fluid and sodium in the body (due to a decrease in the hypotensive effect (due to a decrease in the production of prostaglandins)).
Sympathomimetics, β-mimetics and α-mimetics.
With simultaneous use, there is a risk of developing arterial hypertension and pronounced bradycardia and asystole, as well as a decrease in the beta-adrenergic blocking effect of carvedilol.
Ergotamine.
With simultaneous use, vasoconstriction increases.
Muscle relaxants.
When carvedilol is combined with muscle relaxants, neuromuscular blockade is enhanced.
Xanthine derivatives.
It should be used with caution with xanthine derivatives (aminophylline, theophylline) due to reduced β-adrenergic blocking effect.
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 carvedilol is initiated, adjusted, or discontinued.
Insulin or oral hypoglycemic agents.
Drugs with β-blocking properties may enhance the blood sugar-lowering effect of insulin and oral hypoglycemic agents. The symptoms of hypoglycemia may be masked or attenuated (especially tachycardia). Therefore, regular monitoring of blood glucose levels is recommended for patients taking insulin or oral hypoglycemic agents.
Drugs that reduce catecholamines.
Patients taking both drugs with β-blocking properties and a drug that can deplete catecholamines (e.g. reserpine, guanethidine, methyldopa, guanfacine and monoamine oxidase inhibitors (except MAO-B inhibitors)) should be closely monitored for hypotension and/or severe bradycardia.
Clonidine.
Concomitant administration of clonidine and drugs with β-blocking properties may potentiate the blood pressure and heart rate lowering effects. When concomitant treatment with drugs with β-blocking properties and clonidine is terminated, the β-blocking drug should first be discontinued. Then, after a few days, clonidine therapy can be discontinued by gradually reducing the dosage.
Anesthetics.
Extreme caution should be exercised during anesthesia due to the synergistic, negative inotropic, and hypotensive effects of carvedilol and anesthetics.
Drugs that affect the central nervous system (CNS).
With drugs that affect the CNS (hypnotics, tranquilizers, tricyclic antidepressants and ethyl alcohol) - due to the possibility of mutual enhancement of effects.
Other antihypertensive drugs.
Like other drugs with β-blocking activity, carvedilol may enhance the effect of other concomitantly administered drugs that are antihypertensive in action (e.g. α1-receptor antagonists) or may cause hypotension due to their side effect profile.
Other interactions.
Concomitant use of carvedilol with clonidine, guanethidine, reserpine, α-methyldopa, guanfacine and monoamine oxidase inhibitors (except MAO-B inhibitors) may potentiate the hypotensive effect and reduce heart rate. Therefore, careful monitoring for hypotension and/or severe bradycardia should be established.
Since carvedilol undergoes oxidative metabolism, its pharmacokinetics may change upon induction or inhibition of the cytochrome P450 enzyme system, therefore the effects of:
rifampicin (there is a 70% decrease in carvedilol plasma concentration);
barbiturates (reduce the effectiveness of carvedilol);
cimetidine (increases the bioavailability of carvedilol by 30%);
Digoxin: Carvedilol increases the concentration of digoxin in blood plasma;
CYP2D6 isoenzyme inhibitors (quinidine, fluoxetine, paroxetine, propafenone): an increase in the concentration of the R(+) enantiomer of carvedilol can be assumed;
Carvedilol inhibits the metabolism of cyclosporine.
Two studies in renal and cardiac transplant patients receiving oral ciclosporin have shown an increase in plasma ciclosporin concentrations after initiation of carvedilol treatment. Carvedilol appears to increase the exposure of oral ciclosporin by approximately 10–20%. To maintain therapeutic levels of ciclosporin, the dose of ciclosporin must be reduced by an average of 10–20%. The mechanism of this interaction is unknown, but inhibition of intestinal P-glycoprotein is likely involved. Due to the wide interindividual variability of ciclosporin levels, it is recommended that ciclosporin concentrations be carefully monitored after initiation of carvedilol treatment and that the ciclosporin dose be adjusted accordingly. There is also evidence that CYP3A4 is involved in the metabolism of carvedilol. Since tacrolimus is a substrate of P-glycoprotein and CYP3A4, carvedilol may also affect its pharmacokinetics through these mechanisms of interaction.
Alcohol
Concomitant alcohol consumption may interfere with the antihypertensive effect of carvedilol and may result in various adverse effects. Alcohol consumption has been shown to produce an acute hypotensive effect that may potentiate the blood pressure lowering effect of carvedilol. Since carvedilol is poorly soluble in water but soluble in ethanol, the presence of alcohol may affect the rate and/or extent of intestinal absorption of carvedilol by increasing solubility. In addition, carvedilol has been shown to be partially metabolized by the enzyme CYP2E1, which is both induced and inhibited by alcohol.
Grapefruit juice
A single dose of 300 ml of grapefruit juice resulted in a 1.2-fold increase in AUC of carvedilol compared to water. As the clinical significance of this observation is unknown, patients are advised to avoid concomitant intake of grapefruit juice at least until a stable dose-response relationship is established.
Nifedipine
With the simultaneous use of nifedipine and carvedilol, a significant decrease in blood pressure is possible.
Application features
Arterial hypotension.
The drug is not recommended for use in patients with low blood pressure.
Chronic heart failure.
In most cases, carvedilol should be prescribed in addition to diuretics, ACE inhibitors, digitalis and/or vasodilators in patients with chronic heart failure. Treatment should be initiated in a hospital setting under medical supervision. Therapy should only be initiated if the patient's condition has been stable for at least 4 weeks on standard basic therapy. Patients with severe heart failure (> NYHA class III), electrolyte imbalance, low blood pressure (< 100 mm Hg) or elderly (> 70 years of age) or dehydrated patients should be monitored closely for approximately 2 hours after the first dose or after dose increases, as hypotension may develop. Hypotension due to excessive vasodilation is initially treated by reducing the dose of diuretics, and if symptoms persist, the dose of any ACE inhibitor can be reduced. At the beginning of treatment or during dose increase, worsening of heart failure or fluid retention may occur. In this case, the dose of the diuretic should be increased. However, in some cases, dose reduction or discontinuation of the drug may be necessary. The dose of carvedilol should not be increased until symptoms associated with worsening heart failure or hypotension due to excessive vasodilation are controlled.
Carvedilol should be prescribed with caution to patients with chronic heart failure who are taking digitalis, as this combination prolongs atrioventricular conduction.
Carvedilol may cause bradycardia. If heart rate is < 55 beats/min and symptoms associated with bradycardia occur, the dose of the drug should be reduced.
Because carvedilol has an inherent negative dromotropic effect, it should be administered with caution to patients with first-degree heart block.
If carvedilol is used to treat hypertension or angina in patients with heart failure, therapy with the drug should be carried out according to the regimen recommended for the treatment of heart failure: the initial dose should not exceed 3.125 mg twice daily, and any dose increase should be carried out after at least 2 weeks of treatment with the previous dose of the drug.
The use of carvedilol in patients with hypertension who are already receiving digitalis, diuretics and/or ACE inhibitors requires close medical supervision, as all of these drugs may reduce atrioventricular conduction.
Antiarrhythmic drugs.
When using carvedilol simultaneously with calcium channel blockers such as verapamil and diltiazem, or other antiarrhythmic drugs, especially amiodarone, blood pressure and ECG should be monitored, so their simultaneous intravenous administration should be avoided.
Carvedilol may in very rare cases cause deterioration of liver function. If clinical deterioration is suspected, liver function should be checked. In case of liver failure, the patient should stop taking Corvazan®. As a rule, liver function normalizes after discontinuation of treatment.
Laboratory tests should be performed at the first sign/symptom of liver dysfunction (e.g., pruritus, dark urine, persistent loss of appetite, jaundice, right upper quadrant tenderness, or unexplained flu-like symptoms). If the patient's laboratory findings suggest liver injury or jaundice, carvedilol should be discontinued and not re-administered.
Orthostatic hypotension.
Especially at the beginning of treatment with Corvazan® and when the dose is increased, orthostatic hypotension with dizziness and vertigo, sometimes also with loss of consciousness, may occur. Patients with heart failure, the elderly, and patients taking other antihypertensive drugs or diuretics are at greatest risk. These effects can be prevented by using a low initial dose of Corvazan®, carefully increasing the maintenance dose and taking the drug after a meal. Patients should be told about measures to avoid orthostatic hypotension (caution when standing up; if dizziness occurs, the patient should sit or lie down).
Kidney function in congestive heart failure.
Reversible deterioration of renal function has been observed with carvedilol therapy in patients with chronic heart failure with low blood pressure (systolic blood pressure below 100 mm Hg), ischemic heart disease and diffuse vascular disease and/or underlying renal failure. In patients with congestive heart failure with these risk factors, renal function should be monitored during up-titration of carvedilol and the drug should be discontinued or the dose reduced if renal failure worsens.
Left ventricular dysfunction after acute myocardial infarction.
Before treatment with carvedilol, the patient should be clinically stable and have been taking an ACE inhibitor for at least 48 hours prior to carvedilol administration. The dose of the ACE inhibitor should be stable for at least 24 hours.
The use of the drug for unstable angina, as well as for first-degree atrioventricular block, requires special caution, frequent ECG recording and close medical supervision of patients.
Chronic obstructive pulmonary disease.
Carvedilol should be used with caution in patients with chronic obstructive pulmonary disease with a bronchospastic component who are not taking oral or inhaled medication, and only if the potential benefit outweighs the potential risk.
In patients with a tendency to bronchospasm, respiratory arrest may occur as a result of possible increased resistance. Patients should be closely monitored during initiation and titration of carvedilol, and the carvedilol dose should be reduced if any evidence of bronchospasm is observed during treatment.
Diabetes.
Like other beta-blockers, carvedilol may mask the symptoms of hypoglycemia and adversely affect carbohydrate metabolism. Caution should be exercised when using carvedilol in patients with diabetes mellitus, since early signs of acute hypoglycemia may be masked or reduced. 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 the dose is increased by titration, and appropriate adjustment 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 balanced.
Raynaud's phenomenon.
Carvedilol should be used with caution in patients suffering from peripheral circulatory disorders (e.g. Raynaud's phenomenon) as symptoms may be exacerbated.
Thyrotoxicosis.
Carvedilol may mask the symptoms of thyrotoxicosis. Abrupt withdrawal of the drug may lead to an increase in thyrotoxicosis and the development of a thyrotoxic crisis.
General anesthesia.
β-blockers reduce the risk of arrhythmias during anesthesia, but may also increase the risk of hypotension, so some anesthetics should be used with caution.
Carvedilol should be used with particular caution in patients undergoing surgery under general anesthesia when using anesthetics such as ether, cyclopropane, trichloroethylene, which suppress myocardial function.
Bradycardia.
Carvedilol may cause bradycardia. If the heart rate decreases to 55 beats per minute or less, the carvedilol dose should be reduced.
Caution should be exercised when administering carvedilol to patients with a history of serious hypersensitivity reactions and to patients undergoing desensitization therapy, since β-blockers may increase both sensitivity to allergens and the severity of anaphylactic reactions.
Very rare cases of serious skin adverse reactions, such as toxic epidermal necrolysis and Stevens-Johnson syndrome, have been reported during treatment with carvedilol. Carvedilol should no longer be prescribed to patients who experience serious skin adverse reactions that may be due to carvedilol.
Psoriasis.
Carvedilol treatment of patients with psoriasis requires careful assessment of the risk/benefit ratio, as carvedilol may exacerbate or trigger psoriasis symptoms.
Concomitant use of calcium channel blockers or antiarrhythmic drugs.
Close monitoring of ECG and blood pressure is necessary for patients receiving concomitant therapy with calcium channel blockers such as verapamil or diltiazem or other antiarrhythmic drugs.
Pheochromocytoma.
In patients with pheochromocytoma, an α-receptor blocker should be initiated before any β-receptor blocker is administered. Although carvedilol has pharmacological blocking activity against both α- and β-receptors, there is no experience with the use of carvedilol in this condition. Therefore, caution should be exercised when administering carvedilol to patients suspected of having pheochromocytoma.
Prinzmetal's angina.
In patients with Prinzmetal's angina, nonselective beta-blockers may cause chest pain. 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 administering carvedilol to patients suspected of having Prinzmetal's angina.
Contact lenses.
Patients who wear contact lenses should be warned that carvedilol reduces tear production.
Discontinuation of treatment.
Abrupt discontinuation of carvedilol (as with other beta-blockers) may cause sweating, tachycardia, shortness of breath, worsening of angina pectoris, and even myocardial infarction and ventricular arrhythmias. Patients with angina pectoris who are at risk of a heart attack are at greatest risk. The dose should be reduced gradually over 1-2 weeks. If necessary, replacement therapy can be started at the same time to prevent exacerbation of the disease. If treatment has been temporarily discontinued for more than 2 weeks, it should be resumed starting with the lowest dose.
Important information about the excipient of the drug.
This medicine contains lactose monohydrate. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.
The drug should not be prescribed to patients with the following health problems: galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
Alcohol.
Patients are not recommended to drink alcoholic beverages during treatment, as alcohol may enhance the effects of carvedilol.
Use during pregnancy or breastfeeding
Clinical experience with carvedilol during pregnancy is limited. Reproductive toxicity has been shown in animal studies. The potential risk for humans is unknown.
Beta-blockers reduce placental perfusion, which can lead to intrauterine fetal death, miscarriage, and premature birth.
It is suspected that the use of carvedilol may cause fetal or neonatal distress (bradycardia, hypotension, respiratory depression, hypoglycemia, and hypothermia). Neonates may be at increased risk of cardiac and pulmonary complications in the postpartum period.
Therefore, the use of carvedilol during pregnancy is contraindicated.
Animal studies have shown that carvedilol and/or its metabolites are excreted in the breast milk of rats. Excretion of carvedilol into human milk has not been established. However, most beta-blockers, especially lipophilic substances, penetrate into human milk to varying degrees.
It is not known whether carvedilol passes into breast milk. Since carvedilol may have harmful effects on the infant, treatment with carvedilol should be discontinued during breast-feeding.
Ability to influence reaction speed when driving vehicles or other mechanisms
No relevant studies have been conducted. Due to possible adverse reactions to carvedilol (e.g. dizziness, fatigue), caution should be exercised when driving or operating machinery during treatment. Particular caution is required at the beginning of treatment, after increasing the dose, when changing medications, or when taking in combination with alcohol.
Method of administration and doses
The tablets should be taken with meals and with sufficient liquid.
Essential hypertension.
The recommended initial dose is 12.5 mg once daily for the first two days of treatment. The recommended dose is then 25 mg daily. If necessary, the dose may be gradually increased at intervals of at least two weeks to a maximum recommended dose of 50 mg daily, which should be taken as a single dose or in two divided doses.
The drug can be used both as monotherapy and in combination with other antihypertensive drugs, especially thiazide diuretics.
Elderly patients
The recommended starting dose is 12.5 mg once daily. If the effect is insufficient, the dose can be gradually increased at intervals of at least two weeks to a maximum recommended daily dose of 50 mg.
Chronic stable angina.
The recommended starting dose is 12.5 mg twice daily for the first two days of treatment. The recommended dose is then 25 mg twice daily. If necessary, the dose may be increased at intervals of at least two weeks to a maximum recommended daily dose of 100 mg, which should be divided into two doses.
Elderly patients
The recommended initial dose is 12.5 mg twice daily for two days.
Then continue treatment at a dose of 25 mg 2 times a day, which is the recommended maximum daily dose.
Chronic heart failure.
The dose of the drug should be set individually, and its gradual increase should be carried out under the close supervision of a doctor.
Carvedilol can be used as an adjunct to standard therapy, but it can also be used in patients who are intolerant to ACE inhibitors or in patients receiving digitalis, hydralazine, or nitrates.
Patients taking digoxin, diuretics or ACE inhibitors should receive these drugs at a pre-established dose before starting treatment with carvedilol.
The recommended starting dose is 3.125 mg twice daily for two weeks. If this dose is well tolerated, it may be increased gradually at intervals of at least two weeks, initially to 6.25 mg twice daily, then to 12.5 mg twice daily, and finally to 25 mg twice daily. The dose should be increased to the highest dose that is well tolerated by the patient.
The maximum recommended dose is 25 mg twice daily for all patients with severe congestive heart failure and for patients with mild to moderate congestive heart failure weighing less than 85 kg. For patients with mild to moderate congestive heart failure weighing more than 85 kg, the maximum recommended dose is 50 mg twice daily.
At the beginning of therapy or when increasing the dose, a temporary increase in heart failure symptoms may occur, especially in patients with severe heart failure and/or in those patients receiving high doses of diuretics. Although in this case, discontinuation of treatment is usually not necessary, the dose of the drug should not be increased. During the first two hours after starting treatment with carvedilol or increasing its dose, the patient should be under the supervision of a cardiologist or other physician. Before each increase in the dose of the drug, the patient should be examined for possible symptoms of worsening heart failure or symptoms of excessive vasodilation (e.g., renal function, weight, blood pressure, heart rate and heart rhythm). Symptoms of worsening heart failure or fluid retention in the body are eliminated by increasing the dose of diuretics, but the dose of carvedilol should not be increased until the patient's condition is stabilized. If bradycardia occurs or in the event of prolonged atrioventricular conduction, the plasma digoxin level should be checked first. In some cases, it may be necessary to reduce the carvedilol dose or temporarily discontinue the drug altogether. Even in such cases, carvedilol can be successfully continued to be titrated.
During dose titration, renal function, platelet count and blood glucose levels (in non-insulin-dependent diabetes mellitus and/or insulin-dependent diabetes mellitus) should be monitored regularly. However, once dose titration is complete, the frequency of monitoring may be reduced.
If carvedilol treatment has been interrupted for more than 2 weeks, it should be resumed starting at a dose of 3.125 mg twice daily and gradually increased according to the recommendations above.
Elderly patients
Elderly patients may be more sensitive to the effects of carvedilol and therefore should be monitored more closely.
Patients with hepatic insufficiency
Carvedilol should not be administered to patients with severe hepatic impairment (see section 4.3). Dose adjustment may be required in patients with moderate hepatic impairment.
Patients with renal insufficiency
The dose must be set individually for each patient.
