Carvidil tablets 12.5mg №14×2

Name Carvidil tabl. The 12.5 mg tablets are pink, round, biconvex tablets with dark pink blotches and a notch (for dividing into 2 equal parts / doses, or for ease of swallowing) on one side. The 25 mg tablets are white, round, biconvex tablets with a notch (to divide into 2 equal portions/doses, or to facilitate swallowing) on one side. The main active ingredient of Carvedilol Release form 14 tablets are placed in a blister of PVC film and aluminum foil. 2 blisters with instructions for medical use are placed in a cardboard box. Dosage 12.5 mg in blister pack No. 14×2 Pharmacodynamics Carvedilol is a blocker of adrenergic receptors with a variety of actions and with blocking properties of ?1-, ?1- and ?2-adrenergic receptors. Carvedilol has been shown to have organ-protective effects. Carvedilol is a strong antioxidant and a binding agent for reactive oxygen radicals. Carvedilol is a racemic mixture, and both R(+) and S(-) enantiomers have α-adrenergic blocking and antioxidant properties. Carvedilol acts antiproliferatively on human vascular smooth muscle cells. In clinical trials during long-term treatment of patients with carvedilol, a decrease in oxidative stress has been proven. The α-adrenergic blocking action of carvedilol is non-selective for α1- and β2-adrenergic receptors and is associated with the S(-) enantiomer. Carvedilol has no intrinsic sympathomimetic activity and (like propranolol) has membrane stabilizing properties. Carvedilol inhibits the renin-angiotensin-aldosterone system via ?-blockade, which reduces renin release, so fluid retention is rare. Carvedilol reduces the resistance of peripheral blood vessels by selectively blocking α1-adrenergic receptors. Carvedilol reduces the increase in blood pressure caused by phenylephrine, an ?1-adrenergic agonist, but not the increase in blood pressure caused by angiotensin II. Carvedilol does not adversely affect lipid levels. A normal ratio of high and low density lipoproteins (HDL / LDL) is maintained. Clinical efficacy and safety In clinical studies, the following effects of carvedilol have been proven: Hypertension Carvedilol lowers blood pressure in patients with hypertension through a combination of ?-blockade and vasodilation associated with blockade of ?1-adrenergic receptors. Some of the traditional limitations of β-blockers do not apply to some vasodilatory β-blockers, such as carvedilol. The decrease in blood pressure is not associated with a simultaneous increase in total peripheral resistance, which is observed only in drugs that block ?-receptors. Carvedilol has been shown to preserve systolic volume and reduce total peripheral resistance. Carvedilol does not affect blood delivery to distant organs and blood vessels, as well as to the kidneys, skeletal muscles, forearms, legs, skin, brain, or carotid arteries. Reduces the frequency of cold extremities and early fatigue during exercise. The long-term effect of carvedilol on hypertension has been documented in many double-blind controlled trials. Renal disorders Many open studies have shown that carvedilol is effective in patients with renal hypertension. This also applies to patients with chronic renal failure, patients undergoing hemodialysis and patients after kidney transplantation. Carvedilol produces a gradual decrease in blood pressure both on days when dialysis is performed and on days when dialysis is not performed; the blood pressure lowering effect is comparable to that observed in patients with normal renal activity. Based on the results obtained in comparative clinical studies with patients undergoing dialysis, carvedilol was found to be more effective and better tolerated than calcium channel blockers. Chronic heart failure Carvedilol significantly reduces mortality and hospitalization, and also reduces symptoms and improves left ventricular function in patients with ischemic and non-ischemic chronic heart failure. The effect of carvedilol is dose dependent. Renal impairment In dialysis patients with dilated cardiomyopathy, carvedilol reduces morbidity and mortality. A meta-analysis of placebo-controlled clinical trials involving a large number of patients (>4000) with mild to moderate chronic kidney disease confirms that the use of carvedilol in patients with left ventricular dysfunction with or without symptomatic heart failure reduces all-cause mortality, as well as the incidence of complications associated with heart failure. Left ventricular dysfunction after myocardial infarction In a double-blind, placebo-controlled study in 1959 patients with a recent myocardial infarction and a left ventricular ejection fraction of ?40% or a wall motion index of ?1.3 (with or without symptomatic heart failure), carvedilol did not statistically significantly reduce additional main evaluation characteristic; all-cause mortality or hospitalization due to a cardiovascular event (8% reduction compared with placebo, p=0.297), but significantly reduced all deaths by 23% (p=0.031), all deaths, or non-fatal myocardial infarction myocardial infarction by 29% (p=0.002), mortality from cardiovascular causes by 25% (p=0.024) and hospitalization due to non-fatal myocardial infarction by 41% (p=0.014). In addition, retrospective analyzes showed that carvedilol significantly reduced the number of deaths or the frequency of severe cardiovascular hospitalizations by 17% (p = 0.019). Use in Special Patient Populations Elderly In a study of elderly patients with hypertension, it was shown that the profile of undesirable side effects does not differ compared to younger patients. In another study involving older people with coronary heart disease, no difference was observed in unwanted side effects compared to younger people. Therefore, the elderly do not need to adjust the initial dose. Kidney disorders With prolonged use of carvedilol, self-regulation of the blood supply to the kidneys is preserved, and glomerular filtration does not change. In patients with moderate to severe renal impairment, dose correlation of carvedilol is not required. Liver disorders The use of carvedilol is contraindicated in patients with clinical manifestations of liver dysfunction. In a pharmacokinetic study in patients with cirrhosis of the liver, it was shown that in patients with impaired liver activity, the total effect of carvedilol (AUC) was 6.8 times greater than in clinically healthy people. Patients with diabetes Beta-blockers may increase insulin resistance and mask the symptoms of hypoglycemia. However, beta-blockers that cause vasodilation, such as carvedilol, are associated with positive effects on glucose and lipid levels. It has been proven that carvedilol has a moderate insulin sensitizing effect, and that this can reduce some manifestations of the metabolic syndrome. Carvedilol is an adrenergic blocker with a variety of actions and with blocking properties of ?1-, ?1- and ?2-adrenergic receptors. Carvedilol has been shown to have organ-protective effects. Carvedilol is a strong antioxidant and a binding agent for reactive oxygen radicals. Carvedilol is a racemic mixture, and both R(+) and S(-) enantiomers have α-adrenergic blocking and antioxidant properties. Carvedilol acts antiproliferatively on human vascular smooth muscle cells. In clinical trials during long-term treatment of patients with carvedilol, a decrease in oxidative stress has been proven. The α-adrenergic blocking action of carvedilol is non-selective for α1- and β2-adrenergic receptors and is associated with the S(-) enantiomer. Carvedilol has no intrinsic sympathomimetic activity and (like propranolol) has membrane stabilizing properties. Carvedilol inhibits the renin-angiotensin-aldosterone system via ?-blockade, which reduces renin release, so fluid retention is rare. Carvedilol reduces the resistance of peripheral blood vessels by selectively blocking α1-adrenergic receptors. Carvedilol reduces the increase in blood pressure caused by phenylephrine, an ?1-adrenergic agonist, but not the increase in blood pressure caused by angiotensin II. Carvedilol does not adversely affect lipid levels. A normal ratio of high and low density lipoproteins (HDL / LDL) is maintained. Clinical efficacy and safety In clinical studies, the following effects of carvedilol have been proven: Hypertension Carvedilol lowers blood pressure in patients with hypertension through a combination of ?-blockade and vasodilation associated with blockade of ?1-adrenergic receptors. Some of the traditional limitations of β-blockers do not apply to some vasodilatory β-blockers, such as carvedilol. The decrease in blood pressure is not associated with a simultaneous increase in total peripheral resistance, which is observed only in drugs that block ?-receptors. Carvedilol has been shown to preserve systolic volume and reduce total peripheral resistance. Carvedilol does not affect blood delivery to distant organs and blood vessels, as well as to the kidneys, skeletal muscles, forearms, legs, skin, brain, or carotid arteries. Reduces the frequency of cold extremities and early fatigue during exercise. The long-term effect of carvedilol on hypertension has been documented in many double-blind controlled trials. Renal disorders Many open studies have shown that carvedilol is effective in patients with renal hypertension. This also applies to patients with chronic renal failure, patients undergoing hemodialysis and patients after kidney transplantation. Carvedilol produces a gradual decrease in blood pressure both on days when dialysis is performed and on days when dialysis is not performed; the blood pressure lowering effect is comparable to that observed in patients with normal renal activity. Based on the results obtained in comparative clinical studies with patients undergoing dialysis, carvedilol was found to be more effective and better tolerated than calcium channel blockers. Chronic heart failure Carvedilol significantly reduces mortality and hospitalization, and also reduces symptoms and improves left ventricular function in patients with ischemic and non-ischemic chronic heart failure. The effect of carvedilol is dose dependent. Renal impairment In dialysis patients with dilated cardiomyopathy, carvedilol reduces morbidity and mortality. A meta-analysis of placebo-controlled clinical trials involving a large number of patients (>4000) with mild to moderate chronic kidney disease confirms that the use of carvedilol in patients with left ventricular dysfunction with or without symptomatic heart failure reduces all-cause mortality, as well as the incidence of complications associated with heart failure. Left ventricular dysfunction after myocardial infarction In a double-blind, placebo-controlled study in 1959 patients with a recent myocardial infarction and a left ventricular ejection fraction of ?40% or a wall motion index of ?1.3 (with or without symptomatic heart failure), carvedilol did not statistically significantly reduce additional main evaluation characteristic; all-cause mortality or hospitalization due to a cardiovascular event (8% reduction compared with placebo, p=0.297), but significantly reduced all deaths by 23% (p=0.031), all deaths, or non-fatal myocardial infarction myocardial infarction by 29% (p=0.002), mortality from cardiovascular causes by 25% (p=0.024) and hospitalization due to non-fatal myocardial infarction by 41% (p=0.014). In addition, retrospective analyzes showed that carvedilol significantly reduced the number of deaths or the frequency of severe cardiovascular hospitalizations by 17% (p = 0.019). Use in Special Patient Populations Elderly In a study of elderly patients with hypertension, it was shown that the profile of undesirable side effects does not differ compared to younger patients. In another study involving older people with coronary heart disease, no difference was observed in unwanted side effects compared to younger people. Therefore, the elderly do not need to adjust the initial dose. Kidney disorders With prolonged use of carvedilol, self-regulation of the blood supply to the kidneys is preserved, and glomerular filtration does not change. In patients with moderate to severe renal impairment, dose correlation of carvedilol is not required. Liver disorders The use of carvedilol is contraindicated in patients with clinical manifestations of liver dysfunction. In a pharmacokinetic study in patients with cirrhosis of the liver, it was shown that in patients with impaired liver activity, the total effect of carvedilol (AUC) was 6.8 times greater than in clinically healthy people. Patients with diabetes Beta-blockers may increase insulin resistance and mask the symptoms of hypoglycemia. However, beta-blockers that cause vasodilation, such as carvedilol, are associated with positive effects on glucose and lipid levels. Carvedilol has been shown to have a moderate insulin sensitizing effect and that this may reduce some manifestations of the metabolic syndrome. Pharmacokinetics Absorption After oral administration of 25 mg capsules to clinically healthy people, carvedilol is rapidly absorbed and reaches a maximum plasma concentration Cmax of 21 mg / l after about 1.5 hours (Tmax). Cmax values linearly depend on the dose. Following oral administration, carvedilol undergoes extensive first-pass metabolism, resulting in an absolute bioavailability of approximately 25% in clinically healthy men. Carvedilol is a racemic mixture and the S(-) enantiomer is metabolized faster than the R(+) enantiomer, so its absolute oral bioavailability is 15% compared to 31% of the R(+) enantiomer. The maximum concentration of R-carvedilol in plasma is approximately 2 times greater than the concentration of S-carvedilol. In vitro studies have shown that carvedilol is a substrate for the release of the transport protein P-glycoprotein. The role of P-glycoprotein in the circulation of carvedilol has also been proven in vivo in clinically healthy individuals. Distribution Carvedilol is a highly lipophilic compound and approximately 95% of carvedilol is bound to plasma proteins. The volume of distribution is in the range of 1.5 to 2 l/kg. Biotransformation In humans, carvedilol is extensively metabolized in the liver by oxidation and conjugation to various metabolites, which are primarily excreted in the bile. Prodrug enterohepatic circulation has been proven in animals. Demethylation and hydroxidation at the phenol ring forms 3 metabolites with a blocking effect on α-adrenergic receptors. Based on preclinical studies, the 4′-hydroxyphenol metabolite is approximately 13 times more potent as a ?-blocker than carvedilol. Compared to carvedilol, the three active metabolites have a weak vasodilating effect. In humans, the concentration of the three active metabolites is about 10 times lower than that of the drug. Two of carvedilol’s hydroxycarbazole metabolites are very potent antioxidants that are 30 to 80 times more potent than carvedilol. Pharmacokinetic studies in humans indicate that the oxidative metabolism of carvedilol is stereoselective. The results of an in vitro study indicate that various cytochrome P450 isoenzymes may be involved in oxidation and hydroxylation, including CYP2D6, CYP3A4, CYP2E1, CYP2C9, and CYP1A2. Studies involving clinically healthy volunteers and patients indicate that the R-enantiomer metabolizes mainly CYP2D6. In turn, the S-enantiomer is metabolized mainly by CYP2D6 and CYP2C9. Genetic polymorphism The results of a clinical pharmacokinetic study in humans indicate that the main role in the metabolism of R- and S-carvedilol belongs to CYP2D6. Therefore, in slow metabolizers of CYP2D6, plasma concentrations of R- and S-carvedilol are increased. The significance of the CYP2D6 genotype in the pharmacokinetics of R- and S-carvedilol has been proven in population pharmacokinetic studies, in turn, this observation has not been repeated in other studies, which implies that the genetic polymorphism of CYP2D6 may be of limited clinical significance. Withdrawal After a single oral administration of 50 mg of carvedilol, approximately 60% of the dose is excreted in the bile and in the form of metabolites in the faeces within 11 days. After a single oral dose, only approximately 16% of the dose is excreted in the urine as carvedilol or its metabolites. Less than 2% of the drug is excreted unchanged in the urine. After an intravenous infusion of a dose of 12.5 mg to healthy volunteers, the plasma clearance of carvedilol reaches approximately 600 ml / min, and the elimination half-life is approximately 2.5 hours. The elimination half-life of the 50 mg capsules in these same study participants was 6.5 hours, which is indeed the half-life of absorption from the capsules. After oral administration, the total body clearance of S-carvedilol was twice that of R-carvedilol. Pharmacokinetics in special groups of patients Impaired renal function In patients with hypertension and renal insufficiency, the area under the curve of plasma concentration and time, elimination half-life and maximum plasma concentration do not change significantly. Excretion of unchanged drug through the kidneys is reduced in patients with renal insufficiency; however, changes in pharmacokinetic parameters are moderate. Carvedilol is not eliminated during dialysis because it does not cross the dialysis membrane, possibly because it is highly bound to plasma proteins. Liver dysfunction See Contraindications and Use in special patient populations. Heart failure In a study in which 24 patients with heart failure from Japan participated, the clearance of R- and S-carvedilol was significantly less than in healthy volunteers. These results indicate that heart failure significantly affects the pharmacokinetics of R- and S-carvedilol. Elderly Age did not statistically significantly affect the pharmacokinetics of carvedilol in patients with hypertension. Pediatric population Studies in the pediatric population indicate that clearance in children, standardized for body weight, is substantially greater than in adults. Pharmacokinetics in special groups of patients Impaired renal function In patients with hypertension and renal insufficiency, the area under the curve of plasma concentration and time, elimination half-life and maximum plasma concentration do not change significantly. Excretion of unchanged drug through the kidneys is reduced in patients with renal insufficiency; however, changes in pharmacokinetic parameters are moderate. Carvedilol is not eliminated during dialysis because it does not cross the dialysis membrane, possibly because it is highly bound to plasma proteins. Liver dysfunction See Contraindications and Use in special patient populations. Heart failure In a study in which 24 patients with heart failure from Japan participated, the clearance of R- and S-carvedilol was significantly less than in healthy volunteers. These results indicate that heart failure significantly affects the pharmacokinetics of R- and S-carvedilol. Elderly Age did not statistically significantly affect the pharmacokinetics of carvedilol in patients with hypertension. Pediatric population Studies in the pediatric population indicate that clearance in children, standardized for body weight, is substantially greater than in adults. Indications for use – Arterial hypertension – as monotherapy and in combination with other antihypertensive agents; – Chronic stable angina for the prevention of attacks; – Treatment of stable symptomatic mild, moderate and severe chronic heart failure (class II-IV according to the classification of the New York Heart Association (NYHA)) of ischemic or cardiomyopathic origin in addition to standard therapy (diuretics, digoxin, ACE inhibitors). Dosage and administration Inside, squeezed enough liquid during meals. Arterial hypertension Adults The recommended initial dose is 12.5 mg 1 time per day for the first 2 days, then 25 mg 1 time per day, with a possible gradual increase in dose at intervals of at least 2 weeks up to the maximum recommended dose of 50 mg 1 time per day or divided into 2 doses. Elderly patients In elderly patients, a dose of 12.5 mg in some cases provides a sufficient therapeutic effect. If the desired therapeutic effect does not develop, the dose can be increased to the maximum recommended dose of 50 mg 1 time per day or divided into 2 doses. Chronic stable angina The initial dose is 12.5 mg twice a day. After 2 days, the dose is increased to 25 mg twice a day. If necessary, the dose can be gradually increased at intervals of at least 2 weeks. The recommended maximum daily dose is 100 mg divided into 2 doses. Elderly The recommended starting dose is 12.5 mg twice daily for two days. Then treatment is continued at a dose of 25 mg twice a day, which is the recommended maximum daily dose. Chronic heart failure The dose is selected individually, careful medical supervision is necessary. The recommended starting dose is 3.125 mg (1/2 tablet of 6.25 mg) twice a day for 2 weeks. With good tolerance, the dose is increased at intervals of at least 2 weeks to 6.25 mg 2 times a day, then up to 12.5-25 mg 2 times a day. In patients with severe chronic heart failure, as well as mild and moderate chronic heart failure with a body weight of less than 85 kg, the maximum dose is 25 mg 2 times a day. In patients with mild to moderate chronic heart failure with a body weight of more than 85 kg, the maximum dose is 50 mg 2 times a day. The dose should be increased to the maximum dose that is well tolerated by the patient. Before each increase in dose, the physician should evaluate the kidney function of these patients and check for increased heart failure or symptoms of vasodilation. Short-term worsening of heart failure, vasodilation, and fluid retention can be managed by adjusting the dose of a diuretic or an ACE inhibitor, as well as changing or briefly stopping carvedilol therapy. If treatment is interrupted for more than 1 week, then its use is started with a lower dose, and then increased according to the recommendations. If treatment is interrupted for more than 2 weeks, then its use is started with a dose of 3.125 mg 2 times a day, followed by selection of doses according to the recommendations. Patients with impaired renal function Patients with systolic blood pressure above 100 mm Hg. Art. dose adjustment is not required. Patients with hepatic impairment In patients with mild or moderate hepatic impairment, a dose reduction is necessary. In patients with severe hepatic impairment, carvedilol is contraindicated. Elderly patients Dose adjustment is not required. Pediatric patients The safety and efficacy of carvedilol in children under 18 years of age has not been established. If you miss another dose of the drug, take it immediately. Do not use a double dose to replace a missed one. Continue taking as directed by your doctor. Use during pregnancy and lactation There is no sufficient clinical experience with the use of carvedilol in pregnant women. Animal studies are insufficient to assess the effect on pregnancy, embryonic/fetal development, postpartum development. The potential risk to humans is unknown. The use of carvedilol during pregnancy is possible only in cases where the potential benefit justifies the possible risk. Beta-blockers reduce placental blood flow, which can cause intrauterine fetal death and premature birth. In addition, the fetus and newborn may experience side effects (especially hypoglycemia and bradycardia). In the postpartum period, newborns may be at increased risk of heart and lung complications. In animal studies, the teratogenic effect of carvedilol has not been proven. In animals, carvedilol and its metabolites pass into breast milk. Data on the penetration of carvedilol into human breast milk are not available, so if the drug is necessary during lactation, breastfeeding should be discontinued. PrecautionsChronic heart failure For patients with chronic heart failure, it is necessary to control the clinical condition 2-3 hours after the start of treatment, as well as each time the dose of the drug is increased (renal function should also be monitored). During the period of dose selection, there may be an increase in symptoms of chronic heart failure and fluid retention. If such symptoms occur, it is necessary to increase the dose of diuretics and not increase the dose of carvedilol until hemodynamic indications stabilize. Sometimes it is necessary to reduce the dose of carvedilol or, in rare cases, temporarily stop the drug. Such episodes do not prevent further correct selection of the dose of carvedilol. Use with caution simultaneously with cardiac glycosides (possibly excessive slowing of atrioventricular conduction). Renal Function in Chronic Heart Failure When carvedilol was used in patients with CHF, as well as in patients with low blood pressure, coronary artery disease and diffuse vascular changes and / or renal failure, there was a reversible deterioration in renal function. The dose of the drug is selected depending on the functional state of the kidneys. Left ventricular dysfunction after acute myocardial infarction Before starting treatment with carvedilol, the patient must be clinically stable and must have taken an angiotensin-converting enzyme (ACE) inhibitor for at least the previous 48 hours, and the dose of the ACE inhibitor must be constant for at least previous 24 hours. Atrioventricular conduction disorders Use with caution in patients with impaired atrioventricular conduction, especially those with first-degree atrioventricular block. Bradycardia May cause bradycardia. If the patient’s pulse slows to 55 beats per minute or less, the dose of carvedilol should be reduced. Bronchospastic reactions Patients with a tendency to bronchospastic reactions (eg, chronic bronchitis, emphysema) should not be given beta-blockers. Carvedilol should only be used with caution at the lowest effective dose if no other antihypertensive agents have been effective. Patients with a predisposition to bronchospastic reactions may experience shortness of breath due to increased airway resistance. At the beginning of treatment or when increasing the dose, such patients should be carefully observed, reducing the dose at the onset of initial signs of bronchospasm. Simultaneous use with blockers of “slow” calcium channels In patients simultaneously using calcium channel blockers (verapamil or diltiazem) or other antiarrhythmic drugs, careful monitoring of the electrocardiogram (ECG) and blood pressure is necessary (see section Interactions). Prinzmetal’s angina In this group of patients, drugs with non-selective beta-blocking action can cause chest pain. In patients with suspected Prinzmetal angina, carvedilol should be used with caution. Peripheral vascular disease Use with caution as beta-blockers may cause or exacerbate symptoms of arterial insufficiency. Raynaud’s syndrome Carvedilol should be used with caution in patients with peripheral circulatory disorders – Raynaud’s syndrome, as symptoms may worsen. Peripheral vascular disease Carvedilol should be used with caution in patients with peripheral vascular disease, as beta-blockers may precipitate or exacerbate symptoms of arterial insufficiency. However, due to the drug also having alpha-blocking properties, this action is largely balanced. Diabetes mellitus The drug may mask or reduce the early manifestations of acute hypoglycemia (especially tachycardia). Therefore, for patients with diabetes at the beginning of the use or with an increase in the dose of carvedilol, regular monitoring of blood glucose levels is necessary (see section Interactions). Pheochromocytoma Should only be used after the use of an alpha-blocker. Thyrotoxicosis May mask symptoms of thyrotoxicosis. Severe myasthenia gravis (myasthenia gravis) May mask signs of myasthenia. Psoriasis Should be used with caution in patients with a history of indications of the onset or exacerbation of psoriasis when using beta-blockers (see section Side effects). Severe dermal adverse events Very rare severe cutaneous adverse events, such as toxic epidermal necrolysis and Stevens-Johnson syndrome, have been reported during the use of carvedilol. In patients who develop severe skin adverse reactions possibly related to carvedilol, carvedilol should be discontinued completely. Anesthesia and major surgery When performing general anesthesia, it should be taken into account that the negative inotropic and hypotensive effects of carvedilol and anesthetics can be added up. If it is necessary to continue the use of carvedilol during major surgery, special care is required when using anesthetics that depress myocardial function, such as ether, cyclopropane and trichlorethylene. Therefore, before performing surgery using general anesthesia, it is necessary to warn the anesthesiologist about previous therapy with carvedilol. Hypersensitivity Carvedilol should be used with caution in patients with severe hypersensitivity reactions or a history of allergic disease, as beta-blockers may increase sensitivity to allergens, as well as the severity of anaphylactic reactions. The response to the administration of adrenaline may be weakened. Contact lenses Patients using contact lenses should be warned about a possible decrease in the amount of lacrimal fluid. Intraoperative atonic iris syndrome (IFIS syndrome) There have been reports of cases of intraoperative atonic iris syndrome during cataract surgery in patients treated with alpha1-blockers (carvedilol is an alpha- and beta-blocker). The ophthalmic surgeon should be alerted that the patient has been taking carvedilol in order to be prepared for a change in surgical technique. There is no information on the need and benefit of discontinuing carvedilol before cataract surgery. Lactose The tablets contain lactose and should not be used in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. Discontinuation Syndrome (Withdrawal Syndrome) Like other drugs with beta-blocking properties, carvedilol should not be stopped abruptly. In patients with IHD, cases of exacerbation of severe angina pectoris and the occurrence of myocardial infarction and ventricular arrhythmia are reported. An increase in symptoms of thyrotoxicosis has also been reported in patients with thyrotoxicosis after abrupt discontinuation of therapy with beta-blockers. Carvedilol should be discontinued as gradually as possible over 1-2 weeks. If, nevertheless, the symptoms of angina worsened, it is recommended to immediately resume carvedilol therapy (at least temporarily). The dose is selected individually depending on the needs of the patient. During the period of treatment, the use of alcohol is excluded. Interaction with other drugs Both pharmacodynamic and pharmacokinetic interactions of beta-blockers with other drugs have been reported. Pharmacokinetic interaction Effects of carvedilol on the pharmacokinetics of other drugs Carvedilol is a substrate and inhibitor of P-glycoprotein. Therefore, the bioavailability of drugs transported by P-glycoprotein may increase with the simultaneous use of carvedilol. In addition, P-glycoprotein inducers and inhibitors may alter the bioavailability of carvedilol. Digoxin: When digoxin and carvedilol are used simultaneously, the concentration of digoxin increases by approximately 15%. Both digoxin and carvedilol slow down AV conduction. It is recommended to increase control of digoxin levels by initiating, titrating, or stopping carvedilol therapy. Beta blockers may exacerbate digoxin-induced bradycardia. Cyclosporine: Two studies in kidney and heart transplant patients who received oral cyclosporine found an increase in plasma cyclosporine concentrations after initiation of carvedilol therapy. In approximately 30% of patients, the dose of ciclosporin should be reduced to maintain therapeutic ciclosporin concentrations, but the remaining patients should not have their dose adjusted. In these patients, the dose of cyclosporine was reduced by an average of 20%. Given the wide variation in individual dose adjustments, it is recommended that ciclosporin concentrations be closely monitored after initiation of carvedilol therapy and the ciclosporin dose adjusted accordingly. With intravenous administration of cyclosporine, interaction with carvedilol is not expected. Effects of Other Drugs on Carvedilol Pharmacokinetics Inhibitors and inducers of CYP2D6 and CYP2C9 may stereoselectively alter the systemic and/or first pass metabolism of carvedilol, increasing or decreasing plasma concentrations of R- and S-carvedilol (see Pharmacokinetics; Biotr