Carvedilol-Teva, tablets 25 mg 30 pcs

Pharmacotherapeutic group: alpha and beta adrenoblocker

ATX code: C07AG02

Pharmacological properties

Pharmacodynamics. Carvedilol is a blocker of alpha1-, beta1-, beta2-adrenoreceptors, has an organoprotective effect. It has antiproliferative properties against the smooth muscle cells of the vascular walls; it is a racemic mixture of R(+) and S(-) stereoisomers, each with the same alpha-adrenoblocking properties. Due to the cardione-selective blocking of adrenoreceptors caused by the S(-) stereoisomer, carvedilol reduces blood pressure (BP), decreases heart rate (HR) and cardiac output, reduces pressure in the pulmonary arteries and in the right atrium. Due to blockade of alpha1-adrenoreceptors it causes peripheral vasodilation and reduces peripheral vascular resistance (PVR). It reduces the load on the heart muscle and prevents the development of angina attacks. In patients with chronic heart failure (CHF), it increases left ventricular ejection fraction and reduces the severity of disease symptoms. Similar effects are noted in patients with impaired left ventricular function.

Carvedilol has no intrinsic sympathomimetic activity and, like propranololol, has the property of membrane stabilization. The activity of the renin-angiotensin-aldosterone system (RAAS) is reduced, reducing the release of renin, so fluid retention (characteristic of selective alpha-adrenoblockers) rarely develops. The effect on BP and HR is most pronounced 1 to 2 hours after taking the drug.

Carvedilol has no adverse effect on lipid profile, maintaining normal ratio of high and low density lipoproteins (HDL/LDL).

In patients with arterial hypertension and renal disease, carvedilol reduces renal vascular resistance without significant changes in glomerular filtration rate, renal plasma flow or electrolyte excretion. Peripheral blood flow is preserved, so that the coldness of the hands and feet, often noted with beta-adrenoblockers, rarely develops.

Pharmacokinetics. Carvedilol is rapidly absorbed after oral administration.

The maximum plasma concentration of carvedilol (C_max) is reached after 1 hour. The absolute bioavailability of carvedilol is approximately 25%: carvedilol is a racemate consisting of two enantiomers, the S-stereoisomer is metabolized faster than the R-stereoisomer, the absolute bioavailability when ingested is 15% and 31%, respectively, the maximum plasma concentration of the R-stereoisomer is approximately 2 times higher than the S-stereoisomer.

Carvedilol has a high lipophilicity. Approximately 98-99% of it binds to plasma proteins. The volume of distribution is approximately 2 L/kg and is increased in patients with cirrhosis due to decreased “primary passage” effect through the liver.

Carvedilol is metabolized primarily in the liver by oxidation and conjugation to form a number of metabolites. It is metabolized by “first passage” through the liver.

The metabolism of carvedilol by oxidation is stereoselective. The R(+) isomer is metabolized primarily by the CYP2D6 and CYP1A2 isoenzymes, and the S(-) isomer primarily by the CYP2D9 isoenzyme and, to a lesser extent, by the CYP2D6 isoenzyme. Other cytochrome P450 isoenzymes involved in the metabolism of carvedilol include CYP3A4, CYP2E1, CYP2C19 isoenzymes.

The results of studies on the pharmacokinetics of carvedilol in humans have shown that the CYP2D6 isoenzyme plays a significant role in the metabolism of the R and S stereoisomers of carvedilol. Plasma concentrations of R and S stereoisomers are increased in patients with low CYP2D6 isoenzyme activity. The results of population pharmacokinetic studies confirmed the importance of CYP2D6 isoenzyme genotype in the pharmacokinetics of R and S stereoisomers of carvedilol. Thus, it was concluded that the genetic polymorphism of the CYP2D6 isoenzyme has some clinical relevance.

Demethylation and hydroxylation of the phenolic ring produce 3 metabolites that have less pronounced vasodilatory properties than carvedilol.

The elimination half-life (T½) is about 6 h, plasma clearance is about 500-700 ml/min. Carvedilolol is eliminated mainly in bile through the intestine and partially by the kidneys as metabolites.

Patient age has no statistically significant effect on the pharmacokinetics of carvedilol.

In patients with cirrhosis the bioavailability of Carvedilol increases by 80% due to reduced metabolism during “first passage” through the liver.

Carvedilolol penetrates through the placental barrier and into breast milk. Carvedilolol is almost not removed from the blood plasma by hemodialysis.

Indications

Active ingredient

Composition

1 tablet contains-

the active ingredient: carvedilol 3.125 mg, 6.25 mg, 12.50 mg or 25.00 mg; excipients: Microcrystalline cellulose 28.000/56.00/112.00/224.00 mg, lactose monohydrate 16.770/33.54/67.08/134.16 mg, low substituted hyprolose 4.545/9.09/18.18/36.36 mg corn starch 6,360/12,72/25,44/50,88 mg, talc 0,300/0,60/1,20/2,40 mg, colloidal silica 0,340/0,68/1,36/2,72 mg, magnesium stearate 0,560/1,12/2,24/4,48 mg.

How to take, the dosage

Ingestion, after meals, with water.

The dose of the drug is chosen individually. The treatment should be started with low doses, gradually increasing until the optimal clinical effect is achieved. After the first use of Carvedilol-Teva and after each dose increase to exclude possible arterial hypotension, it is recommended to measure BP 1 hour after taking the drug.

The therapy with Carvedilol-Teva should be stopped gradually, reducing the dose over 1-2 weeks.

If more than 2 weeks have elapsed since discontinuation, it is recommended that therapy be restarted at a lower dose.

Arterial hypertension. The initial dose is 12.5 mg once daily in the morning for the first 2 days, then 25 mg once daily. Thereafter, if necessary, the dose may be increased at intervals of at least 2 weeks, up to a maximum daily dose of 50 mg per day (divided into 2 doses).

Ischemic heart disease: prevention of stable angina attacks. The initial dose is 12.5 mg twice daily for the first 2 days, then 25 mg twice (morning and evening) daily.

Chronic heart failure II and III functional class according to the NYHA classification

The dose is selected individually, the careful observation of the doctor is necessary. The patient’s condition should be monitored during the first 2-3 hours after the first drug administration or after the first dose increase. The dose and use of other drugs, such as digoxin, diuretics and angiotensin-converting enzyme (ACE) inhibitors, should be adjusted before starting therapy with Carvedilol-Teva. Patients should take the tablets with meals (to reduce the risk of orthostatic hypotension).

The recommended starting dose is 3.125 mg twice daily. If this dose is well tolerated, it can be gradually (at 2 week intervals) increased to 6.25 mg twice daily, then to 12.5 mg twice daily, then to 25 mg twice daily. Patients take the maximum tolerated dose. The maximum recommended dose for patients weighing less than 85 kg is 25 mg 2 times a day and for patients weighing more than 85 kg, 50 mg 2 times a day.

Patients with chronic heart failure to prevent orthostatic hypotension are recommended to take the drug with meals.

Before each dose increase, the physician should review the patient to see if there is a possible increase in symptoms of chronic heart failure or vasodilatation. If there is a transient increase in symptoms of chronic heart failure or fluid retention in the body, the dose of diuretics should be increased, although sometimes a reduction in the dose of Carvedilol-Teva or its temporary withdrawal is required. The dose of the drug Carvedilol-Teva should not be increased until the symptoms of increasing heart failure or arterial hypotension are stabilized.

If treatment with Carvedilol-Teva is interrupted for more than 1 week, its use should be resumed at a lower dose and then increased according to the above recommendations. If treatment with Carvedilol-Teva has been interrupted for more than 2 weeks, therapy should be resumed at a dose of 3.125 mg twice daily, then the dose should be adjusted according to the above recommendations.

Elderly patients.

Interaction

Patients should not drink alcohol during treatment with Carvedilol-Teva, as ethanol may potentiate the side effects of Carvedilol.

The concomitant use of Carvedilolol and digoxin increases plasma concentrations of digoxin by approximately 16% and may increase AV conduction time. Regular monitoring of plasma digoxin concentrations is recommended at the beginning of therapy with carvedilol, when adjusting the dose or discontinuing the drug.

Carvedilol may potentiate the effect of insulin and hypoglycemic agents for oral administration, including sulfonylurea derivatives, and the symptoms of hypoglycemia (especially tachycardia) may mask, therefore in diabetic patients, regular monitoring of blood glucose concentration is recommended.

Carvedilol increases the effect of hypotensive agents (ACE inhibitors, thiazide diuretics, vasodilators).

The concomitant use with catecholamine-lowering drugs (reserpine, monoamine oxidase inhibitors) increases the risk of marked BP reduction and marked bradycardia.

When using carvedilol in kidney transplant patients who have developed chronic vascular rejection of the graft, a moderate increase in mean minimum concentrations of cyclosporine has been observed. To maintain cyclosporine concentrations within the therapeutic range, the cyclosporine dose had to be reduced (by an average of 20%) in approximately 30% of patients; the remaining patients did not require dose adjustments. Due to pronounced individual fluctuations of the required daily dose of cyclosporine it is recommended to carefully monitor cyclosporine plasma concentrations after initiation of therapy with carvedilol and, if necessary, to adjust daily dose of cyclosporine accordingly.

The concomitant use of carvedilol with “slow” calcium channel blockers (dihydropyridine-type derivatives) may lead to severe heart failure and severe arterial hypotension.

Sympathomimetics with alpha- and beta-adrenomimetic effects increase the risk of arterial hypertension and severe bradycardia when used concomitantly with carvedilol.

Verapamil, diltiazem and other antiarrhythmic drugs (propranololol, amiodarone) when used concomitantly with carvedilol may increase the risk of AV conduction disturbances.

In concomitant use of carvedilol and diltiazem, there have been isolated cases of abnormal conduction (rarely with abnormal hemodynamic parameters). As with other drugs with beta-adrenoblocking properties, the use of carvedilol together with “slow” calcium channel blockers such as verapamil and diltiazem is recommended under ECG and blood pressure monitoring.

Simultaneous use with clonidine may potentiate the antihypertensive and negative chromotropic effects of carvedilol.

Microsomal oxidation inhibitors (cimetidine, ketoconazole, fluoxetine, haloperidol, verapamil, erythromycin) enhance and inducers (barbiturates, rifampicin) weaken the hypotensive effects of carvedilol.

Nitrates and beta-adrenoblockers (e.g., in the form of eye drops) may potentiate the antihypertensive effect of carvedilol.

The agents for general anesthesia increase the negative inotropic and hypotensive effect of Carvedilol.

Ergotamine increases vasoconstriction when used concomitantly with carvedilol.

Non-steroidal anti-inflammatory drugs decrease the antihypertensive effect of carvedilol.

Special Instructions

Synopsis

3.125 mg tablets Round biconvex tablets, white or almost white, with “CA3” engraved on one side.

Tablets 6.25 mg. Round biconvex tablets white or almost white with “CA6” engraved on one side.

Tablets 12.5 mg. Round biconvex tablets white or almost white with “CA12” engraved on one side.

Tablets 25 mg. Round biconvex tablets white or nearly white with “CA25” engraved on one side.

Contraindications

Side effects

The incidence of side effects developing when taking carvedilol is classified according to the World Health Organization recommendations: very common – at least 10%; common – at least 1%, but less than 10%; infrequent – at least 0.1%, but less than 1%; rare – at least 0.01%, but less than 0.1%; very rare – less than 0.01%, including individual reports.

The incidence of some side effects, such as dizziness, marked BP decrease, bradycardia, and visual disturbances, is dose-dependent. These effects occur more frequently in patients with CHF. The most common side effect of carvedilol is dizziness with or without orthostatic hypotension, which develops in approximately 6% of patients.

If serious side effects develop, treatment with the drug should be discontinued.

Hematopoietic and lymphatic system disorders: rarely – thrombocytopenia; very rarely – leukopenia.

From the nervous system: very often – dizziness, headache (especially at the beginning of treatment); often – depressed mood, depression; rarely – sleep disturbances, mood/thought changes, paresthesias, myasthenia, loss of consciousness.

Sensory organs:often – decreased tear production and eye irritation (pay attention when using contact lenses); very rarely – visual disturbances, eye irritation.

Cardiovascular system side: very common – heart failure, orthostatic hypotension; common – peripheral vascular disease, increased blood pressure, anemia, syncopal, presyncopal states, bradycardia; rarely – worsening of the course of heart failure (especially with increasing dose), cold hands and feet, decreased BP, fainting, conduction disorders, palpitations, aggravation of the course of angina pectoris, occlusive peripheral circulatory disorders, “intermittent” claudication, peripheral edema.

The respiratory system:often – pneumonia, bronchitis, upper respiratory tract infections, pulmonary edema; rarely – shortness of breath, bronchospasm (in predisposed patients), nasal congestion.

Digestive system disorders: often – nausea, abdominal pain (up to 2%), diarrhea, dry oral mucosa; rarely – decreased appetite, vomiting, flatulence, constipation; very rarely – dry oral mucosa, increased activity of “liver” transaminases (alanine aminotransferase (ALT), aspartame transferase (AST), gamma-glutamyltransferase).

Skin disorders: infrequently – skin disorders of the type of psoriasis and lichen planus; very rarely – exacerbation of psoriasis, alopecia, exfoliative dermatitis.

Musculoskeletal system: rarely – pain in the muscles, bones, spine.

Relations of the urinary system:often – urinary tract infections, renal failure and impaired renal function in patients with diffuse vasculitis and/or impaired renal function; rarely – disorders of urination; very rarely – severe renal impairment.

Metabolism:often – weight gain, hypercholesterolemia, in patients with pre-existing diabetes – hyperglycemia or hypoglycemia; rarely – increase in triglyceride concentration

Others: often – pain syndrome, general weakness; infrequent – hypersensitivity reactions (skin itching, rash, urticaria), reduced potency; very rare – “rushes” of blood to the face, sneezing, flu-like syndrome.

Rare cases of urinary incontinence in women have been reported, reversible after discontinuation of the drug.

In postmarketing use of carvedilol, serious skin reactions – toxic epidermal necrolysis, Stevens-Johnson syndrome – have been identified.

Overdose

Symptoms:A marked decrease in BP (systolic BP 80 mmHg or less), marked bradycardia (less than 50 bpm), respiratory dysfunction (including bronchospasm), heart failure, cardiogenic shock, cardiac arrest, generalized convulsions, vomiting, confusion.

Treatment:Monitoring and correction of vital body functions should be performed, if necessary, in the intensive care unit.

In the first hours after an overdose, vomiting and gastric lavage should be induced. Lay the patient on his back (with elevated legs), in marked bradycardia – atropine 0.5-2 mg intravenously, in resistant to therapy bradycardia an operation of an artificial heart pacemaker is indicated; in marked BP decrease – norepinephrine (noradrenaline); in bronchospasm use beta-adrenomimetics for inhalation (ineffective – intravenously) or intravenous aminophylline.

In case of seizures, diazepam or clonazepam is given slowly intravenously.

Because in severe overdose with symptoms of shock, the half-life of carvedilol and withdrawal of carvedilol from depot may be prolonged, maintenance therapy should be continued for a sufficiently long time. The duration of maintenance therapy depends on the severity of overdose, it should be continued until the patient’s clinical condition is stabilized.

Pregnancy use

Similarities