CARVEDILOL PILLS 6.25MG

Trade name: Carvedilol canon

International non-proprietary name: carvedilol

Dosage Form: pills

Composition:
Dosage of 6.25 mg
1 pill contains:
active ingredient: carvedilol 6.25 mg;
excipients: Calcium hydrophosphate dihydrate 38.55 mg, hyprolose (hydroxypropylcellulose) 2.5 mg, croscarmellose sodium (primellose) 2 mg, lactose monohydrate (milk sugar) 50 mg, Magnesium stearate 0.7 mg.
Dosage 12.5 mg
1 pill contains:
active ingredient: carvedilol 12.5 mg;
excipients: calcium hydrophosphate dihydrate 50 mg, hyprolose (hydroxypropylcellulose) 3.5 mg, croscarmellose sodium (primellose) 3 mg, lactose monohydrate (milk sugar) 70 mg, magnesium stearate 1 mg.
Dosage 25 mg
1 pill contains:
active ingredient: carvedilol 25 mg;
excipients: calcium hydrophosphate dihydrate 70 mg, hyprolose (hydroxypropylcellulose) 5.3 mg, croscarmellose sodium (primellose) 4.5 mg, lactose monohydrate (milk sugar) 93.7 mg, magnesium stearate 1.5 mg.

Description:
Tablets are round, flat-cylindrical, with a facet and face, white or almost white. Minor marbling is allowed.

alpha and beta blocker

ATH code: [C07AG02]

Pharmacological properties:
Pharmacodynamics
Carvedilol is an alpha1-, beta1- and beta2-adrenergic receptor blocker; it has a vasodilating, antianginal and antiarrhythmic effect. Carvedilol is a racemic mixture of R (+) - and S (-) - stereoisomers, each of which has the same alpha-adrenergic blocking and antioxidant properties.
The beta-adrenergic blocking effect of carvedilol is non-selective in nature and is due to the levorotatory S (-) - stereoisomer.
Carvedilol does not have its own sympathomimetic activity; it has membrane stabilizing properties. The vasodilating effect is mainly associated with blockade of alpha1-adrenoreceptors. Due to vasodilation, the total peripheral vascular resistance (OPS) is reduced.
By blocking beta-adrenoreceptors, it reduces the activity of the renin-angiotensin-aldosterone system (RAAS), reducing the release of renin, therefore fluid retention, characteristic of selective alpha-blockers, occurs rarely.
Carvedilol does not have a pronounced effect on the lipid profile, while maintaining the normal ratio of high and low density lipoproteins (HDL / LDL).
Efficiency
Arterial hypertension
In patients with arterial hypertension, carvedilol lowers blood pressure (BP) due to a combined blockade of beta and alpha1-adrenergic receptors. Reduction in blood pressure is not accompanied by a simultaneous increase in total peripheral vascular resistance, which is observed when taking non-selective beta-blockers. Heart rate (HR) decreases slightly.Renal blood flow and renal function in patients with arterial hypertension remain. It was shown that carvedilol does not change the stroke volume of the blood and reduces the round fist; does not affect the blood supply to the organs and peripheral blood flow, including in the skeletal muscles, forearms, lower limbs, skin, brain, and carotid artery. Cooling of the limbs and fatigue during exercise are rare. The antihypertensive effect of carvedilol in hypertension persists for a long time.
Coronary heart disease
In patients with ischemic heart disease, carvedilol has anti-ischemic and antianginal effects (an increase in the total duration of exercise, the time until depression of the ST segment is 1 mm deep, and the time until an attack of angina occurs), which is maintained during prolonged therapy. Carvedilol significantly reduces the oxygen demand of the myocardium and the activity of the sympathoadrenal system. Also reduces preload (pulmonary arrest pressure and pulmonary capillary pressure) and afterload (OPS).
Chronic heart failure
Carvedilol reduces mortality and reduces hospitalization rates, reduces symptoms, and improves left ventricular function in patients with chronic heart failure of ischemic and non-ischemic genesis. The effects of carvedilol are dose-dependent.
Pharmacokinetics
Suction
After oral administration, carvedilol is rapidly absorbed from the gastrointestinal tract. Carvedilol is a substrate of the glycoprotein P carrier protein, which acts as a pump in the intestinal lumen. Glycoprotein P plays a major role in the bioavailability of certain drugs. The maximum plasma concentration (Cmax) is reached approximately 1 hour after ingestion. The absolute bioavailability of carvedilol is about 25%: 30% for the R-form and 15% for the S-form. Food intake does not affect bioavailability.
Distribution
Carvedilol has high lipophilicity. About 98-99% of carvedilol binds to plasma proteins. Its volume of distribution is approximately 2 l / kg.
Metabolism
Carvedilol is biotransformed in the liver by oxidation and conjugation to form a number of metabolites. 60-75% of the absorbed drug is metabolized during the "initial passage" through the liver. The existence of enterohepatic circulation of the initial substance is shown.
The metabolism of carvedilol by oxidation is stereoselective. The R-stereoisomer is metabolized mainly by the isoenzymes CYP2D6 and CYP1A2, a
The S-stereoisomer is mainly using the CYP2D9 isoenzyme and to a lesser extent using the CYP2D6 isoenzyme. Other cytochrome P450 isoenzymes involved in carvedilol metabolism include CYP3A4, CYP2E1 and CYP2C19 isoenzymes. The maximum concentration of the R-stereoisomer in plasma is approximately 2 times higher than that for the S-stereoisomer.
The R-stereoisomer is metabolized mainly by hydroxylation.The "slow" metabolizers of the isoenzyme CYP2D6 may increase the plasma concentration of carvedilol, primarily the R-stereoisomer, which results in an increase in the alpha-adreno-blocking activity of carvedilol.
As a result of demethylation and hydroxylation of the phenol ring,
3 metabolites (their concentration is 10 times lower than the concentration of the initial substance) with beta-adreno-blocking activity (in a 4 'hydroxyphenol metabolite it is about 13 times stronger than in carvedilol itself). 3 active metabolites have less pronounced vasodilating properties than carvedilol. Two of the hydroxycarbazole metabolites of carvedilol are extremely powerful antioxidants, and their activity in this regard is 30-80 times higher than that of carvedilol.
Removal
The half-life (T1 / 2) of carvedilol is about 6 hours, the plasma
clearance is about 500-700 ml / min. Excretion occurs mainly through the intestines with bile. A small part of the dose is excreted by the kidneys in the form of various metabolites.
Pharmacokinetics in Special Patient Groups
Patients with impaired renal function
With long-term carvedilol therapy, the intensity of the renal blood flow is maintained, the glomerular filtration rate does not change.
In patients with arterial hypertension and impaired renal function, the area under the concentration-time curve (AUC), T1 / 2 and Cmax do not change. Renal excretion of unchanged carvedilol in patients with renal insufficiency is reduced, but changes in the pharmacokinetic parameters are not very pronounced.
Carvedilol is an effective treatment for patients with renovascular hypertension, including in patients with chronic renal failure, as well as in patients on hemodialysis or undergoing a kidney transplant. Carvedilol causes a gradual decrease in blood pressure both on the day of hemodialysis and on days without hemodialysis, and its antihypertensive effect is comparable to that in patients with normal renal function.
During hemodialysis, carvedilol is not excreted because it does not pass through the dialysis membrane, probably due to the fact that it binds strongly to plasma proteins.
Carvedilol penetrates the placental barrier, penetrates into breast milk.
Patients with impaired liver function
In patients with cirrhosis of the liver, the systemic bioavailability of the drug is increased by 80% due to a decrease in the severity of metabolism during “primary passage” through the liver. Therefore, carvedilol is contraindicated in patients with severely impaired liver function (see section "Contraindications").
Patients with chronic heart failure (CHF)
In patients with CHF, the clearance of R-and S-stereoisomers of carvedilol was significantly lower compared with the previously observed clearance in healthy volunteers. These results suggest that the pharmacokinetics of R- and
Carvedilol S-stereoisomers are significantly altered in heart failure.
Elderly and senile patients
Age does not have a statistically significant effect on the pharmacokinetics of carvedilol in patients with arterial hypertension. According to clinical studies, the tolerability of carvedilol in patients with arterial hypertension or coronary heart disease of elderly and old age does not differ from that of younger patients.
Children
Data on the pharmacokinetics of the drug in patients under 18 years of age are currently limited.
Patients with diabetes
In patients with type 2 diabetes mellitus and arterial hypertension, carvedilol does not affect the fasting blood glucose concentration after eating, the level of glycated hemoglobin (HbA1), or the dose of hypoglycemic agents for oral administration. In some clinical studies, it has been shown that in patients with type 2 diabetes mellitus, carvedilol does not cause a decrease in glucose tolerance. In patients with hypertension who have insulin resistance (Syndrome X), but without concomitant diabetes, carvedilol improves insulin sensitivity. Similar results were obtained in patients with hypertension and type 2 diabetes.

• Arterial hypertension (in monotherapy or in combination with other antihypertensive drugs, for example, blockers of “slow” calcium channels or diuretics).
• Ischemic heart disease (including in patients with unstable angina and painless myocardial ischemia).
• Chronic heart failure
• Treatment of stable and symptomatic mild, moderate and severe chronic heart failure (NYHA classification II-IV functional class) of ischemic or non-ischemic genesis in combination with angiotensin-converting enzyme inhibitors (ACE) and diuretics, with or without cardiac glycosides (standard therapy), in the absence of contraindications.

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Contraindications:

• hypersensitivity to carvedilol or any component of the drug;
• acute and chronic heart failure in the decompensation stage, requiring intravenous administration of inotropic drugs;
• severe liver failure;
• atrioventricular block II and III degree (except for patients with an artificial pacemaker);
• severe bradycardia (heart rate less than 50 beats / min);
• sick sinus syndrome (including sinoauricular block);
• severe hypotension (systolic blood pressure less than 85 mm Hg. Art.);
• cardiogenic shock;
• severe forms of bronchial asthma or bronchospasm (in history);
• pheochromocytoma (without simultaneous use of alpha-blockers);
• lactose intolerance, lactase deficiency, glucose-galactose malabsorption;
• terminal stage of occlusive peripheral vascular disease;
• age up to 18 years (efficacy and safety have not been established).

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Carefully:
With caution, the drug is used for aggravated allergic history, chronic obstructive pulmonary disease (COPD), depression, myasthenia,hypoglycemia, atrioventricular block I degree, thyrotoxicosis, with extensive surgical interventions and general anesthesia, Prinzmetal angina pectoris, diabetes mellitus, occlusive peripheral vascular diseases, suspected pheochromocytoma, renal failure, psoriasis.
Use during pregnancy and during breastfeeding
Beta-blockers reduce placental blood flow, which can lead to fetal death and premature birth. In addition, unwanted reactions may occur in the fetus and newborn, in particular, hypoglycemia and bradycardia, complications of the heart and lungs. Animal studies have not revealed a teratogenic effect in carvedilol.
There is not enough experience with carvedilol in pregnant women. Carvedilol Canon is contraindicated during pregnancy, unless it is absolutely necessary, if the potential benefit to the mother outweighs the risk to the fetus.
Carvedilol and its metabolites penetrate into breast milk, therefore, if taking the drug is necessary during lactation, breastfeeding should be stopped.

Dosage and administration:
Inside, regardless of the meal, squeezed enough liquid.
Arterial hypertension
The recommended initial dose is 6.25 - 12.5 mg (1 pill 6.25 mg or 1/2 tablets 12.5 mg - 1 pill 12.5) once a day for the first 2 days of therapy, then on 25 mg once a day.If necessary, further dose can be increased at intervals of at least 2 weeks, bringing to the maximum recommended dose of 50 mg 1 time per day (or divided into 2 doses).
Coronary heart disease
The recommended initial dose is 12.5 mg 2 times a day for the first 2 days, then 25 mg 2 times a day. If the antianginal effect is insufficient, the dose can be increased at intervals of at least 2 weeks, bringing to a higher daily dose of 100 mg divided into 2 doses.
Chronic heart failure
The dose is selected individually, it is necessary to carefully monitor the doctor. In patients receiving cardiac glycosides, diuretics, and ACE inhibitors, their dose should be adjusted before starting treatment with Carvedilol Canon.
The recommended initial dose is 3.125 mg (1/2 tablets of 6.25 mg) 2 times 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 to 12.5 mg 2 times a day, then to 25 mg 2 times a day. The dose should be increased to a maximum dose that is well tolerated by the patient. The recommended maximum dose is 25 mg 2 times a day for all patients with severe chronic heart failure and for patients with mild and moderate degrees of chronic heart failure with a patient's body weight less than 85 kg. In patients with mild and moderate chronic heart failure and weighing more than 85 kg, the recommended maximum dose is 50 mg 2 times a day.
Before each increase in dose, an examination by a physician is necessary to identify the possible increase in symptoms of chronic heart failure or vasodilation. With a transient increase in symptoms of chronic heart failure or fluid retention in the body, the dose of diuretics should be increased, although sometimes it is necessary to reduce the dose of the drug or temporarily cancel it.
Symptoms of vasodilation can be eliminated by reducing the dose of diuretics. If the symptoms persist, you can reduce the dose of the ACE inhibitor (if the patient is taking it), and then, if necessary, reduce the dose of the drug Carvedilol Canon. In such a situation, the dose of carvedilol canon should not be increased until the symptoms of exacerbated chronic heart failure or arterial hypotension improve.
If treatment with Carvedilol Canon is interrupted for more than 1 week, then its use is resumed at a lower dose, and then increased in accordance with the above recommendations.
If treatment with Carvedilol Canon is interrupted for more than 2 weeks, then its reappointment should be resumed from a dose of 3.125 mg (1/2 tablets of 6.25 mg) 2 times a day, then the dose should be adjusted in accordance with the above recommendations.
Dosing in special patient groups
Renal dysfunction
In patients with moderate and severe renal failure, dose adjustment of the drug Carvedilol Canon is not required.
Liver dysfunction
Carvedilol Canon is contraindicated in patients with clinical manifestations of abnormal liver function (see section "Contraindications").
Elderly patients
Data that would dictate the need for dose adjustment are not available.

Side effect:
WHO classification of the incidence of side effects:
very often - ≥1 / 10 appointments (> 10%)
often from ≥1 / 100 to <1/10 of appointments (> 1% and <10%)
infrequently - from ≥1 / 1000 to <1/100 of appointments (> 0.1% and <1%)
rarely from ≥1 / 10000 to <1/1000 appointments (> 0.01% and <0.1%)
very rarely - <1/10000 appointments (<0.01%)
The frequency of some undesirable effects, such as dizziness, hypotension, bradycardia and visual impairment is proportional to the size of the dose and often develops in patients with CHF. If serious adverse effects develop, treatment of the drug should be discontinued.
Violations of the blood and lymphatic system
Rarely: thrombocytopenia.
Very rare: leukopenia.
Endocrine Disorders
Often: in patients with existing diabetes mellitus - hyperglycemia or hypoglycemia, impaired glycemic control.
The presence of beta-adrenergic blocking properties of the drug does not exclude the possibility of latent diabetes mellitus manifestation, decompensation of the already existing diabetes mellitus or suppression of the counterinsular system.
Metabolic and nutritional disorders
Often: weight gain, hypercholesterolemia.
Nervous system disorders
Often: dizziness, headache (usually light and more common at the beginning of treatment), asthenia (including fatigue), depression.
Seldom: mood / thinking changes, sleep disturbance, paresthesia, loss of consciousness.
Violations by the organ of vision
Often: eye irritation, reduced tearing (pay attention when using contact lenses).
Very rare: visual impairment.
Violations of the cardiovascular system
Very often: orthostatic hypotension.
Often: bradycardia.
Rarely: impaired cardiac conduction, aggravation of angina, deterioration of the clinical picture of heart failure (especially with increasing doses), pronounced decrease in blood pressure, feeling of heartbeat, fainting, cooling hands and feet, fluid retention, hypervolemia, edema (including generalized, peripheral, depending on body position, edema of the perineum, edema of the lower extremities).
Very rarely: syncopal states (including presynopal), occlusive disorders of the peripheral circulation, exacerbation of the syndrome of "intermittent" claudication and Raynaud's syndrome.
Violations of the respiratory system, chest and mediastinum
Rarely: bronchospasm and shortness of breath in predisposed patients, nasal congestion.
Very rarely: sneezing.
Disorders of the gastrointestinal tract
Often: nausea, diarrhea, abdominal pain, dryness of the oral mucosa.
Seldom: vomiting, loss of appetite, flatulence, constipation.
Very rarely: increased activity of liver transaminases - alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyltransferase (GGT).
Violations of the skin and subcutaneous tissues
Very rare: exacerbation of the course of psoriasis, exfoliative dermatitis, alopecia.
Disorders of the musculoskeletal and connective tissue
Rarely: myasthenia gravis, pain in muscles, bones, spine.
Kidney and urinary tract disorders
Rarely: urination disorders, incontinence in women, reversible after discontinuation of the drug.
Very rare: renal failure and impaired renal function in patients with diffuse vasculitis and / or impaired renal function, edema.
Violations of the genitals and breast
Infrequently: decrease in a potentiality.
General disorders and disorders at the site of administration
Often: general weakness.
Infrequently: hypersensitivity reaction (itchy skin, rash, urticaria).
Very rarely: "flushes" of blood to the skin of the face, flu-like syndrome.
Adverse reactions in patients with chronic heart failure
Nervous system disorders
Very often: dizziness, headache (usually light and arising at the beginning of treatment), asthenia (including increased fatigue), depression.
Violations of the cardiovascular system
Often: bradycardia, postural hypotension, marked reduction in blood pressure, edema (including generalized, peripheral, depending on body position, perineal edema, lower limb edema, hypervolemia, fluid retention).
Infrequently: syncopal states (including presinkopalnye), atrioventricular block and heart failure in the period of increasing doses.
Disorders of the gastrointestinal tract
Often: nausea, diarrhea, vomiting.
Violations of the blood and lymphatic system
Rarely: thrombocytopenia.
Very rare: leukopenia.
Metabolic and nutritional disorders
Often: weight gain, hypercholesterolemia; in patients with existing diabetes mellitus - hyperglycemia or hypoglycemia, a violation of carbohydrate metabolism.
Other violations
Often: visual impairment.
Rarely: renal failure and impaired renal function in patients with diffuse vasculitis and / or impaired renal function.

Overdose:
Symptoms: a marked decrease in blood pressure, bradycardia, heart failure, cardiogenic shock, cardiac arrest; respiratory disorders, bronchospasm, vomiting, confusion, and generalized convulsions are possible.
Treatment: in addition to general measures, it is necessary to monitor and correct vital signs, if necessary in the intensive care unit. You can use the following activities:

• Lay the patient on the back with raised legs;
• with severe bradycardia - atropine 0.5-2 mg intravenously;
• for maintenance of cardiovascular activity - glucagon 1-10 mg intravenously in a stream, then 2-5 mg per hour in the form of a long-term infusion;
• sympathomimetics (dobutamine, isoprenaline, orciprenaline or epinephrine (adrenaline)) in various doses, depending on body weight and response to treatment.

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If a marked reduction in blood pressure dominates the clinical picture of overdose, norepinephrine (norepinephrine) is administered; it is prescribed under conditions of continuous monitoring of blood circulation parameters. In case of treatment-resistant bradycardia, the use of an artificial pacemaker is indicated. In case of bronchospasm, beta-adrenomimetics are administered in the form of an aerosol (with intravenous inefficiency) or aminophylline intravenously. For convulsions, diazepam or clonazepam is slowly injected intravenously. Since severe overdose with symptomatic shock may prolong the half-life of carvedilol and remove the drug from the depot, it is necessary to continue maintenance therapy for a long time. The duration of maintenance / detoxification therapy depends on the severity of the overdose, it should be continued until the patient’s clinical condition stabilizes.