Instruction for use: Xarten

Dosage form: tablets

Active substance: Candesartanum

ATX

C09CA06 Candesartan

Pharmacological group

Angiotensin II receptor antagonist [Angiotensin II receptor antagonists (AT1-subtype)]

Nosological classification (ICD-10)

I10 Essential (primary) hypertension: hypertension; Arterial hypertension; Arterial hypertension crisis course; Essential Hypertension; Essential hypertension; Essential hypertension; Essential hypertension; Essential hypertension; Primary hypertension; Arterial hypertension, complications of diabetes; The sudden increase in blood pressure; Hypertensive disorders of blood circulation; hypertensive condition; hypertensive crises; arterial Hypertension; malignant Hypertension; Hypertonic disease; hypertensive crises; accelerated hypertension; malignant hypertension; The aggravation of hypertensive disease; Transient hypertension; Isolated systolic hypertension

I15 Secondary hypertension: Arterial hypertension, complications of diabetes; hypertension; The sudden increase in blood pressure; Hypertensive disorders of blood circulation; hypertensive condition; hypertensive crises; hypertension; arterial Hypertension; malignant Hypertension; hypertensive crises; accelerated hypertension; malignant hypertension; The aggravation of hypertensive disease; Transient hypertension; hypertension; Arterial hypertension; Arterial hypertension crisis course; renovascular hypertension; Hypertension symptomatic; Renal hypertension; Renovascular hypertension; renovascular hypertension; Symptomatic hypertension

I50.0 Congestive heart failure: anasarca heart; Decompensated congestive heart failure; Congestive heart failure; Congestive heart failure with high afterload; Congestive chronic heart failure; Cardiomyopathy with severe chronic heart failure; Compensated chronic heart failure; Swelling with circulatory failure; Edema of cardiac origin; Swelling of the heart; Edematous syndrome in diseases of the heart; Edematous syndrome in congestive heart failure; Edematous syndrome in heart failure; Edematous syndrome in heart failure or liver cirrhosis; right ventricular failure; Congestive Heart Failure; Heart failure stagnant; Heart failure with low cardiac output; Heart failure is a chronic; Cardiac edema; Chronic decompensated heart failure; Chronic Congestive Heart Failure; Chronic heart failure; Change of liver function in heart failure

I50.1 Left ventricular failure: Cardiac asthma; Asymptomatic dysfunction of the left ventricle; Asymptomatic left ventricular heart failure; Diastolic dysfunction of the left ventricle; Left ventricular dysfunction; Changes in the left ventricle with myocardial infarction; Left ventricular heart failure; Violation of the function of the left ventricle; Acute left ventricular failure; Acute cardiac left ventricular failure; Cardiac asthma; Heart failure of left ventricular; Changes in the lungs with left ventricular failure; Precordial abnormal pulsation; Lack of left ventricle

Composition

Tablets -1 table.

active substance: Candesartan cilexetil 8/16/32 mg

Auxiliary substances: lactose monohydrate - 39.9 / 79.8 / 159.6 mg; Corn starch - 10,4 / 20,8 / 41,6 mg; Carmellose calcium (carboxymethylcellulose calcium) - 2.8 (5.6 / 11.2 mg; Giprolose (hydroxypropylcellulose) - 1.95 / 3.9 / 7.8 mg; Macrogol 8000 (polyethylene glycol 8000) - 1.3 / 2.6 / 5.2 mg; Magnesium stearate - 0.65 (1.3 / 2.6 mg

Description of dosage form

Round flat cylindrical tablets white or almost white with chamfer (dosage of 8 mg) and with a facet and a crosswise risk (doses of 16 and 32 mg).

Pharmachologic effect

Mode of action - hypotensive, blocking AT1-receptors of angiotensin II.

Pharmacodynamics

Candesartan is a selective type II ARA II (AT1 receptor). Angiotensin II is the main hormone of RAAS, which plays an important role in the pathogenesis of arterial hypertension, heart failure and other cardiovascular diseases. The main physiological effects of angiotensin II are vasoconstriction, stimulation of aldosterone production, regulation of water-electrolyte homeostasis and stimulation of cell growth. All these effects are mediated by the interaction of angiotensin II with AT1 receptors.

Candesartan does not inhibit ACE which converts angiotensin I into angiotensin II and breaks down bradykinin; Does not affect the ACE and does not lead to the accumulation of bradykinin or a substance of P.

When comparing candesartan with ACE inhibitors, the development of cough was less common in patients receiving candesartan. Candesartan does not bind to the receptors of other hormones and does not block the ion channels involved in the regulation of CCC functions. As a result of blocking of AT1-receptors of angiotensin II, a dose-dependent increase in renin activity, angiotensin I concentration, angiotensin II, and a decrease in plasma aldosterone concentration occur.

Arterial hypertension

With arterial hypertension candesartan causes a dose-dependent long-term decline in blood pressure. The antihypertensive effect of candesartan is due to a decrease in OPSS without a change in heart rate. There were no cases of severe arterial hypotension after taking the first dose of candesartan, as well as withdrawal syndrome (ricochet syndrome) after discontinuation of therapy.

The onset of antihypertensive action after taking the first dose of candesartan usually develops within 2 hours. Against the background of continuing therapy with candesartan at a fixed dose, the maximum decrease in blood pressure is usually achieved within 4 weeks and persists throughout the treatment. Candesartan, administered once a day, provides an effective and smooth decrease in blood pressure within 24 hours with minor fluctuations in blood pressure in the intervals between doses of the next dose of the drug. The use of candesartan in conjunction with hydrochlorothiazide leads to an increased antihypertensive effect. The combined use of candesartan with hydrochlorothiazide, as well as amlodipine, is well tolerated.

The effectiveness of candesartan does not depend on the age and sex of patients.

Candesartan has a less pronounced antihypertensive effect in patients of the Negroid race (a population with predominantly low renin activity in the blood plasma).

Candesartan increases renal blood flow and does not alter or increase GFR, whereas renal vascular resistance and filtration fraction are reduced. Taking candesartan in a dose of 8-16 mg for 12 weeks does not have a negative effect on glucose concentration and lipid profile in patients with arterial hypertension and type 2 diabetes mellitus.

CHF

In patients with CHF and reduced left ventricular systolic function (LVEF ≤40%), candesartan administration contributed to a reduction in OPSS and capillary pressure in the lungs, an increase in renin activity and an angiotensin II concentration in blood plasma, and a decrease in aldosterone levels.

Pharmacokinetics

Candesartan cilexetil is a prodrug for oral administration. Rapidly turns into an active substance - candesartan - by ether hydrolysis when absorbed from the digestive tract, firmly binds to the AT1 receptors and dissociates slowly, does not have the properties of an agonist.

Suction and distribution. Absolute bioavailability of candesartan after oral administration of the solution is about 40%. The relative bioavailability of the tablet form candesartan compared with the oral solution is approximately 34%. Thus, the calculated absolute bioavailability of the tablet form candesartan is 14%.

Cmax in blood plasma is achieved on average 3-4 hours after ingestion. When the dose of candesartan increases in the therapeutic range (up to 32 mg), its concentration in the blood plasma increases linearly.

Candesartan actively binds to plasma proteins (more than 99%). The plasma Vd candesartan is 0.1 l / kg.

Simultaneous food intake does not have a significant effect on AUC, i.e. Does not significantly affect the bioavailability of candesartan.

Metabolism and excretion. Candesartan is mainly excreted from the body by the kidneys and through the intestines in unchanged form. It is slightly metabolized in the liver (20-30%) with the participation of the CYP2C9 isoenzyme with the formation of an inactive derivative. T1 / 2 candesartan is approximately 9 hours. Cumulation of candesartan in the body is not observed.

Candesartan has a total clearance of about 0.37 ml / min / kg, with a kidney clearance of about 0.19 ml / min / kg. Renal excretion of candesartan is carried out by glomerular filtration and active tubular secretion. When administered radically-labeled candesartan, about 26% of the administered amount is excreted by the kidneys unchanged and 7% - in the form of an inactive metabolite, while 56% of the dose is excreted through the intestine with bile in unchanged form and 10% in the form of an inactive metabolite . After a single oral intake within 72 hours, more than 90% of the dose taken is excreted.

Special patient groups

Floor. The pharmacokinetic parameters of candesartan do not depend on the sex of the patient.

Elderly patients. In elderly patients (over 65 years) Cmax and AUC candesartan increase by 50 and 80%, respectively, compared with young patients. However, the antihypertensive effect and incidence of side effects with candesartan do not depend on the age of the patients.

Patients with impaired renal function. In patients with mild and moderate renal dysfunction, Cmax and AUC of candesartan increased by 50 and 70%, respectively, whereas T1 / 2 of candesartan did not change as compared to patients with normal renal function. In patients with impaired renal function, severe Cmax and AUC candesartan increased by 50 and 110%, respectively, and T1 / 2 candesartan increased 2-fold. Patients on hemodialysis were found to have the same pharmacokinetic parameters of candesartan as in patients with impaired renal function of severe severity.

Patients with impaired hepatic function. In patients with mild and moderate liver dysfunction, an increase in AUC of candesartan was observed by 23%. There is no experience of using candesartan in patients with impaired hepatic function.

Indications of the drug Xarten

arterial hypertension;

Chronic heart failure and a violation of the systolic function of the left ventricle (LVEF ≤ 40%) - as an additional therapy for ACE inhibitors or with intolerance to ACE inhibitors.

Contraindications

Hypersensitivity to candesartan or other components of the drug;

Pregnancy and the period of breastfeeding (see "Application in pregnancy and lactation");

Severe liver dysfunction and / or cholestasis;

Lactose intolerance, lactase deficiency, glucose-galactose malabsorption;

Simultaneous use with aliskiren and aliskiren-containing drugs in patients with diabetes mellitus or with renal dysfunction (GFR <60 ml / min / 1.73 m2) (see "Interaction" and "Special instructions");

Age to 18 years (effectiveness and safety not established).

With caution: impairment of renal function of severe severity (Cl creatinine <30 mL / min); hemodialysis; Condition after kidney transplantation; Bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney; Hemodynamically significant stenosis of the aortic and / or mitral valve; Cerebrovascular disorders of ischemic origin and ischemic heart disease; Hyperkalemia in patients with reduced BCC; General anesthesia and surgical interventions (risk of developing hypotension due to RAAS blockade); Primary hyperaldosteronism; Hypertrophic obstructive cardiomyopathy.

Application of pregnancy and breastfeeding

The use of Xarten® during pregnancy is contraindicated (see "Contraindications"). Patients taking Xarten® should be warned about this before planning a pregnancy so that they can discuss alternative therapies with their own doctor. In case of pregnancy, therapy with Xarten® should be immediately discontinued and, if necessary, an alternative therapy is prescribed.

Drugs that have a direct effect on RAAS, when used during pregnancy, can cause fetal developmental disorders or have a negative effect on the newborn, up to a lethal outcome. It is known that therapy with ARA II can cause disturbances in the development of the fetus (renal dysfunction, oligohydramnion, slowing ossification of the skull bones) and development of complications in the newborn (kidney failure, arterial hypotension, hyperkalemia).

Newborns, whose mothers took during the pregnancy drug Xarten®, should be under careful medical supervision because of the likelihood of developing arterial hypotension.

Now it is not known whether candesartan penetrates into breast milk. However, in animal studies, it has been shown that candesartan is secreted with milk from lactating rats. Due to the possible undesirable effect on infants, Xarten® should not be used during breastfeeding.

Side effects

The side effects of candesartan are mild and transient and are comparable in frequency with the placebo group. The overall incidence of side effects associated with candesartan is independent of the dose and age of the patient. The incidence of discontinuation of therapy due to side effects is similar when using candesartan and placebo.

Classification of the incidence of side effects as recommended by WHO: very often ≥1 / 10; Often from ≥1 / 100 to <1/10; Infrequently from ≥1 / 1000 to <1/100; Rarely from ≥1 / 10000 to <1/1000; Very rarely <1/10000, including individual messages; The frequency is unknown - it is not possible to establish the frequency of occurrence from the available data.

Infectious and parasitic diseases: often - respiratory infections, pharyngitis, rhinitis.

From the blood and lymphatic system: very rarely - leukopenia, neutropenia, agranulocytosis.

From the nervous system: often - dizziness, headache, weakness.

From the digestive tract: very rarely - nausea.

From the liver and biliary tract: very rarely - increased activity of liver enzymes, a violation of liver function, hepatitis.

From the musculoskeletal and connective tissue: often - pain in the back; Very rarely - arthralgia, myalgia.

From the immune system: very rarely - angioedema, skin rash, hives, itching.

From the side of the vessels: often - a marked decrease in blood pressure.

From the respiratory system, chest and mediastinum: very rarely - cough.

From the side of the kidneys and urinary tract: often - a violation of kidney function.

Laboratory and instrumental data: often - increasing the concentration of creatinine, urea and potassium content; Very rarely - hyperkalemia, hyponatremia, decreased Hb.

Interaction

Contraindicated the simultaneous use of ARA II, including candesartan, with aliskiren and aliskirenoderzhaschimi drugs in patients with diabetes mellitus (type 1 or 2) or a violation of the kidneys of medium or severe degree (GFR less than 60 ml / min / 1.73 m2) (see " Contraindications "and" Special instructions ").

In pharmacokinetic studies, the simultaneous use of candesartan with hydrochlorothiazide, warfarin, digoxin, oral contraceptives (ethinyl estradiol / levonorgestrel), glibenclamide, nifedipine, and enalapril has been studied. Clinically significant pharmacokinetic interaction was not revealed.

Candesartan is metabolized in the liver to an insignificant extent (isoenzyme CYP2C9). The conducted studies on the interaction did not reveal the effect of candesartan on the isozymes CYP2C9 and CYP3A4, the effect on other isoenzymes of the cytochrome P450 system has not been studied.

The simultaneous use of candesartan with other antihypertensive drugs potentiates the antihypertensive effect.

The experience of using other drugs that act on RAAS shows that concomitant therapy with potassium-sparing diuretics, potassium preparations, salt substitutes containing potassium, and other agents that can increase the potassium content in the blood plasma (eg heparin) can lead to the development of hyperkalemia.

With the combined use of lithium preparations with ACE inhibitors, a reversible increase in lithium content in plasma and development of toxic reactions was reported. Similar reactions can occur with the use of APA II, and therefore it is recommended to monitor the lithium content in blood plasma when combined with these drugs. With the simultaneous use of ARA II and NSAIDs, incl. Selective inhibitors of COX-2, acetylsalicylic acid (more than 3 g / day), there may be a decrease in antihypertensive effect. As with the use of ACE inhibitors, the simultaneous use of APA II and NSAIDs may increase the risk of renal dysfunction, including acute renal failure, an increase in potassium levels in the blood plasma, especially in patients with reduced renal function. Care should be taken when using these drugs at the same time, especially in elderly patients and patients with reduced BCC. Patients need to compensate for fluid loss and regularly monitor kidney function after initiating combination therapy and periodically - against such therapy.

The bioavailability of candesartan is not dependent on food intake.

Dosing and Administration

Inside. The drug Xarten® should be taken once a day, regardless of food intake.

Arterial hypertension

The recommended initial and maintenance dose of Xarten® is 8 mg once daily. Patients who require a further reduction in blood pressure, it is recommended to increase the dose to 16 mg once a day. Patients who failed to sufficiently reduce blood pressure after 4 weeks of taking Xarten® at a dose of 16 mg / day, it is recommended to increase the dose to 32 mg once a day.

Therapy should be adjusted in accordance with the level of blood pressure.

The maximum antihypertensive effect is achieved within 4 weeks from the start of treatment.

In the event that therapy with Xarten® does not lead to a decrease in blood pressure to the optimal level, it is recommended to add a thiazide diuretic to therapy.

Special patient groups

Patients of advanced age. In elderly patients, there is no need to adjust the initial dose of Xarten®.

Patients with impaired renal function. In patients with impaired renal function of mild or moderate degree (Cl creatinine 30-80 ml / min), including patients on hemodialysis, the initial dose of Xarten® is 4 mg (1/4 table to 16 mg). The dose should be selected depending on the therapeutic effect.

Clinical experience with candesartan in patients with severe renal dysfunction (Cl creatinine <30 ml / min) or end-stage renal failure (Cl creatinine <15 ml / min) is limited (see "Special instructions").

Patients with impaired hepatic function. In patients with impaired liver function of mild and moderate severity, it is recommended to begin treatment with a daily dose of 4 mg once a day. It is possible to increase the dose if necessary. The drug Xarten® is contraindicated in patients with severe impairment of liver function and / or cholestasis (see "Contraindications").

Concomitant therapy. The use of Xarten ® together with thiazide type diuretics (eg hydrochlorothiazide) can enhance the antihypertensive effect.

Patients with reduced BCC. In patients at risk of developing arterial hypotension, Xarten® therapy should be started at a dose of 4 mg once daily.

CHF

The recommended initial dose of Xarten® is 4 mg once a day. An increase in the dose to the maximum daily dose of 32 mg once a day or up to the maximum tolerated dose is performed by doubling it at intervals of not less than 2 weeks (see "Special instructions").

Special patient groups

Elderly patients and patients with impaired renal, hepatic or hypovolemic function do not need a correction of the initial dose of Xarten®.

Children and teenagers. Safety and efficacy of candesartan in children and adolescents (under the age of 18 years) have not been established (see "Contraindications").

Concomitant therapy. Xarten® can be administered together with other agents used in the therapy of CHF, for example, ACE inhibitors, beta-blockers, diuretics and cardiac glycosides (see "Special instructions", "Pharmacodynamics").

Overdose

Symptoms: An analysis of the pharmacological properties of candesartan suggests that the main manifestation of an overdose may be a clinically pronounced decrease in blood pressure and dizziness. Individual cases of overdose (up to 672 mg candesartan), which resulted in the recovery of patients without severe consequences, were described.

Treatment: with the development of a clinically pronounced decrease in blood pressure, it is necessary to carry out symptomatic treatment and monitor the patient's condition. It is necessary to lay the patient, lift the foot end of the bed. If necessary, the BCC should be increased, for example by intravenous administration of a 0.9% solution of sodium chloride. If necessary, sympathomimetic preparations may be prescribed. Candesartan is not excreted by hemodialysis.

Special instructions

Impaired renal function. Against the background of therapy with Xarten®, as in the case of other drugs that oppress RAAS, some patients may have impaired renal function.

When using Xarten® in patients with arterial hypertension and impaired renal function of severe degree (Cl creatinine <30 ml / min), it is recommended to periodically monitor the potassium content and creatinine concentration in the blood plasma. Clinical experience with candesartan in patients with severe renal dysfunction or terminal renal failure (Cl creatinine <15 mL / min) is limited. Such patients should carefully select the dose of Xarten® under the careful control of blood pressure.

Patients with CHF need periodic monitoring of kidney function, especially in patients aged 75 years and older, as well as in patients with impaired renal function. With an increase in the dose of Xarten®, it is also recommended to monitor the potassium content and creatinine concentration. Clinical studies of candesartan in CHF did not include patients with a creatinine level greater than 265 μmol / L (more than 3 mg / dL).

Joint use with ACE inhibitors in CHF. When using candesartan in combination with ACE inhibitors, the risk of side effects may increase, especially kidney damage and increased potassium levels in the blood plasma (see "Side effects"). In these cases, careful monitoring and monitoring of laboratory indicators is necessary.

Stenosis of the renal artery. In patients with bilateral renal artery stenosis or stenosis of the single kidney artery, drugs that affect RAAS, in particular ACE inhibitors, can cause an increase in the concentration of urea and creatinine in the blood plasma. Similar effects can be expected with APA II.

Kidney transplantation. Clinical experience of using candesartan in patients who underwent kidney transplantation is limited.

Arterial hypotension. Patients with CHF on the background of candesartan therapy may develop arterial hypotension. As with the use of other drugs that affect RAAS, the cause of the development of arterial hypotension in patients with hypertension may be a decrease in BCC, as observed in patients receiving high doses of diuretics. Therefore, at the beginning of therapy, care should be taken and, if necessary, correct hypovolemia.

Double blockade of RAAS in the use of preparations containing aliskiren. It is not recommended to double the blockade of RAAS by combining candesartan and aliskiren, in view of the increased risk of arterial hypotension, hyperkalemia, and changes in renal function.

The use of candesartan in combination with aliskiren and aliskiren-containing drugs is contraindicated in patients with diabetes mellitus (type 1 or 2) or moderate or severe renal failure (GFR <60 mL / min / 1.73 m2) (see Contraindications).

General anesthesia and surgery. In patients receiving ARA II, during general anesthesia and during surgical interventions, arterial hypotension may result from blockade of RAAS. Very rarely, cases of severe arterial hypotension requiring intravenous administration of plasma-substituting solutions and / or vasopressors can be noted.

Stenosis of the aortic and mitral valve or hypertrophic obstructive cardiomyopathy. Care should be taken when prescribing Xarten® to patients with hypertrophic obstructive cardiomyopathy or hemodynamically significant stenosis of the aortic or mitral valve.

Primary hyperaldosteronism. Patients with primary hyperaldosteronism are usually resistant to therapy with antihypertensive drugs that affect RAAS. In this regard, the drug Xarten ® is not recommended to appoint such patients.

Hyperkalemia. Clinical experience with other drugs that affect the RAAS system shows that the simultaneous administration of candesartan with potassium-sparing diuretics, potassium preparations or salt substitutes containing potassium, or other drugs that can increase the potassium content of the blood plasma (eg heparin) can lead to The development of hyperkalemia in patients with arterial hypertension.

In patients with CHF on the background of candesartan therapy, hyperkalemia may develop. When Xarten® is prescribed, patients with CHF are advised to regularly monitor potassium levels in the blood, especially when co-administered with ACE inhibitors and potassium-sparing diuretics.

Are common. Patients in whom vascular tone and renal function predominantly depend on the activity of RAAS (for example, patients with severe CHF or kidney disease, including renal artery stenosis) are particularly sensitive to drugs acting on RAAS. The appointment of such drugs is accompanied in these patients by severe arterial hypotension, azotemia, oliguria and, more rarely, acute renal failure. The possibility of developing these effects cannot be ruled out when applying ARA II. A sharp decrease in blood pressure in patients with coronary heart disease or cerebrovascular diseases of atherosclerotic genesis with the use of any antihypertensive drugs can lead to the development of myocardial infarction or stroke.

Impact on the ability to drive vehicles and mechanisms. Influence on the ability to drive a car or work with machinery has not been studied, but the pharmacodynamic properties of candesartan indicate that such an effect is absent.

Patients should be informed that dizziness and increased fatigue may occur during treatment. This should be taken into account before working with machinery or driving.

Release form

Tablets, 8 mg, 16 mg and 32 mg. 14, 15, 28 or 30 of Table. In a planar cell box made of PVC film and aluminum foil. 14, 28, 30, 56 or 60 of Table. In a can of HDPE, ukuporennoy cover of HDPE.

1, 2 or 4 contour cell packs of 14 tablets, 2 or 4 contour cell packs of 15 tablets, 1 or 2 contourcell packs of 28 tables, 1 or 2 contourcell packs of 30 tablets. Or 1 bank are placed in a pack of cardboard.

Conditions of supply of pharmacies

On prescription.

Storage conditions of the drug Xarten

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

The shelf life of the drug Xarten

2 years.

Do not use beyond the expiration date printed on the package.