Xarten - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate 39.90 mg; corn starch - 10,40 mg; carmellose calcium (carboxymethylcellulose calcium) - 2.80 mg; giprolose (hydroxypropylcellulose) - 1.95 mg; macrogol 8000 (polyethylene glycol 8000) - 1.30 mg; magnesium stearate - 0.65 mg.

Dosage of 16 mg

active substance: candesartan cilexetil - 16.00 mg;

Excipients: lactose monohydrate - 79.80 mg; corn starch - 20.80 mg; carmellose calcium (carboxymethylcellulose calcium) - 5.60 mg; giprolose (hydroxypropyl cellulose) - 3.90 mg; macrogol 8000 (polyethylene glycol 8000) - 2.60 mg; magnesium stearate - 1.30 mg.

The dosage of 32 mg

active substance: candesartan cilexetil - 32.00 mg;

Excipients: lactose monohydrate - 159,60 mg; corn starch - 41,60 mg; carmellose calcium (carboxymethylcellulose calcium) - 11.20 mg; giprolose (hydroxypropyl cellulose) - 7.80 mg; macrogol 8000 (polyethylene glycol 8000) - 5.20 mg; magnesium stearate - 2.60 mg.

Description:

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 mg and 32 mg).

Pharmacotherapeutic group:Angiotensin II receptor antagonist

ATX: & nbsp

C.09.C.A.06 Candesartan

Pharmacodynamics:

Candesartan is a selective antagonist of angiotensin II receptor type 1 (AT₁receptors). Angiotensin II is the main hormone of the renin-angiotensin-aldosterone system (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 AT₁receptors.

Candesartan does not inhibit angiotensin-converting enzyme (ACE),which performs the conversion of angiotensin I into angiotensin II and destroys bradykinin; does not affect the ACE and does not lead to the accumulation of bradykinin or substance P. When comparing candesartan with ACE inhibitors, the development of cough was less common in patients who received candesartan. Candesartan does not bind to the receptors of other hormones and does not block the ion channels involved in the regulation of the functions of the cardiovascular system. As a result of blocking AT₁receptors of angiotensin II, a dose-dependent increase in renin activity, angiotensin I concentration, angiotensin II, and a decrease in aldosterone in the blood plasma.

Arterial hypertension

With arterial hypertension candesartan causes a dose-dependent long-term reduction in blood pressure (BP). The antihypertensive effect of candesartan is due to a decrease in total peripheral vascular resistance (OPSS) without changing the 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 of candesartan in a fixed dose, the maximum decrease in blood pressure is usually achieved within 4 weeks and persists throughout the treatment. Candesartan, appointed once a day, provides an effective and smooth decrease in blood pressure within 24 hours with insignificant fluctuations of blood pressure in the intervals between the doses of the next dose of the drug. The use of candesartan together with hydrochlorothiazide leads to an increased antihypertensive effect. The combined use of candesartan with hydrochlorothiazide, as well as amlodipine, is well tolerated.

The efficacy of candesartan does not depend on the age and sex of the 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 change or increases the rate of glomerular filtration, while renal vascular resistance and filtration fraction decrease.Taking candesartan in a dose of 8-16 mg for 12 weeks does not adversely affect glucose concentration and lipid profile in patients with arterial hypertension and type 2 diabetes.

Chronic heart failure (CHF)

In patients with CHF and reduced left ventricular systolic function (LVEF 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 the blood plasma, and a decrease in aldosterone levels.

Pharmacokinetics:

Candesartan cilexetil is a prodrug for oral administration. Quickly turns into an active substance - candesartan - by means of ether hydrolysis when absorbed from the gastrointestinal tract, firmly binds to AT₁receptors 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%.

The maximum concentration in the blood plasma (C_mOh) 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%). Plasma volume distribution (Vd) candesartan is 0.1 l / kg.

Simultaneous food intake has no significant effect on the area under the concentration-time curve (AUC), that is, it does not significantly affect the bioavailability of candesartan.

Metabolism and excretion

Candesartan, basically, is 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 isoenzyme CYP2C9 to form an inactive derivative. Half-life (T_1/₂) candesartan is approximately 9 hours. Cumulation of candesartan in the body is not observed.

The total clearance of candesartan is 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 radioactively-labeled candesartan about 26% of the introduced quantity excreted by the kidneys in unchanged form and 7% - as an inactive metabolite while 56% of the dose is excreted through the gut in the bile as unchanged and 10% - in the form of inactive metabolite . After a single oral intake within 72 hours, more than 90% of the dose is taken out.

Pharmacokinetics in specific patient groups

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

Elderly patients

In elderly patients (over 65 years) C_mOh and AUC candesartan increased 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 impaired renal function of mild and moderate degree C_max and AUC of candesartan increased by 50% and 70%, respectively, whereas T_1/₂ candesartan did not change in comparison with patients with normal renal function. In patients with impaired renal function of severe degree C_max and AUC of candesartan increased by 50% and 110%, respectively, and T_1/2candesartan increased 2 times.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 to moderate hepatic impairment, there was an increase AUC candesartan by 23%.

There is no experience of applying candesartan in patients with impaired hepatic function.

Indications:

- 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 the section on "Application during pregnancy and during breastfeeding");

- severe liver dysfunction and / or cholestasis;

- lactose intolerance, lactase deficiency, glucose-galactose malabsorption;

- simultaneous use with aliskiren and aliskirenoderzhaschimi drugs in patients with diabetes mellitus or with impaired renal function (glomerular filtration rate less than 60 ml / min / 1.73 m²) (cm.sections "Interaction with other medicines" and "Special instructions");

- age to 18 years (efficacy and safety not established).

Carefully:

- Violations of the function of the kidneys of severe degree (creatinine clearance (CK) less than 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 (CHD);

- Hyperkalemia in patients with reduced circulating blood volume (BCC);

- general anesthesia and surgical interventions (risk of developing hypotension due to RAAS blockade);

- primary hyperaldosteronism;

- hypertrophic obstructive cardiomyopathy.

Pregnancy and lactation:

Pregnancy

The use of Xanten® during pregnancy is contraindicated (see section "Contraindications"). Patients taking Xarten® should be warned about this before planning a pregnancy so that they can discuss alternative therapies with their health care provider.

In case of pregnancy, therapy with Ksarten® should be immediately discontinued and, if necessary, an alternative therapy is prescribed. Drugs that have a direct effect on RAAS, when applied 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 angiotensin II receptor antagonists can cause disorders in the development of the fetus (renal dysfunction, oligohydramnion, slowing ossification of the bones of the skull) and development of complications in the newborn (kidney failure, arterial hypotension, hyperkalemia).

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

Breastfeeding period

At the present time, it is not known whether candesartan in breast milk. However, in animal studies it was shown that candesartan is excreted with the milk of lactating rats. Due to the possible undesirable effect on infants, the Ksarten® drug should not be used during breastfeeding.

Dosing and Administration:

The drug Ksarten should be taken once a day, regardless of food intake.

Arterial hypertension

The recommended initial and maintenance dose of Ksarten® 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 Ksarten® at a dose of 16 mg per 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.

Elderly patients

In elderly patients, there is no need to adjust the initial dose of Ksarten®.

Patients with impaired renal function

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

Clinical experience with candesartan in patients with severe renal dysfunction (KC less than 30 ml / min) or terminal stage of renal failure (QC less than 15 ml / min) is limited (see section "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 Ksarten® is contraindicated in patients with severe impairment of liver function and / or cholestasis (see section "Contraindications").

Concomitant therapy

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

Patients with reduced BCC

In patients at risk of developing arterial hypotension, Ksarten® therapy should be started at a dose of 4 mg once daily.

Chronic heart failure

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

Special patient groups

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

Application in children and adolescents

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

Concomitant therapy

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

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 according to the recommendations of the World Health Organization (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 according to available data.

Infectious and parasitic diseases:

often - respiratory infections, pharyngitis, rhinitis.

Violations of the blood and lymphatic system:

very rarely - leukopenia, neutropenia, agranulocytosis.

Disturbances from the nervous system:

often - dizziness, headache, weakness.

Disorders from the gastrointestinal tract:

very rarely - nausea.

Disturbances from the liver and bile ducts:

very rarely - increased activity of "hepatic" enzymes, a violation of liver function, hepatitis.

Disturbances from musculoskeletal and connective tissue:

often - pain in the back;

very rarely - arthralgia, myalgia.

Immune system disorders:

very rarely - angioedema, skin rash, hives, itching.

Vascular disorders:

often a marked decrease in blood pressure.

Disturbances from the respiratory system, chest and mediastinal organs:

very rarely - cough.

Disorders from the kidneys and urinary tract:

often - a violation of kidney function.

Laboratory and instrumental data:

often - an increase in the concentration of creatinine, urea and potassium content;

very rarely - hyperkalemia, hyponatremia, a decrease in hemoglobin.

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, raise the foot end of the bed. If necessary, the BCC should be increased, for example, by intravenous administration of 0.9% solution of sodium chloride. If necessary, sympathomimetic preparations may be prescribed. Candesartan is not excreted by hemodialysis.

Interaction:

Contraindicated simultaneous use of angiotensin II receptor antagonists, including candesartan, with aliskiren and aliskirenoderzhaschimi drugs in patients with diabetes mellitus (type 1 or type 2) or with impaired renal function of medium or severe degree (glomerular filtration rate less than 60 ml / min / 1.73 m²) (see the sections "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 degree (isoenzyme CYP2C9). The conducted studies on the interaction did not reveal the influence of candesartan on isoenzymes 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.

Experience with other drugs acting on the RAAS reveals that concomitant treatment by potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, and other agents that can enhance the potassium content in the blood plasma (e.g., heparin) can lead to the development of hyperkalemia .

When combined appointment drugs lithium with ACE inhibitors reported reversible increase lithium content in the blood plasma and development of toxic reactions. Similar reactions can occur when applying and angiotensin II receptor antagonists, and therefore it is recommended to control blood plasma lithium content in the combined use of these drugs.

With simultaneous use of the angiotensin II receptor antagonists and non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 inhibitors, acetylsalicylic acid (more than 3 g / day) may be marked antihypertensive effect reduction. As with ACE inhibitors, angiotensin antagonists simultaneous use of NSAIDs and II receptors may increase the risk of renal impairment,including acute renal failure, an increase in potassium in the blood plasma, especially in patients with reduced renal function. Caution should be exercised when these drugs are used concomitantly, especially in elderly patients and in 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.

Special instructions:

Impaired renal function

Against the background of therapy with Ksarten®, as with other drugs that oppress RAAS, some patients may have renal dysfunction. When using Ksarten® in patients with arterial hypertension and renal dysfunction of severe degree (QC less than 30 ml / min), it is recommended to periodically monitor the potassium content and creatinine concentration in the blood plasma. The clinical experience of using candesartan in patients with impaired renal function of severe degree or terminal stage of renal failure (QC less than 15 ml / min) is limited.Such patients should carefully select the dose of Ksarten® under 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 Ksarten®, 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).

Co-administration with ACE inhibitors in CHF

When applying 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 section "Side effect"). In these cases, careful monitoring and monitoring of laboratory indicators is necessary.

Stenosis of the renal artery

In patients with bilateral stenosis of the renal artery or stenosis of the artery of a single kidney, 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 angiotensin II receptor antagonists.

Kidney transplantation

The clinical experience of using candesartan in patients who underwent kidney transplantation is limited.

Arterial hypotension

In patients with CHF on the background of candesartan therapy, hypotension may develop. As with the use of other drugs that affect RAAS, the cause of the development of arterial hypotension in patients with hypertension can 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 drugs 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 type 1 or type 2 diabetes or with moderate or severe renal failure (glomerular filtration rate less than 60 ml / min / 1.73 m²) (see the section "Contraindications").

General anesthesia and surgery

Patients receiving angiotensin II receptor antagonists can develop arterial hypotension as a result of blockade of RAAS during general anesthesia and during surgical interventions. Very rarely there can be cases of severe arterial hypotension, requiring intravenous injection of plasma-substitution solutions and / or vasopressors.

Stenosis of the aortic and mitral valve or hypertrophic obstructive cardiomyopathy

Caution should be exercised when prescribing Ksarten® for 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 Ksarten® is not recommended for such patients.

Hyperkalemia

The clinical experience of using 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,which can increase the potassium content in the blood plasma (eg, heparin), can lead to the development of hyperkalemia in patients with hypertension.

In patients with CHF on the background of candesartan therapy, hyperkalemia may develop. When prescribing Xarten®, 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 less often acute renal failure. The possibility of developing these effects can not be ruled out when angiotensin II receptor antagonists are used. 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 a heart attackmyocardium or stroke.

Effect on the ability to drive transp. cf. and fur:

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 fatigue may occur during treatment, which should be taken into account before working with machinery or driving.

Form release / dosage:

Tablets, 8 mg, 16 mg and 32 mg.

Packaging:

14, 15, 28 or 30 tablets in a planar cell pack of film polyvinylchloride and aluminum foil.

14, 28, 30, 56 or 60 tablets in a can of high-density polyethylene, sealed with a high-density polyethylene lid.

1, 2 or 4 contourcell packs of 14 tablets, 2 or 4 contour packs of 15 tablets, 1 or 2 contourcell packs of 28 tablets, 1 or 2 contour packs of 30 tablets or one pot together with instructions for use in pack of cardboard.

Storage conditions:

Store in a dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003434

Date of registration:02.02.2016 / 15.03.2017

Expiration Date:02.02.2021

The owner of the registration certificate:VERTEKS, AO VERTEKS, AO Russia

Manufacturer: & nbsp

VERTEKS, AO Russia

Representation: & nbspVERTEKS CJSC VERTEKS CJSC Russia

Information update date: & nbsp05.02.2018

Illustrated instructions

Instructions

Xarten® (Xarten®)