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Active ingredients
Candesartan
Release form
Pills
Composition
1 tab. Kandesartan tsileksetil 8 mg Auxiliary substances: carmellose calcium (carmellose calcium salt) - 5.6 mg, hyprolose (hydroxypropylcellulose) - 4 mg, iron dye red oxide (E172) - 0.065 mg, lactose monohydrate - 89.4 mg, magnesium stearate - 0.4 mg , corn starch - 20 mg, macrogol - 2.6 mg.
Pharmacological effect
Antihypertensive drug, angiotensin II receptor antagonist. Angiotensin II is the main hormone of the RAAS, which plays an important role in the pathogenesis of 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 type 1 angiotensin receptors (AT1 receptors). Candesartan is a selective antagonist of type 1 angiotensin II receptors (AT1 receptors). Does not inhibit ACE, which converts angiotensin I to angiotensin II and destroys bradykinin; does not affect the ACE and does not lead to the accumulation of bradykinin or substance R. When comparing candesartan with ACE inhibitors, the development of cough is less common in patients who received candesartan cilexetil. Candesartan does not bind to receptors of other hormones and does not block the ion channels involved in regulating the functions of the cardiovascular system. The blocking of the AT1 receptor angiotensin II results in a dose-dependent increase in the level of renin, angiotensin I, angiotensin II and a decrease in the concentration of aldosterone in the blood plasma. Arterial hypertension In case of arterial hypertension, candesartan causes a dose-dependent long-term decrease in blood pressure. The antihypertensive effect of the drug is due to the reduction of OPSS, without changing heart rate. There were no cases of severe arterial hypotension after taking the first dose of the drug, as well as the effect of withdrawal (rebound syndrome) after cessation of therapy. The antihypertensive action started after taking the first dose of candesartan cilexetil usually develops within 2 hours. Against the background of continuing therapy with a fixed dose, the maximum decrease Blood pressure is usually reached within 4 weeks and persists throughout treatment.Candesartan cilexetil, administered once a day, provides an effective and smooth decrease in blood pressure over 24 hours with slight fluctuations in blood pressure in the intervals between taking the next dose of the drug. The use of candesartan cilexetil together with hydrochlorothiazide leads to an increase in the hypotensive effect. The combined use of candesartan cilexetil and hydrochlorothiazide (or amlodipine) is well tolerated. The effectiveness of the drug does not depend on the age and sex of patients. Candesartan cilexetil increases renal blood flow and does not change or increases the glomerular filtration rate, whereas the renal vascular resistance and filtration fraction decreases. Taking candesartan cilexetil at 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. Clinical effects of candesartan cilexetil on morbidity and mortality when taken at a dose of 8–16 mg (average dose of 12 mg) 1 times / day was studied in a randomized clinical trial involving 4937 elderly patients (age 70 to 89 years, 21% of patients aged 80 years and older) with mild hypertension and Eren severity receiving therapy with candesartan tsileksetilom for an average of 3.7 years (SSORE study - a study of cognitive function and prognosis in elderly patients). Patients received candesartan or placebo, if necessary in combination with other antihypertensive drugs. Both treatment regimens showed an effective reduction in systolic and diastolic blood pressure (from 166/90 to 145/80 mm Hg in the group of patients who received candesartan, and from 167/90 to 149/82 mm Hg in the control group) on background well tolerated. Cognitive function and quality of life were maintained at a good level in both groups of patients. There were no statistically significant differences in the incidence of cardiovascular complications (cardiovascular death, incidence of non-fatal myocardial infarction and non-fatal stroke) between these two groups of patients.
Pharmacokinetics
Absorption and distributionCandesartan cilexetil is a prodrug for oral administration. Candesartan quickly turns into an active substance through ether hydrolysis during absorption from the digestive tract, binds strongly to AT1 receptors and slowly dissociates, has no agonist properties.The absolute bioavailability of candesartan after ingestion of a solution of candesartan cilexetil is about 40%. The relative bioavailability of the tablet preparation compared to the oral solution is approximately 34%. Thus, the calculated absolute bioavailability of the tablet form of the drug is 14% .Cmax in serum is achieved 3-4 hours after taking the tablet form of the drug. With increasing doses of the drug within the recommended doses, the concentration of candesartan increases linearly. The pharmacokinetic parameters of candesartan do not depend on the sex of the patient. Eating does not have a significant effect on the AUC, i.e. food does not significantly affect the bioavailability of the drug. Candesartan is actively associated with plasma proteins (more than 99%). Vd candesartan is 0.1 l / kg. Metabolism and elimination. Candesartan is mainly excreted from the body with urine and bile unchanged and is only slightly metabolized in the liver. T1 / 2 of candesartan is approximately 9 h. Cumulation of the drug in the body is not observed. The total clearance of candesartan is about 0.37 ml / min / kg, while the renal clearance is about 0.19 ml / min / kg. Renal excretion of candesartan is carried out by glomerular filtration and active tubular secretion. With oral administration of radiolabeled candesartan cilexetil, about 26% of the administered amount is excreted in the urine as candesartan and 7% as an inactive metabolite, whereas 56% of the administered amount is found in candesartan and 10% as an inactive metabolite. Pharmacokinetics in special clinical situations, elderly patients over 65 years of age have increased Cmax and AUC of candesartan by 50% and 80%, respectively, compared with younger patients. However, the hypotensive effect and the incidence of side effects with the use of Atacand do not depend on the age of the patients. In patients with mild and moderate renal impairment, Cmax and AUC of candesartan increased by 50% and 70%, respectively, while the T1 / 2 drug does not change compared to patients with normal renal function. In patients with severely impaired renal function, Cmax and AUC of candesartan increased by 50% and 110%, respectively, and T1 / 2 of the drug increased 2-fold.In patients on hemodialysis, the same pharmacokinetic parameters of candesartan were found as in patients with severe renal dysfunction. In patients with mild and moderate liver dysfunction, there was an increase in candesartan AUC by 23%.
Indications
- arterial hypertension; - chronic heart failure and violation of the systolic function of the left ventricle (reduction of LVEF ≤ 40%) (as an additional therapy to ACE inhibitors or in case of intolerance to ACE inhibitors).
Contraindications
- severe liver dysfunction and / or cholestasis; - pregnancy; - lactation period (breastfeeding); - age up to 18 years (efficacy and safety not established); - lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome; - candesartan use cilexetil in combination with drugs containing aliskiren in patients with diabetes mellitus (type 1 or 2) or with moderate or severe renal insufficiency (GFR less than 60 ml / min / 1.73 m2); - hypersensitivity to candesartan cilexetil or another component drug should be treated with caution in patients with severe renal insufficiency (CC less than 30 ml / min), bilateral renal artery stenosis or single kidney artery stenosis, hemodynamically significant stenosis of the aortic and mitral valve, after a kidney transplant in history, patients with cerebrovascular diseases and Ischemic heart disease, hyperkalemia, reduced bcc, primary hyper aldosteronism (there is not enough data from clinical studies), hypertrophic obstructive carcinoma iomiopatiey.
Precautionary measures
Do not exceed recommended doses.
Use during pregnancy and lactation
Pregnancy The use of the drug Atacand during pregnancy is contraindicated. Patients taking the drug Atacand should be warned about this before planning a pregnancy so that they can discuss alternative therapy options with their doctor. In the event that pregnancy is diagnosed, treatment with Atacand should be immediately discontinued and alternative treatment should be prescribed if necessary. Preparations that have a direct effect on the RAAS can cause fetal development disorders or have a negative effect on the newborn, including death, when used during pregnancy.Treatment with angiotensin II receptor antagonists is known to cause fetal development disorders (renal dysfunction, oligohydramnios, delayed ossification of the skull bones) and the development of complications in the newborn (renal failure, arterial hypotension, hyperkalemia). Breastfeeding is currently unknown, penetrated by, and penetrated. into breast milk. However, candesartan is excreted in the milk of lactating rats. Due to the possible undesirable effect on the infant, Atacand should not be used during lactation (breastfeeding).
Dosage and administration
Atacand should be taken 1 time / day, regardless of the meal. Arterial hypertension The recommended initial and maintenance dose of Atacand is 8 mg 1 time / day. Patients who need a further reduction in blood pressure, it is recommended to increase the dose to 16 mg 1 time / day. If therapy with Atacand does not lead to a decrease in blood pressure to an optimal level, it is recommended to add thiazide diuretic to therapy. The maximum antihypertensive effect is achieved within 4 weeks from the start of treatment. Elderly patients do not need to adjust the initial dose of the drug. or moderate renal impairment (CC 30-80 ml / min), including patients on hemodialysis, the initial dose of the drug is 4 mg (1/2 tab. 8 mg). The dose should be titrated depending on the therapeutic effect of the drug. Clinical experience with the drug in patients with severe renal dysfunction or end-stage renal disease (CC less than 15 ml / min) is limited. Patients with impaired mild or moderate liver function should be started with daily dose of 4 mg (1/2 tab. 8 mg each). May increase the dose if necessary. Atacand is contraindicated in patients with severely impaired liver function and / or cholestasis. The use of Atacand in conjunction with thiazide diuretics (for example, hydrochlorothiazide) may enhance the antihypertensive effect of Atacand. Chronic heart failure A recommended initial dose of Atacand is 4 mg (1/2 tab. 8 mg) 1 time / day.Increasing the dose to 32 mg 1 time / day or to the maximum tolerated dose is carried out by doubling it at intervals of not less than 2 weeks. Elderly patients and patients with impaired renal or liver function do not need to change the initial dose of the drug. children and adolescents under the age of 18 years have not been established. Atakand can be prescribed in conjunction with other drugs used in chronic heart failure, for example, with ACE inhibitors, beta-blockers, diura tics and cardiac glycosides.
Side effects
Arterial hypertension The side effects during clinical trials were moderate and transient and were comparable in frequency with the placebo group. The overall incidence of adverse reactions in patients receiving Atacand did not depend on the dose of the drug, the sex and age of the patient. The incidence of discontinuation due to side effects was similar when using candesartan cilexetil (3.1%) and placebo (3.2%). The analysis of research data reported the following side effects that were often (more than 1/100) occurred while taking candesartan cilexetil . Described adverse reactions were observed with a frequency of at least 1% more than in the placebo group. Side of the CNS: dizziness, weakness, headache. From the musculoskeletal system: back pain. From the laboratory indicators: in general, when using the drug Atacand was not observed clinically significant changes in standard laboratory parameters. As with the use of other agents that affect the RAAS, a slight decrease in hemoglobin can be observed. An increase in the concentration of creatinine and urea, an increase in the potassium content and a decrease in the sodium content were observed. Increased ALT levels were observed somewhat more frequently with the use of the drug Atacand compared with placebo (1.3% instead of 0.5%). When using the drug Atacand usually does not require regular monitoring of laboratory parameters. However, in patients with impaired renal function, it is recommended to periodically monitor the potassium content and serum creatinine concentration. Other: respiratory infections. Chronic heart failure the patient.In clinical trials of CHARM, Atacand was compared in doses up to 32 mg (n = 3803) with placebo (n = 3796), 21% of patients from the group of patients receiving candesartan cilexetil, and 16.1% of patients from the group of patients receiving placebo stopped treatment due to the occurrence of adverse reactions. The most common adverse reactions (≥1 / 100, less than 1/10). From the cardiovascular system: marked decrease in blood pressure. From the urinary system: impaired renal function. From laboratory indicators: increased concentration to eatinina and urea, increased potassium. It is recommended to control creatinine concentration and potassium content in serum. The following adverse reactions during post-marketing use of the drug were reported very rarely (less than 1 / 10,000): From the hematopoietic system: leukopenia, neutropenia and agranulocytosis. metabolism: hyperkalemia, hyponatremia. On the nervous system: dizziness, headache, weakness. On the part of the respiratory system: cough. On the side of the gastrointestinal tract: nausea. On the part of the pech and biliary tract: increased activity of liver enzymes, abnormal liver function or hepatitis. Dermatological and allergic reactions: angioedema, rash, urticaria, pruritus. From the musculoskeletal system: back pain, arthralgia, myalgia. From the urinary system : impaired renal function, including renal insufficiency in susceptible patients.
Overdose
Symptoms: analysis of the pharmacological data of the drug suggests that the main manifestation of overdose may be clinically severe arterial hypotension and dizziness. Individual cases of overdose of the drug (up to 672 mg of candesartan cilexetil) were described, which ended in the recovery of patients without serious consequences. Treatment: With the development of clinically severe arterial hypotension, symptomatic treatment is necessary and the patient’s condition monitored. It is necessary to lay the patient on his back, lower the head of the bed. If necessary, the BCC should be increased, for example, by intravenous administration of a 0.9% sodium chloride solution. If necessary, sympathomimetic drugs may be prescribed.Candesartan is not indicated by hemodialysis.
Interaction with other drugs
The use of candesartan cilexetil in combination with drugs containing aliskiren is contraindicated in patients with diabetes mellitus (type 1 or 2) or in moderate or severe renal insufficiency (GFR less than 60 ml / min / 1.73 m2) and is not recommended in other patients. In pharmacokinetic studies it was studied The combined use of the drug Atacand with hydrochlorothiazide, warfarin, digoxin, oral contraceptives (ethinyl estradiol / levonorgestrel), glibenclamide, nifedipine and enalapril. No clinically significant drug interaction has been identified. Candesartan is metabolized in the liver to a small extent with the help of the isoenzyme CYP2C9. Studies on the interaction did not reveal the effect of the drug on CYP2C9 and CYP3A4, the effect on other isoenzymes of the cytochrome P450 system has not been studied. The combined use of the drug Atacand with other antihypertensive agents potentiates the hypotensive effect. potassium-sparing diuretics, potassium preparations, potassium-containing salt substitutes and other means that can increase the level of potassium in the blood serum (nap Emer, heparin) can lead to lithium giperkaliemii.Pri combined appointment drugs with ACE inhibitors reported reversible increase the concentration of lithium in blood serum and the development of toxic reactions. Similar reactions can occur with the use of angiotensin II receptor antagonists, and therefore it is recommended to control the concentration of lithium in the blood serum with the combined use of these drugs. With the simultaneous use of angiotensin II receptor antagonists and NSAIDs, including selective inhibitors of COX-2, acetylsalicylic acid (more than 3 g / day), a decrease in antihypertensive effect can be observed. As with the use of ACE inhibitors, the simultaneous use of angiotensin II receptor antagonists and NSAIDs can increase the risk of renal dysfunction, including acute renal failure, serum potassium, especially in patients with reduced kidney function.Caution should be exercised with the simultaneous use of these drugs, especially in elderly patients and in patients with reduced BCC. Patients need to compensate for fluid loss and regularly monitor renal function after starting the combination therapy and periodically with this therapy. The bioavailability of candesartan does not depend on food intake.
special instructions
Impaired renal function Against the background of therapy with Atacand, as with the use of other drugs that affect the RAAS, some patients may have impaired renal function. When using Atacand in patients with hypertension and severe renal failure (CC less than 30 ml / min), it is recommended periodically monitor the potassium content and the concentration of creatinine in the serum. Clinical experience with the drug in patients with severe renal impairment or end-stage renal failure (CC less than 15 ml / min) is limited. Such patients should carefully titrate the dose of Atacand under careful control of blood pressure. Patients with chronic heart failure should periodically monitor their renal function, especially in patients 75 years of age and older, as well as in patients with impaired renal function. With an increase in the dose of the drug Atacand, it is also recommended to monitor the potassium content and creatinine concentration. Patients with creatinine concentrations of more than 265 µmol / L (more than 3 mg / dL) were not included in clinical trials of Atacand with chronic heart failure. the use of candesartan in combination with ACE inhibitors may increase the risk of side effects, especially renal dysfunction and hyperkalemia. In these cases, careful monitoring and monitoring of laboratory parameters is necessary. Renal artery stenosis In patients with bilateral renal artery stenosis or with single renal artery stenosis, drugs that affect RAAS, in particular, ACE inhibitors, can cause an increase in serum urea and creatinine. Similar effects can be expected when prescribing angiotensin II receptor antagonists. Kidney transplantation Clinical experience with the use of the drug Atacand in patients who have had a kidney transplant,Arterial hypotension In patients with chronic heart failure during therapy with Atacand, arterial hypotension may develop. As with the use of other drugs that affect the RAAS, the cause of arterial hypotension in patients with arterial hypertension may be a decrease in BCC, as observed in patients receiving high doses of diuretics. Therefore, at the beginning of therapy, caution should be taken and, if necessary, correction of hypovolemia. Double RAAS blockade when using drugs containing aliskiren It is not recommended double RAAS blockade by combining candesartan cilexetil and aliskiren, due to the increased risk of arterial hypotension, hyperkalemia and changes in kidney function. The use of candesartan cilexetil in combination with aliskiren is contraindicated in patients with diabetes mellitus (type 1 or type 2) or with moderate or severe renal insufficiency (GFR less than 60 ml / min / 1.73 m2). General anesthesia and surgery Patients receiving angiotensin II receptor antagonists, during general anesthesia and during surgical interventions arterial hypotension may develop as a result of RAAS blockade. Very rarely, there may be cases of severe arterial hypotension, requiring intravenous plasma-substituting solutions and / or vasopressors. Stenosis of the aortic and mitral valve or obstructive hypertrophic cardiomyopathy When prescribing the drug Atacand, like other vasodilators, patients with obstructive hypertrophic cardiomyopathy, as with other vasodilators, patients with obstructive hypertrophic cardiomyotopia should be prescribed for patients with obstructive hypertrophic cardiomyoarty. valve care should be taken. Primary hyperaldosteronism Patients with primary hyperaldosteronism are usually p zistentny to treatment with antihypertensive drugs affecting RAAS. In this regard, Atacand is not recommended to appoint such patients. Hyperkalemia Clinical experience with other drugs that affect the RAAS, shows that the simultaneous appointment of the drug Atacand with potassium-sparing diuretics, potassium preparations or salt substitutes containing potassium, or other drugs that can increase the potassium content in the blood (for example, heparin), can lead to the development of hyperkalemia in patients with arterial hypertension. In patients with heart failure during therapy with Atacand may develop hyperkalemia.When prescribing Atacand to patients with chronic heart failure, it is recommended to regularly monitor the potassium content in the blood, especially when administered jointly with ACE inhibitors and potassium-sparing diuretics. General Patients whose vascular tone and kidney function mainly depend on the activity of the RAAS (for example, patients with severe chronic heart disease). insufficiency or kidney disease, including renal artery stenosis), are particularly sensitive to drugs acting on the RAAS. In these patients, the administration of such drugs is accompanied by severe arterial hypotension, azotemia, oliguria and, less commonly, acute renal failure. The possibility of the development of these effects can not be excluded when using angiotensin II receptor antagonists. A sharp decrease in blood pressure in patients with coronary artery disease or cerebrovascular atherosclerotic disease when using any antihypertensive drugs can lead to myocardial infarction or stroke. Use in pediatricsEfficiency and safety of the drug in children and adolescents under the age of 18 years have not been established. Effect on ability to drive motor transport and machinery controlThe impact on the ability to drive or work with equipment has not been studied, but the pharmacodynamic properties of the drug proves that such an effect is absent. Patients should be informed that dizziness and increased fatigue may occur during treatment, which should be taken into account before starting to work with vehicles or control vehicles.