Co-Exforge pills 5 mg + 160 mg + 12.5 mg 28 pcs
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Active ingredients
Amlodipine + Valsartan + Hydrochlorothiazide
Release form
Pills
Composition
Amlodipine besylate 6.94 mg, which corresponds to the content of amlodipine 5 mgvalsartan 160 mg hydrochlorothiazide 12.5 mg Auxiliary substances: microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate film film composition: hypromellose, titanium dioxide, membrane coating: hypromellose, titanium dioxide, magnesium coating, hygromellose, titanium dioxide, magnesium coating;
Pharmacological effect
Co-Exforge is a combination of three antihypertensive components with a BP control mechanism that complements each other: amlodipine (a derivative of dihydropyridine), a blocker of slow calcium channels, valsartan, an antagonist of angiotensin II receptors and hydrochlorothiazide, a thiazide diuretic. The combination of these components leads to a more pronounced decrease in blood pressure compared to that on the background of monotherapy with each drug separately. AmlodipineAmlodipine, which is part of Co-Exforge, inhibits transmembrane entry of calcium ions into cardiomyocytes and vascular smooth muscle cells. The mechanism of antihypertensive action of amlodipine is associated with a direct relaxing effect on vascular smooth muscle, causing a decrease in OPSS and a decrease in blood pressure. Experimental data show that amlodipine binds to both dihydropyridine and non-dihydropyridine receptors. Reduction of cardiomyocytes and myocytes of the vascular walls occurs due to calcium ions entering them through calcium channels. After taking therapeutic doses in patients with arterial hypertension, amlodipine causes vasodilation, leading to a decrease in blood pressure (in the position of a patient lying down and standing). Reduction in blood pressure is not accompanied by a significant change in heart rate and catecholamine activity with prolonged use. The plasma concentrations of the drug correlate with the therapeutic response in both young and elderly patients. In hypertension in patients with normal renal function, amlodipine in therapeutic doses reduces resistance of renal vessels, an increase in glomerular filtration rate and effective renal blood flow of the plasma without changing the filtration fraction and the severity of proteinuria .Also as the use of other calcium channel blockers slow,while taking amlodipine, patients with normal left ventricular function showed a change in hemodynamic parameters of heart function at rest and during exercise: a slight increase in cardiac index, without a significant effect on the maximum rate of pressure increase in the left ventricle, on the end-diastolic pressure and the volume of the left ventricle . Hemodynamic studies in intact animals and healthy volunteers showed that a decrease in blood pressure under the influence of amlodipine in the range of therapeutic doses is not accompanied by a negative inotropic effect even when used simultaneously with beta-adrenergic blockers. Amlodipine does not change the function of the sinoatrial node and does not affect AV conductivity in intact animals and healthy volunteers. When using amlodipine in combination with beta-adrenergic blockers in patients with arterial hypertension or with angina pectoris, a decrease in cardiac arterial pressure is not accompanied by undesirable changes in electrocardiographic parameters. Clinical efficacy of amlodipine in patients with stable angina pectoris, vasospastic angina and angiographically coronary coronary artery disease is shown. study (PRAISE-2) in patients with chronic heart failure (III and IV functional class according to NYHA classification) of non-ischemic etiology, when using amlodipine there was an increase in the incidence of pulmonary edema, in the absence of significant differences in the incidence of worsening of chronic heart failure compared with placebo. The risk of myocardial infarction or an increase in the severity of angina pectoris: rarely at the beginning of therapy with slow blockers calcium channels or with an increase in their dose (especially in patients with hypertrophic obstructive cardiomyopathy, severe obstructive coronary disease arteries), an increase in the frequency, duration and severity of strokes or an acute myocardial infarction occurred. Arrhythmia (including ventricular tachycardia and atrial fibrillation) has also been noted with the use of slow calcium channel blockers. These adverse events were impossible to differentiate from the natural course of the disease. Valsartan Valsartan is an active and specific angiotensin II receptor antagonist, intended for ingestion.It acts selectively on the AT1 receptor subtype, which is responsible for the effects of angiotensin II. An increase in plasma concentration of unbound angiotensin II due to blockade of AT1 receptors under the influence of valsartan can stimulate unblocked AT2 receptors, which counteract the effects of stimulation of AT1 receptors. Valsartan does not have any pronounced agonistic activity against AT1 receptors. The affinity of valsartan for the AT1 receptor subtype is about 20,000 times higher than that for the AT2 receptor subtype. Valsartan does not inhibit ACE, which converts angiotensin I to angiotensin II and causes destruction of bradykinin. Since when using angiotensin II antagonists, ACE inhibition and accumulation of bradykinin or substance P do not occur, dry cough development is unlikely. In comparative clinical studies of valsartan with an ACE inhibitor, the incidence of dry cough was significantly lower (p <0.05) in patients who received valsartan (in 2.6% patients treated with valsartan, and in 7.9% who received an ACE inhibitor). In a clinical study that included patients who had previously developed a dry cough when treated with an ACE inhibitor, this complication was observed in 19.5% of cases in treatment with valsartan, and in 19.0% of cases in the treatment with thiazide diuretic. At the same time, in the group of patients receiving treatment with an ACE inhibitor, cough was observed in 68.5% of cases (p <0.05). Valsartan does not interact and does not block receptors of other hormones or ion channels that are important for regulating the functions of the cardiovascular system. When treating patients with arterial hypertension with valsartan, a decrease in blood pressure is observed, which is not accompanied by a change in heart rate. The antihypertensive effect is manifested within 2 hours. most patients after a single dose of valsartan inside. The maximum decrease in blood pressure develops after 4-6 hours. After taking valsartan, the duration of the antihypertensive effect lasts more than 24 hours. With repeated use, the maximum reduction in blood pressure, regardless of the dose, is usually reached within 2-4 weeks and maintained at the reached level during long-term therapy. Abrupt cessation of valsartan is not accompanied by a sharp increase in blood pressure or other undesirable clinical consequences.The use of valsartan in patients with chronic heart failure (functional class II-IV according to the NYHA classification) leads to a significant reduction in the number of hospitalizations for cardiovascular diseases (which is especially pronounced in patients not receiving ACE inhibitors or beta-adrenergic blockers). When taking valsartan in patients with left ventricular insufficiency (with stable hemodynamic parameters) or with impaired left ventricular function after myocardial infarction, cardiovascular mortality decreases. Distal twisted renal tubules are a point of application of thiazide diuretics. When thiazide diuretics are exposed to highly sensitive receptors of the distal tubules of the cortical layer of the kidneys, the reabsorption of sodium ions (Na +) and chlorine (Сl-) is suppressed. Suppression of the co-transport system of Na + and Сl-, apparently, occurs due to the competition for the binding sites of Cl-ions in this system. As a result, the excretion of sodium ions and chlorine increases approximately equally. As a result of the diuretic effect, a decrease in BCC is observed, as a result of which renin activity increases, aldosterone secretion, kidney excretion of potassium, and, consequently, a decrease in the content of potassium in blood serum.
Pharmacokinetics
Pharmacokinetic parameters of amlodipine, valsartan and hydrochlorothiazide are characterized by linearity. Amlodipine Absorption After receiving oral amlodipine in therapeutic doses of Cmax in the blood plasma is achieved in 6-12 hours. The absolute bioavailability is on average 64-80%. Food intake does not affect the bioavailability of amlodipine. The distribution of Vd is approximately 21 l / kg. In vitro studies of amlodipine have shown that in patients with arterial hypertension, approximately 97.5% of the circulating drug binds to plasma proteins. Metabolism Amlodipine is extensively (approximately 90%) metabolized in the liver to form active metabolites. Excretion of plasma excretion is biphasic with T1 / 2 approximately 30 to 50 hours. Css in plasma is reached after prolonged use for 7-8 days. 10% is excreted unchanged, 60% - as metabolites. Valsartan Absorption After ingestion of valsartan Cmax in the blood plasma is achieved in 2-4 hours.The average absolute bioavailability is 23%. The pharmacokinetic curve of valsartan is of a downward multi-exponential nature (T1 / 2α <1 h and T1 / 2β about 9 h). When taken with food, there is a decrease in bioavailability (by AUC value) by 40% and Cmax in blood plasma by almost 50%, although approximately 8 hours after taking the drug inside the concentration of valsartan in blood plasma in people who took it with food, and in the group receiving valsartan on an empty stomach, are aligned. The decrease in AUC, however, is not accompanied by a clinically significant decrease in the therapeutic effect, therefore, valsartan can be prescribed regardless of the meal time. The distribution of Vd of valsartan in the equilibrium state after intravenous administration was about 17 liters, which indicates the absence of an extensive distribution of valsartan in the tissues. Valsartan is largely associated with serum proteins (94-97%), mainly with albumin. Metabolism Valsartan is not subject to pronounced metabolism (about 20% of the dose taken is determined as metabolites). The hydroxyl metabolite is detected in plasma in low concentrations (less than 10% of the AUC of valsartan). This metabolite is pharmacologically inactive. The output of the pharmacokinetic curve of valsartan is of a descending multi-exponential nature (T1 / 2α <1 h and T1 / 2β about 9 h). Valsartan is excreted mainly unchanged through the intestines (about 83% of the dose) and the kidneys (about 13% of the dose). After the on / in the introduction, plasma clearance of valsartan is about 2 l / h and its renal clearance is 0.62 l / h (about 30% of the total clearance). T1 / 2 is 6 hours. Hydrochlorothiazide Absorption Absorption of hydrochlorothiazide after ingestion is fast (time to reach Cmax about 2 hours). On average, the increase in AUC is linear and proportional to the dose in the therapeutic range. With simultaneous ingestion of food, both an increase and a decrease in the systemic bioavailability of hydrochlorothiazide were reported as compared with fasting. The magnitude of this effect is small and clinically insignificant. Absolute bioavailability of hydrochlorothiazide after oral administration is 70%. Distribution The kinetics of distribution and elimination is generally described as a biexponential decreasing function, with T1 / 2 6–15 hours. With repeated use, the kinetics of hydrochlorothiazide does not change and the application of 1 time / day is minimal. The apparent Vd is 4-8 l / kg. 40-70% of the hydrochlorothiazide circulating in the blood plasma is bound to plasma proteins, mainly albumin.Hydrochlorothiazide also accumulates in erythrocytes at concentrations about 3 times higher than those in blood plasma. Metabolism Hydrochlorothiazide is eliminated unchanged. Excretion of T1 / 2 of the final phase is 6-15 hours. With repeated use of the drug, the kinetics of hydrochlorothiazide does not change, with the appointment of the drug 1 time / day the accumulation of the drug is minimal. More than 95% of the absorbed dose of hydrochlorothiazide is excreted unchanged by the kidneys in the urine. Amlodipine + valsartan + hydrochlorothiazide After ingestion of Co-Exforge Cmax of amlodipine, valsartan and hydrochlorothiazide are reached after 6-8, 3 and 2 h, respectively. The speed and extent of absorption of Co-Exforge are equivalent to the bioavailability of amlodipine, valsartan and hydrochlorothiazide when each of them is taken as separate pills. Pharmacokinetics in special clinical situationsPharmacokinetic features of Co-Exforge use in children under 18 years of age have not been established. Time for reaching Cmax of amlodipine in blood plasma young and elderly patients alike. In elderly patients, the clearance of amlodipine is slightly reduced, which leads to an increase in AUC and T1 / 2. In elderly patients, systemic exposure to valsartan was slightly more pronounced than in younger patients, however, this was not clinically significant. There is limited evidence of a decrease in the systemic clearance of hydrochlorothiazide in patients over 65 years of age (healthy volunteers or patients with arterial hypertension) compared with young patients. In patients with impaired renal function, the pharmacokinetic parameters of amlodipine do not change significantly. No correlation was found between kidney function (CC) and systemic valsartan exposure (AUC) in patients with varying degrees of renal dysfunction. In the presence of renal failure, the mean plasma concentration peaks and AUC values of hydrochlorothiazide increase, and the excretion rate decreases. In patients with impaired renal function, mild to moderate severity of T1 / 2 is almost doubled. The renal clearance of hydrochlorothiazide in patients with impaired renal function is reduced compared with normal values (about 300 ml / min). Co-Exforge is contraindicated for use in patients with severe renal insufficiency (CC less than 30 ml / min), anuria, and should be used with caution in patients with patients with impaired moderate renal function (estimated glomerular filtration rate (> 30 ml / min, but <90 ml / min).However, since the excretion of hydrochlorothiazide occurs mainly by the kidneys, impaired renal function can have a significant effect on the pharmacokinetics of hydrochlorothiazide. Patients with impaired liver function have a reduced clearance of amlodipine, which leads to an increase in AUC of approximately 40-60%. On average, in patients with liver disorders with mild (5-6 points on the Child-Pugh scale) and moderate (7-9 points on the Child-Pugh scale), the bioavailability (by AUC) of valsartan is doubled compared with healthy volunteers (appropriate age , sex and body weight). Since abnormal liver function does not have a clinically significant effect on the kinetics of hydrochlorothiazide, it is not necessary to adjust its dose in patients with impaired liver function. Co-Exforge is contraindicated for use in patients with severe hepatic insufficiency (more than 9 on the Child-Pugh scale) with biliary cirrhosis and cholestasis, and should be used with caution in patients with mild and moderate hepatic impairment.
Indications
- Arterial hypertension II and III degrees.
Contraindications
- severe liver dysfunction (more than 9 points on the Child-Pugh scale), biliary cirrhosis and cholestasis; severe kidney dysfunction (CC less than 30 ml / min), anuria, hemodialysis patients; severe arterial hypotension (systolic blood pressure less than 90 mm.rt.), collapse, cardiogenic shock; - clinically significant aortic stenosis; - hypokalemia, hyponatremia, hypercalcemia, and hyperuricemia with clinical manifestations; refractory to adequate therapy; - hereditary angioedema, or edema in patients against previous therapy antagonists of ATII receptors; - pregnancy and pregnancy planning; - breastfeeding period; - age up to 18 years (efficacy and safety not established); - hypersensitivity to amlodipine, valsartan, hydrochlorothiazide, other sulfonamide derivatives, dihydropyridine derivatives and other auxiliary components of the drug. Caution should be exercised in the appointment of the drug to patients with unilateral or bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney, in conditions of condoms due to reduced BCC, in cases of water and electrolyte balance disorders (including hyponatremia, hyperkalemia),patients with mitral or aortic stenosis, hypertrophic obstructive cardiomyopathy, with mild and moderate liver dysfunction, especially against obstruction of the biliary tract (less than 9 points on the Child-Pugh scale), with diabetes mellitus, and systemic lupus erythematosus. Safety of the drug in patients after recent transplantation of the kidney, as well as in patients with heart failure or ischemic heart disease has not been established.
Precautionary measures
During treatment, psoriasis may worsen. During pheochromocytoma, propranolol can only be used after taking an alpha blocker. After a long course of treatment, propranolol should be discontinued gradually, under the supervision of a physician. during anesthesia, you must stop taking propranolol or find a remedy for anesthesia with minimal negative inotropic effects. The impact on the ability to drive vehicles and control mechanisms of patients whose activities require increased attention, the question of the use of propranolol on an outpatient basis should be addressed only after evaluating the individual response of the patient.
Use during pregnancy and lactation
It is known that the appointment of ACE inhibitors that affect the RAAS, pregnant in the II and III trimesters, leads to damage or death of the developing fetus. Given the mechanism of action of angiotensin II receptor antagonists, the risk to the fetus cannot be excluded. According to a retrospective analysis of the use of ACE inhibitors in the first trimester of pregnancy was accompanied by the development of pathology of the fetus and newborn. Hydrochlorothiazide penetrates the placental barrier. When using thiazide diuretics, including hydrochlorothiazide, pregnancy may develop embryonic or neonatal thrombocytopenia, as well as other undesirable reactions observed in adult patients. In case of unintentional use of valsartan in pregnant women, cases of spontaneous abortions, low water, and impaired renal function in newborns are described. Co-Exforge, like any other drug that has a direct effect on the RAAS, should not be prescribed during pregnancy and women planning a pregnancy. Patients of childbearing age should be informed about the potential risk to the fetus associated with the use of drugs that affect the RAAS.If pregnancy was diagnosed during the period of treatment with Co-Exforge, the drug should be canceled as soon as possible. It is not known whether valsartan and / or amlodipine enter breast milk. In experimental studies, the release of valsartan with breast milk was noted. Hydrochlorothiazide is excreted in breast milk. Co-Exforge should not be used during breastfeeding.
Dosage and administration
The drug should be taken orally (preferably in the morning) with a small amount of water, regardless of the meal. For convenience, patients receiving therapy with amlodipine, valsartan and hydrochlorothiazide in separate pills can be transferred to therapy with Co-Exforge containing the same doses of active ingredients , as well as in case of insufficient blood pressure control on the background of double combination therapy (valsartan + hydrochlorothiazide, amlodipine + valsartan and amlodipine + hydrochlorothiazide), patients can be transferred to a triple combination treatment with Co-Exforge in appropriate doses. If a patient has dose-dependent side effects when using dual combination therapy with any of the components of Co-Exforge, Co-Exforge may be prescribed a lower dose of active to achieve a similar reduction in blood pressure. component that caused this side effect. The recommended daily doses of Co-Exforge are: - 5 mg + 160 mg + 12.5 mg (1 tab. containing amlodipine + valsartan + hydrochlorothiazide in doses of 5 mg + 160 mg + 12.5 mg); - 10 mg + 160 mg + 12.5 mg (1 tab., containing amlodipine + valsartan + hydrochlorothiazide in doses of 10 mg + 160 mg + 12.5 mg); - 10 mg + 320 mg + 25 mg (2 pills, containing amlodipine + valsartan + hydrochlorothiazide in doses of 5 mg + 160 mg + 12.5 mg). The maximum antihypertensive effect of the drug is observed 2 weeks after increasing the dose. The maximum dose of the drug is 10 mg + 320 mg + 25 mg / day. In patients over 65 years of age, dose adjustment is not required. Because the safety and efficacy of Co-Exforge in children and adolescents (under 18) is not yet established, the drug is not recommended use in this category of patients. Patients with mild and moderate renal impairment (CC more than 30 ml / min) and liver (5-9 points on the Child-Pugh scale) do not require dose adjustment.
Side effects
Below are all adverse events that were observed with simultaneous use of amlodipine, valsartan and hydrochlorothiazide (Co-Exforge), as well as monotherapy with amlodipine, valsartan and hydrochlorothiazide. Co-Exforge (amlodipine + valsartan + hydrochlorothiazide) Safety of the preparation. more than 2200 patients. When using the drug Co-Exforge, adverse events were mostly few or moderately severe. Termination of drug treatment due to the development of adverse events was required in rare cases. Most often, the drug was discontinued due to the development of dizziness and a pronounced decrease in blood pressure (0.7%). When using the drug Co-Exforge, no new adverse events were detected compared with dual combination therapy and monotherapy with individual components. As with short-term use, good tolerability of the drug Co-Exforge was observed with its long-term use (during the year). The frequency of adverse events was not related to gender, age or race. When using the drug Co-Exforge and Menenius laboratory parameters were minimal and did not differ from those in the monotherapy individual components. With simultaneous use of hydrochlorothiazide together with valsartan (triple combination therapy), a decrease in the hypokalemic effect of hydrochlorothiazide is noted. The most frequent adverse events (frequency more than 2%), noted in clinical studies (regardless of identifying a connection with Co-Exforge) were dizziness ( 7.7%), peripheral edema (4.5%), headache (4.3%), dyspepsia (2.2%), increased fatigue (2.2%), muscle spasm (2.2%), back pain (2.1%), nasopharyngitis (2.1% ), nausea (2.1%). To assess the frequency The following criteria are used (according to WHO classification): very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10,000, <1/1000); very rarely (<1/10 000), the frequency is unknown (not enough data to assess the frequency of development). On the side of metabolism: often - hypokalemia; infrequently - anorexia, hypercalcemia, hyperlipidemia, hyponatremia. For the nervous system: often - dizziness, headache; infrequently - insomnia / sleep disorders, lack of coordination, postural dizziness and dizziness due to exercise, taste disorders, lethargy, paresthesias, neuropathy, incl.peripheral, drowsiness, fainting. From the side of the sense organs: infrequently - visual disturbances, vertigo. From the side of the cardiovascular system: often - marked reduction of blood pressure; infrequently - tachycardia, orthostatic hypotension, phlebitis, thrombophlebitis. On the respiratory system: rarely - cough, shortness of breath, irritation in the throat. On the part of the digestive system: often - dyspepsia; infrequently - abdominal discomfort, pain in the upper abdomen, bad breath, diarrhea, dry mouth, nausea, vomiting. Dermatological reactions: infrequently - increased sweating, itching. Musculoskeletal system and connective tissue: infrequently - pain in the back, swelling in the joints, muscle spasms, muscle weakness, myalgia, pain in the limbs. From the urinary system: often - pollakiuria; infrequently - an increase in plasma creatinine concentration, acute renal failure. From the reproductive system: rarely - erectile dysfunction. From the organism as a whole: often - peripheral edema, increased fatigue; infrequently - abasia, gait disturbances, asthenia, general weakness, pain in the chest. From the laboratory parameters: infrequently - an increase in the urea nitrogen content in the blood plasma, hyperuricemia, an increase in body weight. Amlodipine : very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10,000, <1/1000); very rarely (<1/10 000), the frequency is unknown (not enough data to estimate the frequency of development). From the hematopoietic system: very rarely - leukopenia, thrombocytopenia. From the immune system: very rarely - hypersensitivity reactions. From the metabolic side: very rarely - hyperglycemia. From the nervous system: often - dizziness, headache, drowsiness; infrequently - insomnia / sleep disorders, mood lability, paresthesias, syncope, tremor; very rarely - muscle hypertension, peripheral neuropathy, neuropathy; frequency unknown - extrapyramidal disorders. From the sense organs: infrequently - visual disturbances, tinnitus, taste disturbances. From the cardiovascular system: often - feeling of a strong heartbeat, flushing of the face; infrequently - pronounced decrease in blood pressure; very rarely - vasculitis, arrhythmias (including bradycardia, ventricular tachycardia,atrial fibrillation). On the part of the respiratory system: infrequently - shortness of breath, rhinitis; very rarely - cough. From the digestive system: often - abdominal discomfort, pain in the upper abdomen, nausea; infrequently - change in the frequency of bowel movements, diarrhea, dry mouth, dyspepsia, vomiting; very rarely - gastritis, gingival hyperplasia, pancreatitis. From the side of the liver and biliary tract: very rarely - increased activity of liver enzymes, increased plasma bilirubin concentration, hepatitis, intrahepatic cholestasis, jaundice. rash, incl. exanthema, purpura, discoloration of the skin; very rarely - angioedema, erythema multiforme, urticaria. On the side of the musculoskeletal system and connective tissue: rarely - arthralgia, back pain, muscle spasms, myalgia. reproductive system: infrequently - erectile dysfunction, gynecomastia. On the part of the organism as a whole: often - increased fatigue, edema; infrequently - asthenia, discomfort, general weakness, pain in the chest, pain of different localization. From laboratory indicators: infrequently - increase or decrease in body weight. Valsartan For assessing the frequency, the following criteria were used (according to the WHO classification): very often (≥1 / ten); often (≥1 / 100, <1/10); infrequently (≥ 1/1000, <1/100); rarely (≥ 1/10 000, <1/1000); very rarely (<1/10 000), the frequency is unknown (not enough data to estimate the frequency of development). From the hematopoietic system: the frequency is unknown - decrease in hemoglobin and hematocrit, leukopenia, thrombocytopenia. From the immune system: frequency is unknown - hypersensitivity reactions. On the part of the organ of hearing: infrequently - vertigo. On the part of the cardiovascular system: frequency is unknown - vasculitis. On the part of the respiratory system: rarely - cough. On the part of the digestive system: rarely - abdominal discomfort, pain in the upper Asti zhivota.So of the liver and biliary tract: unknown frequency - elevated liver enzymes, increased bilirubin plasma concentration krovi.Allergicheskie reaction frequency is unknown - angioedema, pruritus,rash. From the musculoskeletal system: frequency unknown - myalgia. From the urinary system: frequency unknown - increased creatinine concentration in the blood plasma, renal dysfunction, including acute renal failure. On the whole body: infrequently - increased fatigue. side of laboratory parameters: the frequency is unknown - an increase in the content of potassium in the blood plasma. In clinical studies with the use of valsartan in monotherapy, the following adverse events were noted (regardless of a causal relationship to the study drug): viral infection, upper respiratory tract infection, sinusitis, rhinitis, neutropenia, bessonnitsa.V rare cases, valsartan may be associated with the use of a decrease in hemoglobin and hematocrit. In controlled studies, 0.8% and 0.4% of patients treated with valsartan showed a significant decrease (over 20%) in hematocrit and hemoglobin, respectively. For comparison, in patients receiving placebo, a decrease in both hematocrit and hemoglobin was observed in 0.1% of cases. Neutropenia was detected in 1.9% of patients receiving valsartan and 1.6% of patients receiving an ACE inhibitor. In controlled studies, 3.9 % and in 16.6% of patients with chronic heart failure who received valsartan, there was an increase in the concentration of creatinine and blood urea nitrogen by more than 50%, respectively. For comparison, in patients receiving placebo, an increase in the concentration of creatinine and urea nitrogen was observed in 0.9% and 6.3% of cases. A duplication of serum creatinine was detected in 4.2% of patients after myocardial infarction who received valsartan and 3.4% who received captopril. In studies in 10% of patients with chronic heart failure, an increase in serum potassium was noted by more than 20%. For comparison, in patients receiving placebo, an increase in potassium content was observed in 5.1% of cases. Hydrochlorothiazide For assessing the frequency, the following criteria were used (according to the WHO classification): very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10,000, <1/1000); very rarely (<1/10 000), the frequency is unknown (not enough data to assess the frequency of development). From the hematopoietic system: rarely - thrombocytopenia; very rarely - agranulocytosis,oppression of bone marrow hematopoiesis, hemolytic anemia, leukopenia. On the immune system side: very rarely - hypersensitivity reactions. On the side of metabolism: often - hypokalemia; infrequently - hyperuricemia, hypomagnesemia, hyponatremia; rarely - hypercalcemia, hyperglycemia; very rarely - hypochloremic alkalosis. From the nervous system: rarely - insomnia / sleep disorders, depression, dizziness, headache, lethargy. From the organ of vision: infrequently - visual disturbances. From the cardiovascular system: infrequently - orthostatic hypotension; rarely - arrhythmias (including bradycardia, ventricular tachycardia, atrial fibrillation). On the respiratory system: very rarely - respiratory distress syndrome, pulmonary edema and pneumonitis. On the part of the diet