Expiration date: 01/2025

The composition and form of issue:

Tablets, film-coated. 1 tablet contains:

amlodipine besilat of 6.94 mg

(corresponds to 5 mg amlodipine base) 

valsartan 160 mg

hydrochlorothiazide 12.5 mg

other ingredients: microcrystalline crospovidone silicon dioxide colloidal magnesium stearate 

shell film: hypromellose titanium dioxide (E171) macrogol talc 

blister of 7 or 14 PCs. in cardboard pack 1, 4, 18 (7 pieces) or 1, 2, 4, 7 (14 PCs) blisters.

Tablets, film-coated. 1 tablet contains:

amlodipine besylate 13,87 mg

(corresponds to 10 mg amlodipine base) 

valsartan 160 mg

hydrochlorothiazide 12.5 mg

other ingredients: microcrystalline crospovidone silicon dioxide colloidal magnesium stearate 

shell film: hypromellose titanium dioxide (E171) macrogol talc colorant iron oxide yellow (E172), the colorant iron oxide red (E172) 

blister of 7 or 14 PCs. in cardboard pack 1, 4, 18 (7 pieces) or 1, 2, 4, 7 (14 PCs) blisters.

Description pharmaceutical form:

Tablets, film-coated, 5 mg + 160 mg + 12.5 mg: oblong, biconvex tablets with beveled edges, film-coated white color with embossed "NVR" on one side and "VCL" on the other.

Tablets, film-coated, 10 mg + 160 mg + 12.5 mg: oblong, biconvex tablets with beveled edges, film-coated pale yellow embossed with "NVR" on one side and "VDL" on the other.

Pharmacokinetics:

The pharmacokinetic parameters of amlodipine, valsartan and hydrochlorothiazide are characterized by linearity.

Amlodipine

Suction. After intake of amlodipine in therapeutic doses, Cmax in plasma is reached after 6-12 h. the Absolute bioavailability is in average 64-80%. Eating does not affect the bioavailability of amlodipine.

Distribution. VSS is approximately 21 l/kg In studies with amlodipine in vitro it was shown that in patients with arterial hypertension approximately 97.5% of circulating drug binds with blood plasma proteins.

Metabolism. Amlodipine intensively (approximately 90%) metabolised in the liver with formation of active metabolites.

Excretion. Elimination from plasma is biphasic with T1/2 approximately 30 to 50 h. the Equilibrium concentrations in plasma are reached after prolonged application for 7-8 days. 10% is excreted unchanged, 60% metabolites.

Valsartan

Suction. After intake of valsartan Cmax in plasma achieved through 2-4 h. the Average absolute bioavailability of 23%. The pharmacokinetic curve is downward valsartan multiexponential character (T1/2&alpha <1 h and T1/2&beta about 9 hours). When taken with food there is a decrease in bioavailability (AUC) by 40% and Cmax in plasma by almost 50%, although about 8 h after administration of the drug inside the concentration of valsartan in plasma in people taking it with food, and in the group receiving the drug on an empty stomach, even. The decrease in AUC is not, however, a clinically significant reduction in therapeutic effect, therefore, valsartan can be assigned regardless of mealtime.

Distribution. VSS valsartan during the period of equilibrium after the on/in the introduction was about 17 l, indicating the absence of extensive distribution of valsartan in the tissues. Valsartan is largely associated with serum proteins (94-97%), mainly to albumin.

Metabolism. Valsartan is not exposed to significant metabolism (about 20% of the dose is determined in the form of metabolites). The hydroxyl metabolite determined in plasma at low concentrations (less than 10% from the AUC valsartan). This metabolite is pharmacologically inactive.

Excretion. Valsartan is excreted primarily in unchanged form through the intestine with the faeces (about 83% of dose) and renal (around 13% of the dose). After I/V administration, plasma Cl valsartan is about 2 l/h and its renal Cl of 0.62 l/h (about 30% of total Cl). T1/2 is 6 h.

Hydrochlorothiazide

Suction. Hydrochlorothiazide absorption after ingestion is rapid (time to reach Cmax is about 2 hours). On average, the increase in AUC is linear and dose proportional in the therapeutic range. Simultaneous food intake was reported as on the increase and the decrease in systemic bioavailability of hydrochlorothiazide compared to drug intake on an empty stomach. The magnitude of this effect is small and clinically insignificant. Absolute bioavailability of hydrochlorothiazide after oral — 60-80%.

Distribution. Kinetics of distribution and elimination in General is described as bieksponencialny decreasing function, with a T1/2 6-15 h. by repeated application of the kinetics of hydrochlorothiazide does not change when applying 1 time per day accumulation is minimal. The apparent VSS — 4-8 l/kg 40-70% of circulating in the blood plasma of hydrochlorothiazide binds to plasma proteins, mainly to albumin. Hydrochlorothiazide also accumulates in erythrocytes at concentrations approximately 3 times those in plasma.

Metabolism. Hydrochlorothiazide is excreted unchanged.

Excretion. More than 95% of the absorbed dose of hydrochlorothiazide is excreted unchanged by the kidneys with urine.

Amlodipine + valsartan + hydrochlorothiazide

After ingestion of the drug Co-Exforge Cmax of amlodipine, valsartan and hydrochlorothiazide are reached in 6-8, 3 and 2 h, respectively. The rate and extent of absorption of the drug Co-Exforge equivalent to the bioavailability of amlodipine, valsartan and hydrochlorothiazide when taking each of them in separate pills.

Pharmacokinetics in special clinical cases

Patients under the age of 18. Pharmacokinetic features of the drug Co-Exforge in children under 18 years not installed.

Patients older than 65 years. Tmax of amlodipine in plasma of young and elderly patients alike. The elderly patients amlodipine Cl is slightly reduced, leading to increase in AUC and T1/2.

In elderly patients, the systemic exposure to valsartan was slightly more pronounced than in young patients, however, this was not clinically significant.

There are limited data on the decline in systemic Cl of hydrochlorothiazide in patients over 65 years of age (healthy or with hypertension) compared with younger patients.

Patients with impaired renal function. In patients with impaired renal function the pharmacokinetic parameters of amlodipine did not significantly change. There was no correlation between renal function (Cl creatinine) and systemic exposure valsartan (AUC) in patients with various degrees of renal dysfunction. However, because the elimination of hydrochlorothiazide is mainly through the kidneys, impaired renal function may have a significant effect on the pharmacokinetics of hydrochlorothiazide.

Patients with impaired liver function. Patients with impaired liver function have a reduced Cl of amlodipine, which leads to an increase in AUC of approximately 40-60%. On average, patients with impaired liver light (5-6 points on a scale Child-Pough), and moderate (7-9 points on a scale Child-Pough) extent bioavailability (AUC) of valsartan is doubled compared to healthy volunteers (appropriate age, sex and body mass).

Description pharmacological action:

The drug Co-Exforge is a combination of 3 antihypertensive components with complementary mechanism of control of blood pressure: amlodipine (dihydropyridine derivative) is a bmkk, valsartan antagonist of the angiotensin II receptor (ATII) and hydrochlorothiazide — thiazide diuretic. The combination of these components leads to a more pronounced reduction in BP compared with those on monotherapy each drug separately.

The amlodipine. Amlodipine, a part of the drug Co-Exforge inhibits transmembrane influx of calcium ions in and cardiomiotita gladkomyshechne cells receptacles. Mechanism of antigipertenzivnogo action of amlodipine is associated with direct relaxing effect on vascular smooth muscle causing reduction in peripheral vascular resistance and reduction in blood pressure.

After administration of therapeutic doses to patients with hypertension amlodipine causes vasodilation leading to decrease in blood pressure (with the patient "lying" and "standing"). Blood pressure reduction is not accompanied by significant changes in heart rate and activity of catecholamines with long-term use.

Drug concentrations in plasma correlate with therapeutic response in both young and elderly patients.

Hypertension in patients with normal renal function amlodipine in therapeutic doses leads to a decrease in renal vascular resistance, increasing glomerular filtration rate and effective renal plasma flow without change in filtration fraction and severity of proteinuria. As well as the application of other bmkk, on a background of reception of amlodipine in patients with normal left ventricular function (LV) there was a change in hemodynamic indicators of cardiac function at rest and during exercise: a small increase in cardiac index without significant influence on the maximum rate of pressure rise in LV, end-DBP and the volume of the left ventricle. Hemodynamic studies in intact animals and healthy volunteers showed that the blood pressure decrease under the influence of amlodipine in the range of therapeutic doses is not accompanied by negative inotropic effects even in case of simultaneous use with beta-blockers.

Amlodipine does not change sinoatrial node function and does not affect AV conduction in intact animals and in healthy volunteers. When using amlodipine in combination with beta-blockers in patients with hypertension or angina pectoris reduction in blood pressure is not accompanied by undesirable changes in electrocardiographic parameters. Proven clinical efficacy of amlodipine in patients with stable angina, vasospastic angina and angiographic proven coronary artery disease.

In the long placebo-controlled study (PRAISE-2) in patients with chronic heart failure (III and IV functional class NYHA classification) non-ischemic etiologies, with the use of amlodipine was noted to increase the incidence of pulmonary edema in the absence of significant differences in the incidence of worsening of chronic heart failure in comparison with placebo.

The risk of myocardial infarction or increase in severity of angina: rarely at the beginning of therapy bmkk or when increasing the dose in patients, especially those with hypertrophic obstructive cardiomyopathy, severe obstructive disease of the coronary arteries, there were increases in the frequency, duration and severity of angina or developed acute myocardial infarction. Arrhythmia (including ventricular tachycardia and atrial fibrillation) was recorded at application of bmkk. These adverse events were impossible to differentiate from natural course of disease.

Valsartan. Valsartan is an active and specific receptor antagonist AT intended for ingestion. It acts selectively on the receptor subtype AT1, which is responsible for the effects AT. The increase in the plasma concentration of unbound AT as a consequence of the blockade AT1-receptors is influenced by valsartan may stimulate the 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 approximately 20,000 times higher than for the AT2 receptor subtype.

Valsartan does not inhibit ACE, which converts ATI to AT and causes the destruction of bradykinin. Because the application of antagonists AT not is the inhibition of ACE and the accumulation of bradykinin or substance P, the development of dry cough is unlikely. In comparative clinical studies with valsartan, an ACE inhibitor, the incidence of dry cough was significantly lower (p<0.05) in patients who received valsartan (2.6% of patients treated with valsartan and 7.9 percent receiving ACE inhibitor). In a clinical study involving patients earlier in the treatment of ACE inhibitor developed a dry cough, the treatment with valsartan, this complication was noted in 19.5% of cases in the treatment of thiazide diuretic — in 19,0% of cases. At the same time, in the group of patients treated with ACE inhibitor, cough was observed in 68.5% of cases (p<0.05). Valsartan does not enter into interaction and does not block the hormone receptors or ion channels of importance for the regulation of the functions of the cardiovascular system.

The treatment with valsartan in patients with arterial hypertension there is a decrease in AD, is not accompanied by changes in heart rate.

The antihypertensive effect is evident within 2 h in most patients after a single dose valsartan inside. The maximum decrease in blood pressure develops within 4-6 hours After taking valsartan duration of antihypertensive effect persists over 24 h. With repeated use, the maximum reduction in AD regardless of the dose is usually achieved within 2-4 weeks and maintained at that level during long-term therapy. Abrupt discontinuation of the 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 (II–IV functional class classification of chronic heart failure new York heart Association — NYHA) leads to a significant reduction in the number of hospitalizations for cardiovascular diseases (especially in patients, not receiving ACE inhibitors or beta-blockers). When receiving valsartan in patients with left ventricular failure (stable clinical course) or with impaired LV function after myocardial infarction there is a decrease in cardiovascular mortality.

The point of application of action thiazide diuretics are the distal convoluted renal tubules. Under the influence of thiazide diuretics on sensitive receptors in the distal tubules of the cortical layer of the kidneys is suppressed reabsorption of sodium ions (Na+) and chlorine (CL-). The suppression of co-transport system the Na+ and CL-, apparently, is due to competition for binding sites of ions CL - in the system. As a result, the excretion of sodium and chlorine ions increases approximately equally. The result is diuretic effect a decrease in volume of circulating blood plasma, resulting in increased renin activity, aldosterone secretion, renal excretion of potassium and hence reduce the amount of potassium in the blood serum.

Amlodipine + valsartan + hydrochlorothiazide. With the use of triple combination therapy with amlodipine + valsartan + hydrochlorothiazide, was noted a more pronounced decrease in SBP and DBP, compared with the application of dual combinations: valsartan + hydrochlorothiazide, amlodipine + valsartan and amlodipine + hydrochlorothiazide. In patients with arterial hypertension of II and III degree (initial mean arterial pressure 170/107 mm Hg.St.) when using combination therapy with amlodipine + valsartan + hydrochlorothiazide in a daily dose of 10 mg + 320 mg + 25 mg for 8 weeks the mean reduction in SBP and DBP were $ 39.7/24.7 mm Hg.St. (compared to 32.0/19,7 mm Hg.St., Of 33.5/21.5 mm Hg.St., And 31.5/19.5 mm Hg.St. on the background of combined therapy with valsartan + hydrochlorothiazide in a dose of 320 mg + 25 mg, amlodipine and valsartan at a dose of 10 mg + 320 mg and amlodipine and hydrochlorothiazide in the dose of 10 mg + 25 mg, respectively).

The greatest antihypertensive effect of the drug Co-Exforge observed after 2 weeks after the start of use of the drug in the maximum individual dose inside. In applying the drug To Exforge achieving target BP (less than 140/90 mm Hg.St.) it was noted in 71% of patients, compared to 45-54% with application of the double combinations.

After taking the drug antihypertensive effect persists over 24 h. Therapeutic efficacy of the drug Co-Exforge not depend on the age, sex and race of patients.

Indications:

Arterial hypertension II and III degree.

Contraindications:

• hypersensitivity to amlodipine, valsartan, hydrochlorothiazide, other derivatives of sulfonamide, a derivative of dihydropyridine and other auxiliary components of the drug
  
• pregnancy and breastfeeding
  
• expressed violations of the liver (more 9 points on a scale Child-Pough)
  
• expressed disturbances of the function of the nights (Cl creatinine less than 30 ml/min), anuria
  
• refractory to adequate therapy hypokalemia, hyponatremia, hypercalcemia, and hyperuricemia with clinical manifestations
  
• the age of 18 years (efficacy and safety not established).
  

With caution:

• unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney
  
• state, accompanied by a decrease in BCC
  
• violations of water-electrolyte balance (including hyponatremia, hyperkalemia)
  
• mitral or aortic stenosis, and hypertrophic obstructive cardiomyopathy
  
• light and moderate liver dysfunction, especially on the background of biliary tract obstruction (less than 9 points on a scale Child-Pough)
  
• diabetes
  
• systemic lupus erythematosus.
  

The safety of the drug in patients after recent kidney transplantation, and in patients with heart failure or ischemic heart disease is not established.

Application of pregnancy and breast-feeding:

It is known that the appointment of ACE inhibitors that affect the renin-angiotensin-aldosterone system (RAAS), pregnant women in II and III trimester, causes damage or death to the developing fetus. Given the mechanism of action of receptor antagonists AT, we can not exclude the risk to the fetus. 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 crosses the placenta. In the application of thiazide diuretics, including hydrochlorothiazide during pregnancy may develop fetal or neonatal thrombocytopenia, and other adverse reactions observed in adult patients. When accidental receiving valsartan in pregnant described cases of spontaneous abortions, water shortage and renal dysfunction in newborns. The drug Co-Exforge, like any other drug that has a direct impact on the RAAS, should not be administered during pregnancy and women planning pregnancy. Patients of childbearing age should be informed about the possible risk to the fetus associated with the use of drugs that affect the RAAS. If pregnancy is diagnosed during treatment with a drug Co-Exforge, the drug should be discontinued as soon as possible.

Unknown, penetrates whether valsartan and/or amlodipine in breast milk. In experimental studies noted the allocation of valsartan with breast milk. Hydrochlorothiazide is excreted in breast milk. The drug Co-Exforge should not be used during breastfeeding.

Side effects:

Below are all adverse events (AES) observed with simultaneous use of amlodipine, valsartan and hydrochlorothiazide (drug Co-Exforge), as well as monotherapy with amlodipine, valsartan and hydrochlorothiazide.

The drug Co-Exforge (amlodipine + valsartan + hydrochlorothiazide)

The safety of the drug Co-Export was estimated at more than 2200 patients. In applying the drug To Export AES were mainly low or moderate. Cessation of treatment due to the development of adverse events was required in rare cases. Most often the drug was discontinued because of dizziness and decrease in blood pressure (0,7%).

In applying the drug To Expore did not identify new adverse events compared with dual combination therapy and monotherapy with the individual components. As with the short admission, a good tolerance of the drug Co-Exforge was observed with its prolonged use (during the year).

The incidence of AES was not associated with gender, age or race.

In applying the drug To Export changes in laboratory parameters were minimal and did not differ from those on the individual monotherapy components. While taking hydrochlorothiazide together with valsartan (dual combination therapy), there is a decrease in the hypokalemic action of hydrochlorothiazide.

The most common AES (frequency more than 2%) observed in clinical studies (regardless of detection of application of the drug Co-Exforge), were dizziness (7.7%) and peripheral edema (4,5%), headache (4.3 per cent), dyspepsia (2,2%), fatigue (2.2%), muscle spasm (2.2%), back pain (or 2.1%), nasopharyngitis (2.1 percent), nausea (2.1 percent).

To assess the frequency used, the following criteria (according to who classification): very often (&ge1/10) frequently (&GE. 1/100, <1/10) uncommon (&ge1/1000, <1/100) rare (&ge1/10000, <1/1000) very rare (<1/10000) frequency unknown (insufficient data to assess the frequency of development).

Violations of metabolism and nutrition: often — hypokalemia infrequent — anorexia, hypercalcemia, hyperlipidemia, hyponatremia.

Mental disorders: rarely — insomnia/sleep disturbances, drowsiness.

From the nervous system: often — dizziness, headache, rarely — impaired coordination of postural dizziness and dizziness, caused by physical activity, taste disorders, confusion, paresthesia, neuropathy, including peripheral, syncope.

On the part of the organ of vision: infrequent — visual disturbances.

On the part of the organ of hearing and labyrinth disorders: infrequent — vertigo.

Of the cardiovascular system: often- expressed lower AD rare — tachycardia, orthostatic hypotension, phlebitis, thrombophlebitis.

The respiratory system of the chest and mediastinum: rarely — cough, shortness of breath, irritation in the throat.

From the digestive system: often — neuralgia rarely, abdominal discomfort, pain in upper abdomen, bad breath, diarrhea, dry mouth, nausea, vomiting.

The skin and subcutaneous fat: often — increased sweating, itching.

On the part of the musculoskeletal system and connective tissue: uncommon — back pain, swelling in the joints, muscle spasms, muscular weakness, myalgia, pain in extremities.

The kidneys and urinary tract: often — pollakiuria rarely — increased concentration of creatinine in plasma, acute renal failure.

From the genital organs and mammary glands: rarely — erectile dysfunction.

General disorders injection site: often — peripheral edema, fatigue, rarely — Abaza, gait disturbance, asthenia, General weakness, pain in the chest.

Laboratory and instrumental data: rarely is the increase in the content of urea nitrogen in plasma, hyperuricemia, increase in body weight.

Amlodipine

To assess the frequency used, the following criteria (according to who classification): very often (&ge1/10) frequently (&GE. 1/100, <1/10) uncommon (&ge1/1000, <1/100) rare (&ge1 /10000, <1/1000) very rare (<1/10000) frequency unknown (insufficient data to assess the frequency of development).

The blood and lymphatic system: very rarely — leukopenia, thrombocytopenia.

The immune system: very rarely — hypersensitivity reactions.

Violations of metabolism and nutrition: very rarely — hyperglycemia.

Mental disorders: rarely — insomnia/sleep disturbances, drowsiness, mood lability.

From the nervous system: often — dizziness, headache uncommon taste disorders, paresthesia, syncope, tremor very rare hypertonia, peripheral neuropathy, neuropathy frequency unknown — extrapyramidal disorders.

On the part of the organ of vision: infrequent — visual disturbances.

On the part of hearing and labyrinth disorders: infrequent — tinnitus.

Of the cardiovascular system: often-feeling of palpitations, tides blood to a person not often — expressed lower AD very rarely — vasculitis, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation).

The respiratory system of the chest and mediastinum: infrequently — shortness of breath, rhinitis very rare cough.

From the digestive system: often — abdominal discomfort, pain in the upper abdomen, nausea, rarely — change in the frequency of bowel movements, diarrhea, dry mouth, dyspepsia, vomiting, rarely — gastritis, gingival hyperplasia, pancreatitis.

The liver and biliary tract: rarely — increased activity of liver enzymes, increased concentration of bilirubin in blood plasma, hepatitis, intrahepatic cholestasis, jaundice.

The skin and subcutaneous fat: often — alopecia, increased sweating, pruritus, rash, including rash, purpura, skin discoloration very rare — angioedema, erythema multiforme, urticaria.

On the part of the musculoskeletal system and connective tissue: infrequent — arthralgia, back pain, muscle spasms, myalgia.

The kidneys and urinary tract: rarely — violation of urination, nocturia, pollakiuria.

From the genital organs and breast cancer: infrequent — erectile dysfunction, gynecomastia.

General disorders injection site: often — fatigue, edema uncommon — asthenia, discomfort, General weakness, pain in the chest, pain of various localization.

Laboratory and instrumental data: rare — increase or decrease in body mass.

Valsartan

To assess the frequency used, the following criteria (according to who classification): very often (&ge1/10 appointments) often (&ge1/100, <1/10) uncommon (&ge1/1000, <1/100) rare (&ge1/10000, <1/1000) very rare (<1/10000) frequency unknown (insufficient data to assess the frequency of development).

The blood and lymphatic system: unknown speed — reduction of hemoglobin and hematocrit, leukopenia, thrombocytopenia.

The immune system: frequency unknown — hypersensitivity reactions.

On the part of hearing and labyrinth disorders: infrequent — vertigo.

From the side of cardiovascular system: frequency unknown — vasculitis.

The respiratory system of the chest and mediastinum: rarely — cough.

From the digestive system: rarely, abdominal discomfort, pain in the upper abdomen.

The liver and biliary tract: the frequency is unknown — increase in liver enzymes, increased concentration of bilirubin in plasma.

The skin and subcutaneous fat: frequency unknown — angioedema, pruritus, rash.

On the part of the musculoskeletal system and connective tissue: frequency unknown — myalgia.

The kidneys and urinary tract: frequency is unknown — increase in the concentration of creatinine in the blood plasma, impaired renal function, including acute renal failure.

General disorders injection site: often — fatigue.

Laboratory and instrumental data: the frequency is unknown — increase in the content of potassium in the blood plasma.

In clinical studies with the use of valsartan in monotherapy, was observed following adverse events (irrespective of causal relationship with study drug): a viral infection of upper respiratory tract infection, sinusitis, rhinitis, neutropenia, insomnia.

In rare cases, valsartan may be accompanied by decrease in hemoglobin and hematocrit. In controlled trials in 0.8% and 0.4% of patients treated with valsartan, there was a marked decrease (over 20%) in hematocrit and hemoglobin, respectively. For comparison — in patients treated with placebo, reduced as the hematocrit and hemoglobin observed in 0.1% of cases. Neutropenia was detected in 1.9% of patients treated with valsartan and 1.6% of patients receiving ACE inhibitor.

In controlled studies in 3.9 and 16.6% of patients with chronic heart failure treated with valsartan was shown to increase the concentration of creatinine and urea nitrogen the blood by more than 50%, respectively. For comparison — in patients, receiving placebo, increasing the concentration of creatinine and urea nitrogen are observed at 0.9 and 6.3% of cases.

Doubling the concentration of serum creatinine was detected in 4.2% of patients after myocardial infarction treated with valsartan and 3.4% treated with captopril.

In controlled trials, 10% of patients with chronic heart failure increased the potassium content of the blood serum of more than 20%. For comparison, in patients, receiving placebo, increasing the content of potassium was observed in 5.1% of cases.

Hydrochlorothiazide

To assess the frequency used, the following criteria (according to who classification): very often (&ge1/10) frequently (&GE. 1/100, <1/10) uncommon (&ge1/1000, <1/100) rare (&ge1/10000, <1/1000) very rare (<1/10000) frequency unknown (insufficient data to assess the frequency of development).

The blood and lymphatic system: rarely — thrombocytopenia very rare agranulocytosis, suppression of bone marrow hematopoiesis, hemolytic anemia, leukopenia.

The immune system: very rarely — hypersensitivity reactions.

Violations of metabolism and nutrition: often — hypokalemia, rarely — hyperuricemia, hypomagnesemia, hyponatremia rarely hypercalcemia, hyperglycemia, rarely — gipohloremichesky alkalosis.

Mental disorders: rarely — insomnia/sleep disturbances, depression.

From the nervous system: rarely — dizziness, headache, confusion.

On the part of the organ of vision: infrequent — visual disturbances.

From the side of cardiovascular system: rarely — orthostatic hypotension rarely arrhythmias (including bradycardia, ventricular tachycardia and atrial fibrillation).

The respiratory system, chest and mediastinum disorders: very rare — respiratory distress syndrome, pulmonary edema and pneumonitis.

From the digestive system: rarely — loss of appetite, nausea, vomiting rare abdominal discomfort, pain in upper abdomen, constipation, diarrhoea very rare pancreatitis.

The liver and biliary tract: rarely — hepatitis, intrahepatic cholestasis, jaundice.