Composition, form of production and packaging
The tablets covered with a film shell of white color, oblong, biconcave, with bevelled edges, with an embossed "NVR" on one side and "VCL" on the other.
1 tab.
amlodipine besylate 6.94 mg,
which corresponds to the content of amlodipine 5 mg
valsartan 160 mg
hydrochlorothiazide 12.5 mg
Excipients: microcrystalline cellulose, crospovidone, silicon dioxide colloid, magnesium stearate.
The composition of the film shell: hypromellose, titanium dioxide (E171), macrogol, talc.
7 pcs. - blisters (1) - packs of cardboard.
7 pcs. - blisters (4) - packs of cardboard.
7 pcs. - blisters (18) - packs of cardboard.
14 pcs. - blisters (1) - packs of cardboard.
14 pcs. - blisters (2) - packs of cardboard.
14 pcs. - blisters (4) - packs of cardboard.
14 pcs. - blisters (7) - packs of cardboard.
14 pcs. - blisters (14) - packs of cardboard.
The tablets covered with a film membrane of pale yellow color, oblong, biconcave, with oblique margins, with an embossed "NVR" on one side and "VDL" on the other.
1 tab.
amlodipine besylate 13.87 mg,
which corresponds to the content of amlodipine 10 mg
valsartan 160 mg
hydrochlorothiazide 12.5 mg
Excipients: microcrystalline cellulose, crospovidone, silicon dioxide colloid, magnesium stearate.
Composition of the film shell: hypromellose, titanium dioxide (E171), macrogol, talc, iron dye oxide yellow (E172), iron oxide red (E172).
7 pcs. - blisters (1) - packs of cardboard.
7 pcs. - blisters (4) - packs of cardboard.
7 pcs. - blisters (18) - packs of cardboard.
14 pcs. - blisters (1) - packs of cardboard.
14 pcs. - blisters (2) - packs of cardboard.
14 pcs. - blisters (4) - packs of cardboard.
14 pcs. - blisters (7) - packs of cardboard.
14 pcs. - blisters (14) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2013.
PHARMACHOLOGIC EFFECT
Co-Exforge is a combination of three antihypertensive components with a complementary mechanism for monitoring blood pressure: amlodipine (a derivative of dihydropyridine) - a blocker of slow calcium channels, valsartan - an antagonist of angiotensin II receptors (ATII) and hydrochlorothiazide - a thiazide diuretic. The combination of these components leads to a more pronounced decrease in blood pressure compared to that of monotherapy with each drug alone.
Amlodipine
Amlodipine, which is part of the preparation Ko-Exforzh, inhibits transmembrannoe intake of calcium ions in cardiomyocytes and smooth muscle cells of blood vessels. The mechanism of antihypertensive action of amlodipine is associated with a direct relaxing effect on the smooth muscle of the vessels, causing a decrease in OPSS and a decrease in blood pressure.
Experimental data show that amlodipine binds both to dihydropyridine and to non-dihydropyridine receptors. Reduction of cardiomyocytes and myocytes of the vessel walls is due to the ingress of calcium ions through calcium channels.
After taking in therapeutic doses in patients with arterial hypertension, amlodipine causes vasodilation, leading to a decrease in blood pressure (in the position of the patient "lying" and "standing"). Reduction of blood pressure is not accompanied by a significant change in heart rate and activity of catecholamines for prolonged use.
Concentrations of the drug in the blood plasma correlate with the therapeutic response, both in young and elderly patients.
With arterial hypertension in patients with normal renal function, amlodipine in therapeutic doses leads to a decrease in renal vascular resistance, an increase in the glomerular filtration rate and effective renal blood flow of the plasma without changing the filtration fraction and the expression of proteinuria.
Similar to the use of other slow calcium channel blockers, amlodipine treatment in patients with normal left ventricular function showed a change in hemodynamic parameters of heart function at rest and under physical exertion: a small increase in the cardiac index, without significantly affecting the maximum rate of pressure build-up in the left ventricle, 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 with simultaneous application with beta-blockers.
Amlodipine does not change the function of the sinoatrial node and does not affect AV conduction in intact animals and healthy volunteers. When using amlodipine in combination with beta-blockers in patients with arterial hypertension or with angina, a decrease in blood pressure is not accompanied by undesirable changes in electrocardiographic parameters.
The clinical efficacy of amlodipine in patients with stable angina pectoris, vasospastic angina and angiographically confirmed coronary artery disease was demonstrated.
In a prolonged placebo-controlled trial (PRAISE-2) in patients with chronic heart failure (NYHA III and IV functional classes) of non-ischemic etiology, amlodipine showed an increase in the incidence of pulmonary edema, with no significant differences in the incidence of worsening chronic course heart failure compared with placebo.
The risk of myocardial infarction or increased severity of angina pectoris: rarely at the beginning of therapy with slow calcium channel blockers or with an increase in their dose (especially in patients with hypertrophic obstructive cardiomyopathy, severe obstructive coronary artery disease), there was an increase in the frequency, duration and severity of angina attacks or developed acute myocardial infarction. Arrhythmia (including ventricular tachycardia and atrial fibrillation) has also been observed with the use of slow calcium channel blockers. These undesirable phenomena could not be differentiated from the natural course of diseases.
Valsartan
Valsartan - an active and specific antagonist of angiotensin II receptors, intended for oral administration. It acts selectively on AT 1 receptor subtypes, which are responsible for the effects of angiotensin II. An increase in the plasma concentration of unbound angiotensin II due to blockade of AT 1 -receptors under the influence of valsartan can stimulate unblocked AT 2 receptors, which counteract the effects of stimulation of AT 1 -receptors. Valsartan does not have any marked agonistic activity against AT 1 -receptors. The affinity of valsartan for AT 1 subtype receptors is about 20,000 times higher than for AT 2 receptor subtypes.
Valsartan does not inhibit ACE, which converts angiotensin I into angiotensin II and causes destruction of bradykinin. Because when angiotensin II antagonists are used, there is no inhibition of ACE and accumulation of bradykinin or substance P, the development of a dry cough 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 receiving valsartan (2.6% of patients receiving valsartan and 7.9% receiving ACE inhibitor). In a clinical study that included patients who previously developed a dry cough in the treatment with an ACE inhibitor, this complication was observed in 19.5% of cases with valsartan treatment, in 19.0% of cases with a thiazide diuretic. At the same time, cough was observed in 68.5% of cases in the group of patients treated with an ACE inhibitor (p <0.05). Valsartan does not interact and does not block the receptors of other hormones or ion channels, which are important for the regulation of the functions of the cardiovascular system.
In the treatment of valsartan in patients with arterial hypertension, a decrease in blood pressure is noted, not accompanied by a change in heart rate.
The antihypertensive effect is manifested for 2 h in most patients after a single intake of valsartan inside. The maximum decrease in blood pressure develops after 4-6 hours. After taking valsartan, the duration of the antihypertensive effect persists for more than 24 hours. For repeated use, the maximum decrease in blood pressure, regardless of the dose taken, is usually achieved within 2-4 weeks and maintained at the achieved level during prolonged therapy. A sharp discontinuation 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 cardiac insufficiency (NYHA class II-IV) leads to a significant reduction in the number of hospitalizations for cardiovascular disease (which is especially pronounced in patients who do not receive ACE inhibitors or beta-blockers). With the use of valsartan in patients with left ventricular failure (with stable hemodynamic parameters) or with left ventricular dysfunction after a previous myocardial infarction, cardiovascular mortality is reduced.
Hydrochlorothiazide
The point of application of the action of thiazide diuretics is distal convoluted renal tubules. When thiazide diuretics are exposed to highly sensitive receptors in the distal tubules of the cortical layer of the kidneys, the reabsorption of sodium (Na + ) ions and chlorine (Cl-) is suppressed. Suppression of the co-transport system Na +and Cl - , apparently, occurs due to competition for the binding sites of Cl ions - in this system. As a result, the removal of sodium and chlorine ions increases approximately equally. As a result of diuretic action, a decrease in bcc is observed, as a result of which renin activity, aldosterone secretion, kidney potassium removal and, consequently, a decrease in potassium in serum are increased.
PHARMACOKINETICS
The pharmacokinetic parameters of amlodipine, valsartan and hydrochlorothiazide are characterized by linearity.
Amlodipine
Suction
After oral administration of amlodipine in therapeutic doses, Cmax in blood plasma is reached after 6-12 hours. Absolute bioavailability averages 64-80%. Eating food does not affect the bioavailability of amlodipine.
Distribution
V d is approximately 21 l / kg. In studies with amlodipine in vitro, it was shown that in patients with arterial hypertension, approximately 97.5% of the circulating drug binds to plasma proteins.
Metabolism
Amlodipine is intensively (approximately 90%) metabolized in the liver with the formation of active metabolites.
Excretion
Excretion from blood plasma is biphasic with T 1/2 approximately 30 to 50 hours. C ss in blood plasma are reached after prolonged use for 7-8 days. 10% is excreted unchanged, 60% - in the form of metabolites.
Valsartan
Suction
After ingestion of valsartan C max in the blood plasma is achieved after 2-4 hours. The average absolute bioavailability is 23%.
The pharmacokinetic curve of valsartan has a downward multiexponential character (T 1/2? <1 h and T 1/2? About 9 h). When taken with food, there is a decrease in bioavailability (by AUC value) by 40% and C max in blood plasma by almost 50%, although approximately 8 hours after taking the drug inside the valsartan plasma concentration in people taking it with food and in The group receiving valsartan on an empty stomach is equalized. The decrease in AUC, however, is not accompanied by a clinically significant decrease in the therapeutic effect, so valsartan can be administered regardless of the time of ingestion.
Distribution
V d of valsartan in the equilibrium state after intravenous administration was about 17 liters, indicating a lack of extensive distribution of valsartan in the tissues.Valsartan largely binds to serum proteins (94-97%), mainly with albumins.
Metabolism
Valsartan does not undergo a pronounced metabolism (about 20% of the dose is determined in the form of metabolites). The hydroxyl metabolite is determined in blood plasma at low concentrations (less than 10% of the valsartan AUC). This metabolite is pharmacologically inactive.
Excretion
The pharmacokinetic curve of valsartan has a downward multiexponential character (T 1/2? <1 h and T 1/2? About 9 h). Valsartan is excreted mainly unchanged through the intestine (about 83% of the dose) and kidneys (about 13% of the dose). After iv introduction, the plasma clearance of valsartan is about 2 l / h and its renal clearance is 0.62 l / h (about 30% of the total clearance). T 1/2 is 6 hours.
Hydrochlorothiazide
Suction
Absorption of hydrochlorothiazide after ingestion is rapid (time to reach C max about 2 h). On average, the increase in AUC is linear and proportional to the dose in the therapeutic range. With simultaneous intake of food, both the increase and decrease in the systemic bioavailability of hydrochlorothiazide were reported compared with the administration of the drug on an empty stomach. The magnitude of this effect is small and clinically insignificant. The absolute bioavailability of hydrochlorothiazide after oral administration is 70%.
Distribution
The kinetics of distribution and elimination as a whole is described as a bi-exponential decay function, with T 1/2 6-15 hours. With repeated use, the hydrochlorothiazide kinetics does not change and when used once / day, the cumulation is minimal. Apparent V d is 4-8 l / kg. 40-70% of the hydrochlorothiazide circulating in the blood plasma binds to blood plasma proteins, mainly with albumins. Hydrochlorothiazide also accumulates in erythrocytes in concentrations about 3 times higher than those in blood plasma.
Metabolism
Hydrochlorothiazide is excreted unchanged.
Excretion
T 1/2 of the final phase is 6-15 hours. With repeated use of the drug the kinetics of hydrochlorothiazide does not change, with the prescription 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 in kidneys with urine.
Amlodipine + valsartan + hydrochlorothiazide
After ingestion of Ko-Exforge C max, amlodipine, valsartan and hydrochlorothiazide are reached after 6-8, 3 and 2 hours, respectively. The rate and degree of absorption of Co-Exforge are equivalent to the bioavailability of amlodipine, valsartan and hydrochlorothiazide when taken in each of them as separate tablets.
Pharmacokinetics in special clinical cases
Pharmacokinetic features of the use of Ko-Exforge in children under 18 years of age have not been established.
The time to achieve C max amlodipine in blood plasma in young and elderly patients is the same. In elderly patients, the clearance of amlodipine is slightly reduced, which leads to an increase in AUC and T 1/2 . In elderly patients, the systemic effect of valsartan was somewhat more pronounced than in young patients, however, this was not clinically significant. There are limited data on the reduction in systemic clearance of hydrochlorothiazide in patients over 65 years of age (healthy volunteers or patients with hypertension) compared with young patients.
In patients with impaired renal function, the pharmacokinetic parameters of amlodipine do not change significantly. There was no correlation between renal function (CC) and systemic exposure to valsartan (AUC) in patients with varying degrees of renal impairment.
In the presence of renal insufficiency, the average plasma concentration peaks and AUC values ​​of hydrochlorothiazide increase, and the rate of excretion decreases. In patients with impaired renal function from mild to moderate severity, T 1/2 increases almost in half. The renal clearance of hydrochlorothiazide in patients with impaired renal function is reduced compared to normal indices (about 300 ml / min). Co-Exforge is contraindicated in patients with severe renal insufficiency (QC less than 30 ml / min), anuria, and should be used with caution in patients with impaired renal function of moderate severity (calculated glomerular filtration rate (> 30 ml / min, but <90 ml / min.) However, since the excretion of hydrochlorothiazide occurs mainly in the kidneys, renal dysfunction may have a significant effect on the pharmacokinetics of hydrochlorothiazide.
Patients with impaired hepatic function have reduced clearance of amlodipine, which leads to an increase in AUC of approximately 40-60%. On average, in patients with hepatic impairment with a mild (5-6 points on the Child-Pugh scale) and moderate (7-9 on the Child-Pugh scale), the bioavailability (AUC) of valsartan is doubled compared to healthy volunteers (of the corresponding age , sex and body weight). Since the dysfunction of the liver does not have a clinically significant effect on the kinetics of hydrochlorothiazide, correction of its dose in patients with impaired liver function is not required. The drug Ko-Exforzh is contraindicated 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 impairment of liver function.
INDICATIONS
- Arterial hypertension II and III degree.
DOSING MODE
The drug should be taken orally (preferably in the morning), washed down with a small amount of water, regardless of food intake.
For convenience, patients treated with amlodipine, valsartan, and hydrochlorothiazide in individual tablets can be transferred to Co-Exforge therapy containing the same doses of active components, as well as inadequate control of blood pressure on a background of double combination therapy (valsartan + hydrochlorothiazide, amlodipine + valsartan and amlodipine + hydrochlorothiazide), patients can be transferred to triple combined treatment with Ko-Exforge in appropriate doses.
In the case where the patient marked dose-related adverse effects when using a dual combination therapy by any components of the formulation Ko Exforge, to achieve a similar reduction in blood pressure in patients may be assigned Ko Exforge preparation containing a lower dose of the active ingredient which caused this side effect.
Recommended daily dose Ko Exforge comprise:
- 5 mg + 160 mg + 12.5 mg (1 tablet containing amlodipine + valsartan + hydrochlorothiazide in a dose of 5 mg + 160 mg + 12.5 mg.);
- 10 mg + 160 mg + 12.5 mg (1 tablet containing amlodipine + valsartan + hydrochlorothiazide in a dose of 10 mg + 160 mg + 12.5 mg.);
- 10 mg + 320 mg + 25 mg (2 tablets containing amlodipine + valsartan + hydrochlorothiazide in a dose of 5 mg + 160 mg + 12.5 mg.).
The maximum antihypertensive effect of the drug observed after 2 weeks after increasing dose. The maximum dose is 10 mg + 320 mg + 25 mg / day.
In patients older than 65 years of correction dose is not required.
Since the safety and efficacy of the drug Co-Exforge in children and adolescents (under 18 years) have not been established, the drug is not recommended in these patients.
In patients with mild and moderate renal impairment (creatinine clearance of more than 30 ml / min) and liver (5-9 points on the Child-Pugh) correction dose is not required.
SIDE EFFECT
Below are all adverse events noted while the use of amlodipine, valsartan and hydrochlorothiazide (Preparation Exforge Ko) and amlodipine monotherapy, valsartan and hydrochlorothiazide.
Co-Exforge (amlodipine + valsartan + hydrochlorothiazide)
Security co-formulation of Exforge has been evaluated in more than 2200 patients. In applying the drug Ko Exforge adverse events were mostly low to moderate. Discontinuation of treatment due to adverse events was required in rare cases. Most often the drug was discontinued because of dizziness and pronounced reduction in blood pressure (0.7%).
In applying the drug Co-Exforge found no new adverse events compared to the double combination therapy and monotherapy with the individual components.
As for short-term reception, good tolerability of Exforge Koh observed when long-term use (over the year).
The frequency of adverse events was not related to gender, age or race.
In applying the drug Ko Exforge changes in laboratory parameters were minimal and did not differ from those in monotherapy individual components. When simultaneous administration of hydrochlorothiazide together with valsartan (triple combination therapy), there is a decrease gipokaliemicheskogo action of hydrochlorothiazide.
The most common adverse events (frequency 2%) noted in clinical studies (regardless of detection of application of the drug Ko Exforge) were dizziness (7.7%), peripheral edema (4.5%), headache (4.3%) dyspepsia (2.2%), fatigue (2.2%), muscle spasm (2.2%), back pain (2.1%), nasopharyngitis (2.1%), nausea (2.1%).
To assess the frequency of use of the following criteria (according to the WHO classification): very common (1/10?); common (1/100, <1/10?); rarely (1/1000, <1/100?); rarely (1/10 000, <1/1000?); very rare (<1/10 000), the frequency is unknown (not enough data to assess the incidence).
From a metabolism: often - hypokalemia; rarely - anorexia, hypercalcemia, hyperlipidemia, hyponatremia.
From the nervous system: often - dizziness, headache; rarely - insomnia / sleep disorders, impaired coordination, postural dizziness and vertigo, caused by physical stress, taste disturbances, confusion, paresthesia, neuropathy, including peripheral, somnolence, syncope.
From the sensory organs: rarely - visual disturbances, vertigo.
Cardio-vascular system: often - marked reduction of blood pressure; rarely - tachycardia, orthostatic hypotension, phlebitis, thrombophlebitis.
The respiratory system: rarely - cough, shortness of breath, throat irritation.
From the digestive system:often - indigestion; infrequently - abdominal discomfort, pain in the upper abdomen, halitosis, diarrhea, dry mouth, nausea, and vomiting.
Dermatological reactions: seldom - increased sweating, itching.
On the part of the musculoskeletal system and connective tissue disorders: rarely - back pain, swelling in the joints, muscle spasms, muscular weakness, myalgia, pain in the limbs.
From the urinary system: often - pollakiuria; Infrequent - increased creatinine concentration in blood plasma, acute renal failure.
On the part of the reproductive system: rarely - erectile dysfunction.
On the part of the body as a whole:often - peripheral edema, increased fatigue; infrequently - abasia, gait disturbance, asthenia, fatigue, pain in the chest area.
From the laboratory parameters: rarely - elevated levels of urea nitrogen in the blood plasma, hyperuricemia, increased body weight.
Amlodipine
To assess the frequency of use of the following criteria (according to the WHO classification): very common (1/10?); common (1/100, <1/10?); rarely (1/1000, <1/100?); rarely (1/10 000, <1/1000?); very rare (<1/10 000), the frequency is unknown (not enough data to assess the incidence).
From hemopoiesis system: very rarely - leukopenia, thrombocytopenia.
Immune system: very rarely - hypersensitivity reactions.
From a metabolism: very rarely - hyperglycemia.
From the nervous system: often - dizziness, headache, drowsiness; rarely - insomnia / sleep disorders, mood lability, paresthesia, syncope, tremor; very rarely - muscle hypertension, peripheral neuropathy, neuropathy; the frequency is unknown - extrapyramidal disorders.
From the sensory organs: rarely - visual impairment, tinnitus, taste disturbances.
Cardio-vascular system: often - a sense of palpitations, flushing; infrequently - marked reduction of blood pressure; very rarely - vasculitis, arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation).
The respiratory system:rarely - dyspnea, rhinitis; very rarely - cough.
From the digestive system: often - abdominal discomfort, pain in the upper abdomen, nausea; infrequently - the change in frequency of bowel movements, diarrhea, dry mouth, dyspepsia, vomiting; very rarely - gastritis, gingival hyperplasia, pancreatitis.
Of the liver and biliary tract: rarely - increased activity of liver enzymes, increased bilirubin concentration in blood plasma, hepatitis, intrahepatic cholestasis, jaundice.
Dermatological reactions: rare - alopecia, increased sweating, itching, rash, including rash, purpura, skin discoloration; very rarely - angioedema, erythema multiforme, urticaria.
On the part of the musculoskeletal system and connective tissue:Infrequent - arthralgia, back pain, muscle cramps, myalgia.
From the urinary system: rarely - a violation of urination, nocturia, pollakiuria.
On the part of the reproductive system: rarely - erectile dysfunction, gynecomastia.
On the part of the body as a whole: often - fatigue, edema; rarely - fatigue, discomfort, weakness, pain in the chest, pain of various localization.
From the laboratory parameters: rarely - increased or decreased body weight.
valsartan
To assess the frequency of use of the following criteria (according to the WHO classification): very common (1/10?); common (1/100, <1/10?); rarely (1/1000, <1/100?); rarely (1/10 000, <1/1000?); very rare (<1/10 000), the frequency is unknown (not enough data to assess the incidence).
From hemopoiesis system: the frequency is unknown - decrease in hemoglobin and hematocrit, leukopenia, thrombocytopenia.
Immune system: the frequency is unknown - hypersensitivity reactions.
On the part of the organ of hearing: rare - vertigo.
Cardio-vascular system: the frequency is unknown - vasculitis.
The respiratory system: rarely - cough.
From the digestive system:Infrequent - abdominal discomfort, pain in the upper abdomen.
Of the liver and biliary tract: frequency not known - elevated liver enzymes, increased bilirubin concentration in the blood plasma.
Allergic reactions: the frequency is unknown - angioedema, pruritus, rash.
On the part of the musculoskeletal system: the frequency is unknown - myalgia.
From the urinary system: frequency not known - increase in creatinine concentration in blood plasma of renal function, including acute renal failure.
On the part of the body as a whole: rarely - fatigue.
From the laboratory parameters:the frequency is unknown - an increase potassium in the blood plasma.
In clinical studies, the application of valsartan monotherapy were noted following adverse events (irrespective of causal relationship to the study drug): viral infections, upper respiratory tract infection, sinusitis, rhinitis, neutropenia, insomnia.
In rare cases, the use of valsartan may be associated with a decrease in hemoglobin and hematocrit. In controlled trials in 0.8% and 0.4% of patients receiving valsartan, there was a marked reduction (over 20%) in hemoglobin and hematocrit, respectively. For comparison - in patients treated with placebo, decreased as the hematocrit and hemoglobin was noted in 0.1% of cases.
Neutropenia was present in 1.9% of patients receiving valsartan, and 1.6% of patients receiving ACE inhibitor.
In controlled trials in 3.9% and 16.6% of patients with chronic heart failure treated with valsartan, it noted increasing the concentration of creatinine and blood urea nitrogen more than 50%, respectively. For comparison - in patients who received placebo, increasing the concentration of creatinine and urea nitrogen were observed in the 0.9% and 6.3% of cases.
Doubling the concentration of serum creatinine was observed in 4.2% of patients after myocardial infarction treated with valsartan and captopril-treated 3.4%.
In controlled trials, 10% of patients with chronic heart failure, elevated levels of serum potassium was observed in more than 20%. For comparison, in patients treated with placebo, the potassium content increase was observed in 5.1% of cases.
Hydrochlorothiazide
To assess the frequency of use of the following criteria (according to the WHO classification): very common (1/10?); common (1/100, <1/10?); rarely (1/1000, <1/100?); rarely (1/10 000, <1/1000?); very rare (<1/10 000), the frequency is unknown (not enough data to assess the incidence).
From hemopoiesis system: rarely - thrombocytopenia; very rarely - agranulocytosis, inhibition of bone marrow hematopoiesis, hemolytic anemia, leukopenia.
Immune system:very rarely - hypersensitivity reactions.
From a metabolism: often - hypokalemia; infrequently - hyperuricemia, hypomagnesemia, hyponatremia; rarely - hypercalcemia, hyperglycemia; very rarely - gipohloremichesky alkalosis.
From the nervous system: rarely - insomnia / sleep disorders, depression, dizziness, headache, lethargy.
On the part of the organ of vision: rarely - visual impairment.
Cardio-vascular system: rarely - orthostatic hypotension; rare - arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation).
The respiratory system: very rare - respiratory distress syndrome, pulmonary edema and pneumonitis.
From the digestive system: rare - loss of appetite, nausea, vomiting; rare - abdominal discomfort, pain in the upper abdomen, constipation, diarrhea; very rarely - pancreatitis.
Of the liver and biliary tract: rarely - hepatitis, intrahepatic cholestasis, jaundice.
Dermatological reactions: seldom - rash, hives; rarely - increased photosensitivity, purpura; very rarely - necrotizing vasculitis, toxic epidermal necrolysis, lupus-like reactions, exacerbation of cutaneous manifestations of systemic lupus erythematosus.
From the urinary system: rarely - impaired renal function, including acute renal failure.
On the part of the reproductive system: rarely - erectile dysfunction.
From the laboratory parameters: often - hyperlipidemia; rarely - glycosuria.
CONTRAINDICATIONS
- expressed human liver (more than 9 points on the Child-Pugh), biliary cirrhosis and cholestasis;
- severe renal impairment (creatinine clearance less than 30 mL / min), anuria, patients on hemodialysis;
- severe hypotension (systolic blood pressure less than 90 mmHg), collapse, cardiogenic shock;
- clinically significant aortic stenosis;
- refractory to adequate therapy, hypokalemia, hyponatremia, hypercalcemia and hyperuricemia with clinical manifestations;
- hereditary angioedema, or swelling of the patients on the background of previous therapy ATII receptor antagonists;
- pregnancy and pregnancy planning;
- the period of breastfeeding;
- age under 18 years (efficiency and safety not established);
- increased sensitivity to amlodipine, valsartan, hydrochlorothiazide, other sulfonamide derivatives, dihydropyridine derivatives and other auxiliary ingredients.
Care should be cautious when administering the drug to patients with unilateral or bilateral renal artery stenosis or stenosis of the artery only kidneys, for conditions involving reduction of the bcc, disorders of water and electrolyte balance (including hyponatremia, hyperkalemia), patients with mitral or aortic stenosis, hypertrophic obstructive cardiomyopathy with mild to moderate hepatic impairment, especially against biliary obstruction (less than 9 points on the Child-Pugh), sugar m diabetes, systemic lupus erythematosus.
Safety of the drug in patients after recently undergone kidney transplantation, as well as in patients with heart failure or coronary artery disease has not been established.
PREGNANCY AND LACTATION
It is known that administration of ACE inhibitors that affect the RAAS in pregnant trimesters II and III, leading to damage or destruction of the developing fetus. Considering the mechanism of action of angiotensin II receptor antagonists, we can not exclude the risk to the fetus. According to a retrospective analysis of ACE inhibitors in I trimester accompanied by the development of the fetus and newborn pathology. Hydrochlorothiazide crosses the placental barrier. When the use of thiazide diuretics, including hydrochlorothiazide during pregnancy may develop fetal or neonatal thrombocytopenia, and other adverse reactions, observed in adult patients. Accidental reception valsartan pregnant described cases of spontaneous abortion, oligohydramnios and renal impairment in newborns. Co-Exforge,like any other drug, has a direct impact on the RAAS, should not be given during pregnancy and women planning pregnancy.
Patients of childbearing in
