Amlodipine-Valsartan-Richter - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate 26 mg, microcrystalline cellulose 57.556 mg, povidone-K30 6 mg, croscarmellose sodium 9.5 mg, talc 2 mg, magnesium stearate 2 mg.

Film sheath (Opadrai Pink 03F240002) 5 mg: hypromellose-6sR 3.125 mg, titanium dioxide 1.4915 mg, macrogol-4000 0.3125 mg, talc 0.05 mg, iron-dye oxide yellow 0.02 mg, ferric oxide red oxide 0.001 mg.

Dosage of 5 mg + 160 mg:

Active substances: valsartan 160 mg, amlodipine besylate 6.944 mg (equivalent to 5 mg of amlodipine).

Excipients: lactose monohydrate 52 mg, microcrystalline cellulose 117,056 mg, povidone-K30 12 mg, croscarmellose sodium 19 mg, talc 4 mg, magnesium stearate 4 mg.

Film sheath (Opadrai Pink 03F240003) 10 mg: hypromellose-6PC 6.25 mg, titanium dioxide 2.965 mg, macrogol-4000 0.625 mg, talc 0.1 mg, iron-dye oxide yellow 0.04 mg, ferric oxide red oxide 0.02 mg.

Dosage of 10 mg + 160 mg:

Active substances: valsartan 160 mg, amlodipine besylate 13.889 mg (equivalent to 10 mg of amlodipine).

Excipients: lactose monohydrate 52 mg, cellulose microcrystalline 115,111 mg, povidone-K30 12 mg, croscarmellose sodium 19 mg, talc 4 mg, magnesium stearate 4 mg.

Film sheath (Opadrai Pink 03F240002) 10 mg: hypromellose-6sR 6.25mg, titanium dioxide 2.983mg, macrogol-4000 0.625mg, talc 0.1mg, iron-dye oxide yellow 0.04mg, iron oxide dye 0.002mg red.

Description:

Dosage of 5 mg + 80 mg:

Round, biconvex tablets, covered with a film shell, light beige color, engraved "CI3 "on one side.

Dosage of 5 mg + 160 mg:

Capsule-shaped, biconvex tablets, covered with a film shell, pink, engraved "CI4 "on one side.

Dosage of 10 mg + 160 mg:

Capsule-shaped, biconvex tablets, covered with a film shell, light-beige, engraved "CI5 "on one side.

Pharmacotherapeutic group:A combined hypotensive drug (BCCA + angiotensin II receptor antagonist)

ATX: & nbsp

C.08.C.A.01 Amlodipine

C.09.C.A.03 Valsartan

Pharmacodynamics:

Amlodipine-Valsartan-Richter is a drug containing a fixed combination of components that have complementary mechanisms of action, allowing control of blood pressure (BP): amlodipine. derivative of dihydropyridine, belongs to the class of blockers of "slow" calcium channels (BCCC), and valsartan - to the class of angiotensin II receptor antagonists (ARA II). This combination has an antihypertensive effect, providing a more pronounced decrease in blood pressure than monotherapy with each drug individually.

Amlodipine

Amlodipine inhibits the transmembrane intake 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 the smooth muscle of the vessels, which causes a decrease in the overall peripheral vascular resistance and a subsequent decrease in blood pressure.

In patients with hypertension, the use of amlodipine in therapeutic doses causes vasodilation, leading to a decrease in blood pressure (in the standing and lying position). With prolonged use of amlodipine, a decrease in blood pressure is not accompanied by a significant change in the heart rate (heart rate) and the concentration of catecholamines in the blood plasma.

With arterial hypertension in patients with normal renal function amlodipine in therapeutic doses leads to a decrease in the resistance of renal vessels, an increase in the rate of glomerular filtration and improvement of renal blood flow without changing the filtration fraction and the degree of proteinuria.

As with other BCCI, in patients with normal left ventricular function, amlodipine treatment caused a change in the hemodynamic parameters of heart function both at rest and during physical activity: there was a slight increase in the cardiac index not associated with the maximum rate of increase in pressure in the left ventricle , end-diastolic pressure and volume of the left ventricle. Hemodynamic studies in intact animals and humans showed that a decrease in blood pressure caused by the use of amlodipine in therapeutic doses is not accompanied by a negative inotropic effect even when used simultaneously with beta-blockers.

Amlodipine does not change the function of the sinoatrial node or atrioventricular conduction in intact animals and humans.When using amlodipine in combination with beta-blockers in patients with arterial hypertension or angina, a decrease in blood pressure is not accompanied by undesirable changes in the parameters of the electrocardiogram.

The clinical efficacy of amlodipine for the treatment of patients with chronic stable angina, vasospastic angina and angiographically confirmed coronary artery disease has been proved.

Valsartan

Valsartan is an active and specific antagonist of angiotensin II receptors, intended for oral administration. It acts selectively on the AT subtype receptors₁, which are responsible for the known effects of angiotensin II. The intake of valsartan leads to an increase in the concentration of free angiotensin II in the blood plasma due to the blockade of AT₁-receptors; this can stimulate a blocked AT₁-receptors, which counteract the effect of stimulation of AT₁receptors. Valsartan has no pronounced agonist activity against AT₁receptors. The affinity of valsartan for AT subtype receptors₁ approximately 20,000 times higher than to the AT subtype receptors₂.

Valsartan does not inhibit angiotensin-converting enzyme (ACE), also known as kininase II. which turns angiotensin I into angiotensin II and causes destruction of bradykinin.

When angiotensin II antagonists are used, there is no inhibition of ACE and accumulation of bradykinin or substance P; the development of dry cough is unlikely.

In the context of comparative clinical studies of valsartan with an ACE inhibitor, it was demonstrated that the incidence of dry cough was significantly lower (p <0.05) in patients who received valsartan, compared with patients receiving ACE inhibitors (2.6% and 7.9% of patients, respectively). In a clinical study involving patients previously treated with an ACE inhibitor, dry cough was noted in 19.5% of patients who received valsartan. and in 19% of patients receiving a thiazide diuretic.

In the group treated with an ACE inhibitor, dry cough was observed in 68.5% of patients (p <0.05). Valsartan does not affect the receptors of other hormones or ion cables involved in the regulation of the functions of the cardiovascular system.

In patients with hypertension taking valsartan, a decrease in blood pressure is not accompanied by a change in heart rate.

In most patients, the effect of the drug manifests itself within 2 hours after a single oral intake. The maximum decrease in blood pressure is observed after 4-6 hours. The antihypertensive effect of the drug persists for more than 24 hours. Multiple administration of the drug causes a decrease in blood pressure independent of the accepted dose within 2-4 weeks, the achieved result persists 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 heart failure (II-IV functional class by classification NYHA) leads to a significant decrease in the number of hospitalizations. This effect is most pronounced in patients who do not receive ACE inhibitors or beta-blockers. The use of valsartan for the treatment of patients with left ventricular failure (in a stable state) or with a violation of left ventricular function after a myocardial infarction suffered leads to a decrease in cardiovascular mortality.

Amlodipine + valsartan

In patients with hypertension who received amlodipine + valsartan once a day, the antihypertensive effect persisted for 24 hours.

In patients with baseline systolic blood pressure (SBP) 153-157 mm Hg. Art. and diastolic blood pressure (DBP) ≥ 95 mm Hg. Art. and <110 mm Hg. Art. reception of a combination amlodipine + valsartan in doses of 5 mg + 80 mg and 5 mg + 160 mg caused a decrease in blood pressure by 20-28 / 14-19 mm Hg. Art. (compared with 7-13 / 7-9 mm Hg when taking placebo).

Combination amlodipine + valsartan at the dose of 10 mg + 160 mg and 5 mg + 160 mg normalizes blood pressure (by the end of the study DBP was reduced to <90 mm Hg) in 75% and in 62% of patients with inadequate BP control who received monotherapy with valsartan 160 mg / day.

Combination amlodipine + valsartan in a dose of 10 mg + 160 mg normalizes blood pressure in 78% of patients with inadequate control of blood pressure who received amlodipine monotherapy in a dose of 10 mg.

Patients with hypertension who received a combination of valsartan 160 mg and amlodipine at doses of 10 mg and 5 mg achieved an additional reduction in SBP and DBP by 6.0 / 4.8 mm Hg. Art. and 3.9 / 2.9 mm Hg. Art. respectively, compared with patients receiving only valsartan in a dose of 160 mg or only amlodipine in a dose of 5 and 10 mg.

Combination dose titration amlodipine + valsartan from 5 mg + 160 mg to 10 mg + 160 mg in patients with arterial hypertension with DBP ≥ 110 mm Hg. Art. and <120 mm Hg. , leads to a decrease in blood pressure by 36/29 mm Hg. Art. (in the "sitting" position), which is comparable to a decrease in blood pressure when titrating the dose of the combination of an ACE inhibitor and a thiazide diuretic.

In the course of two long-term studies, the effect of the combination amlodipine + valsartan persisted for 1 year. Sudden discontinuation of the drug containing amlodipine + valsartan, was not accompanied by a sharp increase in blood pressure.

In patients with adequate control of blood pressure, but developed with amlodipine monotherapy with severe peripheral edema, a comparable control of BP with a lesser risk of peripheral edema development was achieved with combined therapy.

The therapeutic efficacy of the drug containing amlodipine + valsartan, does not depend on the age, gender and race of the patient.

Pharmacokinetics:

Amlodipine and valsartan have linear pharmacokinetics.

Amlodipine

Suction

The maximum concentration (C_mOh) of amlodipine in the blood plasma is achieved 6-12 hours after taking amlodipine inward at therapeutic doses. Absolute bioavailability averages 64-80%. Eating food does not affect the bioavailability of amlodipine.

Distribution

Volume of distribution (V_d) is approximately 21 l / kg. In studies with amlodipine in vitro it was proved that in patients with arterial hypertension, approximately 97.5% of the circulating blood of amlodipine binds to blood plasma proteins.

Amlodipine concentrations in the blood plasma correlate with the clinical effect in both the elderly and young patients.

Metabolism

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

Excretion

Excretion of amlodipine from the blood plasma is biphasic; half-life (T_1/2) is 30-50 hours. Equilibrium concentrations in the blood plasma are reached within 7-8 days after the start of the drug. Amlodipine is excreted by the kidneys: 10% - unchanged and 60% - in the form of metabolites.

Amlodipine has a linear pharmacokinetic profile with a pronounced positive correlation between the dose taken and the maximum concentration in the blood plasma (C_mOh) or the area under the curve "concentration-time" (AUC).

Valsartan

Suction

FROM_mOh Valsartan in the blood plasma is achieved 2-3 hours after ingestion.The average absolute bioavailability is 23%.

The pharmacokinetic curve of valsartan has a downward multiexponential character (T_1/2α <1 h and T_1/2β - about 9 hours). When taking valsartan at the same time as food intake, there is a decrease in bioavailability (by value AUC) by 40% and by almost 50% decrease in C_mOh; However, approximately 8 hours after taking the drug, valsartan concentrations in the blood plasma in the group of patients taking it with food and in the group taking on an empty stomach are equalized. Decrease AUC is not accompanied by a clinically significant decrease in the therapeutic effect, so valsartan can be used regardless of the time of meal.

Distribution

V_d valsartan in the equilibrium state after intravenous administration is about 17 l, indicating that there is no extensive distribution of valsartan in the tissues. Valsartan is largely associated with blood plasma proteins (94-97%), mainly with albumins.

Metabolism

Valsartan is not subjected to intensive metabolism (it is metabolized by about 20% of the dose taken). The hydroxyl metabolite is determined in blood plasma at low concentrations (less than 10% of AUC valsartan). This metabolite is pharmacologically active.

Excretion

Valsartan is excreted mainly unchanged through the intestine (about 83% of the dose) and kidneys (about 13% of the dose). After intravenous administration, the plasma clearance of valsartan is about 2 l / h. renal clearance - 0.62 l / h (about 30% of the total ground clearance). T_1/2valsartan is 6 hours.

Values AUC and C_mOh Valsartan is increased linearly, in proportion to the dose taken in the dose range used in clinical practice.

Amlodipine + valsartan

After ingestion combination amlodipine + valsartan FROM_mOh Valsartan and amlodipine are achieved after 3 and 6-8 hours, respectively. The speed and degree of absorption of the combination amlodipine + valsartan are equivalent to the bioavailability of amlodipine and valsartan with each drug taken separately.

Pharmacokinetics in specific patient groups

Children

Pharmacokinetic features of the drug in children under 18 years of age have not been established.

Elderly patients

Time to reach C_mOh 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 AUC and T_1/2.

In elderly patients, the systemic effect of valsartan was somewhat more pronounced than in young patients, but this difference was not clinically significant.Since the drug is well tolerated by both young and elderly patients, dose adjustment is not required.

Patients with impaired renal function

In patients with impaired renal function, the pharmacokinetic parameters of amlodipine do not change significantly. There was no correlation between renal function (creatinine clearance - QC) and systemic exposure to valsartan (AUC) in patients with varying degrees of impaired renal function.

In patients with impaired renal function of mild and moderate degree (CK - 30-50 ml / min), correction of the initial dose is not required.

Patients with impaired hepatic function

In patients with hepatic insufficiency, the clearance of amlodipine is somewhat reduced, resulting in an increase AUC by 40-60%. In patients with mild (5-6 points on the Child-Pugh scale) and moderate (7-9 points on the Child-Pugh scale), the degree of liver dysfunction is bioavailability (by AUC) valsartan is doubled in comparison with healthy volunteers (corresponding age, sex and body weight).

Indications:

Arterial hypertension (patients who are shown combined therapy).

Contraindications:

- Hypersensitivity to amlodipine, other dihydropyridine derivatives, valsartan and other components of the drug;

- severe (> 9 on the Child-Pugh scale) degree of liver function abnormalities, biliary cirrhosis, cholestasis;

- severe renal dysfunction (CC less than 30 ml / min);

- pregnancy planning, pregnancy and the period of breastfeeding;

- primary hyperaldosteronism;

- severe arterial hypotension (systolic blood pressure less than 90 mm Hg), collapse, cardiogenic shock;

- obstruction of the outflow tract of the left ventricle (including severe aortic stenosis);

- hemodynamically unstable heart failure after acute myocardial infarction;

- simultaneous use with aliskiren and aliskiren-containing drugs in patients with diabetes mellitus and / or moderate or severe renal dysfunction (glomerular filtration rate (GFR) of less than 60 ml / min / 1.73 m²);

- deficiency of lactase, intolerance to galactose, impaired absorption of glucose-galactose.

The safety of Amlodipine-Valsartan-Richter in patients with unilateral or bilateral stenosis of the renal arteries or stenosis of the single kidney artery has not been established in patients after recent kidney transplantation, as well as in children and adolescents under the age of 18.

Carefully:

Angioedema

Special care should be taken when using the drug in patients with hereditary angioedema, or edema on the background of previous therapy with angiotensin receptor antagonists II (APA II) or ACE inhibitors.

Infringements фFunctions liver

Valsartan is excreted mainly unchanged with bile, while amlodipine intensively metabolized in the liver. Amlodipine-Valsartan-Richter should be used with caution in the treatment of patients with mild to moderate liver disease (less than 9 on the Child-Pugh scale), as well as in obstructive biliary tract diseases.

Renal impairment

In patients with mild to moderate renal impairment (KK - 30-50 ml / min), dose adjustment is not required. It is necessary to regularly monitor the potassium content and serum creatinine concentration with moderate renal dysfunction.

Heart failure

It is recommended to use with caution the blockers of "slow" calcium channels (amlodipine) in patients with heart failure III-IV functional class (by NYHA). In patients with heart failure, renal function may depend on the activity of the renin-angiotensin-aldosterone system (RAAS), and treatment with ACE inhibitors or APA II they may be associated with the development of oliguria and / or progressive azotemia and in rare cases lead to acute renal failure and death. Evaluation of the condition of patients with heart failure should always include an assessment of kidney function.

Mitral or aortic stenosis and hypertrophic obstructive cardiomyopathy

Like other vasodilators Amlodipine-Valsartan-Richter should be used with caution in patients with mild to moderate stenosis of the mitral and aortic valve or hypertrophic obstructive cardiomyopathy.

Hyperkalemia. A sodium deficiency and / or a decrease in the volume of circulating blood

Amlodipine-Valsartan-Richter should be used with caution in patients with hyperkalemia, sodium deficiency, and / or reduced circulating blood volume (BCC).

Care should be exercised simultaneous use of drugs containing APA II, including Amlodipine-Valsartan-Richter, with other preparations inhibiting RAAS, such as ACE inhibitors or aliskiren, including in patients with impaired renal function.

Pregnancy and lactation:

The use of Amlodipine-Valsartan-Richter is contraindicated in pregnancy.

Given the mechanism of action of angiotensin receptor antagonists II, you can not exclude the risk to the fetus. The use of ACE inhibitors that affect RAAS in II and III trimesters of pregnancy, leads to damage or death of the developing fetus. According to a retrospective analysis, the use of ACE inhibitors during the first trimester of pregnancy was accompanied by the development of fetal and newborn pathology. The occasional use of valsartan by pregnant women led to spontaneous miscarriages, low blood pressure, and impaired renal function in newborns. Like any other drug that directly affects RAAS, Amlodipine-Valsartan-Richter should not be given to pregnant women and women planning a pregnancy. Patients of childbearing age should be informed of the possible risk to the fetus associated with the use of these drugs.If the pregnancy occurred during the period of treatment with the drug Amlodipine-Valsartan-Richter, the drug should be canceled as soon as possible and, if necessary, transferred to an alternative hypotensive therapy with a proven safety profile during pregnancy.

It is not known whether the valsartan and / or amlodipine in breast milk. Since in experimental studies, the isolation of valsartan with breast milk is noted, it is not recommended to use the drug Amlodipine-Valsartan-Richter during the period of breastfeeding.

Dosing and Administration:

The drug should be taken orally, washed down with a small amount of water, once a day, regardless of the time of ingestion. The recommended daily dose is 1 tablet containing amlodipine + valsartan in a dose of 5 mg + 80 mg, or 5 mg + 160 mg, or 10 mg + 160 mg.

It is recommended to start taking the drug at a dose of 5 mg + 80 mg once a day. You can increase the dose 1-2 weeks after the start of therapy. In patients who can not achieve adequate control of blood pressure, the daily dose of the drug can be gradually increased under the supervision of the doctor: the recommended maximum daily doseamlodipine) 10 mg + 160 mg; the maximum daily dose of the drug: 10 mg + 320 mg (2 tablets of the drug Amlodipine-Valsartan-Richterin a dosage of 5 mg +160 mg once a day).

For elderly patients (over 65 years) and for patients with impaired liver function or liver disease without the phenomena of cholestasis it is possible to reduce the initial dose of the drug to the lowest-dose amlodipine, i.e. 1 tablet containing amlodipine + valsartan in a dose of 5 mg + 80 mg or 5 mg + 160 mg.

For patients with impaired renal function light and moderate severity (QC more than 30 ml / min) correction of the initial dose is not required.

Side effects:

Safety of combination application amlodipine + valsartan estimated more than 2,600 patients.

Undesirable adverse reactions are presented according to the system-organ classes according to the classification MedDRA. and frequency of occurrence: very often (≥ 1/10), often (≥ 1/100, <1/10), infrequently (≥ 1/1000, <1/100), rarely (≥ 1/10000, <1 / 1000), very rarely (<1/10000), including individual messages, the frequency is unknown (it is impossible to estimate based on available data).

Within each group, adverse reactions are distributed in order of decreasing importance.

Infectious and parasitic diseases

Often: nasopharyngitis, influenza.

Immune system disorders

Rarely: hypersensitivity.

Disorders of the psyche

Rarely: anxiety.

Disturbances from the nervous system

Often: headache;

Infrequent: dizziness, drowsiness, postural dizziness, impaired coordination, paresthesia.

Disturbances on the part of the organ of sight

Infrequent: vision impairment;

Rarely: visual impairment.

Hearing disorders and labyrinthine disorders

Infrequently: vertigo;

Rarely: noise in the ears.

Heart Disease

Infrequent: tachycardia, palpitations;

Rarely: faint.

Vascular disorders

Often: pastozhnost, edema of the face, peripheral edema, "hot flashes" of blood to the skin of the face, a feeling of heat;

Infrequent: orthostatic hypotension;

Rarely: marked decrease in blood pressure.

Onrespiratory system, thoracic and mediastinal disorders

Infrequent: cough, sore throat and larynx.

Disorders from the gastrointestinal tract

Infrequent: diarrhea, nausea, abdominal pain, constipation, dryness of the oral mucosa.

Disturbances from the skin and subcutaneous tissues

Infrequent: skin rash, erythema;

Rarely: hyperhidrosis, exanthema, itchy skin.

Disturbances from musculoskeletal system and connective tissue

Infrequently: swelling of the joints, back pain, arthralgia;

Rarely: muscle spasms, a sense of heaviness in the whole body.

Disorders from the kidneys and urinary tract

Rarely: pollakiuria, polyuria.

Violations of the genitals and mammary gland

Rarely: erectile dysfunction.

General disorders and disorders at the site of administration

Often: increased fatigue, asthenia.

The incidence of peripheral edema was lower in the patients who received the combination amlodipine + valsartan (5.8%) than in patients receiving amlodipine monotherapy (9%).

Impact on the results of laboratory and instrumental studies

An increase in the concentration of urea nitrogen in the serum (more than 3.1 mmol / L) was more frequent in the groups receiving amlodipine + valsartan (5.5%) and valsartan in the form of monotherapy (5.5%), compared with the group receiving a placebo (4.5%).

Undesirable effects characteristic of each component of the drug may occur with the use of the Amlodipine-Valsartan-Richter preparation, even if they have not been reported in clinical trials.

Amlodipine

Violations of the blood and lymphatic system

Very rarely: leukopenia, thrombocytopenia.

Immune system disorders

Very rarely: hypersensitivity reactions.

Disorders from the metabolism and nutrition

Very rarely: hyperglycemia.

Disorders of the psyche

Infrequently: insomnia / sleep disorders, mood lability.

Disturbances from the nervous system

Often: dizziness, headache, drowsiness;

Infrequently: flavors, paresthesia, fainting, tremor;

Very rarely: muscle hypertension, peripheral neuropathy;

Frequency unknown: extrapyramidal disorders.

Disturbances on the part of the organ of sight

Infrequent: visual impairment.

Hearing disorders and labyrinthine disorders

Infrequent: noise in the ears.

Heart Disease

Often: a strong palpitation;

Very rarely: arrhythmias (including bradycardia, ventricular tachycardia, atrial fibrillation).

Vascular disorders

Often: "hot flashes" of blood to the skin of the face;

Infrequent: marked decrease in blood pressure;

Very rarely: vasculitis.

Disturbances from the respiratory system, chest and mediastinal organs

Infrequent: shortness of breath, rhinitis;

Very rarely: cough.

Disorders from the digestive system

Often: discomfort in the abdomen, pain in the upper abdomen, nausea;

Infrequent: changes in the frequency of bowel movements, diarrhea, dryness of the oral mucosa, dyspepsia, vomiting;

Very rarely: gastritis, gingival hyperplasia, pancreatitis.

Disturbances from the liver and bile ducts

Very rarely: increased activity of "liver" enzymes, increased bilirubin concentration in blood plasma, hepatitis, intrahepatic cholestasis, jaundice.

Disturbances from the skin and subcutaneous tissues

Infrequently: alopecia, increased sweating, itchy skin, rash, incl. exanthema, thrombocytopenic purpura, discoloration of the skin;

Very rarely: angioedema, Stevens-Johnson syndrome, multiple-form exudative erythema, urticaria.

Disturbances from musculoskeletal system and connective tissue

Infrequently: arthralgia, back pain, muscle spasms, myalgia.

Disorders from the kidneys and urinary tract

Infrequent: urination, nocturia, pollakiuria.

Violations of the genitals and mammary gland

Infrequently: erectile dysfunction, gynecomastia.

General disorders and disorders at the site of administration

Often: increased fatigue, peripheral edema (ankles, feet);

Uncommon: asthenia, discomfort, weakness, pain in the chest, pain of various localization.

Impact on the results of laboratory and instrumental studies

Infrequent: increase or decrease in body weight.

In patients with chronic heart failure (III and IV functional class by classification NYHA) of non-ischemic etiology with amlodipine, there was an increase in the incidence of pulmonary edema; significant differences in the incidence of deterioration of chronic heart failure as compared to placebo, was found.

The risk of myocardial infarction or increase the severity of angina: in rare cases at the beginning of therapy BCCI or increasing their dose in patients, especially those with hypertrophic obstructive cardiomyopathy, severe obstructive coronary artery disease, showed an increase in the frequency, duration and severity of anginal attacks or the development of acute myocardial infarction .

Also, when BCCC was used, there were cases of arrhythmia (including ventricular tachycardia and fibrillationauricles). These undesirable phenomena could not be differentiated from the natural course of diseases.

Valsartan

Violations of the blood and lymphatic system

The frequency is unknown: a decrease in hemoglobin and hematocrit, leukopenia, neutropenia, thrombocytopenia.

Immune system disorders

The frequency is unknown: reactions of increased hypersensitivity, including serum sickness.

Hearing disorders and labyrinthine disorders

Infrequently: vertigo.

Vascular disorders

The frequency is unknown: vasculitis.

Disturbances from the respiratory system, chest and mediastinal organs

Infrequently: cough.

Disorders from the digestive system

Uncommon: discomfort in the abdomen, pain in the upper abdomen.

Ondestruction from the liver and biliary tract

The frequency is unknown: a violation of the liver, increased activity of "liver" enzymes, an increase in the concentration of bilirubin in the blood plasma.

Disturbances from the skin and subcutaneous tissues

Very rarely: angioedema;

Frequency is unknown: itching, rash, bullous dermatitis.

Disturbances from musculoskeletal system and connective tissue

The frequency is unknown: myalgia.

Disorders from the kidneys and urinary tract

The frequency is unknown: an increase in the concentration of creatinine in the blood plasma, impaired renal function, including acute renal failure.

General disorders and disorders at the site of administration

Infrequent: increased fatigue, asthenia.

Impact on the results of laboratory and instrumental studies

The frequency is unknown: an increase in the potassium content in the blood plasma.

In clinical trials with valsartan as monotherapy, the following adverse events were noted (regardless of their causal relationship with the study drug): viral infections, upper respiratory tract infections, sinusitis, rhinitis, neutropenia, insomnia.

In rare cases, the use of valsartan may be accompanied by a decrease in hemoglobin and hematocrit. In controlled trials, 0.8% and 0.4% of patients who received valsartan, a significant decrease (more than 20%) of hematocrit and hemoglobin, respectively, was noted. For comparison, in patients receiving placebo, a decrease in both hematocrit and hemoglobin was noted in 0.1% of cases.

Neutropenia was registered in 1.9% of patients who received valsartan, and in 1.6% of patients receiving an ACE inhibitor.

In controlled clinical trials, it was found that 3.9% and 16.6% of patients with chronic heart failure who received valsartan. an increase in the concentration of creatinine and blood urea nitrogen by more than 50%, respectively. In the placebo group, an increase in the concentration of creatinine and urea nitrogen was observed in 0.9% and 6.3% of cases, respectively.

Doubling the serum creatinine concentration was found in 4.2% of patients after myocardial infarction who received valsartan, and 3.4% of patients who received captopril.

In controlled clinical trials, in 10% of patients with chronic heart failure, there was an increase in serum potassium in more than 20%. In the group of patients receiving placebo, an increase in potassium content was observed in 5.1% of cases.

Overdose:

There are no data on drug overdose cases at the present time. With an overdose of valsartan, the main manifestation is a marked decrease in blood pressure, which can lead to depression, collapse and / or shock.An overdose of amlodipine can lead to excessive peripheral vasodilation and possible reflex tachycardia. There was also reported the occurrence of severe, prolonged systemic arterial hypotension up to the development of shock with a lethal outcome.

Treatment: In case of accidental overdose, you should induce vomiting (if the drug has been taken recently) or to wash the stomach. The use of activated carbon in healthy volunteers immediately or within 2 hours after taking amlodipine significantly reduced its absorption. With a marked decrease in blood pressure caused by Amlodipine-Valsartan-Richter, the patient should be placed on his back, lifting his legs; take active measures to support the activity of the cardiovascular system, including regular monitoring of heart and respiratory system function, BCC and volume of excreted urine. In the absence of contraindications to restore vascular tone and blood pressure, it is possible to use (with caution) a vasoconstrictor. Intravenous administration of calcium gluconate can be effective in eliminating blockade of calcium channels.

The excretion of valsartan and amlodipine during hemodialysis is unlikely.

Interaction:

Amlodipine

Simvastatin

Simultaneous long-term use of simvastatin in a dose of 80 mg / day and amlodipine at a dose of 10 mg / day leads to an increase in the exposure of simvastatin by 77%. It is recommended to reduce the dose of simvastatin in patients taking amlodipine, up to 20 mg / day.

Inhibitor inhibitors CYP3A4

When amlodipine is used together with diltiazem in elderly patients slowed metabolism of amlodipine. probably due to inhibition of the isoenzyme CYP3A4, which leads to an increase in the concentration of amlodipine in the blood plasma by approximately 50% and enhance the therapeutic effect. When using amlodipine together with potent inhibitors of isoenzyme CYP3A4 (e.g., ketoconazole, itraconazole and ritonavir) a marked increase in the systemic exposure of amlodipine.

In connection with inhibition of the isoenzyme CYP3A4 with simultaneous administration with grapefruit juice, the bioavailability of amlodipine may increase. However, in a clinical study, healthy volunteers showed no significant changes in pharmacokinetics when taking amlodipine at a dose of 10 mg with 240 ml of grapefruit juice.

Inductors of isoenzyme CYP3A4

Since the use of amlodipine together with isoenzyme inducers CYP3A4 (e.g., carbamazepine, phenobarbital, phenytoin. phosphenytoin, primidon, rifampicin, herbal preparations containing Hypericum perforated) can lead to a marked decrease in its concentration in the blood plasma, with the use of amlodipine with inducers of isoenzyme CYP3A4 should monitor its therapeutic effect.

At monotherapy with amlodipine there is no clinically significant interaction with thiazide diuretics, beta-adrenoblockers. ACE inhibitors, long-acting nitrates, nitroglycerin for sublingual use, digoxin. warfarin, atorvastatin. sildenafil, magnesium hydroxide and aluminum hydroxide, simethicone, cimetidine, nonsteroidal anti-inflammatory drugs, antibiotics and hypoglycemic agents for oral administration.

Simultaneous reception of amlodipine and ethanol does not affect the pharmacokinetics of the latter.

Valsartan

It was found that with monotherapy valsartan there is no clinically significant interaction with cimetidine, warfarin, furosemide, digoxin, atenolol, indometacin, hydrochlorothiazide,amlodipine, glibenclamide.

Drugs and substances that affect the potassium content in blood serum

When used simultaneously with dietary supplements containing potassium, potassium-sparing diuretics, potassium-containing salt substitutes or with other drugs that can cause an increase in potassium in the blood (for example, with heparin), care should be taken and regular monitoring of potassium in the blood.

Lithium preparations

With simultaneous use of lithium preparations with ACE inhibitors or ARA II, a reversible increase in lithium content in serum and an increase in toxic effects were noted. The experience of the joint use of valsartan with lithium preparations is not available, so in this case it is recommended to monitor the lithium content in the blood serum. The risk of toxic manifestations associated with the use of lithium drugs may be further increased with simultaneous use with the drug Amlodipine-Valsartan-Richter and diuretics.

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of cyclooxygenase-2 (COX-2)

The use of ARA II concomitantly with NSAIDs, including COX-2 inhibitors, can lead to a weakening of the antihypertensive effect. In elderly patients, patients with reduced BCC (including those receiving diuretic therapy) or with renal dysfunction, simultaneous use of ARA II and NSAIDs. including COX-2 inhibitors, may lead to an increased risk of impaired renal function. At the beginning of therapy or when adjusting the dosing regimen in patients taking both ARA II and NSAIDs, including COX-2 inhibitors, regular monitoring of renal function is recommended.

Protein-carriers

The simultaneous use of valsartan with inhibitors of the carrier protein OATP1B1 (rifampicin, ciclosporin) and with an inhibitor of carrier protein MRP2 (ritonavir) can lead to an increase in systemic bioavailability of valsartan.

Double blockade of RA AS with the use of angiotensin II receptor antagonists, ACE inhibitors or aliskiren

Simultaneous use of angiotensin II receptor antagonists, including valsartan, with other drugs that affect RAAS, leads to an increased incidence of cases of arterial hypotension, hyperkalemia and renal dysfunction.It is recommended to monitor blood pressure, kidney function and the content of plasma electrolytes in patients taking Amlodipine-Valsartan-Richter and other drugs that affect RAAS.

Special instructions:

If it is necessary to cancel beta-blockers before starting therapy with Amlodipine-Valsartan-Richter, the dose of beta-blockers should be reduced gradually. As amlodipine is not a beta-adrenoblocker, the use of the drug Amlodipine-Valsartan-Richter does not prevent the development of the "withdrawal" syndrome, resulting from the abrupt cessation of treatment with beta-blockers.

Angioedema, including Quincke's edema

Angioedema, including swelling of the larynx and vocal cords leading to airway obstruction, and / or swelling of the face, lips, pharynx, and / or tongue edema, occurred in patients who received valsartan, some of these patients had angioedema earlier with other drugs, including ACE inhibitors. The drug Amlodipine-Valsartan-Richter in the case of angioedema development should be immediately canceled, the resumption of the drug is prohibited.

Deficiency in the body of sodium and / or decrease in BCC

In placebo-controlled studies in patients with uncomplicated arterial hypertension, severe arterial hypotension was observed in 0.4% of cases. In patients with activated RAAS (eg, with a deficiency of bcc and / or sodium in patients receiving high doses of diuretics), the development of symptomatic arterial hypotension may occur with ARA II. Before starting treatment with Amlodipine-Valsartan-Richter, you should correct the sodium content in the body and / or BCC, or begin therapy under close medical supervision.

In case of a pronounced decrease in blood pressure, the patient should be placed on his back, raise his legs; if necessary, an intravenous infusion of 0.9% sodium chloride solution. After stabilization of blood pressure, treatment with Amlodipine-Valsartan-Richter can be continued.

Hyperkalemia

With the simultaneous use of the drug Amlodipine-Valsartan-Richter with biologically active additives containing potassium, potassium-sparing diuretics, potassium-containing salt substitutes or with other drugs that can cause an increase in the potassium content in the blood (for example,with heparin), care should be taken and regular monitoring of potassium in the blood.

Double blockade of RAAS

The development of arterial hypotension, fainting, stroke, hyperkalemia, and renal dysfunction (including acute renal failure) in susceptible patients has been reported, especially if combined therapy with drugs affecting the RAAS is used (see "Interactions with Other Drugs"). .

It is not recommended to conduct a double blockade of RAAS by the combined use of drugs containing ARA II, with ACE inhibitors or aliskiren. In some cases, when joint use is absolutely indicated, careful monitoring of the specialist and mandatory monitoring of kidney function, water-electrolyte balance, blood pressure should be performed.

Contraindicated simultaneous use of the drug Amlodipine-Valsartan-Richter with aliskiren or aliskirenoderzhaschimi drugs in patients with diabetes mellitus and / or moderate or severe renal dysfunction (GFR less than 60 ml / min / 1.73 m²) (see the section "Contraindications").

Lactose

Amlodipine-Valsartan-Richter, film-coated tablets, 5 mg + 80 mg contain 26 mg of lactose monohydrate.

Amlodipine-Valsartan-Richter, film-coated tablets, 5 mg + 160 mg and 10 mg + 160 mg contain 52 mg of lactose monohydrate.

Patients with such rare hereditary diseases as galactose intolerance, lactase deficiency or impaired absorption of glucose-galactose, should not take this medication.

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

Data on the effect of the drug on the ability to drive vehicles and work with mechanisms are absent. In connection with the possible occurrence of dizziness or increased fatigue, care should be taken when driving vehicles and working with mechanisms.

Form release / dosage:Tablets, film-coated, 5 mg + 80 mg.

Tablets, film-coated, 5 mg + 160 mg and 10 mg + 160 mg.

Packaging:

Tablets, film-coated, 5 mg + 80 mg. For 14 tablets in a blister of PA / Al / PVC - aluminum foil. For 1, 2 or 4 blisters in a cardboard box together with instructions for use.

Tablets, film-coated, 5 mg + 160 mg and 10 mg + 160 mg. For 7 tablets in a blister of PA / Al / PVC - aluminum foil. For 2, 4 or 8 blisters in a cardboard box together with instructions for use.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003980

Date of registration:24.11.2016 / 29.03.2017

Expiration Date:24.11.2021

The owner of the registration certificate:GEDEON RICHTER, OJSC GEDEON RICHTER, OJSC Hungary

Manufacturer: & nbsp