Universal reference book for medicines
Product name: EGIPRES ® (EGIPRES)

Active substance: amlodipine, ramipril

Type: Antihypertensive drug

Manufacturer: EGIS Pharmaceuticals (Hungary)
Composition, form of production and packaging
Capsules
hard gelatinous, CONI-SNAP 3, self-closing, with a base and a lid of light-burgundy color;
contents of capsules - a mixture of granules and powders of white or almost white color, without or almost no odor.
1 caps.

amlodipine besylate 6.95 mg,

which corresponds to the content of amlodipine 5 mg

ramipril 5 mg

Excipients: crospovidone - 20 mg, hypromellose - 1.18 mg, microcrystalline cellulose - 114.82 mg, glyceryl dibehenate - 2.05 mg.

Composition of hard gelatin capsule (CONI-SNAP 3), cover and base color code 51072: brilliant blue (E133) dye, red charming (E129), titanium dioxide, gelatin.

10 pieces.
- blisters (3) - packs of cardboard.
Capsules hard gelatinous, CONI-SNAP 0, self-closing, with a base of light pink color and a lid of light-burgundy color;
contents of capsules - a mixture of granules and powders of white or almost white color, without or almost no odor.
1 caps.

amlodipine besylate 6.95 mg,

which corresponds to the content of amlodipine 5 mg

ramipril 10 mg

Excipients: crospovidone - 40 mg, hypromellose - 2.36 mg, microcrystalline cellulose - 229.64 mg, glyceryl dibehenate - 4.1 mg.

Composition of hard gelatin capsule (CONI-SNAP 0), color code of cover and base 51072/37350: cover - titanium dioxide, brilliant blue dye (E133), dye red enchanting (E129), gelatin;
base - titanium dioxide, iron oxide red (E172), gelatin.
10 pieces.
- blisters (3) - packs of cardboard.
Hard gelatin capsules, CONI-SNAP 0, self-closing, with a base of light pink color and a lid of maroon color;
contents of capsules - a mixture of granules and powders of white or almost white color, without or almost no odor.
1 caps.

amlodipine besylate 13.9 mg,

which corresponds to the content of amlodipine 10 mg

ramipril 5 mg

Excipients: crospovidone - 40 mg, hypromellose - 2.36 mg, microcrystalline cellulose - 229.64 mg, glyceryl dibehenate - 4.1 mg.

Composition of hard gelatin capsule (CONI-SNAP 0), color code of cover and base 33007/37350: cover - titanium dioxide, dye azorubin (E122), indigocarmine (E132), gelatin;
base - titanium dioxide, iron oxide red (E172), gelatin.
10 pieces.
- blisters (3) - packs of cardboard.
Capsules hard gelatinous, CONI-SNAP 0, self-closing, with a base and a lid of maroon color;
contents of capsules - a mixture of granules and powders of white or almost white color, without or almost no odor.
1 caps.

amlodipine besylate 13.9 mg,

which corresponds to the content of amlodipine 10 mg

ramipril 10 mg

Excipients: crospovidone - 40 mg, hypromellose - 2.36 mg, microcrystalline cellulose - 229.64 mg, glyceryl dibehenate - 4.1 mg.

Composition of hard gelatin capsule (CONI-SNAP 0), color code of cover and base 33007: dye azorubin (E122), indigocarmine (E132), titanium dioxide, gelatin.

10 pieces.
- blisters (3) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2017.

PHARMACHOLOGIC EFFECT

The fixed combination is an antihypertensive drug containing a blocker of slow calcium channels and an ACE inhibitor.

Amlodipine

Amlodipine is a dihydropyridine derivative.
By binding to dihydropyridine receptors, it blocks slow calcium channels, inhibits the transmembrane transition of calcium into the cells of the smooth muscles of the blood vessels and heart (mostly to the smooth muscle cells of the vessels, rather than to the cardiomyocytes). Has antihypertensive and antianginal effects.
The mechanism of antihypertensive action of amlodipine is due to a direct relaxing effect on the smooth muscle of the vessels.

Amlodipine reduces myocardial ischemia in two ways:

1) expands the peripheral arterioles and, thus, reduces OPSS (afterload), with the heart rate practically unchanged, which leads to a decrease in energy consumption and myocardial oxygen demand;

2) dilates the coronary and peripheral arteries and arterioles in both normal and ischemic zones of the myocardium, which increases the oxygen supply to the myocardium in patients with vasospastic angina (Prinzmetal angina) and prevents the development of coronarospasm caused by smoking.

In patients with hypertension, the daily dose of amlodipine provides a reduction in blood pressure for 24 hours (both in the position on the back and standing).
Due to the slow onset of action, amlodipine does not cause a sharp decrease in blood pressure.
In patients with angina, a single daily dose of the drug increases the duration of exercise, delays the development of another episode of angina and ST depression (by 1 mm) against the background of physical activity, reduces the frequency of angina attacks and the need for nitroglycerin.

The use of amlodipine in patients with ischemic heart disease

In patients with cardiovascular diseases (including coronary atherosclerosis with lesions from one vessel to stenosis of 3 or more arteries and carotid artery atherosclerosis) who underwent myocardial infarction, percutaneous transluminal angioplasty of coronary arteries (TPL) or those suffering from angina, the use of amlodipine prevents development thickening intima-media of carotid arteries, significantly reduces the mortality from cardiovascular causes, myocardial infarction, stroke, pulmonary tuberculosis, coronary artery bypass grafting, leads to a decrease
th number of hospitalizations for unstable angina and progression of chronic heart failure, reduces the frequency of interventions aimed at restoring coronary blood flow.
The use of amlodipine in patients with heart failure

Amlodipine does not increase the risk of death or the development of complications and fatalities in patients with chronic cardiac insufficiency III-IV functional class by NYHA on the background of therapy with digoxin, diuretics and ACE inhibitors.
In patients with chronic cardiac insufficiency III-IV functional class of NYHA non-ischemic etiology with the use of amlodipine, there is a possibility of pulmonary edema. Amlodipine does not cause adverse metabolic effects, incl. it does not affect the content of the lipid profile.
Ramipril

Ramipril is an ACE inhibitor.
Ramiprilat, formed with the participation of hepatic enzymes, an active metabolite of ramipril, is a long-acting inhibitor of the enzyme dipeptidylcarboxypeptidase I (synonyms: ACE, kininase II). In plasma and in tissues, this kinase II enzyme catalyzes the conversion of angiotensin I into an active vasoconstrictor substance, angiotensin II, and also promotes the breakdown of bradykinin. Reducing the formation of angiotensin II and inhibiting the breakdown of bradykinin leads to vasodilation and a decrease in blood pressure. The increased activity of kallikrein-kinin system in blood and tissues causes cardioprotective and endothelioprotective action of ramipril due to activation of the prostaglandin system and, correspondingly, an increase in the synthesis of prostaglandins stimulating the formation of nitric oxide (NO) in endotheliocytes.
Angiotensin II stimulates the production of aldosterone, therefore, taking ramipril leads to a decrease in the secretion of aldosterone and an increase in the content of potassium ions in the serum.

When the content of angiotensin II in the blood decreases, its inhibitory effect on renin secretion by the negative feedback type is eliminated, which leads to an increase in renin plasma activity.

It is assumed that the development of some unwanted reactions (in particular, dry cough) is associated with an increase in bradykinin activity.

In patients with arterial hypertension, taking ramipril leads to a decrease in blood pressure in the position on the back and standing, without compensatory increase in heart rate.
Ramipril significantly reduces OPSS, almost without causing changes in the renal blood flow and GFR. Antihypertensive effect begins to appear 1-2 hours after ingestion of a single dose of the drug, reaching the highest value in 3-6 hours, and persists and persists for 24 hours. At the course of treatment, the antihypertensive effect can gradually increase, usually stabilizing by 3-4 weeks Regular intake of the drug and then persisting for a long time. A sudden discontinuation of the drug does not lead to a rapid and significant increase in blood pressure (no withdrawal syndrome).
In patients with arterial hypertension, ramipril slows the development and progression of myocardial hypertrophy and vascular wall.

In patients with chronic heart failure, ramipril reduces OPSS (decreased heart afterload), increases the capacity of the venous bed and reduces the filling pressure of the left ventricle, which, accordingly, leads to a decrease in preload on the heart.
In these patients, when taking ramipril, there is an increase in cardiac output, ejection fraction and improvement of exercise tolerance.
With diabetic and nondiabetic nephropathy , ramipril slows the rate of progression of renal failure and the time of onset of the terminal stage of renal insufficiency and, as a result, reduces the need for hemodialysis or kidney transplantation procedures.
At the initial stages of diabetic or nondiabetic nephropathy, ramipril reduces the severity of albuminuria.
In patients with a high risk of developing cardiovascular diseases due to the presence of vascular lesions (diagnosed with coronary artery disease), obliterating peripheral arterial disease in history, a history of stroke) or diabetes mellitus with at least one additional risk factor (microalbuminuria, hypertension, increased content total cholesterol, lower HDL cholesterol, smoking) addition of ramipril to standard therapy significantly reduces the incidence of myocardial infarction, ins
lta and death from cardiovascular causes. In addition, ramipril reduces the overall mortality rate, as well as the need for revascularization procedures, slows the onset or progression of chronic heart failure.
In patients with heart failure, developed during the first days of acute myocardial infarction (2-9 days), the risk of death rate (by 27%), risk of sudden death (by 30%) is reduced with the use of ramipril, from 3 to 10 days of acute myocardial infarction %), the risk of progression of chronic heart failure to severe - III-IV functional class according to NYHA classification resistant to therapy (by 27%), the probability of subsequent hospitalization due to the development of heart failure (by 26%).

In the general population of patients, as well as in patients with diabetes mellitus, both with arterial hypertension and with normal BP indices, ramipril significantly reduces the risk of developing nephropathy and the occurrence of microalbuminuria.

PHARMACOKINETICS

Amlodipine

Suction

After oral administration in therapeutic doses, amlodipine is well absorbed, the time to reach C max in blood plasma for oral administration is 6-12 hours. Absolute bioavailability is 64-80%.
Food intake does not affect the absorption of amlodipine.
Distribution

V d is approximately 21 l / kg.
Binding to plasma proteins is approximately 97.5%. The drug penetrates through the BBB.
C ss is 5-15 ng / ml and is achieved after 7-8 days of constant admission of amlodipine.

Excretion with breast milk is unknown.

Metabolism and excretion

Metabolized in the liver with the formation of inactive metabolites.
10% of unchanged substance and 60% of metabolites are excreted by the kidneys, 20% - through the intestine.
T 1/2 from the blood plasma is about 35-50 hours, which corresponds to the purpose of the drug 1 time / day.
The total ground clearance is 0.43 l / h / kg.
Pharmacokinetics in special clinical cases

In patients with hepatic insufficiency and severe chronic heart failure, T 1/2 increases to 56-60 hours.

In patients with renal insufficiency, T 1/2 from plasma is increased to 60 h. The change in the concentration of amlodipine in the blood plasma does not correlate with the degree of impaired renal function.
During hemodialysis, amlodipine is not removed.
In elderly patients, T max and C max of amlodipine practically do not differ from those in younger patients.
In elderly patients with chronic heart failure, there is a tendency to decrease the clearance of amlodipine, which leads to an increase in AUC and T 1/2 to 65 hours.
Ramipril

Suction and distribution

After ingestion, ramipril is rapidly absorbed from the digestive tract (50-60%).
Eating slows down its absorption, but does not affect the degree of absorption.
The bioavailability of ramipril after ingestion varies from 15% (for a dose of 2.5 mg) to 28% (for a dose of 5 mg).
The bioavailability of ramiprilat after ingestion of 2.5 mg and 5 mg of ramipril is approximately 45% (compared to its bioavailability after intravenous administration at the same doses).
After taking ramipril inside Cmax in the blood plasma, ramipril and ramiprilata are reached after 1 and 2-4 hours, respectively.
The decrease in plasma ramiprilate concentration occurs in several stages: the distribution and elimination phase with T 1/2 ramiprilata of about 3 hours, then the intermediate phase with T 1/2ramiprilata, about 15 hours, and the final phase with a very low concentration of ramiprilate in blood plasma and T 1/2 ramiprilate, which is approximately 4-5 days.This final phase is due to the slow release of ramiprilata from a strong bond with ACE receptors. Despite a prolonged final phase with a single daily ramipril intake of 2.5 mg or more, C ss ramiprilata is reached after approximately 4 days of treatment. With the prescription of the drug "effective" T 1/2 , depending on the dose is 13-17 hours.
Binding to plasma proteins of ramipril is approximately 73%, ramiprilata - 56%.

After intravenous administration, V d of ramipril and ramiprilate are approximately 90 and 500 liters, respectively.

Metabolism

Ramipril undergoes intensive pre-systemic metabolism / activation (mainly in the liver by hydrolysis), resulting in its only active metabolite ramiprilat, whose activity for inhibiting ACE is about 6 times that of ramipril.
In addition, as a result of the metabolism of ramipril, diketopiperazine, which does not possess pharmacological activity, is formed, which is then subjected to conjugation with glucuronic acid. Ramiprilate is also glucuronized and metabolized to diketopiperazic acid.
Excretion

After ingestion of radically labeled ramipril (10 mg), 39% of the radioactivity is excreted through the intestine and about 60% by the kidneys.
After intravenous administration of ramipril, a 50-60% dose is detected in the urine in the form of ramipril and its metabolites. After intravenous administration of ramiprilat, about 70% of the dose is found in the urine in the form of ramiprilata and its metabolites, in other words, with / in the administration of ramipril and ramiprilate, a significant proportion of the dose is excreted through the intestines with bile, bypassing the kidneys (50% and 30%, respectively) . After ingestion of ramipril in a dose of 5 mg in patients with bile duct drainage, virtually identical amounts of ramipril and its metabolites are excreted by the kidneys and through the intestine within the first 24 hours after ingestion.
Approximately 80-90% of metabolites in urine and bile were identified as ramiprilate and metabolites of ramiprilate.
Ramipril glucuronide and ramipril diketopiperazine constitute approximately 10-20% of the total, and the urinary content of unchanged ramipril is approximately 2%.
Pharmacokinetics in special clinical cases

With violations of kidney function with a CK of less than 60 ml / min, excretion of ramiprilata and its metabolites by the kidneys slows down.
This leads to an increase in the concentration of ramiprilate in the blood plasma, which decreases more slowly than in patients with normal renal function. When taking ramipril in high doses (10 mg), a violation of liver function leads to a slowing of the pre-system metabolism of ramipril to active ramiprilate and a slower elimination of ramiprilate.
In healthy volunteers and in patients with hypertension after 2 weeks of ramipril in a daily dose of 5 mg, there is no clinically significant accumulation of ramipril and ramiprilate.

In patients with chronic heart failure after 2 weeks of ramipril in a daily dose of 5 mg 1.5-1.8-fold increase in plasma ramiprilate concentrations and AUC is noted.

In healthy elderly volunteers (65-76 years old), the pharmacokinetics of ramipril and ramiprilate are not significantly different from that of young healthy volunteers.

INDICATIONS

- arterial hypertension (patients who are shown combined therapy with amlodipine and ramipril in doses corresponding to the drug Egipres ® ).

DOSING MODE

Egipres ® is prescribed inside adults 1 capsule 1 time / day, at the same time, regardless of food intake.

The dose of the drug Egipres ® is selected after previous titration of the doses of individual components of the preparation of ramipril and amlodipine in patients with arterial hypertension.
Egipres® with fixed doses of active ingredients is not used for initial therapy. If patients need dose adjustment, then it should be done only by titrating the doses of the active ingredients with monotherapy. Only then is it possible to use the drug Egipres ® with fixed doses of the active ingredients in the following combinations.
For therapeutic needs, the dose of the drug Egipres® can be changed on the basis of individual titration of individual component doses: 5 mg of amlodipine + 5 mg of ramipril or 5 mg of amlodipine + 10 mg of ramipril or 10 mg of amlodipine + 5 mg of ramipril or 10 mg of amlodipine + 10 mg of ramipril.

The maximum daily dose of the drug Egipres ® is 10 mg of amlodipine + 10 mg of ramipril;
exceeding the maximum dose is not recommended. Dosages of 10 mg + Amlodipine 5 mg ramipril (as amlodipine) 5 mg amlodipine and 10 mg of ramipril + (ramipril on) are the maximum daily doses.
Precautions should be prescribed to patients receiving diuretics, due to the risk of violations of water-electrolyte balance. These patients should be monitored renal function and potassium content of the blood.
In elderly patients and patients with renal insufficiency the excretion of amlodipine or ramipril and its metabolites is slowed down. Therefore, such patients should regularly monitor the content of creatinine and potassium in the blood plasma. Egipres ® can be given to patients with CC? 60 ml / min. When CC <60 ml / min,as well as patients with hypertension who are on hemodialysis , Egipres ® recommended to assign only if they receive Ramipril at 2.5 mg or 5 mg as an optimal maintenance dose during the titration of an individual dose. There is no need of individual titration of the dose of amlodipine in patients with impaired renal function . Egipres ® is contraindicated in patients with creatinine clearance <20 mL / min / 1.73 m 2 body surface area. Change amlodipine plasma concentrations are not correlated with the severity of renal failure.
Precautions should be prescribed Egipres ® patients with hepatic insufficiencydue to the lack of recommendations for dosage adjustment in these patients. Egipres® it recommended only in patients who received ramipril 2.5 mg as the optimal maintenance dose during the titration of an individual dose.
SIDE EFFECT

Determination of the frequency of adverse reactions WHO grade: very often -> 1/10 (> 10%); often -> 1/100, but <1.10 (> 1% but <10%); infrequently -> 1/1000 but <1/100 (> 0.1% but <1%); rare -> 1/10 000, but <1/1000 (> 0.01% and <0.1%); very rarely - <1/10 000 (<0.01%).
Amlodipine

Cardio-vascular system: often - peripheral edema (ankles and feet), palpitations; rare - an excessive fall in blood pressure, orthostatic hypotension, vasculitis; rarely - the development or exacerbation of congestive heart failure; very rarely - cardiac arrhythmias (including bradycardia, ventricular tachycardia and atrial fibrillation), heart attack, chest pain, migraine.
On the part of the musculoskeletal system and connective tissue disorders: rarely - arthralgia, muscle cramps, myalgia, back pain, arthritis; rarely - myasthenia gravis.
From the nervous system:often - a sense of warmth and a rush of blood to the skin, fatigue, dizziness, headache, drowsiness; infrequently - malaise, fainting, sweating, asthenia, hypesthesia, paresthesia, peripheral neuropathy, tremor, insomnia, mood lability, abnormal dreams, nervousness, depression, anxiety; rarely - seizures, apathy; very rarely - ataxia, amnesia, isolated cases registered extrapyramidal syndrome.
From the digestive system:often - abdominal pain, nausea; infrequently - vomiting, defecation mode change (including constipation, flatulence), dyspepsia, diarrhea, anorexia, dryness of the oral mucosa, thirst; rarely - gingival hyperplasia, increased appetite; very rarely - gastritis, pancreatitis, hyperbilirubinemia, jaundice (usually cholestatic), increased liver enzymes, hepatitis.
From hemopoiesis system: very rarely - thrombocytopenic purpura, thrombocytopenia, leukopenia.
Metabolic disorders: very rarely - hyperglycemia.
The respiratory system: rarely - dyspnea, rhinitis, epistaxis; very rarely - cough.
From the urinary system:infrequent - frequent urination, painful urination, nocturia, impotence; very rarely - dysuria, polyuria.
Allergic reactions: rarely - itching, rash; very rarely - angioedema, erythema multiforme, urticaria.
From the sensory organs: rarely - ringing in the ears, blurred vision, diplopia, disturbance of accommodation, xerophthalmia, conjunctivitis, eye pain, taste perversion;
very rarely - parosmia.
Dermatological reactions: rare - alopecia;
rarely - dermatitis; very rarely - dermatoxerasia, violation of skin pigmentation.
Other: rarely - gynecomastia, increase / decrease in body weight, chills; very rare - the "cold" sweat.
Ramipril
From the cardiovascular system: often - an excessive fall in blood pressure, impaired postural regulation of vascular tone (orthostatic hypotension), syncope; infrequently - "tides" of blood to the skin, myocardial ischemia, including the development of angina attack, or myocardial infarction, tachycardia, arrhythmia (new or worsening), palpitations, peripheral edema; rarely - the emergence or strengthening of circulatory disorders in the background of stenotic vascular lesions, vasculitis; frequency is unknown - Raynaud's syndrome.
From the nervous system:often - headache, a feeling of "lightness" in the head; rarely - dizziness, ageusia (loss of taste sensitivity), dysgeusia (impaired taste sensitivity), paresthesia (a burning sensation); rarely - tremor, imbalance; frequency is unknown - cerebral ischemia, including ischemic stroke and transient ischemic attack, impaired psychomotor reactions parosmiya (disturbance of sense of smell).
On the part of the organ of vision: rarely - visual impairment, including blurred vision; rarely - conjunctivitis.
On the part of the organ of hearing: rarely - hearing loss, ringing in the ears.
On the part of the psyche:infrequently - depressed mood, anxiety, nervousness, restlessness, sleep disorders including somnolence; rarely - confusion; the frequency is unknown - impaired concentration.
The respiratory system: often - dry cough (worse at night and in the supine position), bronchitis, sinusitis, shortness of breath; rarely - bronchospasm, including weighting of bronchial asthma, nasal congestion.
From the digestive system:often - inflammatory reactions in the stomach and intestines, digestive disorders, discomfort in the abdomen, dyspepsia, diarrhea, nausea, vomiting; rarely - pancreatitis, including and fatal (pancreatitis cases fatal taking ACE inhibitors rarely observed), increased activity of pancreatic enzymes in the blood plasma, intestinal angioneurotic edema, pain in the abdomen, gastritis, constipation, dryness of the oral mucosa; rarely - glossitis; frequency is unknown - aphthous stomatitis (inflammatory reaction of the oral mucosa).
On the part of the hepatobiliary system:rarely - increased activity of liver enzymes and the content of conjugated bilirubin in the blood plasma; rarely - cholestatic jaundice, hepatocellular injury; frequency is unknown - acute liver failure, or cytolytic and cholestatic hepatitis (death rarely observed).
From the urinary system: infrequently - impaired renal function, including the development of acute renal failure, increase the amount of urine release, enhancing the pre-existing proteinuria, increasing concentrations of urea and creatinine in the blood.
On the part of the reproductive system: rarely - transient impotence due to erectile dysfunction, decreased libido; the frequency is unknown - gynecomastia.
From hemopoiesis system:infrequently - eosinophilia; rarely - leukopenia, including neutropenia and agranulocytosis, decrease in the number of red blood cells in peripheral blood, decreased hemoglobin, thrombocytopenia; the frequency is unknown - inhibition of bone marrow hematopoiesis, pancytopenia, haemolytic anemia.
For the skin and subcutaneous tissue disorders:often - skin rash, in particular maculo-papular; infrequently - angioedema, including and fatal (laryngeal edema may cause obstruction of the airways leading to death), pruritus, hyperhidrosis (excessive sweating); rarely - exfoliative dermatitis, urticaria, onycholysis; very rarely - photosensitivity reactions; frequency is unknown - toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, psoriasis weighting currents, psoriasiform dermatitis, and lichenoid pemfigoidnaya (lishaevidnaya) or enanthema exanthema, alopecia.
On the part of the musculoskeletal system: often - muscle cramps, myalgia; Infrequent - arthralgia.
From a metabolism:often - increasing the content of potassium in the blood; rarely - anorexia, decreased appetite; frequency is unknown - reducing the concentration of sodium in the blood, syndrome of inappropriate secretion of ADH.
Immune system: the frequency is unknown - anaphylactic or anaphylactoid reactions (with ACE inhibition increases the number of anaphylactic or anaphylactoid reactions to insect venoms), increase in titer of antinuclear antibodies.
General disorders: often - pain in the chest, feeling tired; Infrequent - increased body temperature; rarely - asthenia (weakness).
CONTRAINDICATIONS

Amlodipine

- increased sensitivity to amlodipine and other dihydropyridine derivatives;
- severe hypotension (systolic blood pressure less than 90 mmHg), shock (including cardiogenic);
- obstructive process impeding ejection of blood from the left ventricle (e.g., clinically significant aortic stenosis);
- hemodynamically unstable heart failure after myocardial infarction;
- Pregnancy;

- the period of lactation (breastfeeding);

- child and adolescence to 18 years (the safety and effectiveness are not determined).
Ramipril
- Hypersensitivity to ramipril, other ACE inhibitors;
- history of angioneurotic edema (hereditary or idiopathic, but also associated with the prior therapy with ACE inhibitors);
- hypotension (systolic blood pressure <90 mm Hg) or unstable state with hemodynamics;
- hemodynamically significant stenosis of aortic or mitral valve, or hypertrophic obstructive cardiomyopathy;
- the acute phase of myocardial infarction in patients with diseases such as severe heart failure (IV functional class NYHA), life-threatening ventricular cardiac arrhythmias, "pulmonary" heart;
- primary aldosteronism;
- hemodynamically significant renal artery stenosis (bilateral or unilateral in the case of a solitary kidney);
- severe renal failure (creatinine clearance <20 mL / min / 1.73 m 2 );
- hemodialysis (clinical application experience insufficient);
- nephropathy, treatment which is carried corticosteroids, NSAIDs, immunomodulators and / or other cytotoxic agents (clinical application experience insufficient);
- hemodialysis or hemofiltration using certain membranes with a negatively charged surface such as a membrane of polyacrylonitrile vysokoprotochnyh (risk of developing hypersensitivity reactions);
- chronic decompensated heart failure (clinical application experience insufficient);
- LDL-apheresis using a dextran sulfate (risk of developing hypersensitivity reactions);
- desensitization therapy for hypersensitivity reactions to poison insects - bees, wasps;
- simultaneous application of preparations containing aliskiren in patients with renal impairment (creatinine clearance less than 60 mL / min) and patients with diabetes mellitus;
- Pregnancy;

- the period of lactation (breastfeeding);

- child and adolescence to 18 years (clinical application experience is insufficient).
Amlodipine, ramipril +
- hypersensitivity to the components of the drug;

- severe renal failure (creatinine clearance <20 mL / min / 1.73 m 2 );
- Pregnancy;

- the period of breastfeeding;

- child and adolescence to 18 years (clinical application experience is insufficient).
Precautions to use a combination of amlodipine + ramipril in the following diseases and conditions:
- atherosclerotic coronary and cerebral arteries (risk of excessive reduction in blood pressure);
- increase in activity of the RAAS, wherein when there is a risk of ACE inhibition sharp decrease in blood pressure with the deterioration of kidney function;
- expressed, particularly malignant hypertension;
- chronic heart failure, especially heavy or over which the received other drugs with an antihypertensive action;
- hemodynamically significant unilateral renal artery stenosis (in the presence of both kidneys);
- prior to diuretics;
- violations of water-electrolyte balance, a decrease in the bcc (including the intake of diuretics, a low-salt diet, diarrhea, vomiting, profuse sweating);
- simultaneous application of preparations containing aliskiren (in double RAAS blockade increases the risk of abrupt reduction in blood pressure, hyperkalemia and worsening renal function);
- liver disorders (lack of application experience) may both amplification and attenuation of effects of ramipril; in the presence of cirrhosis in patients with ascites and edema can be significant RAAS activation;
- renal dysfunction (creatinine clearance of> 20 ml / min);
- state after renal transplantation;
- systemic connective tissue diseases, including systemic lupus erythematosus, scleroderma, concomitant therapy with drugs that can cause changes in the pattern of peripheral blood (including allopurinol, procainamide) - possible inhibition of bone marrow hematopoiesis, the development of neutropenia or agranulocytosis;
- diabetes - the risk of hyperkalemia;
- old age - the risk of amplification of antihypertensive action;
- Hyperkalemia;

- hyponatremia;
- non-ischemic chronic heart failure etiology III-IV NYHA functional class classification;
- aortic stenosis;

- SSSU;

- mitral stenosis;
- arterial hypotension;

- the only functioning kidney;
- renovascular hypertension;
- simultaneous use of dantrolene, estramustine, and potassium-sparing diuretic drugs, nutritional substitutes potassium-salt, lithium preparations;
- surgery / general anesthesia;
- hemodialysis using vysokoprotochnyh membranes (e.g., AN69 ® ).
PREGNANCY AND LACTATION

The drug is contraindicated for use during pregnancy because ramipril may have adverse effects on the fetus: fetal developmental disorder of the kidneys, lowering blood pressure of the fetus and newborn, renal dysfunction, hyperkalemia, hypoplasia of the skull bones, oligohydramnios, limb contractures, deformation of the skull bones, hypoplasia of the lungs. Before you start taking the drug in women of childbearing age should exclude pregnancy.
If a woman is planning to become pregnant, treatment with the drug should be discontinued. In case of pregnancy during treatment with the drug should be as soon as possible to stop taking it and move the patient to the treatment with other drugs, the application of which the risk to the child will be the smallest.
If you need to use the drug during lactation, breastfeeding should be discontinued.
It is not known whether amlodipine is allocated and ramipril with breast milk in humans.
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