Expiration date: 03/2025

Active substance:

Amlodipine + Ramipril

ATX

C09BB07 Amlodipine + Ramipril

Pharmacological groups

Hypotensive agent combined (angiotensin converting enzyme inhibitor + blocker "slow" calcium channels) [ACE Inhibitors in combinations]

Hypotensive agent combined (angiotensin converting enzyme inhibitor + blocker "slow" calcium channels) [calcium channel Blockers in combinations]

Nosological classification (ICD-10)

I10 Essential (primary) hypertension

I15 Secondary hypertension

Composition

Capsules

1 capsule contains active substance:

amlodipine besylate: 6, 95/6, 95/13, 9/13, 9 mg (corresponds to amlodipine-5/5/10/10 mg)

ramipril: 5/10/5/10 mg

excipients: crosspovidone-20/40/40 mg; hypromellose— 1, 18/2, 36/2, 36/2, 36 mg; MCC— 114, 82/229, 64/229, 64/229, 64 mg; glyceryl dibegenate— 2, 05/4, 1/4, 1/4, 1 mg.

Capsules, 5 mg+5 mg; hard gelatin capsule (CONI-SNAP 3), cap and base color code-51072: diamond blue dye (E133), red charming dye (E129), titanium dioxide, gelatin

Capsules, 5 mg+10 mg; hard gelatin capsule (CONI-SNAP 0), color identification lids and bases — 51072/37350: cover — titanium dioxide; the dye brilliant blue (E133), a charming red dye (E129); gelatin; base — titanium dioxide, colouring agent iron oxide red (E172); gelatin

Capsules, 10 mg+5 mg; hard gelatin capsule (CONI-SNAP 0), color identification lids and bases — 33007/37350: cover — titanium dioxide; dye azorubin (E122); Indigo Carmine (E132); gelatin; base — titanium dioxide, colouring agent iron oxide red (E172); gelatin

Capsules, 10 mg+10 mg; hard gelatin capsule (CONI-SNAP 0), color identification lids and bases — 33007: dye azorubin (E122), Indigo Carmine (E132), titanium dioxide, gelatin

Description of dosage form

Capsules 5 mg+5 mg: solid gelatine CONI-SNAP 3, self-closing, with a base and lid of light maroon color.

Capsules 5 mg+10 mg: hard gelatin CONI-SNAP 0, self closing, with the base a light pink color and the cover is light maroon color.

Capsules 10 mg+5 mg: solid gelatin CONI-SNAP 0, self-closing, with light pink base and dark Burgundy lid.

Capsules 10 mg+10 mg: solid gelatin capsules CONI-SNAP 0, self-closing, with a base and lid maroon.

The contents of the capsules: a mixture of granules and powder white or nearly white, without or almost without smell.

Pharmacological action

Pharmacological action the antihypertensive.

Pharmacodynamics

Amlodipine

A derivative of dihydropyridine. Communicating with digidropiridinovmi receptors, blocking slow calcium channels ingibiruet transmembranny transition of calcium inside the cells of smooth muscles of blood vessels, and heart (more in gladkomyshechne cells receptacles, than cardiomiotita). It has antihypertensive and antianginal effects.

The mechanism of antihypertensive action of amlodipine is due to the direct relaxing effect on the smooth muscles of blood vessels.

Amlodipine reduces myocardial ischemia in the following two ways:

1. It expands peripheral arterioles and thus reduces OPSS (postnagruzku), while the heart rate does not change, which leads to a decrease in energy consumption and myocardial oxygen demand.

2. Dilates 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's angina) and prevents the development of koronarospazm caused by Smoking.

In patients with hypertension (AH) daily dose of amlodipine provides blood PRESSURE reduction for 24 hours (both in the supine and standing). Due to the slow onset of action, amlodipine does not cause a sharp decrease in blood PRESSURE.

In patients with angina pectoris, a single daily dose of the drug increases the duration of physical activity, delays the development of another attack of angina and depression of the ST segment (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 coronary artery disease. In patients with CCC diseases (including coronary atherosclerosis with lesions from one vessel to stenosis of 3 or more arteries and atherosclerosis of the carotid arteries) who have suffered myocardial infarction (MI), percutaneous transluminal angioplasty of the coronary arteries (TLP) or suffering from angina), the use of amlodipine prevents the development of thickening of intima-carotid, significantly reduces mortality from cardiovascular causes, MI, stroke, TLP, coronary artery bypass grafting, leads to a decrease in the number of hospitalizations for unstable angina and progression of CHF, reduces the frequency of interventions aimed at restoring coronary blood flow.

The use of amlodipine in patients with heart failure (SN). Amlodipine does not increase the risk of death or complications and death in patients with functional class III–IV CHF (FC) as classified by the new York Association of cardiology (NYHA) during therapy with digoxin, diuretics, and ACE inhibitors. In patients with CHF III–IV FC NYHA nonischemic etiology in the application of amlodipine there is a possibility of occurrence of pulmonary edema. Amlodipine does not cause adverse metabolic effects, including it does not affect the lipid profile.

Ramipril.

Ramiprilat produced with the participation of hepatic enzymes, the active metabolite of ramipril, is a long-acting inhibitor of the enzyme dipeptidylcarboxypeptidase I (synonyms —ACE, kininase II). In blood plasma and tissues, this enzyme kininase II catalyzes the conversion of angiotensin I into the active vasoconstrictor — angiotensin II, and also promotes the decay of bradykinin. Reduction in the formation of angiotensin II and the inhibition of decay of bradykinin leads to vasodilation and decrease in blood pressure. Increased activity of the kallikrein-kinin system in the blood and tissues and causes the cardioprotective endotheliopathy action of ramipril due to the activation of PG-system and respectively — increase PG synthesis, stimulating the formation of nitric oxide (NO) in endothelial cells. Angiotensin II stimulates the production of aldosterone, so taking ramipril reduces the secretion of aldosterone and increases the content of potassium ions in the serum.

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

It is assumed that the development of some undesirable reactions (in particular dry cough) is associated with increased activity of bradykinin.

In patients with hypertension ramipril leads to a decrease in blood PRESSURE in the supine and standing, without compensatory increase in heart rate. Ramipril significantly reduces OPSS, practically without causing changes in renal blood flow and glomerular filtration rate. Antihypertensive effect is seen after 1-2 hours after ingestion of a single dose of the drug, reaching the highest values after 3-6 hours and lasts for 24 h When taking the course of antihypertensive effect may gradually increase, usually stabilizing to 3-4 weeks of regular administration of the drug and then maintained for a long time. Sudden discontinuation of the drug does not lead to a rapid and significant increase in blood pressure (no withdrawal syndrome).

In patients with AG ramipril slows the development and progression of myocardial and vascular wall hypertrophy.

In patients with CHF ramipril reduces OPSS (decrease in postnagruzki heart), increases the capacity of the venous bed and reduces the pressure of filling the left ventricle (LV), 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 improved tolerability of physical activity.

In diabetic and nondiabetic nephropathy, ramipril administration slows down the rate of progression of renal failure and the time of the onset of end-stage renal failure and thereby reduces the need for hemodialysis procedures or kidney transplantation. In the initial stages of diabetic or nondiabetic nephropathy ramipril reduces the degree of severity of albuminuria.

In patients with high risk of development of diseases of the SSS due to the presence of vascular lesions (diagnosed as coronary artery disease, obliterating peripheral arterial disease history of stroke history) or diabetes with at least one additional risk factor (microalbuminuria, hypertension, increased total cholesterol, decreased HDL cholesterol, Smoking) add ramipril to standard therapy significantly reduces the incidence of mi, stroke and mortality from cardiovascular causes.

In addition, ramipril reduces the overall mortality rate, as well as the need for revascularization procedures, slows the occurrence or progression of CHF.

In patients with SN, developed in the first days of acute MI (AMI) (2-9-day), when taking ramipril, from 3 to 10 days of AMI, reduced risk of mortality (27%), the risk of sudden death (30%), the risk of progression to severe CHF-III-IV of NYHA FC, resistant to therapy (27%), the probability of subsequent hospitalization due to the development of CH (26%). In the General population of patients, as well as in patients with diabetes, both with hypertension and with normal blood PRESSURE, ramipril significantly reduces the risk of nephropathy and microalbuminuria.

Pharmacokinetics

Amlodipine

After oral administration in therapeutic doses amlodipine is well absorbed, the time of achievement of plasma levels in oral administration is 6-12 h. Absolute bioavailability is 64-80%. Vd is approximately 21 l/kg. the Relationship with blood plasma proteins is about 97, 5%. Eating does not affect the absorption of amlodipine. The drug penetrates the BBB.

T1 / 2 of the blood plasma is about 35-50 hours, which corresponds to the drug 1 time per day. In patients with hepatic insufficiency and severe CHF T1 / 2 increases to 56-60 no.

Total clearance — 0, 43 l/h/kg.

Stable Css (5-15 ng/ml) is achieved after 7-8 days of constant intake of amlodipine, it is metabolized in the liver to form inactive metabolites. 10% of the original drug and 60% of metabolites excreted by the kidneys, and 20% — through the intestine. Excretion of breast milk is unknown. During hemodialysis amlodipine is not removed.

Special patient groups

Renal failure. T1/2 from blood plasma in patients with renal insufficiency is increased to 60 h. the Change in the concentration of amlodipine in plasma does not correlate with the degree of renal dysfunction.

Elderly patient. The time to reach Cmax and Cmax of amlodipine are virtually identical to those in younger patients. In elderly patients suffering from CHF, a tendency to reduce the clearance of amlodipine, which leads to an increase in AUC and T1 / 2 to 65 hours.

Ramipril.

After oral administration is rapidly absorbed from the gastrointestinal tract (50-60%). Eating slows its absorption, but does not affect the degree of absorption. Ramipril undergoes extensive first-pass metabolism/activation (mainly in the liver, by hydrolysis) to form its only active metabolite, ramiprilat, whose activity in respect of inhibition Opprimere 6 times more than the activity of ramipril. In addition, as a result of the metabolism of ramipril formed without pharmacological activity diketopiperazin, which is then subjected to conjugation with glucuronic acid. Ramiprilat also glukuronidiruetsa and metabolized to diketopiperazine acid. The bioavailability of ramipril after oral administration ranges from 15% (for a dose of 2, 5 mg) to 28% (for a dose of 5 mg). The bioavailability of ramiprilat after oral administration of 5 mg of ramipril is approximately 45% (compared to its bioavailability after I/o in the same doses).

After the reception ramiprila inside the time to reach Cmax of ramipril and ramiprilat is 1 and 2-4 h, respectively. Low concentration of ramiprilat in plasma occurs in several stages: phase distribution and excretion with T1/2 of ramiprilat approximately 3 h, and then the intermediate phase with a T1/2 of ramiprilat approximately 15 h, and the final phase with a very low concentration of ramiprilat in plasma and T1/2 of ramiprilat approximately 4-5 days. This final phase is due to the slow release of ramiprilate from a strong bond with ACE receptors. Despite the long-term final phase with a single day of admission ramipril inside at a dose of 2, 5 mg or more, Css ramiprilata achieved after about 4 days of treatment. In the course of appointment of the drug effective T1 /2 (depending on the dose) is 13-17 no.

Linking blood plasma proteins is approximately equivalent to ramipril 73% and of ramiprilat is 56%.

After the on/in V Vd ramipril and ramiprilat are approximately 90 and 500 l, respectively.

After ingestion labeled with radioactive isotope ramipril (10 mg), 39% of radioactivity is excreted through the intestine and about 60% — kidneys. After the / in ramipril, 50-60% dose is found in the urine in the form of ramipril and its metabolites. After the / in ramiprilat-about 70% of the dose is found in the urine in the form of ramiprilat and its metabolites, in other words, in/vvvedenii ramipril and ramiprilat significant part of the dose is excreted through the intestine with bile, bypassing the kidneys (50 and 30%, respectively). After oral administration of 5 mg of ramipril in patients with bile duct drainage, almost the same amount of ramipril and its metabolites are excreted by the kidneys and through the intestine during the first 24 hours after administration.

Approximately 80-90% of the metabolites in the urine and bile were identified as metabolite ramiprilat and the ramiprilat. Ramipril glucuronide and ramipril diketopiperazine make up approximately 10-20% of the total, and the urinary content of non-metabolized ramipril is approximately 2%.

When violations of the kidney with Cl creatinine less than 60 ml/min excretion of ramiprilat and its metabolites by the kidneys slows down. This leads to an increase in the concentration of ramiprilat in 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 slowdown in the presystemic metabolism of ramipril to active ramiprilat and slower excretion of ramiprilat. In healthy volunteers and patients with hypertension after 2 weeks of treatment with ramipril at a daily dose of 5 mg there is no clinically significant accumulation of ramipril and ramiprilat. In patients with CHF after 2ned treatment with ramipril at a daily dose of 5 mg there is an increase in 1, 5-1, 8 times the concentration of ramiprilat in blood plasma and AUC.

In healthy elderly volunteers (65-76 years) pharmacokinetics ramipril and ramiprilat does not differ significantly from that in young healthy volunteers.

The testimony of the drug Egipres®

Arterial hypertension (patients who are shown to be in combination therapy with amlodipine and ramipril in doses, as in combination).

Contraindications

Amlodipine

• increased sensitivity to amlodipine and other dihydropyridine derivatives;
  
• severe arterial gipotenzia (sad less than 90 mm Hg. St.), shock (including cardiogenic);
  
• obstructive process that makes it difficult to release blood from the left ventricle (e.g. clinically significant aortic stenosis);
  
• hemodynamically unstable heart failure after myocardial infarction;
  
• pregnancy;
  
• breastfeeding period;
  
• the age of 18 years (safety and effectiveness not defined).
  

Ramipril.

• increased sensitivity to ramipril, other ACE inhibitors;
  
• angioedema in history (hereditary or idiopathic, as well as associated with previous therapy with ACE inhibitors);
  
• hemodynamically significant renal artery stenosis (bilateral or unilateral, in the case of a single kidney);
  
• arterial gipotenzia (sad less than 90 mm Hg. Hg), or condition with unstable hemodynamics;
  
• hemodynamically significant stenosis of the aortic or mitral valve, or hypertrophic obstructive cardiomyopathy;
  
• primary hyperaldosteronism;
  
• severe renal failure (Cl creatinine <20 ml / min / 1, 73 m2);
  
• hemodialysis (clinical experience is insufficient);
  
• nephropathy, which is treated with GCS, NSAIDs, immunomodulators and / or other cytotoxic agents (clinical experience is insufficient);
  
• decompensated chronic heart failure (clinical experience is insufficient);
  
• hemodialysis or hemofiltration with the use of some types of membranes with a negatively charged surface, such as high-flow membranes of polyacrylnitrile (risk of hypersensitivity reactions);
  
• apheresis of LDL with the use of dextran sulfate (risk of hypersensitivity reactions);
  
• desensitizing therapy in reactions of increased sensitivity to insect venom-bees, wasps;
  
• the acute phase of myocardial infarction in patients with diseases such as severe heart failure (functional class IV NYHA); life-threatening ventricular arrhythmias; pulmonary heart;
  
• simultaneous use of drugs containing aliskiren in patients with impaired renal function (creatinine Cl less than 60 ml / min) and patients with diabetes;
  
• pregnancy;
  
• breastfeeding period;
  
• age up to 18 years (clinical experience is insufficient).
  

Amlodipine + ramipril

• hypersensitivity to the auxiliary substances included in the preparation;
  
• renal failure (creatinine Cl <20 ml / min / 1, 73 m2);
  
• pregnancy;
  
• breastfeeding period;
  
• age up to 18 years (clinical experience is insufficient).
  

With care for the combination of amlodipine and ramipril: atherosclerotic lesions of the coronary and cerebral arteries (risk of excessive loss AD); increased activity of the RAAS, in which the inhibition of ACE has a risk of a sharp decline in blood pressure with deterioration of renal function; expressed, especially malignant hypertension; CHF, especially heavy or about where you take other drugs with antihypertensive effect; hemodynamically significant unilateral renal artery stenosis (in the presence of both kidneys); prior administration of diuretics, disorders of water and electrolyte balance, the decrease in BCC (including against the background of taking diuretics, salt-free diet, diarrhea, vomiting, excessive sweating); simultaneous use with drugs containing aliskiren (with double blockade of RAAS increases the risk of a sharp decrease in blood PRESSURE, hyperkalemia and deterioration of kidney function); liver function disorders (lack of experience: it is possible both to increase and decrease the effects of ramipril; in the presence of patients with liver cirrhosis with ascites and edema, significant activation of RAAS is possible); impaired renal function( Cl creatinine more than 20 ml / min) ; condition after kidney transplantation; systemic connective tissue diseases, including systemic lupus erythematosus, scleroderma, concomitant therapy with drugs that can cause changes in the peripheral blood (including allopurinol, procainamide) — possible inhibition of bone marrow hematopoiesis, the development of neutropenia or agranulocytosis; diabetes (risk of hyperkalemia); old age (the risk of increased antihypertensive effect); hyperkalemia; hyponatremia; CHF of nonischemic etiology III–IV functional class NYHA classification; aortic stenosis; syndrome weakness sinusnogo hub; mitral stenosis; arterial hypotension; the only functioning kidney; renovascular hypertension; simultaneous use of dantrolene, estramustine, potassium-sparing diuretics and potassium preparations, potassium-containing substitutes for dietary salt, lithium preparations; surgery/General anesthesia; hemodialysis with the use of high-flow membranes (for example, AN69®).

Use during pregnancy and breast-feeding

The drug is contraindicated because ramipril may have an adverse effect on the fetus — a violation of the development of the kidneys of the fetus, reducing AD the fetus and newborn, violation of the kidney, hyperkalemia, hypoplasia of the skull bones, oligohydramnios, contracture of the limbs, deformation of the skull bones, hypoplasia of the lungs. Before taking the drug in women of childbearing age should exclude pregnancy.

If a woman is planning a pregnancy, the treatment with the drug should be discontinued. In the case of pregnancy during treatment with the drug should stop taking it as soon as possible and transfer the patient to take other drugs, the use of which the risk for the child will be the least.

If treatment with the drug is necessary during breastfeeding, it should be discontinued (data on the removal of amlodipine and ramipril with breast milk of women are not available).

Fertility

Amlodipine. Some patients treated with CCL, caused a reversible biochemical changes in the head of spermatozoa. Clinical data are insufficient to assess the potential effect of amlodipine on fertility.

Side effect

The following undesirable effects are given in accordance with the following graduations of the frequency of their occurrence according to the who classification: very common — more than 1/10 (10%); often — more than 1/100 but less than 1/10 (more than 1% but less than 10%); infrequently — more than 1/1000 but less than 1/100 (more than 0, 1%, but less than 1%); rare — 1/10000 more, but less than 1/1000 (more than 0, 01% but less than 0, 1%); very rarely — less than 1/10000 (less than 0, 01%).

Amlodipine

From the CCC: often-peripheral edema (ankles and feet), a feeling of heartbeat; infrequently — excessive decrease in blood PRESSURE, orthostatic hypotension, vasculitis; rarely — the development or worsening of sleep; very rarely — heart rhythm disorders (including bradycardia, ventricular tachycardia and atrial flicker), MI, chest pain, migraine.

From the musculoskeletal system and connective tissue: infrequently — arthralgia, muscle cramps, myalgia, back pain, arthrosis; rarely — myasthenia gravis.

CNS and peripheral nervous system: often — feeling of heat and flushing to the skin, fatigue, dizziness, headache, drowsiness; infrequently — malaise, fainting, sweating, asthenia, hypoesthesia, paresthesia, peripheral neuropathy, tremor, insomnia, mood lability, unusual dreams, nervousness, depression, anxiety; rare — cramps, apathy; very rarely — ataxia, amnesia, occasional cases of extrapyramidal syndrome.

From the digestive system: often-abdominal pain, nausea; infrequent-vomiting, changes in defecation (including constipation, flatulence), dyspepsia, diarrhea, anorexia, dry mouth, thirst; rarely — hyperplasia of the gums, increased appetite; very rarely — gastritis, pancreatitis, hyperbilirubinemia, jaundice (usually cholestatic), increased activity of hepatic transaminases, hepatitis.

The blood: very rarely — thrombocytopenic purpura, thrombocytopenia, leukopenia.

Metabolic disorders: very rare — hyperglycemia.

From the respiratory system: infrequently — shortness of breath, rhinitis; very rarely-cough.

From the kidneys and urinary tract: infrequently — frequent urination, painful urination, nicturia, impotence; very rarely — dysuria, polyuria.

Allergic reactions: infrequently-skin itching, rash; very rarely-angioedema, erythema multiforme, urticaria.

Other: rarely — alopecia, tinnitus, gynecomastia, increase/decrease in body weight, blurred vision, diplopia, violation ccomodation, xerophthalmia, conjunctivitis, eye pain, taste perversion, chills, nasal bleeding; rare — dermatitis; very rarely — parosmia, xeroderma, cold sweat, disturbance of skin pigmentation.

Ramipril.

From the heart: infrequently-myocardial ischemia, including the development of angina attack or MI, tachycardia, arrhythmia (appearance or enhancement), a feeling of heartbeat, peripheral edema.

On the part of the vessels: often-excessive blood PRESSURE reduction, violation of orthostatic regulation of vascular tone (orthostatic hypotension), syncopal conditions; infrequently — blood flushes to the skin; rarely — the occurrence or increase of circulatory disorders against the background of stenotic vascular lesions, vasculitis; the frequency is unknown — Raynaud's syndrome.

CNS: frequently — headache, feeling of lightness in the head; rarely, dizziness, ageusia (loss of taste sensitivity), dysgeusia (violation of taste sensitivity) paresthesia (burning sensation); rarely tremor, balance disorder; frequency is unknown cerebral ischemia including ischemic stroke and transient disorders of cerebral circulation, disturbance of psychomotor reactions, parosmia (impaired perception of odors).

On the part of the organ of vision: infrequent — visual disturbances, including blurred vision; rare — conjunctivitis.

On the part of the organ of hearing: rarely is hearing loss, ringing in the ears.

On the part of the psyche: infrequently-depressed mood, anxiety, nervousness, motor anxiety, sleep disorders, including drowsiness; rarely — confusion; the frequency is unknown — a violation of concentration.

On the part of the respiratory system: often-dry cough (increasing at night and lying down), bronchitis, sinusitis, shortness of breath; infrequently — bronchospasm, including weighting of bronchial asthma, nasal congestion.

From the digestive system: often — inflammatory response in the stomach and intestines, indigestion, a feeling of discomfort in the abdomen, indigestion, diarrhea, nausea, vomiting; rarely, pancreatitis including fatalities (cases of pancreatitis with a fatal outcome while taking the ACE inhibitors were observed very rarely), increased activity of pancreatic enzymes in the blood plasma, intestinal angioedema, abdominal pain, gastritis, constipation, dry mucous membranes of the oral cavity; rarely glossitis; the frequency is unknown-aphthous stomatitis (inflammatory reaction of the oral mucosa).

Hepatobiliary system: rarely — increased activity of liver enzymes and the content of conjugated bilirubin in blood plasma; rarely cholestatic jaundice, hepatocellular lesions; the frequency is unknown acute hepatic failure, cholestatic or cytolytic hepatitis (fatal outcome has been observed very rarely).

From the kidneys and urinary tract: infrequently — impaired renal function, including the development of acute renal failure, increased urinary excretion, increased pre-existing proteinuria, increased concentration of urea and creatinine in the blood.

On the part of the reproductive system and mammary glands: infrequent — transient impotence due to erectile dysfunction, decreased libido; the frequency is unknown — gynecomastia.

From the blood and lymphatic system: infrequently-eosinophilia; rarely-leukopenia, including neutropenia and agranulocytosis, reducing the number of red blood cells in the peripheral blood, decreased hemoglobin, thrombocytopenia; the frequency is unknown — oppression of bone marrow hematopoiesis, pancytopenia, hemolytic anemia.

With the skin and mucous membranes: often — skin rash in particular maculopapular; rarely angioedema, including fatal (edema of the larynx may cause airway obstruction, leading to death), pruritus, hyperhidrosis (excessive sweating), rarely — exfoliative dermatitis, urticaria, onycholysis; very rare — photosensitivity reaction; the frequency is unknown-toxic epidermal necrolysis, Stevens-Johnson syndrome, multiform erythema, pemphigus, psoriasis-like dermatitis, pemphigoid or lichenoid exanthema or enanthema, alopecia.

From the musculoskeletal system and connective tissue: often — muscle cramps, myalgia; infrequently — arthralgia.

On the part of metabolism, nutrition and laboratory parameters: often — an increase in potassium in the blood; infrequently — anorexia, decreased appetite; the frequency is unknown — a decrease in the concentration of sodium in the blood, the syndrome of inadequate secretion of ADH.

From the immune system: the frequency is unknown-anaphylactic or anaphylactoid reactions (when inhibiting ACE increases the number of anaphylactic or anaphylactoid reactions to insect poisons), titer of antinuclear antibodies.

General disorders: often — pain in the chest, feeling tired; rare — fever, rarely — asthenia (weakness).

Interaction

Amlodipine

It can be expected that inhibitors of enzymes of microsomal liver oxidation (erythromycin-in young, diltiazem-in the elderly, ketoconazole, Itraconazole, ritonavir) will increase the concentration of amlodipine in the blood plasma, increasing the risk of side effects, and inducers of enzymes of microsomal liver oxidation — reduce. With the simultaneous use of amlodipine with cimetidine, the pharmacokinetics of amlodipine does not change.

Simultaneous single reception of 240 ml of grapefruit juice and 10 mg of amlodipine inside is not accompanied by a significant change in the pharmacokinetics of amlodipine. Unlike other BCC, there was no clinically significant interaction of amlodipine (BCC generation III) in co-administration with NSAIDs, especially indomethacin.

It is possible to increase the antianginal and antihypertensive effects of BCC in combination with thiazide and loop diuretics, verapamil, ACE inhibitors, beta-blockers and nitrates, as well as increasing their antihypertensive action in combination with alpha1-adrenoblockers, neuroleptics. Although the study of amlodipine did not usually show a negative inotropic effect, some BCC may increase the severity of the negative inotropic effect of antiarrhythmic drugs that cause QT prolongation (for example, amiodarone and quinidine).

With the joint use of BCC with lithium drugs (for amlodipine data are not available), it is possible to increase the manifestation of their neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus).

Amlodipine does not affect the degree of in vitro binding to plasma proteins digoxin, phenytoin, warfarin and indomethacin.

Single administration of aluminum / magnesium-containing antacids does not have a significant effect on the pharmacokinetics of amlodipine.

A single dose of 100 mg of sildenafil in patients with essential hypertension does not affect the parameters of the pharmacokinetics of amlodipine.

Repeated use of amlodipine at a dose of 10 mg and atorvastatin at a dose of 80 mg is not accompanied by significant changes in the pharmacokinetics of atorvastatin. While the use of amlodipine with digoxin in healthy volunteers digoxin content in serum and renal clearance does not change. In a single and repeated use at a dose of 10 mg amlodipine does not have a significant effect on the pharmacokinetics of ethanol.

Amlodipine does not affect the change in PV caused by warfarin. Amlodipine does not cause significant changes in the pharmacokinetics of cyclosporine.

Deprecated combinations

The simultaneous use of dantrolene (in/in the introduction), inducers of isoenzyme system cytochrome's CYP3A4 (e.g. rifampicin, medicines St. John's wort) and inhibitors of the isoenzyme cytochrome CYP3A4 (protease inhibitors, antifungal medications of the group of azoles, macrolides (e.g. erythromycin or clarithromycin), verapamil, or diltiazem).

Ramipril.

Contraindicated in combination

The use of some high — flow membranes with a negatively charged surface (eg polyacrylnitrile membranes) during hemodialysis or hemofiltration; the use of dextran sulfate in aferez LPNP-the risk of severe anaphylactic reactions.

Deprecated combinations

With potassium salts, potassium-sparing diuretics (eg amiloride, triamterene, spironolactone) and other drugs, including antagonists of angiotensin II receptors (ARA II), trimethoprim, tacrolimus, cyclosporine — perhaps the development of hyperkalemia (while the application requires regular monitoring of potassium in the blood serum).

Combinations to be used with caution

With antihypertensive drugs (especially diuretics) and other drugs that reduce blood PRESSURE(nitrates, tricyclic antidepressants, means for General and local anesthesia, ethanol, baclofen, alfusosin, doxazosin, prazosin, tamsulosin, terazosin), — potentiation of the antihypertensive effect. In combination with diuretics should monitor the sodium content in the blood serum.

With sleeping pills, drugs and other painkillers — perhaps a more pronounced decrease in blood PRESSURE.

With vasopressor sympathomimetics (epinephrine, isoproterenol, dobutamine, dopamine) — reducing the antihypertensive effect of ramipril, regular blood PRESSURE monitoring is required.

With allopurinol, procainamide, cytostatics, immunosuppressants, systemic corticosteroids and other means that can affect hematological parameters, joint use increases the risk of leukopenia.

With lithium salts-increase of lithium content in serum and increase of cardio - and neurotoxic action of lithium.

With hypoglycemic agents for oral administration (sulfonylurea derivatives, biguanides), insulin — due to the decrease in insulin resistance under the influence of ramipril may increase the hypoglycemic effect of these drugs, up to the development of hypoglycemia.

Concomitant use of drugs containing aliskiren in patients with diabetes and renal insufficiency (creatinine Cl less than 60 ml/min), as well as with vildagliptin — due to an increase in the frequency of angioedema with simultaneous use of ACE inhibitors.

Combinations to be taken into account

With NSAIDs (indomethacin, acetylsalicylic acid) — possible weakening of ramipril, increased risk of renal dysfunction and increased potassium content in the blood serum.

With heparin-may increase the potassium content in the blood serum.

With sodium chloride-the weakening of the antihypertensive effect of ramipril and less effective treatment of symptoms of CHF.

With ethanol - increased symptoms of vasodilation. Ramipril may increase the adverse effects of ethanol on the body.

With estrogen-weakening of the antihypertensive effect of ramipril (fluid retention).

Desensitizing therapy with increased sensitivity to insect venom — ACE inhibitors, including ramipril, increase the likelihood of severe anaphylactic or anaphylactoid reactions to insect venom.

Dosage and administration

Inside, and 1 caps. 1 time per day, at the same time, regardless of the meal.

The dose of the drug Egipres® is chosen after previously conducted dose titration of the individual components of the drug: ramipril and amlodipine in patients with hypertension. Drug Egipres® fixed-dose active ingredients can not be used for initial therapy. If patients need dose correction, it should be carried out only by titration of doses of active components in monotherapy. Only after this possible use of the drug Egipres® fixed-dose active components in the following combinations.

At the therapeutic dose of the drug Egipres® can be changed on the basis of individual titration of the doses of the individual components: amlodipine 5 mg + 5 mg or ramipril 5 mg amlodipine + 10 mg of ramipril or amlodipine 10 mg + 5 mg of ramipril or amlodipine 10 mg + 10 mg of ramipril.

Egipres® at a dose of 10 mg amlodipine + 10 mg of ramipril is the maximum daily dose of the drug which should not be exceeded. Dosages of 10 mg amlodipine + 5 mg ramipril (amlodipine) and 5 mg amlodipine + 10 mg ramipril (ramipril) are the maximum daily doses.

Adult patient

In patients taking diuretics, the drug should be administered with caution, due to the risk of violation of the water-electrolyte balance. In these patients, renal function and potassium content in the blood should be monitored.

Elderly patients and patients with renal insufficiency. The excretion of amlodipine and ramipril and its metabolites in elderly patients and patients with renal insufficiency is slowed. Therefore, in such patients, it is necessary to regularly monitor the content of creatinine and potassium in the blood plasma. Egipres® may be prescribed to patients with Cl creatinine equal to or greater than 60 ml/min. In case of creatinine Cl <60 ml / min, as well as in patients with AH who are on hemodialysis, Egipres® is recommended only for patients who received 5 mg of ramipril, as an optimal maintenance dose during the titration of the individual dose. There is no need to titrate an individual dose of amlodipine in patients with impaired renal function. Egipres® is contraindicated in patients with creatinine Cl <20 ml/min/1, 73 m2. The change in the concentration of amlodipine in blood plasma is not correlated with the degree of severity of renal failure.

Patients with liver failure. Care should be taken when administering the drug Egipres® patients with hepatic insufficiency due to the lack of recommendations for dosage adjustment in such patients. Egipres® is recommended only for patients 2, 5 mg of ramipril as the optimal maintenance dose in the titration of individual doses.

Children and adolescents

Egipres® should not be administered to children and adolescents under 18 years due to the lack of data on the effectiveness and safety of the use of ramipril and amlodipine in these groups of patients both in the form of monotherapy and in the form of combination therapy.

Overdose

Information about overdose of the drug Egipres® missing.

Amlodipine

Symptoms: a marked decrease in blood pressure WITH the possible development of reflex tachycardia and excessive peripheral vasodilation (there is a possibility of severe and persistent arterial hypotension, including the development of shock and death).

Treatment: the appointment of activated charcoal (especially in the first 2 hours after an overdose), gastric lavage, giving elevated position of the limbs, active maintenance of the functions of CCC, monitoring of heart and lung function, control of BCC and diuresis. To restore vascular tone and blood PRESSURE, if there are no contraindications, it may be useful to use vasoconstrictive drugs. Use/in the introduction of calcium gluconate. Amlodipine is largely associated with serum proteins, therefore, dialysis is ineffective.

Ramipril.

Symptoms: excessive peripheral vasodilation with the development of a marked decrease in blood PRESSURE, shock; bradycardia or reflex tachycardia, water-electrolyte disorders, acute renal failure, stupor.

Treatment: gastric lavage, the appointment of adsorbents, sodium sulfate (if possible during the first 30 minutes). In the case of a marked decrease in blood PRESSURE of the patient should be laid, legs raised, actively support the functions of the CCC; to therapy to replenish the CCC and restore the electrolyte balance, the introduction of alpha1-adrenergic agonists (norepinephrine, dopamine) and angiotensinamide may be added. In the case of refractory to medical treatment of bradycardia, it may be necessary to install a temporary artificial pacemaker. In case of overdose, it is necessary to monitor the content of creatinine and electrolytes in the blood serum. Ramiprilat poorly excreted from the blood by hemodialysis.

Special instruction

Information relating to ramipril and amlodipine applicable to the drug Egipres®.

Amlodipine

In the treatment of hypertension amlodipine can be combined with thiazide diuretics, alpha - and beta-blockers, ACE inhibitors, nitrates of prolonged action, sublingual nitroglycerin, NSAIDs, antibiotics and hypoglycemic agents for oral administration.

In the treatment of angina pectoris, amlodipine can be prescribed in combination with other antianginal agents, including patients refractory to treatment with nitrates and/or beta-blockers in adequate doses.

Amlodipine does not have any adverse effect on blood plasma metabolism and lipids and can be used in the treatment of patients with bronchial asthma, diabetes and gout.

Amlodipine can also be used in cases where the patient is predisposed to vasospasm/vasoconstriction.

Patients with low body weight, low growth and patients with severe liver dysfunction may require a lower dosage.

During treatment, it is necessary to control body weight and supervision at the dentist (to prevent pain, bleeding and hyperplasia of the gums).

Ramipril.

Before starting treatment with ramipril, hyponatremia and hypovolemia must be eliminated. Patients who have previously taken diuretics, they need to cancel or at least reduce their dose for 2-3 days before taking ramipril (in this case, you should regularly monitor the condition of patients with CNS due to the possibility of developing their decompensation with increasing BCC).

After taking the first dose of the drug, as well as increasing its dose and/or dose of diuretics (especially loop), it is necessary to ensure regular medical supervision of the patient for at least 8 hours for timely adoption of appropriate measures in case of excessive blood PRESSURE reduction.

If ramipril is used for the first time or in a high dose in patients with increased RAAS activity, then they should regularly monitor blood PRESSURE, especially at the beginning of treatment, because these patients have an increased risk of excessive blood PRESSURE reduction. In malignant hypertension and SN, especially in the acute stage of MI, treatment with ramipril should be started only in a hospital.

In patients with CHF, drug administration can lead to the development of a marked decrease in blood PRESSURE, which in some cases is accompanied by oliguria or azotemia and rarely — the development of acute renal failure.

Caution should be exercised in the treatment of elderly patients, as they may be particularly sensitive to ACE inhibitors; in the initial phase of treatment is recommended to monitor the performance of kidney function.

In patients for whom blood PRESSURE reduction may pose a certain risk (for example, patients with atherosclerotic narrowing of the coronary or cerebral arteries), treatment should begin under strict medical supervision.

Caution should be exercised during exercise and/or hot weather due to the risk of increased sweating and dehydration with the development of hypotension due to the reduction of BCC and lower sodium content in the blood.

During treatment is not recommended to drink alcohol.

Transient hypotension is not a contraindication to continue treatment after stabilization of blood PRESSURE. In the case of repeated occurrence of severe hypotension should reduce the dose or cancel the drug. Patients treated with ACE inhibitors had cases of angioedema of the face, limbs, lips, tongue, pharynx or larynx. In case of swelling in the face (lips, eyelids) or tongue, or violation of swallowing or breathing, the patient should immediately stop taking the drug. Angioedema, localized in the region of the tongue, pharynx or larynx (possible symptoms: impaired swallowing or breathing), may be life-threatening and requires urgent measures for its relief: p/to the introduction of 0, 3-0, 5 mg or/drip in a 0, 1 mg epinephrine (under the control of blood pressure, heart rate and ECG), with subsequent primeneniem (in/in, in/m or in); it is also recommended to/in the introduction of antihistamines (antagonists H1 - and H2-histamine receptors), and in the case of insufficiency of inactivators of the enzyme C1-esterase can be considered the need for the introduction in addition to epinephrine inhibitors of the enzyme C1-esterase. The patient should be hospitalized and monitored until the symptoms are completely relieved, but not less than 24 hours.

Patients, receiving ACE inhibitors, there were cases of intestinal angioedema, which manifested itself in abdominal pain with nausea and vomiting or without them; in some cases, both observed and angioedema of the face. When the patient appears on the background of treatment with ACE inhibitors of the above symptoms, it is necessary to consider the possibility of developing intestinal angioedema during the differential diagnosis.

Treatment aimed at desensitizing to insect venom (bees, wasps) and simultaneous administration of ACE inhibitors can initiate anaphylactic and anaphylactoid reactions (e.g. lowering blood PRESSURE, shortness of breath, vomiting, allergic skin reactions), which can sometimes be life-threatening. During treatment with ACE inhibitors, reactions of increased sensitivity to insect venom (e.g. bees, wasps) develop faster and are more severe. If desensitization to insect venom is necessary, the ACE inhibitor should be temporarily replaced by a corresponding class of another.

When using ACE inhibitors have been described life-threatening, rapidly developing anaphylactoid reactions, sometimes until the development of shock during hemodialysis or plasmafiltration with the use of certain high-flow membranes (e.g. polyacrylonitrile membranes) (see also the instructions of the manufacturers of the membranes). It is necessary to avoid the joint use of ramipril and such membranes (for example, for urgent hemodialysis or hemofiltration). In this case, it is preferable to use other membranes or to exclude the use of an ACE inhibitor. Similar reactions were observed in LDL apheresis using dextran sulfate. Therefore this method should not be used in patients receiving ACE inhibitor. In patients with impaired liver function, the reaction to treatment with ramipril may be either enhanced or weakened. In addition, in patients with severe liver cirrhosis with edema and/or ascites, significant activation of RAAS is possible, therefore, in the treatment of these patients, special care should be taken.

Prior to surgery (including dental surgery), the surgeon/anesthesiologist should be warned about the use of an ACE inhibitor.

The use of ACE inhibitors in patients undergoing extensive surgery and/or General anesthesia, can lead to a marked decrease in blood pressure, if funds are used for General anesthesia with hypotensive action. This is due to blocking the formation of angiotensin II against the background of compensatory increase in renin activity. In this case, the volume of circulating liquid should be increased. It is recommended to stop taking ACE inhibitor for 24 hours before surgery. Based on the results of epidemiological studies, it is assumed that simultaneous administration of ACE inhibitors and insulin, as well as hypoglycemic agents for oral administration can lead to the development of hypoglycemia. The greatest risk of development is observed during the first weeks of combination therapy, as well as in patients with impaired renal function.

Patients with diabetes require regular glycemic control, especially during the first month of therapy with ACE inhibitors.

It is recommended to conduct careful monitoring of newborns who were exposed to intrauterine exposure to ACE inhibitors, to detect hypotension, oliguria and hyperkalemia.

If oliguria is necessary to maintenance of blood pressure and renal perfusion through the introduction of appropriate fluids and vasoconstrictor.

These newborns have a risk of developing oliguria and neurological disorders, possibly due to a decrease in renal and cerebral blood flow due to a decrease in blood PRESSURE caused by ACE inhibitors.

Dry cough may occur during therapy with ACE inhibitors. The long-term remains cough on a background of reception of preparations of this group and disappears after their cancellation. When a patient has a dry cough, it should be remembered about the possible iatrogenic nature of this symptom.

In patients blacks more likely than members of other races, in patients receiving ingibitorov of developing angioedema. Ramipril, like other ACE inhibitors, may have less pronounced antihypertensive effect in patients of Negroid race compared to other races. Perhaps this difference is due to the fact that patients with a Negroid race with hypertension are more likely to have low renin activity.

Control of laboratory parameters before and during treatment with ramipril (up to 1 time per month in the first 3-6 months of treatment) includes:

• control of renal function (determination of serum creatinine). In the treatment of ACE inhibitors in the first weeks of treatment and in the future it is recommended to monitor renal function. Especially careful monitoring is required for patients with SN, renal dysfunction, after kidney transplantation, patients with renovascular diseases, including patients with hemodynamically significant unilateral renal artery stenosis in the presence of two kidneys (in such patients, even a slight increase in serum creatinine may be an indicator of reduced renal function).
  
• control of electrolytes. Regular monitoring of serum potassium is recommended. Especially careful monitoring of potassium content in the blood serum is required in patients with impaired renal function, significant violations of water-electrolyte balance, CHF.
  
• control of hematological parameters (hemoglobin content, number of leukocytes, red blood cells, platelets, leukocyte formula). It is recommended to monitor the indicators of General blood analysis to identify possible leukopenia. More regular monitoring is recommended at the beginning of treatment and in patients with impaired renal function, as well as in patients with connective tissue diseases or in patients receiving other drugs at the same time, capable of changing the picture of peripheral blood.
  

Control of the number of leukocytes is necessary for early detection of leukopenia, which is especially important in patients with an increased risk of its development, as well as at the first signs of infection. When detecting neutropenia (the number of neutrophils less than 2000/µl), treatment with ramipril is required. With the appearance of symptoms caused by leukopenia (eg fever, enlarged lymph nodes, tonsillitis), it is necessary to urgently control the picture of peripheral blood. In the case of signs of bleeding (the smallest petechia, red-brown rash on the skin and mucous membranes), it is also necessary to control the number of platelets in the peripheral blood.

• determination of the activity of liver enzymes, bilirubin concentration in the blood. If jaundice or significant increases in liver enzymes therapy with ramipril should be discontinued and to provide medical monitoring of the patient.
  

Influence on the ability to drive and operate machinery. During treatment, the drug is recommended to refrain from driving vehicles and occupation of other potentially hazardous activities, require high concentration and psychomotor speed reactions (dizziness, especially early in treatment, and in patients taking diuretic drugs, a decrease in concentration) After the first dose and after significant dose increase of the drug is not recommended to drive vehicles and work with technical equipment for several hours.

Form release

Capsules, 5 mg+5 mg, 5 mg+10 mg, 10 mg+5 mg, 10 mg+10 mg. For 7 or 10 capsules. in the blister of the combined film "cold" (polyamide/aluminum foil/PVC)/aluminum foil. 4 or 8 blisters (7 caps each.) or 3 or 9 blisters (10 caps each.) in a cardboard box.

Manufacturer

JSC "Pharmaceutical factory EGIS". 1106 Budapest, building, Keresturi, 30-38, Hungary.

Phone: (36 1) 803-55-55; Fax: (36 1) 803-55-29.

Representation of JSC "EGIS Pharmaceutical plant" (Hungary) in Moscow. 121108, Moscow, 8 Ivan Franko street.

Phone: (495) 363-39-66.

Storage conditions of the drug Egipres®

At a temperature not exceeding 25 °C.

Keep out of reach of children.

The shelf life of the drug Egipres®

3 years.

Do not use after the expiration date specified on the package.