Egipres® (Egipres®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceAmlodipine + RamiprilAmlodipine + Ramipril
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    Sandoz d.     Slovenia
  • Egipres®
    capsules inwards 
    Egis Pharmaceutical Plant OJSC     Hungary
    • Dosage form: & nbspcapsules
    Composition:

    Composition per 1 capsule:

    Active substances: amlodipine besylate 3,475 / 6,95 / 6,95 / 13,9 / 13,9 mg (which corresponds to amlodipine 2.5 / 5/5/10/10 mg) and ramipril 2.5 (5/10) 10 mg.

    Excipients: crospovidone 10/20/40/40/40 mg, hypromellose 0,59 / 1.18 / 2.36 / 2.36 / 2.36 mg, microcrystalline cellulose 57.41 / 114.82 / 229.64 / 229.64 / 229.64 mg, glyceryl dibehenate 1.025 / 2.05 (4.1 / 4.1 / 4.1 mg).

    Composition of hard gelatin capsule (CONI-SNAP 3), the color code of the lid and base 37350 (capsules 2.5 mg + 2.5 mg): iron oxide red (E172), titanium dioxide, gelatin.

    Composition of hard gelatin capsule (CONI-SNAP 3), cover and base color code 51072 (5 mg capsules + 5 mg): blue diamond dye (E133), red enchanting dye (E129), titanium dioxide, gelatin.

    Composition of hard gelatin capsule (CONI-SNAP 0), cover and base color code: 51072/37350 (capsules 5 mg + 10 mg): lid: titanium dioxide, brilliant blue dye (E133), red enchanting dye (E129), gelatin; base: titanium dioxide, iron dye red oxide (E172), gelatin.

    Composition of hard gelatin capsule (CONI-SNAP 0), cover and base color code: 33007/37350 (capsules 10 mg + 5 mg): lid: titanium dioxide, dye azorubin (E122), indigocarmine (E132), gelatin; base: titanium dioxide, iron dye red oxide (E172), gelatin.

    Composition of hard gelatin capsule (CONI-SNAP 0), cover and base color code: 33007 (capsules 10 mg + 10 mg): dye azorubin (E122), indigocarmine (E132), titanium dioxide, gelatin.

    Description:

    Capsules 2.5 mg + 2.5 mg: Hard gelatin capsules CONI-SNAP 3, self-closing, with a base and a lid of light pink color, containing a mixture of granules and powders of white or almost white color, without or almost no odor.

    Capsules 5 mg + 5 mg: Hard gelatin capsules CONI-SNAP 3, self-closing, with a base and a lid of light-burgundy color, containing a mixture of granules and powders of white or almost white color, without or almost no odor.

    Capsules 5 mg + 10 mg: Hard gelatin capsules CONI-SNAP 0, self-closing, with a base of light pink color and a lid of light-burgundy color, containing a mixture of granules and powders of white or almost white color, without or almost no odor.

    Capsules 10 mg + 5 mg: Hard gelatin capsules CONI-SNAP 0, self-closing, with a base of light pink color and a lid of maroon color, containing a mixture of granules and powders of white or almost white color, without or almost no odor.

    Capsules 10 mg + 10 mg: Hard gelatin capsules CONI-SNAP 0, self-closing, with a base and a lid of maroon color, containing a mixture of granules and powders of white or almost white color, without or almost no odor.

    Pharmacotherapeutic group:antihypertensive agent combined (angiotensin-converting enzyme inhibitor + blocker of "slow" calcium channels)
    ATX: & nbsp

    C.09.B.B   ACE inhibitors in combination with calcium channel blockers

    Pharmacodynamics:

    Amlodipine

    Amlodipine is a dihydropyridine derivative. Linking with dihydropyridine receptors, 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 the following two ways:

    - Expands peripheral arterioles and, thus, reduces OPSS (afterload), with the heart rate practically unchanged, which leads to a reduction in energy consumption and myocardial oxygen demand.

    - Expands coronary and peripheral arteries and arterioles in both normal and ischemic zones of the myocardium,which increases the flow of oxygen into the myocardium in patients with vasospastic angina (Prinzmetal angina) and prevents the development of coronarospasm caused by smoking.

    In patients with AH, the daily dose of amlodipine provides a decrease in blood pressure for 24 hours (both in the position on the back and standing). Due to the slow start of the 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 attack of angina and depression of the segment ST (by 1 mm) against the background of exercise, reduces the frequency of angina attacks and the need for nitroglycerin.

    The use of amlodipine in patients with ischemic heart disease

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

    Use of amlodipine in patients from SP.

    Amlodipine does not increase the risk of death or the development of complications and fatalities in patients with CHF III-IV FC on NYHA on the background of therapy with digoxin, diuretics and inhibitors of AMP. In patients with CHF III-IV FC on NYHA non-ischemic etiology in the use of amlodipine, there is a possibility of pulmonary edema.

    Amlodipine does not cause adverse metabolic effects, including it does not affect the content of lipid profile.

    Ramipril

    Ramiprilat, formed with the participation of "liver" enzymes active metabolite ramipril, is a long-acting inhibitor of the enzyme dipeptidylcarboxypeptidase I (synonyms: angiotensin converting enzyme (AIF), 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.Reduction of the formation of angiotensin II and inhibition of the decay of bradykinin leads to vasodilation and a decrease in blood pressure (BP). The increased activity of kallikrein-kinin system in blood and tissues causes cardioprotective and endothelioprejective action of ramipril due to activation of the prostaglandin system and, accordingly, an increase in the synthesis of prostaglandins (PG) stimulating the formation of nitric oxide (N0) 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 activity of the blood plasma.

    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 hypertension (AH), taking ramipril leads to a decrease in blood pressure in the position on the back and standing, without compensatory increase in the heart rate (heart rate). Ramipril significantly reduces the overall peripheral vascular resistance (OPSS), virtually without causing changes in the renal blood flow and glomerular filtration rate. 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 for 24 hours. At the course of treatment, the antihypertensive effect can gradually increase, usually stabilizing to 3-4 weeks of regular intake drug and then persisting for a long time. Sudden discontinuation of the drug does not lead to a rapid and significant increase in blood pressure (the absence of the "withdrawal" syndrome).

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

    In patients with chronic heart failure (CHF) ramipril reduces OPSS (decrease in postload on the heart), increases the capacity of the venous bed and reduces the filling pressure of 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 improvement of exercise tolerance.

    With diabetic and nondiabetic nephropathy taking ramipril slows down speed progression of renal failure and the time of the onset of the terminal stage renal failure and, as a result, reduces the need for hemodialysis or kidney transplant 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 (CVS) due to the presence of vascular lesions (diagnosed coronary heart disease (CHD), obliterans of peripheral arterial disease in history, a history of stroke) or diabetes mellitus with at least one additional risk factor (microalbuminuria, hypertension, increased total cholesterol, a decrease in high density lipoprotein cholesterol (HDL) , smoking) the addition of ramipril to standard therapy significantly reduces the incidence of myocardial infarction (MI), stroke and cardiovascular mortality. In addition, ramipril reduces the overall mortality rate, as well as the need for revascularization procedures,slows the onset or progression of CHF.

    In patients with heart failure (CH), developed in the early days of acute myocardial infarction (AMI) (2-9 days), the risk of death rate (by 27%), risk of sudden death (by 30%), risk of progression of CHF to severe is decreasing when taking ramipril from 3 to 10 days of AMI, III-IV functional class (FC) according to the classification of the New York Association of Cardiology (NYHA) - 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 AH and normal BP, ramipril significantly reduces the risk of developing nephropathy and the occurrence of microalbuminuria.

    Pharmacokinetics:

    Amlodipine

    After oral administration at therapeutic doses amlodipine is well absorbed, the time to reach the maximum concentration in the blood plasma (TCmOh) with oral intake is 6-12 hours. Absolute bioavailability leaves 64-80%. Vd is approximately 21 l / kg. The connection with plasma proteins is approximately 97.5%. Food intake does not affect the absorption of amlodipine.The drug penetrates the blood-brain barrier.

    T1/2 from the blood plasma is about 35-50 hours, which corresponds to the appointment of the drug once a day. In patients with hepatic insufficiency and severe CHF, T1 / 2 increases to 56-60 hours. The total clearance is 0.43 l / h / kg.

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

    Use in patients with renal insufficiency

    T1/2 from blood plasma in patients with renal insufficiency increases to 60 h. The change in the concentration of amlodipine in the blood plasma does not correlate with the degree of impaired renal function.

    Application in elderly patients

    In elderly patients, TCmax and CmOh Amlodipine practically do not differ from those in younger patients. In elderly patients with CHF, there is a tendency to decrease the clearance of amlodipine, which leads to an increase AUC and T1/2 up to 65 hours.

    Ramipril

    After oral administration ramipril quickly absorbed from the gastrointestinal tract (GIT) (50-60%).Eating slows down its absorption, but does not affect the degree of absorption. Ramipril is subjected to intense presystemic metabolism / activation (mainly in the liver by hydrolysis), which results in the formation of its only active metabolite, ramiprilate, whose activity with respect to ACE inhibition 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. 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 the maximum concentration in the blood plasma (Ctmax) ramipril and ramiprilate are achieved after 1 and 2-4 h, respectively. The decrease in the concentration of ramiprilate in the blood plasma occurs in several stages: the phase of distribution and excretion with a half-life (T1 / 2) of ramiprilate,about 3 hours, then an intermediate phase with T1 / 2 ramiprilata of about 15 hours, and the final phase with a very low concentration of ramiprilata in the blood plasma and T1 / 2 ramiprilata, 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 the long-term final phase with a single daily ramipril intake in a dose of 2.5 mg or more, the equilibrium plasma concentration (Css) ramiprilata is reached after approximately 4 days of treatment. With the prescription of the drug "effective" T1/2 depending on the dose is 13-17 hours.

    Binding to blood plasma proteins approximately makes up 73% for ramipril, and 56% for ramiprilate.

    After intravenous (iv) administration volumes of distribution (Vd) ramipril and ramiprilate are approximately 90 and 500 liters, respectively.

    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 ramiprilate and its metabolites, in other words, with / in the administration of ramipril and ramiprilate, a significant portion of the dose is excreted through the intestines with bile, bypassing the kidneys (50 and 30%, respectively) . After ingesting 5 mg of ramipril in patients with bile duct drainage, virtually equal 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 urine content of unmetabolized ramipril is approximately 2%.

    In cases of renal dysfunction with creatinine clearance (CK) of less than 60 ml / min, excretion of ramiprilate 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 AH 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 CHF after 2 weeks of ramipril treatment at a daily dose of 5 mg, there is a 1.5-1.8-fold increase in plasma ramiprilate concentrations and the area under the pharmacokinetic curve of plasma concentration, as a function of time (AUC).

    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, as in combination).

    Contraindications:

    Amlodipine

    Hypersensitivity to amlodipine and other dihydropyridine derivatives; Severe arterial hypotension (SBP less than 90 mm Hg), shock (including cardiogenic);

    Obstructive process that hampers the release of blood from the left ventricle (eg, clinically significant aortic stenosis)

    Hemodynamically unstable heart failure after myocardial infarction; Pregnancy;

    The period of breastfeeding;

    Age under 18 years (safety and efficacy not determined).

    Ramipril

    Hypersensitivity to ramipril, other inhibitors of angiotensin-converting enzyme (ACE);

    Angioedema in history (hereditary or idiopathic, and also associated with previous therapy with ACE inhibitors);

    Hemodynamically significant stenosis of the renal arteries (bilateral or unilateral, in the case of a single kidney);

    Arterial hypotension (systolic blood pressure (SBP) <90 mm Hg) or a condition with unstable hemodynamics;

    Hemodynamically significant stenosis of the aortic or mitral valve, or hypertrophic obstructive cardiomyopathy;

    Primary hyperaldosteronism;

    Severe renal failure (CC <20 mL / min / 1.73 m2 surface area of ​​the body)

    Hemodialysis (clinical experience is not enough);

    Pregnancy;

    The period of breastfeeding;

    Nephropathy, which is treated with glucocorticosteroids (GCS), nonsteroidal anti-inflammatory drugs (NSAIDs), immunomodulators and / or other cytotoxic agents (clinical experience is inadequate);

    Decompensated chronic heart failure (clinical experience is inadequate);

    Age under 18 years (clinical experience is insufficient);

    Hemodialysis or hemofiltration using certain membranes with a negatively charged surface such as a membrane of polyacrylonitrile vysokoprotochnyh (risk of developing hypersensitivity reactions);

    Apoferez low density lipoproteins (LDL) using dextran sulfate (risk of developing hypersensitivity reactions);

    Desensitization therapy for hypersensitivity reactions to poison insects - bees, wasps;

    The acute stage of myocardial infarction in patients with such diseases as:

    - severe heart failure (IV functional class according to NYHA);

    - life-threatening ventricular arrhythmias;

    - "pulmonary" heart.

    Simultaneous use of drugs containing aliskirenPatients with renal impairment (creatinine clearance less than 60 mL / min) and patients with diabetes mellitus.

    Amlodipine + ramipril

    Hypersensitivity to the excipients included in the preparation;

    Pregnancy;

    The period of breastfeeding;

    Renal failure: CC <20 ml / min at 1.73 m body surface area;

    Age under 18 years (clinical experience is insufficient).

    Carefully:

    Use the combination with caution. amlodipine + ramipril with the following diseases and conditions:

    - Atherosclerotic lesions of the coronary and cerebral arteries (the risk of excessive blood pressure lowering);

    - increased activity of the renin-angiotensin-aldosterone system (RAAS), in which, with ACE inhibition, there is a risk of a sharp decrease in blood pressure with impaired renal function:

    - marked, especially malignant hypertension,

    - CHF, especially severe or about which other medicines (drugs) with antihypertensive action are taken,

    - hemodynamically significant unilateral stenosis of the renal artery (in the presence of both kidneys),

    - previous intake of diuretics,

    - Violations of the water-electrolyte balance, decrease in the volume of circulating blood (BCC) (including against the background of diuretics, salt-free diets, diarrhea, vomiting, excessive sweating);

    - simultaneous use with preparations containing aliskiren (with a double blockade of RAAS, the risk of a sharp decrease in blood pressure, hyperkalemia and impaired renal function increases);

    - impaired hepatic function - insufficient experience of application: it is possible both to enhance and weaken the effects of ramipril; in the presence of cirrhosis of the liver with ascites and edemas, significant activation of RAAS is possible;

    - renal dysfunction (KC more than 20 ml / min.);

    - condition after kidney transplantation;

    - Systemic diseases of connective tissue, including systemic lupus erythematosus, scleroderma, concomitant therapy with drugs that can cause changes in the picture of peripheral blood (including allopurinol, procainamide) - oppression of bone marrow hematopoiesis, development of neutropenia or agranulocytosis;

    - diabetes mellitus - the risk of hyperkalemia;

    - elderly age - the risk of intensifying antihypertensive action;

    - Hyperkalemia;

    - hyponatremia;

    - CHF of non-ischemic etiology III-IV functional class by classification NYHA;

    - aortic stenosis;

    - syndrome of weakness of the sinus node;

    - 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 edible salt, lithium preparations;

    - surgical intervention / general anesthesia;

    - carrying out hemodialysis using high-flow membranes (for example, AN69®).

    Pregnancy and lactation:

    Pregnancy

    The drug is contraindicated for use, since ramipril may have an adverse effect on the fetus: impairment of fetal kidney development, fetal and newborn fetal loss, renal dysfunction, hyperkalemia, skull bones hypoplasia, oligohydramnia, limb contracture, skull bones deformation, and lung hypoplasia. Before starting the drug in women of childbearing age, pregnancy should be excluded.

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

    Breastfeeding period

    If treatment with the drug is necessary during breastfeeding, it should be discontinued (there is no data on excretion of amlodipine and ramipril with breast milk of women).

    Fertility

    Amlodipine

    Some patients who received calcium channel blockers experienced reversible biochemical changes in the sperm heads. Clinical data are insufficient to assess the potential effect of amlodipine on fertility.

    Dosing and Administration:

    Apply Egipress inside, 1 capsule 1 time per 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 drug: ramipril and amlodipine in patients with AE. The drug Egipres with fixed doses of active ingredients can not be used for initial therapy. If patients need dose adjustment, then it should be done only by titration of doses of active components in monotherapy. Only then is it possible to use the drug Egipres with fixed doses of active ingredients in the following combinations.

    With therapeutic necessity, the dose of the drug Egipres can be changed on the basis of individual titration of the doses of individual components:

    2.5 mg of amlodipine + 2.5 mg of ramipril or 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.

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

    Adults

    In patients taking diuretics, the drug should be administered with caution, due to the risk of disturbance of the water-electrolyte balance. These patients should monitor kidney function and potassium levels in the blood.

    Older patients and patients with renal insufficiency Removal 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 creatinine and potassium content in the blood plasma.

    Egipres can be administered to patients with QC equal to or greater than 60 ml / min.With CC <60 ml / min, as well as in patients with AH who are on hemodialysis, Egipres is recommended only for patients receiving 2.5 mg or 5 mg of ramipril as the optimal maintenance dose during the titration of an 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 CC <20 ml / min / 1.73 m body surface area. The change in the concentration of amlodipine in the blood plasma does not correlate with the degree of renal insufficiency.

    Patients with hepatic insufficiency

    Caution should be exercised when prescribing the drug Egipres to patients with hepatic insufficiency due to the lack of recommendations for dosing the drug in such patients. Egipres is recommended only for patients receiving 2.5 mg of ramipril as the optimal maintenance dose during the titration of an individual dose.

    Children and teens

    Egipres should not be given to children and adolescents under 18 years of age because of the lack of data on the efficacy and safety of ramipril and amlodipine in these patient groups, either as monotherapy or as combination therapy.

    Side effects:

    The following undesirable effects are given in accordance with the following grades of their frequency according to WHO classification: very frequent: more than 1/10 (more than 10%); Frequent: more than 1/100 but less than 1/10 (more than 1%, but less than 10%); infrequent: more than 1/1000 but less than 1/100 (more than 0.1%, but less than 1%); rare: more than 1/10000 but less than 1/1000 (more than 0.01%, but less than 0.1%); very rare: less than 1/10000 (less than 0.01%).

    Amlodipine

    From the CCC: often - peripheral edema (ankles and feet), palpitations; infrequently - excessive reduction of blood pressure, orthostatic hypotension, vasculitis; rarely - development or exacerbation of heart failure; rarely - heart rhythm disturbances (including bradycardia, ventricular tachycardia and atrial fibrillation), MI, chest pain, migraine.

    From the musculoskeletal and connective tissues: infrequently - Arthralgia, muscle cramps, myalgia, back pain, arthrosis; rarely - Myasthenia gravis.

    From the side of the central nervous system and peripheral nervous system: often - a feeling of heat and tides of blood to the skin of the face, increased fatigue, dizziness, headache, drowsiness; infrequently - malaise, fainting, increased sweating, asthenia, hypoesthesia, paresthesia, peripheral neuropathy, tremor, insomnia,lability of mood, unusual dreams, nervousness, depression, anxiety; rarely - cramps, apathy; rarely - Ataxia, amnesia, individual cases of extrapyramidal syndrome have been reported.

    From the digestive system: often - abdominal pain, nausea; infrequently - vomiting, changes in the bowel movement (including constipation, flatulence), dyspepsia, diarrhea, anorexia, dryness of the oral mucosa, thirst; rarely - gingival hyperplasia, increased appetite; rarely - gastritis, pancreatitis, hyperbilirubinemia, jaundice (usually cholestatic), increased activity of "liver" transaminases, hepatitis.

    From the side of the blood: rarely - thrombocytopenic purpura, thrombocytopenia, and leukopenia.

    Metabolic disorders: rarely hyperglycemia.

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

    From the side of the kidneys and urinary tract: infrequently - Frequent urination, painful urination, nocturia, impotence; rarely - dysuria, polyuria. Allergic reactions: infrequently - skin itching, rash; rarely - angioedema, erythema multiforme, urticaria.

    Other: infrequently - alopecia, ringing in the ears, gynecomastia, weight gain / increase, vision impairment, diplopia, accommodation disorder, xerophthalmia, conjunctivitis, eye pain, taste distortion, chills, nosebleeds; rarely - dermatitis; rarely - parosmia, xeroderma, "cold" sweat, a violation of skin pigmentation.

    Ramipril

    From the heart: infrequently - Myocardial ischemia, including the development of an attack of angina or myocardial infarction, tachycardia, arrhythmias (appearance or gain), palpitations, peripheral edema.

    From the side of the vessels: often - excessive decrease in blood pressure, violation of orthostatic regulation of vascular tone (orthostatic hypotension), syncopal conditions; infrequently - "tides" of blood to the skin of the face; rarely - occurrence or strengthening of circulatory disorders against the background of stenosing vascular lesions, vasculitis; frequency unknown - Raynaud's syndrome.

    From the central nervous system (CNS): often - headache, a feeling of "lightness" in the head; infrequently - dizziness, agevzia (loss of taste sensitivity), dysgeusia (a violation of taste sensitivity), paresthesia (burning sensation); rarely - tremor, imbalance; frequency unknown - cerebral ischemia, including ischemic stroke and transient impairment of cerebral circulation, violation of psychomotor reactions, parosmia (impaired perception of odors).

    From the side of the organ of vision: infrequently - visual impairment, including blurred vision; rarely - conjunctivitis.

    Hearing disorders: rarely - Hearing impairment, ringing in the ears.

    From the side of the psyche: infrequently - Depressed mood, anxiety, nervousness, motor anxiety, sleep disturbances, including drowsiness; rarely confusion of consciousness; frequency unknown - violation of concentration of attention.

    From the respiratory system: often - "dry" cough (worse at night and lying down), bronchitis, sinusitis, dyspnea; infrequently - bronchospasm, including weighting of the course of bronchial asthma, nasal congestion.

    From the digestive system: often - inflammatory reactions in the stomach and intestines, digestive disorders, abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting; infrequently - pancreatitis, incl.and fatal cases (cases of pancreatitis with a lethal outcome with the intake of ACE inhibitors were very rare), increased activity of pancreatic enzymes in the blood plasma, intestinal angioedema, abdominal pain, gastritis, constipation, dryness of the oral mucosa; rarely - glossitis; frequency unknown - aphthous stomatitis (inflammatory reaction of the mucous membrane of the oral cavity).

    From the hepatobiliary system: infrequently - Increased activity of "liver" enzymes and the content of conjugated bilirubin in blood plasma; rarely - cholestatic jaundice, hepatocellular lesions; frequency unknown - acute hepatic insufficiency, cholestatic or cytolytic hepatitis (lethal outcome was observed extremely rarely).

    From the side of the kidneys and urinary tract: infrequently - impaired renal function, including the development of acute renal failure, increased urine output, increased pre-existing proteinuria, increased urea and creatinine concentrations in the blood.

    On the part of the reproductive system and mammary glands: infrequently - Transient impotence due to erectile dysfunction, decreased libido; frequency unknown - gynecomastia.

    From the blood and lymphatic system: infrequently - eosinophilia; rarely - leukopenia, including neutropenia and agranulocytosis, a decrease in the number of erythrocytes in peripheral blood, a decrease in hemoglobin, thrombocytopenia; frequency unknown - oppression of bone marrow hematopoiesis, pancytopenia, hemolytic anemia.

    From the skin and mucous membranes: often - skin rash, in particular, maculopapular; infrequently - angioedema, incl. and fatal (laryngeal edema can cause airway obstruction leading to death), skin itching, hyperhidrosis (increased sweating); rarely - exfoliative dermatitis, urticaria, onycholysis; rarely - Photosensitivity reactions; frequency unknown - toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, weight gain of psoriasis, psoriasis-like dermatitis, pemphigoid or lichenoid (lichen) exanthema or enanthema, alopecia.

    From the musculoskeletal and connective tissue: often - muscle cramps, myalgia; infrequently - Arthralgia.

    From the side of metabolism, nutrition and laboratory indicators: often - Increase in the content of potassium in the blood; infrequently - Anorexia, decreased appetite; frequency unknown - a decrease in the concentration of sodium in the blood, a syndrome of inadequate secretion of an antidiuretic hormone.

    From the side of the immune system, the frequency is unknown - Anaphylactic or anaphylactoid reactions (with the inhibition of ACE, the amount of anaphylactic or anaphylactoid reactions to insect venoms increases), an increase in the titer of antinuclear antibodies.

    Common violations: often - pain in the chest, a feeling of fatigue; infrequently - fever; rarely - asthenia (weakness).

    Overdose:

    Information about an overdose of the drug Egipres is absent.

    Amlodipine

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

    Treatment: The purpose of activated charcoal (especially in the first 2 hours after an overdose), gastric lavage, elevating limbs, active maintenance of CAS functions, monitoring of heart and lung function, control of bcc and diuresis.

    To restore the tone of blood vessels and blood pressure, if there are no contraindications, it may be useful to use vasoconstrictors. Intravenous administration of calcium gluconate is used.

    Amlodipine is largely associated with serum proteins, so hemodialysis is ineffective.

    Ramipril

    Symptoms: excessive peripheral vasodilation with the development of pronounced 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 for the first 30 minutes). In the case of a pronounced reduction in blood pressure, the patient should be laid, legs elevated, actively support CAS functions; to therapy for replenishment of BCC and restoration of electrolyte balance, addition of alpha 1-adrenergic agonists (norepinephrine, dopamine) and angiotensinamide. In the case of refractory to medical treatment of bradycardia, it may be necessary to install a temporary artificial pacemaker. In case of an overdose it is necessary to monitor the content of creatinine and electrolytes in the blood serum. Ramiprilate is poorly excreted from the blood by hemodialysis.

    Interaction:

    Amlodipine

    It can be expected that inhibitors of microsomal liver enzymes (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 inductors of microsomal liver oxidase enzymes - reduce.

    With the simultaneous use of amlodipine with cimetidine, the pharmacokinetics of amlodipine does not change.

    Simultaneous single intake 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 "slow" calcium channel blockers (BCCI), there was no clinically significant interaction of amlodipine (III generation BCCC) when combined with NSAIDs, especially indomethacin.

    It is possible to enhance the anti-anginal and antihypertensive action of BCCC when combined with thiazide and loop diuretics, verapamil, ACE inhibitors, beta-blockers and nitrates, as well as increase their antihypertensive effect when combined with alpha 1-blockers, antipsychotics.

    Although no negative inotropic effect was usually observed in the study of amlodipine, nevertheless, some BCCCs can increase the negative inotropic effect of antiarrhythmic drugs that cause lengthening of the interval QT (eg, amiodarone and quinidine).

    When BCCC is combined with lithium preparations (there are no data for amlodipine), it is possible to intensify the manifestation of their neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, and tinnitus).

    Amlodipine is not affected in vitro on the degree of binding to blood proteins of digoxin, phenytoin, warfarin and indomethacin.

    A single intake of aluminum / magnesium-containing antacids does not significantly affect the pharmacokinetics of amlodipine.

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

    The repeated use of amlodipine in a dose of 10 mg and atorvastatin at a dose of 80 mg is not accompanied by significant changes in the pharmacokinetics of atorvastatin.

    With the simultaneous use of amlodipine with digoxin in healthy volunteers, the serum digoxin content and its renal clearance do not change.

    At a single and repeated application in a dose of 10 mg amlodipine has no significant effect on the pharmacokinetics of ethanol.

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

    Not recommended combinations

    Simultaneous use of dantrolene (iv introduction), inducers of isoenzymes of the cytochrome SURZA4 system (for example, rifampicin, Hypericum fever preparations) and inhibitors of cytochrome SURCA4 isoenzymes (protease inhibitors, antifungal agents of the azole group, macrolides, for example, erythromycin or clarithromycin, verapamil or diltiazem).

    Ramipril

    Contraindicated combinations

    The use of some high-flow membranes with a negatively charged surface (for example,polyacrylonitrile membranes) during hemodialysis or hemofiltration; The use of dextran sulfate in the apheresis of LDL is a risk of developing severe anaphylactic reactions.

    Unrecommended combinations

    With potassium salts, potassium-sparing diuretics (eg, amiloride, triamterespironolactone) and other drugs (including with receptor antagonists angiotensin II (ARA II), with trimethoprim, tacrolimus, cyclosporin) - it is possible to develop hyperkalemia (with simultaneous use, regular monitoring of potassium content in serum is required).

    Combinations that should be used with caution

    With antihypertensive agents (especially diuretics) and other drugs that lower blood pressure (nitrates, tricyclic antidepressants, agents for general and local anesthesia, ethanol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin) - potentiation of antihypertensive effect.

    When combined with diuretics should monitor the sodium content in the serum.

    With sleeping pills, narcotics and anesthetics - perhaps a more pronounced decrease in blood pressure.

    With vasopressor sympathomimetics (epinephrine, isoproterenol, dobutamine, dopamine) - reduction of antihypertensive action of ramipril, regular monitoring of blood pressure is required.

    With allopurinol, procainamide, cytostatics, immunosuppressants, systemic GCS, and other means that can affect hematologic indices - joint use increases the risk of developing leukopenia.

    With lithium salts, an increase in the lithium content in serum and an increase in the cardio- and neurotoxic effects of lithium.

    With hypoglycemic agents for oral administration (derivatives of sulfonylurea, biguanides), insulin - in connection with a decrease in insulin resistance under the influence of ramipril, it is possible to increase the hypoglycemic effect of these drugs, up to the development of hypoglycemia.

    Simultaneous use of drugs containing aliskiren, in patients with diabetes mellitus and renal insufficiency (KC less than 60 ml / min), as well as with vildagliptin - in connection with an increase in the frequency of angioedema development with simultaneous use with ACE inhibitors.

    Combinations that should be taken into account

    With NSAIDs (indomethacin, acetylsalicylic acid) - it is possible to weaken the action of ramipril, increase the risk of impaired renal function and increase the potassium content in the blood serum.

    With heparin - it is possible to increase the potassium content in the blood serum.

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

    With ethanol - increased symptoms of vasodilation. Ramipril can enhance the adverse effects of ethanol on the body.

    With estrogens, weakening of the antihypertensive action of ramipril (fluid retention).

    Desensitizing therapy with hypersensitivity to insect venoms - ACE inhibitors, including ramipril, increase the likelihood of developing severe anaphylactic or anaphylactoid reactions to insect venoms.

    Special instructions:

    Special instructions relating to ramipril and amlodipine are applicable to the drug Egipres.

    Special instructions regarding the administration of amlodipine

    In the treatment of hypertension amlodipine can be combined with the use of thiazide diuretics, alpha and beta-adrenoblockers, ACE inhibitors, prolonged-action nitrates, 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 in patients refractory to treatment with nitrates and / or beta-adrenoblockers in adequate doses.

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

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

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

    During treatment, it is necessary to control body weight and monitor the dentist (to prevent soreness, bleeding and gingival hyperplasia).

    Special instructions related to taking ramipril

    Before starting treatment with ramipril, it is necessary to eliminate hyponatremia and hypovolemia. Patients who have previously taken diuretics, they must be canceled or at least reduced their dose 2-3 days before the start of ramipril (in this case it should be regularly monitor the condition of patients with CHF, 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 provide regular medical supervision of the patient for at least 8 hours for timely taking appropriate measures in case of excessive blood pressure lowering.

    If ramipril is used for the first time or in a high dose in patients with increased activity of RAAS, then they should regularly monitor blood pressure, especially at the beginning of treatment, tk. these patients have an increased risk of excessive blood pressure lowering.

    In malignant hypertension and HF, especially in the acute stage of MI, treatment with ramipril should be started only in a hospital.

    In patients with CHF, taking the drug may lead to a marked decrease in blood pressure, which in some cases is accompanied by oliguria or azotemia and rarely - the development of acute renal failure.

    Care should be taken when treating elderly patients. they may be particularly sensitive to ACE inhibitors; it is recommended to monitor the renal function in the initial phase of treatment.

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

    Care should be taken with physical activity and / or hot weather because of the risk of increased sweating and dehydration with the development of arterial hypotension due to a decrease in BCC and a decrease in the sodium content in the blood.

    During treatment, it is not recommended to drink alcohol.

    Transient arterial hypotension is not a contraindication for continuing treatment after stabilizing blood pressure. In the case of repeated occurrence of severe arterial hypotension, the dose should be reduced or the drug should be withdrawn.

    Patients treated with ACE inhibitors experienced cases of angioedema of the face, extremities, lips, tongue, pharynx or larynx. If there is swelling in the face (lip, eyelid) or tongue, or a violation of swallowing or breathing, the patient should immediately stop taking the drug. Angioedema, localized in the area of ​​the tongue, pharynx,or larynx (possible symptoms: violation of swallowing or breathing), can be life threatening and requires urgent measures for its reduction: subcutaneous injection of 0.3-0.5 mg or intravenous drip 0.1 mg epinephrine (under the control of blood pressure, heart rate and ECG) followed by the use of GCS (in / in, in / m, or inside); It is also recommended intravenous administration of antihistamines (antagonists H1- and H2-histamine receptors), and in the case of inactivation of enzyme inactivators C1-esterase can consider the need to introduce in addition to epinephrine enzyme inhibitors C1-esterase. The patient should be hospitalized and monitored until the symptoms come to a complete relief, but not less than 24 hours.

    In patients receiving ACE inhibitors, there were cases of intestinal angioedema, which manifested itself with abdominal pain with or without nausea and vomiting; in some cases, angioedema has also been observed. When a patient appears on the background of treatment with ACE inhibitors of the above-described symptoms, it is necessary to consider the possibility of developing an intestinal angioedema in the course of a differential diagnosis.

    Treatment aimed at desensitization to insect venoms (bees, wasps), and simultaneous administration of ACE inhibitors can initiate anaphylactic and anaphylactoid reactions (eg, lowering blood pressure, dyspnea, vomiting, allergic skin reactions), which can sometimes be life threatening. Against the background of treatment with ACE inhibitors, hypersensitivity reactions to insect venom (eg, bees, wasps) develop more rapidly and take more severe course. If desensitization to insect venom is required, the ACE inhibitor must be temporarily replaced by a corresponding drug of another class.

    With the use of ACE inhibitors, life-threatening, rapidly developing anaphylactoid reactions have been described, sometimes until the shock develops during hemodialysis or plasma filtration using certain high-flow membranes (for example, polyacrylonitrile membranes) (see also membrane manufacturers instructions). 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 the apheresis of LDL with the use of dextran sulfate. Therefore, this method should not be used in patients receiving an ACE inhibitor. In patients with impaired hepatic function, the response to Ramipril therapy may be either increased or decreased. In addition, in patients with severe cirrhosis of the liver with edema and / or ascites, significant activation of RAAS is possible, therefore, special care must be taken in the treatment of these patients.

    Before surgery (including dental surgery), the surgeon / anesthesiologist should be alerted to the use of an ACE inhibitor. Use of an inhibitor ACE in patients undergoing extensive surgery and / or general anesthesia may result in a marked decrease in blood pressure if general anesthetics with hypotensive action are used. This is due to the blocking of the formation of angiotensin II against a background of compensatory enhancement of renin activity. In this case, the volume of the circulating fluid should be increased. It is recommended to stop taking an ACE inhibitor 24 hours before surgery.

    Based on the results of epidemiological studies, it is assumed that the simultaneous administration of ACE inhibitors and insulin, as well as hypoglycemic agents for oral administration may 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 monitoring of glycemia, especially during the first month of therapy with ACE inhibitors. It is recommended to closely monitor newborns who have been exposed to intrauterine exposure to ACE inhibitors for the detection of arterial hypotension, oliguria and hyperkalemia.

    In oliguria it is necessary to maintain BP and renal perfusion by introducing appropriate fluids and vasoconstrictors. In such newborns, there is a risk of developing oliguria and neurological disorders, possibly due to a reduction in renal and cerebral blood flow due to a reduction in blood pressure caused by ACE inhibitors.

    Against the background of therapy with ACE inhibitors, a "dry" cough may occur. Cough persists for a long time against the background of taking this group's drugs and disappears after their withdrawal.When a patient has a "dry" cough, remember the possible iatrogenic nature of this symptom.

    In patients of the Negroid race, angioneurotic edema develops more often than in representatives of other races against the background of the administration of ACE inhibitors. Ramipril, like other ACE inhibitors, may have a less pronounced antihypertensive effect in patients of the Negroid race as compared to representatives of other races. Perhaps this difference is due to the fact that patients with hypertensive blacks often have a low renin activity.

    Monitoring 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 kidney function (determination of serum creatinine content)

    In the treatment of ACE inhibitors in the first weeks of treatment and in the following it is recommended to monitor the function of the kidneys. Particularly careful monitoring is required for patients with heart failure, renal dysfunction, kidney transplantation, patients with renovascular disease, including patients with hemodynamically significant unilateral renal artery stenosis in the presence of two kidneys (in such patients, even a slight increaseserum creatinine levels may be indicative of decreased renal function).

    Control of the content of electrolytes

    Regular monitoring of potassium content in serum is recommended. Particularly careful monitoring of potassium in the blood serum is required for patients with impaired renal function, significant disturbances in the water-electrolyte balance, CHF.

    Control of hematological parameters (hemoglobin content, leukocyte count, erythrocyte, platelet count, leukocyte formula)

    It is recommended to monitor the parameters of a general blood test to detect 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 concomitantly other drugs capable of altering the picture of peripheral blood. Controlling the number of leukocytes is necessary for the early detection of leukopenia, which is especially important in patients with an increased risk of developing it, and also at the first signs of infection. If neutropenia is detected (neutrophil count is less than 2000 / μL), discontinuation of ramipril treatment is required.

    When symptoms appear due to leukopenia (eg, fever, enlargement of lymph nodes, tonsillitis), urgent monitoring of the picture of peripheral blood is needed. In case of signs of bleeding (the smallest petechiae, red-brown rashes 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, the concentration of bilirubin in the blood If jaundice or a significant increase in the activity of "liver" enzymes, treatment with ramipril should be stopped and medical supervision of the patient should be provided.

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

    During drug treatment it is recommended to refrain from driving and other potentially hazardous activities, requiring increased concentration of attention and speed of psychomotor reactions (possibly dizziness, especially at the beginning of treatment, and in patients taking diuretic drugs, reduced concentration of attention). After the first dose, and aftera significant increase in the dose of the drug is not recommended to drive vehicles and work with technical equipment for several hours.

    Form release / dosage:

    Capsules 2.5 mg + 2.5 mg, 5 mg + 5 mg, 5 mg + 10 mg, 10 mg + 5 mg, 10 mg + 10 mg.

    Packaging:7 or 10 capsules in a blister from a combination film "cold" (polyamide / aluminum foil UPVH) // aluminum foil. 4 or 8 blisters (7 capsules) or 3 or 9 blisters (10 capsules each) in a cardboard box together with instructions for use.
    Storage conditions:

    At a temperature of no higher than 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    3 years.

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

    Terms of leave from pharmacies:On prescription
    Registration number:LP-002402
    Date of registration:18.03.2014
    The owner of the registration certificate:Egis Pharmaceutical Plant OJSCEgis Pharmaceutical Plant OJSC Hungary
    Manufacturer: & nbsp
    Representation: & nbspEGIS ZAO Pharmaceutical Plant EGIS ZAO Pharmaceutical Plant Hungary
    Information update date: & nbsp20.10.2014
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