Egipres, 10mg+10mg capsules 30pcs

Composition

1 capsule contains:

active ingredients:

amlodipine bezylate 13.9 mg (equivalent to amlodipine 10 mg),

ramipril 10 mg;

excipients:

crospovidone — 20/40/40/40 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,10 mg+5 mg hard gelatin capsule (CONI-SNAP 0), color code the lids and bases — 33007/37350: cover — titanium dioxide; dye azorubin (E 122); Indigo Carmine (E 132); gelatin; base — titanium dioxide; dye iron oxide red (E 172); gelatin

Pharmacological action

Pharmacodynamics

Amlodipine

A dihydropyridine derivative. Binding to dihydropyridine receptors, it blocks slow calcium channels, inhibits the transmembrane transfer of calcium into vascular smooth muscle cells and the heart (to a greater extent-into vascular smooth muscle cells than into cardiomyocytes). It has antihypertensive and antianginal effects.

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

Amlodipine reduces myocardial ischemia in the following two ways:

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

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

In patients with arterial hypertension (AH), a daily dose of amlodipine reduces blood pressure for 24 hours (both in the supine and standing positions). 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 angina attack and ST-segment depression (by 1 mm) against the background of physical activity, reduces the frequency of angina attacks and the need for nitroglycerin.

Use of amlodipine in patients with CHD. In patients with cardiovascular diseases (including coronary atherosclerosis with damage from one vessel to stenosis of 3 or more arteries and carotid artery atherosclerosis), who have had a myocardial infarction (MI), percutaneous transluminal angioplasty of the coronary arteries (TLP), or who suffer from angina pectoris), the use of amlodipine prevents the development of thickening of the intima-media of the carotid arteries, significantly reduces mortality from cardiovascular causes, Myocardial infarction, stroke, TLP, aorto-coronary bypass surgery, leads to a decrease in the number of hospitalizations for unstable angina and the progression of CHF, reduces the frequency of interventions aimed at restoring coronary blood flow.

Use of amlodipine in patients with heart failure (HF). Amlodipine does not increase the risk of death or the development of complications and deaths in patients with CHF of functional class III–IV (FC) according to the classification of the New York Heart Association (NYHA) against the background of therapy with digoxin, diuretics and ACE inhibitors. In patients with NYHA FC III–IV CHF of non-ischemic etiology, amlodipine is likely to cause pulmonary edema. Amlodipine does not cause adverse metabolic effects, including it does not affect the parameters of the lipid profile.

Ramipril

Ramiprilate, formed with the participation of liver enzymes, the active metabolite of ramipril, is a long-acting inhibitor of the enzyme dipeptidyl carboxypeptidase I (synonyms-ACE, kininase II). In blood plasma and in tissues, this enzyme kininase II catalyzes the conversion of angiotensin I into an active vasoconstrictor substance-angiotensin II, and also contributes to the breakdown of bradykinin. A decrease in angiotensin II production and inhibition of bradykinin breakdown leads to vasodilation and a decrease in blood pressure. An increase in the activity of the kallikrein-kinin system in blood and tissues causes cardioprotective and endothelioprotective effects of ramipril due to activation of the prostaglandin system and, accordingly, an increase in the synthesis of PG, which stimulates the formation of nitric oxide (NO) in endotheliocytes. Angiotensin II stimulates the production of aldosterone, so taking ramipril leads to a decrease in aldosterone secretion and an increase in the content of potassium ions in the serum.

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

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

In patients with hypertension, taking ramipril leads to a decrease in blood pressure in the supine and standing positions, without a compensatory increase in heart rate. Ramipril significantly reduces OPSS, causing virtually no changes in renal blood flow and glomerular filtration rate. The antihypertensive effect begins to manifest itself 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. With a course of taking the antihypertensive effect may gradually increase, usually stabilizing by the 3rd-4th week of regular use of the 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 (no withdrawal syndrome).

In patients with hypertension, ramipril slows down the development and progression of myocardial and vascular wall hypertrophy.

In patients with CHF, ramipril reduces OPSS( reduction of afterload 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. These patients experience increased cardiac output, ejection fraction, and improved exercise tolerance when taking ramipril.

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

In patients at high risk of developing CVD diseases due to the presence of vascular lesions (diagnosed CHD, a history of peripheral artery obliterating diseases, a history of stroke) or diabetes mellitus with at least one additional risk factor (microalbuminuria, hypertension, increased total cholesterol, reduced HDL cholesterol, smoking), the addition of ramipril to standard therapy significantly reduces the incidence of MI, stroke, and mortality from cardiovascular causes.

In addition, ramipril reduces overall mortality rates, as well as the need for revascularization procedures, and slows down the onset or progression of CHF.

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

Pharmacokinetics

Amlodipine

After oral use in therapeutic doses, amlodipine is well absorbed, the time to reach Cmax in blood plasma with oral use is 6-12 hours. Absolute bioavailability is 64-80%. The Vd is approximately 21 l / kg. The binding to plasma proteins is approximately 97.5%. Food intake does not affect the absorption of amlodipine. The drug penetrates through the BBB.

T1 / 2 from the blood plasma is about 35-50 hours, which corresponds to the appointment of the drug 1 time per day. In patients with hepatic insufficiency and severe CHF, T1 / 2 increases to 56-60 hours.

The total ground clearance is 0.43 l / h / kg.

Stable Css (5-15 ng / ml) is achieved after 7-8 days of continuous use of amlodipine, it is metabolized in the liver with the formation of inactive metabolites. 10% of the initial drug and 60% of its metabolites are excreted by the kidneys, and 20% – through the intestines. Excretion in breast milk is unknown. Amlodipine is not removed during hemodialysis.

Special patient groups

Kidney failure. T1 / 2 from blood plasma in patients with renal insufficiency increases to 60 hours. Changes in the concentration of amlodipine in blood plasma do not correlate with the degree of impaired renal function.

Elderly patients.  The time to reach the Cmax and Cmax of amlodipine practically does 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 in AUC and T1 / 2 to 65 hours.

Ramipril

After oral use, it is rapidly absorbed from the gastrointestinal tract (50-60%). Food intake slows down its absorption, but does not affect the degree of absorption.Ramipril undergoes intensive presystemic metabolism / activation (mainly in the liver, by hydrolysis), resulting in the formation of its only active metabolite, ramiprilate, whose activity with respect to ACE inhibition is approximately 6 times higher than that of ramipril. In addition, as a result of ramipril metabolism, diketopiperazine, which does not have pharmacological activity, is formed, which then undergoes conjugation with glucuronic acid. Ramiprilate is also glucuronidated and metabolized to diketopiperazic acid. The bioavailability of ramipril after oral use ranges from 15% (for a dose of 2.5 mg) to 28% (for a dose of 5 mg). The bioavailability of ramiprilate after oral use of 5 mg of ramipril is approximately 45% (compared to its bioavailability after intravenous use at the same doses).

After oral use of ramipril, the time to reach the Cmax of ramipril and ramiprilate is 1 and 2-4 hours, respectively. The decrease in plasma ramiprilate concentration occurs in several stages: a distribution and elimination phase with a T1 / 2 ramiprilate of approximately 3 hours, followed by an intermediate phase with a T1 / 2 ramiprilate of approximately 15 hours, and an end phase with a very low plasma ramiprilate concentration and a T1 / 2 ramiprilate of approximately 4-5 days. This final phase is due to the slow release of ramiprilate from a strong binding to ACE receptors. Despite the prolonged end-phase with a single oral dose of 2.5 mg or more per day of ramipril, Css of ramiprilate is achieved after approximately 4 days of treatment. With a course of use of the drug, the effective T1 / 2 (depending on the dose) is 13-17 hours.

Plasma protein binding is approximately 73% for ramipril and 56% for ramiprilate.

After intravenous use, the Vds of ramipril and ramiprilate are approximately 90 and 500 L, respectively.

After ingestion of radiolabeled ramipril (10 mg),39% of the radioactivity is eliminated through the intestines and about 60% – by the kidneys. After intravenous use of ramipril,50-60% of the dose is detected in the urine in the form of ramipril and its metabolites. After intravenous use of ramiprilate-about 70% of the dose is detected in the urine in the form of ramiprilate and its metabolites, in other words, with intravenous use of ramipril and ramiprilate, a significant part of the dose is excreted through the intestine with bile, bypassing the kidneys (50 and 30%, respectively). After oral use of 5 mg ramipril in patients with bile duct drainage, almost identical amounts of ramipril and its metabolites are excreted by the kidneys and through the intestines within the first 24 hours after ingestion.

Approximately 80-90% of the metabolites in the urine and bile were identified as ramiprilate and ramiprilate metabolites. Ramipril glucuronide and ramipril diketopiperazine account for approximately 10-20% of the total amount, and the urinary content of unmetabolized ramipril is approximately 2%.

In patients with impaired renal function with a creatinine clearance of less than 60 ml / min, the elimination 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), impaired liver function leads to a slowdown in the presystemic metabolism of ramipril to active ramiprilate and a slower elimination of ramiprilate. No clinically significant accumulation of ramipril and ramiprilate was observed in healthy volunteers and patients with hypertension after 2 weeks of treatment with ramipril at a daily dose of 5 mg. In patients with CHF after 2 weeks of treatment with ramipril in a daily dose of 5 mg, an increase of 1.5–1.8 times in the concentration of ramiprilate in blood plasma and AUC is noted.

In healthy elderly volunteers (65-76 years), the pharmacokinetics of ramipril and ramiprilat did not significantly differ from those in young healthy volunteers.

Indications

Arterial hypertension (patients who are indicated for combination therapy with amlodipine and ramipril in doses as in combination).

Use during pregnancy and lactation

Egipres is contraindicated because ramipril may have adverse effects on the fetus: impaired fetal kidney development, decreased fetal and neonatal blood pressure, impaired renal function, hyperkalemia, cranial hypoplasia, oligohydramnion, limb contracture, cranial bone deformity, and lung hypoplasia. Before starting taking the drug in women of childbearing age, pregnancy should be excluded.

If a woman is planning pregnancy, then treatment with the drug should be discontinued. If pregnancy occurs during treatment with the drug, you should stop taking it as soon as possible and transfer the patient to other medications that will reduce the risk to the child.

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

Fertility

Amlodipine. Reversible biochemical changes in sperm heads were observed in some patients treated with BCC. Clinical data are insufficient to assess the potential effect of amlodipine on fertility.

Contraindications

Amlodipine

• increased sensitivity to amlodipine and other derivatives of dihydropyridine;
• severe hypotension (SBP less than 90 mm Hg. calendar), shock (including cardiogenic);
• obstructive process that impede the ejection of blood from the left ventricle (e. g., clinically significant aortic stenosis);
• hemodynamically unstable heart failure after myocardial infarction;
• pregnancy;
• breastfeeding;
• age to 18 years (safety and effectiveness are not determined).

Ramipril

• hypersensitivity to ramipril, other ACE inhibitors;
• a history of angioedema (hereditary or idiopathic and associated with previous therapy with ACE inhibitors);
• hemodynamically significant renal artery stenosis (bilateral or unilateral, in the case of a solitary kidney);
• hypotension (SBP less than 90 mm Hg. Hg), or condition with unstable hemodynamics;
• hemodynamically significant stenosis of the aortic or mitral valve disease or hypertrophic obstructive cardiomyopathy;
• primary aldosteronism;
• severe renal insufficiency (Cl creatinine 2);
• hemodialysis (clinical experience is insufficient);
• nephropathy, treatment of which is corticosteroids, NSAIDs, immunomodulators and/or other cytotoxic agents (clinical experience is insufficient);
• decompensated chronic heart failure (clinical experience is insufficient);
• hemodialysis or hemofiltration by the use of certain types of membranes with negatively charged surface, such as high-flow membrane of polyacrylnitrile (risk of hypersensitivity reactions);
• LDL apheresis using dextran sulfate (risk of hypersensitivity reactions);
• desensitizing therapy for hypersensitivity reactions to poisons insects — bees, wasps;
• acute phase of myocardial infarction in patients with diseases such as severe heart failure (IV functional class NYHA); life-threatening ventricular arrhythmias; heart lung;
• concomitant use of drugs containing aliskiren, in patients with impaired renal function (Cl creatinine less than 60 ml/min) and patients with diabetes mellitus;
• pregnancy;
• breastfeeding;
• age to 18 years (clinical experience is insufficient).

Amlodipine + ramipril

• hypersensitivity to excipients included in the drug;
• renal failure (creatinine clearance 2);
• pregnancy;
• breast-feeding period;
• age up to 18 years (experience of clinical use is insufficient).

Use caution for the combination of amlodipine + ramipril: atherosclerotic lesions of the coronary and cerebral arteries (risk of excessive lowering of blood pressure); increased activity of the RAAS, in which ACE inhibition has a risk of a sharp decrease in blood pressure with deterioration of renal function; severe, especially malignant hypertension; CHF, especially severe or for which other drugs with antihypertensive effects are taken; hemodynamically significant unilateral renal artery stenosis (in the presence of both kidneys); previous use of diuretics; impaired water-electrolyte balance, reduced blood pressure, BCC (including against the background of taking diuretics, salt-free diet, diarrhea, vomiting, heavy sweating); simultaneous use with drugs containing aliskiren (with double blockade of the RAAS, the risk of a sharp decrease in blood pressure, hyperkalemia and deterioration of renal function increases); liver function disorders (insufficient experience of use: ramipril may both increase and weaken the effects of ramipril; in the presence of cirrhosis of the liver with ascites and edema, significant activation of the RAAS is possible); impaired renal function (Creatinine clearance greater 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 picture (includingallopurinol, procainamide) – possible suppression of bone marrow hematopoiesis, development of neutropenia or agranulocytosis; diabetes mellitus (risk of hyperkalemia); elderly age (risk of increased antihypertensive effect); hyperkalemia; hyponatremia; CHF of non–ischemic etiology of NYHA functional class III-IV; aortic stenosis; sinus node weakness syndrome; mitral stenosis; arterial hypotension; a single functioning kidney; renovascular accident hypertension; concomitant use of dantrolene, estramustine, potassium-sparing diuretics and potassium preparations, potassium-containing salt substitutes, lithium preparations; surgical intervention/general anesthesia; hemodialysis using high-flow membranes (for example, AN69).

Side effects

The undesirable effects listed below are given according to the following gradations of their occurrence according to the WHO classification: very often — more than 1/10 (more than 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%); rarely — more than 1/10000, 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 side: often-peripheral edema (ankles and feet), palpitation sensation; infrequently-excessive decrease in blood pressure, orthostatic hypotension, vasculitis; rarely – development or aggravation of HF; very rarely – cardiac arrhythmias (including bradycardia, ventricular tachycardia and atrial fibrillation), MI, chest pain, migraine.

Musculoskeletal and connective tissue disorders: infrequently-arthralgia, muscle cramps, myalgia, back pain, osteoarthritis; rarely-myasthenia gravis.

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

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

From the blood side: very rarely — thrombocytopenic purpura, thrombocytopenia, leukopenia.

Metabolic disorders: very rarely — hyperglycemia.

Respiratory system disorders: infrequently-shortness of breath, rhinitis; very rarely — cough.

From the side of the kidneys and urinary tract: infrequently-frequent urination, painful urination, nocturia, impotence; very rarely-dysuria, polyuria.

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

Other services: infrequently-alopecia, tinnitus, gynecomastia, weight gain/loss, visual impairment, diplopia, accommodation disorders, xerophthalmia, conjunctivitis, eye pain, taste distortion, chills, nosebleeds; rarely-dermatitis; very rarely-parosmia, xeroderma, cold sweat, skin pigmentation disorder.

Ramipril

From the side of the heart: infrequently — myocardial ischemia, including the development of an angina attack or MI, tachycardia, arrhythmias (appearance or increase), palpitation, peripheral edema.

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

From the central nervous system: often-headache, a feeling of lightness in the head; infrequently-dizziness, ageusia (loss of taste sensitivity), dysgeusia (violation of taste sensitivity), paresthesia (burning sensation); rarely-tremor, balance disorder; frequency unknown – cerebral ischemia, including ischemic stroke and transient cerebrovascular accident, violation of psychomotor reactions, parosmia (violation of smell perception).

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

From the side of the hearing organ: rarely — hearing disorders, ringing in the ears.

From the side of the psyche: infrequently — depressed mood, anxiety, nervousness, motor restlessness, sleep disorders, including drowsiness; rarely-confusion; frequency unknown-impaired concentration of attention.

Respiratory system disorders: often — dry cough (worse at night and lying down), bronchitis, sinusitis, shortness of breath; infrequently — bronchospasm, including worsening 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, including with a fatal outcome (cases of pancreatitis with a fatal outcome when taking ACE inhibitors were observed extremely rarely), increased activity of pancreatic enzymes in blood plasma, intestinal angioedema, abdominal pain, gastritis, constipation, dryness of the oral mucosa; rarely — glossitis; frequency unknown — aphthous stomatitis (inflammatory reaction of the oral mucosa).

From the side of 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 liver failure, cholestatic or cytolytic hepatitis (fatal outcome was extremely rare).

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

From the side of the reproductive system and mammary glands: infrequently — transient impotence due to erectile dysfunction, decreased libido; frequency unknown-gynecomastia.

Blood and lymphatic system disorders: infrequently — eosinophilia; rarely-leukopenia, including neutropenia and agranulocytosis, a decrease in the number of red blood cells in the peripheral blood, a decrease in hemoglobin, thrombocytopenia; frequency unknown — inhibition of bone marrow hematopoiesis, pancytopenia, hemolytic anemia.

From the skin and mucous membranes: often — skin rash, in particular maculopapular; infrequently — angioedema, including with a fatal outcome (laryngeal edema can cause airway obstruction leading to death), pruritus, hyperhidrosis (increased sweating); rarely — exfoliative dermatitis, urticaria, onycholysis; very rarely — photosensitization reactions; frequency unknown — toxic epidermal necrolysis, syndrome Stevens-Johnson syndrome, erythema multiforme, pemphigus, psoriasis aggravation, psoriasis-like dermatitis, pemphigoid or lichenoid (lichen-like) exanthema or enanthema, alopecia.

Musculoskeletal and connective tissue disorders: often-muscle cramps, myalgia; infrequently-arthralgia.

From the side of metabolism, nutrition and laboratory parameters: often-increased blood potassium; infrequently — anorexia, decreased appetite; frequency unknown-decreased blood sodium concentration, syndrome of inadequate ADH secretion.

From the immune system: the frequency is unknown — anaphylactic or anaphylactoid reactions (when ACE inhibition increases the number of anaphylactic or anaphylactoid reactions to insect poisons), an increase in the titer of antinuclear antibodies.

General violations: often-chest pain, feeling tired; infrequently-fever; rarely-asthenia (weakness).

Interaction

Amlodipine

It can be expected that inhibitors of microsomal liver oxidation enzymes (erythromycin in the young, diltiazem in the elderly, ketoconazole, itraconazole, ritonavir) will increase the concentration of amlodipine in blood plasma, increasing the risk of side effects, and inducers of microsomal liver oxidation enzymes will decrease. When amlodipine is co-administered with cimetidine, the pharmacokinetics of amlodipine do not change.

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

It is possible to enhance the antianginal and antihypertensive effects of BCC 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, neuroleptics. Although no negative inotropic effect has usually been observed in the study of amlodipine, however, some BCCs may increase the severity of the negative inotropic effect of antiarrhythmic drugs that cause prolongation of the QT interval (for example, amiodarone and quinidine).

When BCC is co-administered with lithium preparations (no data available for amlodipine), their neurotoxicity may increase (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus).

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

A single dose 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.

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. When amlodipine was co-administered with digoxin in healthy volunteers, the serum digoxin content and its renal clearance did not change. With a single and repeated use at a dose of 10 mg, amlodipine does not significantly affect 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.

Not recommended combinations

Concomitant use of dantrolene (iv use), inducers of cytochrome CYP3A4 isoenzymes (for example rifampicin, St. John’s wort preparations) and inhibitors of cytochrome CYP3A4 isoenzymes (protease inhibitors, azole antifungal drugs, macrolides (for example erythromycin or clarithromycin), verapamil or diltiazem).

Ramipril

Contraindicated combinations

Application of some high-flow membranes with a negatively charged surface (e. g. polyacrylonitrile membranes) during hemodialysis or hemofiltration; the use of dextran sulfate in LDL apheresis — the risk of severe anaphylactic reactions.

Not recommended combinations

With potassium salts, potassium-sparing diuretics (for example, amiloride, triamterene, spironolactone) and other drugs, including angiotensin II receptor antagonists (ARA II), trimethoprim, tacrolimus, cyclosporine – hyperkalemia may develop (with simultaneous use, regular monitoring of serum potassium content is required).

Combinations that should be used with caution

With antihypertensive agents (especially diuretics) and other drugs that reduce blood pressure (nitrates, tricyclic antidepressants, general and local anesthesia, ethanol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin) — potentiation of the antihypertensive effect. When combined with diuretics, serum sodium levels should be monitored.

With sleeping pills, narcotic drugs, and other painkillers, a more pronounced decrease in blood pressure is possible.

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

With allopurinol, procainamide, cytostatics, immunosuppressants, systemic corticosteroids and other agents that may affect hematological parameters-combined use increases the risk of leukopenia.

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

With hypoglycemic agents for oral use (sulfonylureas, biguanides), insulin-due to 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.

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

Combinations to take into account

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

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

With sodium chloride — 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 estrogens-weakening of the antihypertensive effect of ramipril (fluid retention).

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

How to take, course of use and dosage

Inside,1 capsule 1 time a day, at the same time, regardless of food intake.

The dose of Egipres is selected after previously titrated doses of individual components of the drug: ramipril and amlodipine in patients with hypertension. Egipres with fixed doses of active ingredients cannot be used for initial therapy. If patients need dose adjustment, then it should be carried out only by titrating the doses of active components in monotherapy. Only after that it is possible to use the drug Aegipres with fixed doses of active ingredients in the following combinations.

If necessary, the dose of Egipres can be changed based on individual titration of the individual components: 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 at a dose of 10 mg of amlodipine + 10 mg of ramipril is the maximum daily dose of the drug, which is not recommended to be exceeded. Dosages of 10 mg of amlodipine + 5 mg of ramipril (according to amlodipine) and 5 mg of amlodipine + 10 mg of ramipril (according to ramipril) are the maximum daily doses.

Adult patients

In patients taking diuretics, the drug should be prescribed with caution, due to the risk of impaired water-electrolyte balance. Renal function and blood potassium levels should be monitored in these patients.

Elderly patients and patients with renal insufficiency. The elimination 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 can be prescribed to patients with a creatinine clearance equal to or greater than 60 ml / min. When creatinine clearance is less than 60 ml/min, as well as in patients with hypertension on hemodialysis, Aegipres is recommended only for patients who received 5 mg of ramipril, as the optimal maintenance dose during titration of the individual dose. There is no need to titrate the individual dose of amlodipine in patients with impaired renal function. Egipres is contraindicated in patients with a creatinine clearance of less than 20 ml / min/1.73 m2. Changes in the concentration of amlodipine in blood plasma do not correlate with the severity of renal failure.

Patients with hepatic insufficiency. Caution should be exercised when prescribing Aegipres to patients with hepatic insufficiency due to the lack of recommendations on the dosage of the drug in such patients. Aegipres is recommended only for patients who received 2.5 mg of ramipril as the optimal maintenance dose during the individual dose titration process.

Children and teenagers

Egipres should not be prescribed to children and adolescents under 18 years of age due to the lack of data on the efficacy and safety of ramipril and amlodipine in these groups of patients, both as monotherapy and as combination therapy.

Overdose

There is no information about overdose of Egipres.

Amlodipine

Symptoms: 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 shock and death).

Treatment: use of activated charcoal (especially in the first 2 hours after an overdose), gastric lavage, elevation of the limbs, active maintenance of CVS functions, monitoring of heart and lung performance, control of BCC and diuresis. To restore vascular tone and blood pressure, if there are no contraindications, the use of vasoconstrictor drugs may be useful. Use intravenous use of calcium gluconate. Amlodipine is largely bound to serum proteins, so hemodialysis is ineffective.

Ramipril

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

Treatment: gastric lavage, use of adsorbents, sodium sulfate (if possible during the first 30 minutes). In the case of a marked decrease in blood pressure, the patient should be laid down, legs raised, and CVS functions actively supported; the use of alpha-1-adrenergic agonists (norepinephrine, dopamine) and angiotensinamide can also be added to therapy to replenish BCC and restore electrolyte balance. If bradycardia is refractory to medical treatment, 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. Ramiprilate is poorly excreted from the blood by hemodialysis.

Special instructions

Information related to ramipril and amlodipine is applicable to Aegipres.

Amlodipine

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

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

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

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

Patients with low body weight, short stature and patients with severe hepatic impairment may require a lower dosage.

During treatment, it is necessary to monitor body weight and follow up with a dentist (to prevent soreness, bleeding and gum hyperplasia).

Ramipril

Before starting treatment with ramipril, hyponatremia and hypovolemia should be eliminated. Patients who have previously taken diuretics should cancel them or at least reduce their dose 2-3 days before starting ramipril (in this case, the condition of patients with CHF should be regularly monitored due to the possibility of decompensation with an increase in BCC).

After taking the first dose of the drug, as well as when increasing its dose and / or the dose of diuretics (especially loop diuretics), it is necessary to ensure regular medical monitoring of the patient for at least 8 hours in order to take timely appropriate measures in case of an excessive decrease in blood pressure.

If ramipril is used for the first time or at a high dose in patients with increased RAAS activity, then their blood pressure should be regularly monitored, especially at the beginning of treatment, since these patients have an increased risk of excessive blood pressure reduction. In patients with malignant hypertension and HF, especially in the acute stage of MI, treatment with ramipril should be initiated only in a hospital setting.

In patients with CHF, taking the drug can lead to the development of a pronounced 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, it is recommended to monitor the indicators of renal function.

In patients for whom a decrease in blood pressure 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 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 blood sodium.

During treatment, it is not recommended to drink alcohol.

Transient arterial hypotension is not a contraindication for continuing treatment after BP stabilization. In case of repeated occurrence of severe hypotension, the dose should be reduced or the drug should be discontinued. Angioedema of the face, extremities, lips, tongue, pharynx, or larynx has been reported in patients treated with ACE inhibitors. If there is swelling in the face (lips, eyelids) or tongue, or if swallowing or breathing is impaired, the patient should immediately stop taking the drug. Angioedema localized in the tongue, pharynx or larynx (possible symptoms: swallowing or breathing disorders) can be life–threatening and requires urgent measures to stop it: subcutaneous use of 0.3 – 0.5 mg or intravenous drip use of 0.1 mg of epinephrine (under the control of blood pressure, heart rate and ECG), followed by the use of corticosteroids (iv, iv or inside); intravenous use of antihistamines (H1-and H2-histamine antagonists) is also recommended. C1-esterase inhibitors may be considered in addition to epinephrine, and in the case of insufficient C1-esterase inactivators. The patient should be hospitalized and monitored until symptoms are completely relieved, but not less than 24 hours.

In patients treated with ACE inhibitors, cases of intestinal angioedema were observed, which was manifested by abdominal pain with or without nausea and vomiting; in some cases, angioedema of the face was also observed simultaneously. If a patient develops the above symptoms during treatment with ACE inhibitors, the possibility of developing intestinal angioedema should also be considered during the differential diagnosis.

Treatment aimed at desensitization to insect venom (bees, wasps) and simultaneous use of ACE inhibitors can initiate anaphylactic and anaphylactoid reactions (for example, a decrease in blood pressure, shortness of breath, vomiting, allergic skin reactions), which can sometimes be life-threatening. Against the background of treatment with ACE inhibitors, hypersensitivity reactions to insect venom (for example, bees, wasps) develop faster and are more severe. If desensitization to insect venom is necessary, the ACE inhibitor should be temporarily replaced with a corresponding drug of a different class.

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

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

The use of an ACE inhibitor in patients undergoing extensive surgery and / or general anesthesia may lead to a marked decrease in blood pressure if general anesthesia agents with a hypotensive effect are used. This is due to blocking the formation of angiotensin II against the background of a compensatory increase in renin activity. In this case, the volume of 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 simultaneous use of ACE inhibitors and insulin, as well as hypoglycemic agents for oral use, 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.

In patients with diabetes mellitus, regular glycemic control is required, especially during the first month of ACE inhibitor therapy.

Careful monitoring of newborns who have been exposed to intrauterine ACE inhibitors is recommended to detect hypotension, oliguria, and hyperkalemia.

With oliguria, it is necessary to maintain blood pressure and renal perfusion by introducing appropriate fluids and vasoconstrictors.

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

During ACE inhibitor therapy, a dry cough may occur. Cough persists for a long time against the background of taking drugs of this group and disappears after their cancellation. If a patient has a dry cough, you should be aware of the possible iatrogenic nature of this symptom.

Patients of the black race are more likely than those of other races to develop angioedema while taking ACE inhibitors. Ramipril, like other ACE inhibitors, may have a less pronounced antihypertensive effect in black patients compared to representatives of other races. Perhaps this difference is due to the fact that black patients with hypertension often have 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:

– monitoring of renal function (determination of serum creatinine). During treatment with ACE inhibitors, monitoring of renal function is recommended during the first weeks of treatment and thereafter. Especially careful monitoring is required in patients