Egipres, 10 mg+5 mg capsules 30 pcs

Pharmacodynamics

Amlodipine

A dihydropyridine derivative. Binds to dihydropyridine receptors, blocks slow calcium channels, inhibits transmembrane calcium transfer inside vascular and heart smooth muscle cells (more so in vascular smooth muscle cells than in cardiomyocytes). It has antihypertensive and antianginal effects.

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

Amlodipine reduces myocardial ischemia in the following two ways:

1. It dilates the peripheral arterioles and thus decreases the RPS (post-load), with little or no change in heart rate, resulting in a decrease in energy consumption and myocardial oxygen demand.

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

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

In patients with angina a single daily dose of the drug increases duration of exercise, delays onset of another angina attack and ST-segment depression (by 1 mm) with exercise, reduces angina attack frequency and decreases nitroglycerin requirement.

The use of amlodipine in patients with CHD. In patients with CHD (including coronary atherosclerosis with lesions from one vessel to stenosis of 3 or more arteries and carotid atherosclerosis, who have had myocardial infarction (MI), percutaneous transluminal angioplasty (PTA) or suffering from angina), use of amlodipine prevents the development of carotid artery intima-media thickening, significantly reduces mortality from cardiovascular causes, MI, stroke, THA, coronary artery bypass grafting, leads to fewer hospitalizations for unstable angina and CHF progression, and reduces the frequency of interventions to restore coronary blood flow.

The use of amlodipine in patients with heart failure (HF). Amlodipine does not increase the risk of death or complications and fatal outcomes in patients with New York Heart Association (NYHA) Class III-IV CHF during therapy with digoxin, diuretics and ACE inhibitors. In patients with CHF class III-IV according to NYHA nonischemic etiology, there is a possibility of pulmonary edema when using amlodipine. Amlodipine does not cause adverse metabolic effects, including those of lipid profile.

Ramipril

The active metabolite of ramipril is a long-acting inhibitor of the enzyme dipeptidylcarboxypeptidase I (synonyms: ACE, kininase II). In blood plasma and tissues, this enzyme kininase II catalyzes the conversion of angiotensin I into the active vasoconstrictor, angiotensin II, and also promotes the breakdown of bradykinin. Reduction of angiotensin II formation and inhibition of bradykinin decomposition leads to vasodilation and BP reduction. The increase of kallikrein-kinin system activity in blood and tissues causes cardioprotective and endothelioprotective effects of ramipril due to the activation of prostaglandin system and correspondingly – increase of PG synthesis, which stimulate nitric oxide (NO) formation in endotheliocytes. Angiotensin II stimulates the production of aldosterone, so taking ramipril leads to a decrease in aldosterone secretion and an increase in serum potassium ions.

When angiotensin II is reduced in blood, its negative feedback inhibitory effect on renin secretion is eliminated, resulting in increased plasma renin activity.

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

In patients with AH, administration of ramipril leads to a decrease in BP in the supine and standing positions, without a compensatory increase in HR. Ramipril significantly reduces RPS with little or no change in renal blood flow and glomerular filtration rate. Antihypertensive effect begins to appear 1-2 hours after oral administration of a single dose of the drug, reaching its greatest value after 3-6 hours, and lasts for 24 hours. When taking a course of the drug, the antihypertensive effect may gradually increase, stabilizing usually by the 3rd-4th week of regular drug intake and then remaining for a long time. Sudden discontinuation of the drug does not lead to a rapid and significant increase in BP (no withdrawal syndrome).

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

In patients with CHF, ramipril decreases PEEP (decreased post-loading on the heart), increases venous system capacity and decreases left ventricular (LV) filling pressure, which leads to a corresponding decrease in cardiac preload. In these patients, taking ramipril increases cardiac output, ejection fraction and improves exercise tolerance.

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

. In patients at high risk of CHD due to the presence of vascular lesions (diagnosed CHD, peripheral artery obliterative disease in the past, stroke in the past) or diabetes with at least one additional risk factor (microalbuminuria, AH, increase in total cholesterol, decrease in HDL cholesterol, smoking) addition of ramipril to standard therapy significantly reduces the rate 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 the onset or progression of CHF.

. In patients with CHF developed in first days of acute AMI (days 2-9) taking ramipril, beginning from day 3 to day 10 of AMI, the risk of mortality rate decreases (by 27%), the risk of sudden death (by 30%), the risk of CHF progression to severe – III-IV class NYHA, resistant to therapy (by 27%), the probability of subsequent hospitalization due to CHF development (by 26%). In the general patient population, as well as in patients with diabetes mellitus with both AH and normal BP, ramipril significantly reduces the risk of nephropathy and microalbuminuria.

Pharmacokinetics

Amlodipine

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

The T1/2 from blood plasma is about 35-50 h, which corresponds to administration of the drug once daily. In patients with hepatic insufficiency and severe CHF the T1/2 is increased to 56-60 h.

The total clearance is 0.43 l/h/kg.

The stable Css (5-15 ng/ml) is reached after 7-8 days of continuous amlodipine administration; it is metabolized in the liver to form inactive metabolites. 10% of the original drug and 60% of the metabolites are excreted by the kidneys, and 20% are excreted through the intestine. Excretion with breast milk is unknown. Amlodipine is not eliminated during hemodialysis.

Patient special groups

Renal insufficiency. T1/2 from blood plasma in patients with renal failure is increased up to 60 h. Changes in plasma concentration of amlodipine do not correlate with the degree of renal impairment.

Elderly patients. The time of reaching Cmax and Cmax of amlodipine is practically the same as in younger patients. In elderly patients with CHF there is a tendency to decrease clearance of amlodipine which leads to increase of AUC and T1/2 up to 65 h.

Ramipril

After oral administration, it is rapidly absorbed from the GI tract (50-60%). Food intake slows its absorption, but does not affect the degree of absorption. Ramipril undergoes intensive presystemic metabolism/activation (mainly in the liver, by hydrolysis), as a result of which its only active metabolite is formed – ramiprilat, which activity with regard to ACE inhibition is approximately 6 times higher than activity of ramipril. In addition, ramipril metabolism produces diketopiperazine, which has no pharmacological activity and then undergoes conjugation with glucuronic acid. Ramiprilat is also glucuronized and metabolized to diketopiperazine acid. The bioavailability of ramipril after oral administration ranges from 15% (for a dose of 2.5 mg) to 28% (for a dose of 5 mg). The bioavailability of ramipril after oral administration of 5 mg ramipril is approximately 45% (compared to its bioavailability after intravenous administration at the same doses).

After oral administration of ramipril, the time to reach Cmax of ramipril and ramiprilate is 1 and 2-4 h, respectively. The decrease in plasma concentration of ramiprilat occurs in several phases: a distribution and excretion phase with a T1/2 of ramiprilat of approximately 3 h, followed by an intermediate phase with a T1/2 of ramiprilat of approximately 15 h, and a final phase with a very low plasma concentration of ramiprilat and a T1/2 of ramiprilat of approximately 4-5 days. This end phase is due to the slow release of ramiprilat from strong binding to ACE receptors. Despite the prolonged terminal phase when ramipril is administered orally at a single daily dose of 2.5 mg or more, the Css of ramiprilat is reached after approximately 4 days of treatment. When the drug is administered in courses, the effective T1/2 (depending on the dose) is 13-17 h.

The plasma protein binding is approximately 73% for ramipril and 56% for ramiprilat.

After intravenous administration, the Vd of ramipril and ramiprilat are approximately 90 and 500 L, respectively.

After intravenous administration of radioactive isotope-labeled ramipril (10 mg), 39% of the radioactivity is excreted through the intestine and about 60% by the kidneys. After intravenous administration of ramipril, 50-60% of the dose is detected in the urine as ramipril and its metabolites. After intravenous administration of ramiprilat – about 70% of the dose is detected in the urine as ramiprilat and its metabolites, in other words, after intravenous administration of ramipril and ramiprilat, a significant part of the dose is excreted through the intestine with the bile, bypassing the kidneys (50 and 30% respectively). After oral administration of 5 mg of ramipril in patients with bile duct drainage, almost equal amounts of ramipril and its metabolites are excreted by the kidneys and through the intestine during the first 24 h after administration.

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

In impaired renal function with a creatinine Cl less than 60 mL/min, excretion of ramiprilat and its metabolites by the kidneys is delayed. This leads to increased plasma concentration of ramiprilat, which decreases more slowly than in patients with normal renal function. When taking ramipril at high doses (10 mg), impaired liver function leads to slower presystemic metabolism of ramipril to active ramiprilate and slower excretion of ramiprilate. No clinically significant accumulation of ramipril and ramiprilate was observed in healthy volunteers and patients with AH 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 at a daily dose of 5 mg there was a 1.5-1.8-fold increase in plasma concentrations of ramiprilat and AUC.

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

Indications

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

Pharmacological effect

Pharmacodynamics

Amlodipine

Dihydropyridine derivative. By binding to dihydropyridine receptors, it blocks slow calcium channels, inhibits the transmembrane transition of calcium into vascular and cardiac smooth muscle cells (to a greater extent into vascular smooth muscle cells than into cardiomyocytes). It has antihypertensive and antianginal effects.

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

Amlodipine reduces myocardial ischemia in the following two ways:

1. Dilates peripheral arterioles and thus reduces TPSS (afterload), while heart rate remains virtually unchanged, which leads to a decrease in energy consumption and myocardial oxygen demand.

2. Dilates coronary and peripheral arteries and arterioles in both normal and ischemic areas of the myocardium, which increases the supply of oxygen 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 provides a decrease in blood pressure over 24 hours (both in the supine and standing positions). Due to its 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 the next attack of angina and ST segment depression (by 1 mm) during physical activity, reduces the frequency of angina attacks and the need for nitroglycerin.

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

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 III–IV functional class (FC) according to the New York Heart Association (NYHA) classification during therapy with digoxin, diuretics and ACE inhibitors. In patients with NYHA class III–IV CHF of non-ischemic etiology, when using amlodipine, there is a risk of pulmonary edema. Amlodipine does not cause adverse metabolic effects, incl. it does not affect the lipid profile.

Ramipril

Ramiprilat, 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 the blood plasma and tissues, this enzyme kininase II catalyzes the conversion of angiotensin I into the active vasoconstrictor substance angiotensin II, and also promotes the breakdown of bradykinin. Reducing the formation of angiotensin II and inhibiting the breakdown of bradykinin leads to vasodilation and a decrease in blood pressure. An increase in the activity of the kallikrein-kinin system in the blood and tissues determines the cardioprotective and endothelioprotective effects of ramipril due to the activation of the prostaglandin system and, accordingly, an increase in the synthesis of PGs that stimulate the formation of nitric oxide (NO) in endothelial cells. 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.

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

It is assumed that the development of some undesirable 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 peripheral vascular resistance, causing virtually no changes in renal blood flow and glomerular filtration rate. The antihypertensive effect begins to appear 1–2 hours after oral administration of a single dose of the drug, reaching its greatest value after 3–6 hours, and persists for 24 hours. With a course of administration, the antihypertensive effect can gradually increase, usually stabilizing by the 3–4th 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 the peripheral vascular resistance (reducing 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. In these patients, when taking ramipril, there is an increase in cardiac output, ejection fraction and improved exercise tolerance.

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

In patients at high risk of developing cardiovascular diseases due to the presence of vascular lesions (diagnosed coronary artery disease, history of peripheral arterial occlusive disease, history of stroke) or diabetes mellitus with at least one additional risk factor (microalbuminuria, hypertension, increased total cholesterol, decreased 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 that developed in the first days of acute myocardial infarction (AMI) (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 class III–IV, resistant to therapy (by 27%), and the likelihood 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 administration in therapeutic doses, amlodipine is well absorbed, the time to reach Cmax in blood plasma after oral administration is 6–12 hours. Absolute bioavailability is 64–80%. 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 the BBB.

T1/2 from blood plasma is about 35–50 hours, which corresponds to the administration of the drug once a day. In patients with liver failure and severe CHF, T1/2 increases to 56–60 hours.

Total clearance – 0.43 l/h/kg.

Stable Css (5–15 ng/ml) is achieved after 7–8 days of continuous administration of amlodipine; it is metabolized in the liver to form inactive metabolites. 10% of the parent drug and 60% of metabolites are excreted by the kidneys, and 20% through the intestines. Excretion into breast milk is unknown. During hemodialysis, amlodipine is not removed.

Special patient groups

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

Elderly patients. The time to reach Cmax and Cmax of amlodipine are practically no different from those in younger patients. In elderly patients suffering from CHF, there was a tendency to decrease the clearance of amlodipine, which leads to an increase in AUC and T1/2 up to 65 hours.

Ramipril

After oral administration, it is quickly absorbed from the gastrointestinal tract (50–60%). Eating slows down its absorption, but does not affect the degree of absorption. Ramipril undergoes extensive first-pass metabolism/activation (mainly in the liver, by hydrolysis), resulting in the formation of its only active metabolite, ramiprilat, whose ACE inhibitory activity is approximately 6 times greater than that of ramipril. In addition, as a result of the metabolism of ramipril, diketopiperazine, which does not have pharmacological activity, is formed, which is then conjugated with glucuronic acid. Ramiprilat is also glucuronidated and metabolized to diketopiperazic acid. The bioavailability of ramipril after oral administration ranges from 15% (for a dose of 2.5 mg) to 28% (for a dose of 5 mg). The bioavailability of ramiprilat after oral administration of 5 mg ramipril is approximately 45% (compared to its bioavailability after intravenous administration in the same doses).

After taking ramipril orally, the time to reach Cmax for ramipril and ramiprilat is 1 and 2–4 hours, respectively. The decrease in the concentration of ramiprilat in the blood plasma occurs in several stages: a distribution and elimination phase with a T1/2 of ramiprilat of approximately 3 hours, then an intermediate phase with a T1/2 of ramiprilat of approximately 15 hours, and a final phase with a very low concentration of ramiprilat in the blood plasma and a T1/2 of ramiprilat of approximately 4–5 days. This final phase is due to the slow release of ramiprilat from its strong binding to ACE receptors. Despite the long final phase with a single oral dose of ramipril during the day at a dose of 2.5 mg or more, Css of ramiprilat is achieved after approximately 4 days of treatment. With a course prescription 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 ramiprilat.

After intravenous administration, the Vd of ramipril and ramiprilat are approximately 90 and 500 L, respectively.

After oral administration of radiolabeled ramipril (10 mg), 39% of the radioactivity is excreted through the intestines and about 60% by the kidneys. After intravenous administration of ramipril, 50–60% of the dose is found 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 ramiprilat and its metabolites, in other words, with intravenous administration of ramipril and ramiprilat, a significant part of the dose is excreted through the intestines with bile, bypassing the kidneys (50 and 30%, respectively). After oral administration of 5 mg of ramipril in patients with bile duct drainage, almost equal amounts of ramipril and its metabolites are excreted by the kidneys and intestines during the first 24 hours after administration.

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

In case of impaired renal function with creatinine Cl less than 60 ml/min, the excretion of ramiprilat and its metabolites by the kidneys slows down. This leads to an increase in the plasma concentration of ramiprilat, 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 slower first-pass metabolism of ramipril to active ramiprilat and a slower elimination of ramiprilat. In healthy volunteers and patients with hypertension, after 2 weeks of treatment with ramipril at a daily dose of 5 mg, no clinically significant accumulation of ramipril and ramiprilat was observed. In patients with CHF, after 2 weeks of treatment with ramipril at a daily dose of 5 mg, an increase of 1.5–1.8 times in plasma ramiprilat concentrations and AUC was observed.

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

Special instructions

Information relating to ramipril and amlodipine applies to Egipres.

Amlodipine

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

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

Amlodipine does not have any adverse effects on 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 liver dysfunction may require a lower dosage.

During treatment, weight control and dental supervision are necessary (to prevent pain, bleeding and gum hyperplasia).

Ramipril

Before starting treatment with ramipril, hyponatremia and hypovolemia must be corrected. Patients who have previously taken diuretics should discontinue 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 their developing decompensation with an increase in blood volume).

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

If ramipril is used for the first time or in a high dose in patients with increased RAAS activity, their blood pressure should be regularly monitored, especially at the beginning of treatment, because these patients have an increased risk of excessive reduction in blood pressure. In case of malignant hypertension and heart failure, especially in the acute stage of myocardial infarction, treatment with ramipril should be started 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 by the development of acute renal failure.

Caution should be exercised when treating elderly patients, because they may be particularly sensitive to ACE inhibitors; In the initial phase of treatment, it is recommended to monitor renal function indicators.

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 physical activity and/or hot weather due to the risk of increased sweating and dehydration with the development of arterial hypotension due to a decrease in blood volume and a decrease in sodium content in the blood.

It is not recommended to drink alcohol during treatment.

Transient arterial hypotension is not a contraindication for continuing treatment after stabilization of blood pressure. If severe arterial hypotension reoccurs, the dose should be reduced or the drug discontinued. Cases of angioedema of the face, extremities, lips, tongue, pharynx or larynx have been observed in patients treated with ACE inhibitors. If swelling occurs in the face (lips, eyelids) or tongue, or difficulty swallowing or breathing, the patient should immediately stop taking the drug. Angioedema, localized in the area of ​​the tongue, pharynx or larynx (possible symptoms: difficulty swallowing or breathing), can be life-threatening and requires urgent measures to relieve it: subcutaneous injection of 0.3–0.5 mg or intravenous drip of 0.1 mg of epinephrine (under the control of blood pressure, heart rate and ECG) followed by the use of corticosteroids (iv, intramuscular or orally); IV administration of antihistamines (H1- and H2-histamine receptor antagonists) is also recommended, and in case of insufficiency of C1-esterase enzyme inactivators, the need to administer C1-esterase enzyme inhibitors in addition to epinephrine can be considered. The patient should be hospitalized and monitored until symptoms are completely relieved, but not less than 24 hours.

Cases of intestinal angioedema, manifested by abdominal pain with or without nausea and vomiting, have been observed in patients receiving ACE inhibitors; in some cases, angioedema of the face was simultaneously observed. If a patient develops the symptoms described above during treatment with ACE inhibitors, the possibility of developing intestinal angioedema should be considered when making a differential diagnosis.

Treatment aimed at desensitization to insect venom (bees, wasps) and concomitant use of ACE inhibitors can initiate anaphylactic and anaphylactoid reactions (for example, decreased blood pressure, shortness of breath, vomiting, allergic skin reactions), which can sometimes be life-threatening. During 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 an appropriate drug of a different class.

Life-threatening, rapidly developing anaphylactoid reactions, sometimes leading to shock, have been described with the use of ACE inhibitors during hemodialysis or plasma filtration using certain high-flux membranes (for example, polyacrylonitrile membranes) (see also membrane manufacturer’s instructions). The combined use of ramipril and this type of membrane (for example, for emergency hemodialysis or hemofiltration) should be avoided. In this case, it is preferable to use other membranes or avoid taking an ACE inhibitor. Similar reactions were observed with LDL apheresis using 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 liver cirrhosis 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), it is necessary to warn the surgeon/anesthesiologist about the use of an ACE inhibitor.

The use of an ACE inhibitor in patients undergoing major surgery and/or general anesthesia can lead to a significant decrease in blood pressure if general anesthetic 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 the ACE inhibitor 24 hours before surgery. Based on the results of epidemiological studies, it is assumed that the simultaneous use of ACE inhibitors and insulin, as well as oral hypoglycemic agents, can lead to the development of hypoglycemia. The greatest risk of development is observed during the first weeks of combination therapy, as well as in patients with impaired renal function.

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

It is recommended that neonates exposed in utero to ACE inhibitors be closely monitored for hypotension, oliguria, and hyperkalemia.

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

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

During therapy with ACE inhibitors, a dry cough may occur. The cough persists for a long time while taking drugs of this group and disappears after their discontinuation. If a patient develops a dry cough, one should be aware of the possible iatrogenic nature of this symptom.

In patients of the Negroid race, angioedema develops more often than in representatives of other races while taking ACE inhibitors. Ramipril, like other ACE inhibitors, may have a less pronounced antihypertensive effect in patients of the Black race compared to representatives of other races. This difference may be due to the fact that black patients with hypertension are more likely to have low renin activity.

Monitoring 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 kidney function (determining serum creatinine levels). When treating with ACE inhibitors, it is recommended to monitor renal function in the first weeks of treatment and subsequently. Particularly careful monitoring is required in patients with heart failure, impaired renal function, after kidney transplantation, patients with renovascular diseases, including patients with hemodynamically significant unilateral renal artery stenosis in the presence of two kidneys (in such patients, even a slight increase in serum creatinine levels may be an indicator of decreased renal function).

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

– control of hematological parameters (hemoglobin content, number of leukocytes, erythrocytes, platelets, leukocyte formula). It is recommended to monitor the complete blood count to identify possible leukopenia. More regular monitoring is recommended at the beginning of treatment and in patients with impaired renal function, as well as in patients with connective tissue diseases or in patients simultaneously receiving other drugs that can change the peripheral blood picture.

Monitoring the number of leukocytes is necessary for the early detection of leukopenia, which is especially important in patients with an increased risk of its development, as well as at the first signs of infection. If neutropenia is detected (the number of neutrophils is less than 2000/μl), discontinuation of treatment with ramipril is required. If symptoms due to leukopenia appear (for example, fever, swollen lymph nodes, tonsillitis), urgent monitoring of the peripheral blood picture is necessary. If signs of bleeding appear (tiny petechiae, red-brown rashes on the skin and mucous membranes), monitoring the number of platelets in the peripheral blood is also necessary.

– determination of liver enzyme activity, bilirubin concentration in the blood. If jaundice or a significant increase in the activity of liver enzymes occurs, treatment with ramipril should be discontinued and the patient should be monitored medically.

Influence on the ability to drive vehicles and operate machinery. During the period of treatment with the drug, it is recommended to refrain from driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions (dizziness is possible, especially at the beginning of treatment, and in patients taking diuretic drugs – decreased concentration). After the first dose, as well as after a significant increase in the dose of the drug, it is not recommended to drive vehicles and work with technical equipment for several hours.

Active ingredient

Amlodipine, Ramipril

Composition

1 capsule contains:

active ingredients:

amlodipine besilate 13.9 mg (corresponding to amlodipine 10 mg),

ramipril 5 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 dibehenate – 2.05/4.1/4.1/4.1 mg;

Capsules, 10 mg+5 mg; hard gelatin capsule (CONI-SNAP 0), cap and base color code – 33007/37350: cap – titanium dioxide; Azorubine dye (E122); indigo carmine (E132); gelatin; base – titanium dioxide; red iron oxide dye (E172); gelatin

Pregnancy

The drug Egipres is contraindicated for use, because Ramipril may have an adverse effect on the fetus: impaired development of the fetal kidneys, decreased blood pressure in the fetus and newborns, impaired renal function, hyperkalemia, hypoplasia of the skull bones, oligohydramnios, contracture of the limbs, deformation of the skull bones, pulmonary hypoplasia. Before starting to take the drug in women of childbearing age, pregnancy should be excluded.

If a woman is planning a pregnancy, 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 take other drugs, the use of which will have the least risk for the child.

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

Fertility

Amlodipine. Some patients receiving CCBs experienced reversible biochemical changes in the sperm heads. Clinical data are insufficient to assess the potential effect of amlodipine on fertility.

Contraindications

Amlodipine

hypersensitivity to amlodipine and other dihydropyridine derivatives;
severe arterial hypotension (SBP less than 90 mm Hg), shock (including cardiogenic);
an obstructive process that impedes the ejection of blood from the left ventricle (for example, clinically significant aortic stenosis);
hemodynamically unstable heart failure after myocardial infarction;
pregnancy;
breastfeeding period;
age under 18 years (safety and effectiveness have not been determined).

Ramipril

hypersensitivity to ramipril and other ACE inhibitors;
history of angioedema (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 solitary kidney);
arterial hypotension (SBP less than 90 mm Hg) or conditions with unstable hemodynamic parameters;
hemodynamically significant stenosis of the aortic or mitral valve or hypertrophic obstructive cardiomyopathy;
primary hyperaldosteronism;
severe renal failure (creatinine Cl < 20 ml/min/1.73 m2); hemodialysis (experience of clinical use is insufficient); nephropathy, which is treated with corticosteroids, NSAIDs, immunomodulators and/or other cytotoxic agents (experience of clinical use is insufficient); decompensated chronic heart failure (experience of clinical use is insufficient); hemodialysis or hemofiltration using certain types of membranes with a negatively charged surface, such as high-flow polyacrylonitrile membranes (risk of hypersensitivity reactions); apheresis of LDL using dextran sulfate (risk of developing hypersensitivity reactions); desensitizing therapy for hypersensitivity reactions to insect poisons - bees, wasps; acute stage of myocardial infarction in patients with diseases such as severe heart failure (NYHA functional class IV); life-threatening ventricular arrhythmias; pulmonary heart; simultaneous 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 period; age under 18 years (experience of clinical use is insufficient).

Amlodipine + ramipril

hypersensitivity to the excipients included in the drug;
renal failure (creatinine Cl < 20 ml/min/1.73 m2); pregnancy; breastfeeding period; age under 18 years (experience of clinical use is insufficient).

With caution for the combination of amlodipine + ramipril: atherosclerotic lesions of the coronary and cerebral arteries (risk of excessive reduction in blood pressure); increased activity of the RAAS, in which, with ACE inhibition, there is 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 being taken; hemodynamically significant unilateral renal artery stenosis (in the presence of both kidneys); previous use of diuretics; disturbances in water and electrolyte balance, decrease in blood volume (including while taking diuretics, a salt-free diet, diarrhea, vomiting, profuse sweating); simultaneous use with drugs containing aliskiren (double blockade of the RAAS increases the risk of a sharp decrease in blood pressure, hyperkalemia and deterioration of renal function); liver function disorders (lack of experience with use: it is possible to either enhance or weaken the effects of ramipril; in patients with cirrhosis of the liver with ascites and edema, significant activation of the RAAS is possible); impaired renal function (creatinine Cl more than 20 ml/min); condition after kidney transplantation; systemic connective tissue diseases, incl. systemic lupus erythematosus, scleroderma, concomitant therapy with drugs that can cause changes in the peripheral blood picture (including allopurinol, procainamide) – possible inhibition of bone marrow hematopoiesis, development of neutropenia or agranulocytosis; diabetes mellitus (risk of developing hyperkalemia); old age (risk of increased antihypertensive effect); hyperkalemia; hyponatremia; CHF of non-ischemic etiology, functional class III–IV according to the NYHA classification; aortic stenosis; sick sinus syndrome; 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 table salt, lithium preparations; surgery/general anesthesia; hemodialysis using high-flow membranes (for example AN69).

Side Effects

The following undesirable effects are given in accordance with the following gradations of the frequency 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%); uncommon – 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 cardiovascular system: often – peripheral edema (ankles and feet), palpitations; uncommon – excessive decrease in blood pressure, orthostatic hypotension, vasculitis; rarely – development or worsening of heart failure; very rarely – cardiac arrhythmias (including bradycardia, ventricular tachycardia and atrial fibrillation), myocardial infarction, chest pain, migraine.

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

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

From the digestive system: often – abdominal pain, nausea; uncommon – vomiting, changes in bowel habits (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.

Blood disorders: very rarely – thrombocytopenic purpura, thrombocytopenia, leukopenia.

Metabolic disorders: very rarely – hyperglycemia.

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

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

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

Other: infrequently – alopecia, tinnitus, gynecomastia, weight gain/loss, blurred vision, diplopia, accommodation disturbance, xerophthalmia, conjunctivitis, eye pain, taste disturbance, chills, nosebleeds; rarely – dermatitis; very rarely – parosmia, xeroderma, cold sweat, skin pigmentation disorder.

Ramipril

From the heart: uncommon – myocardial ischemia, including the development of an attack of angina or MI, tachycardia, arrhythmias (appearance or intensification), palpitations, peripheral edema.

From the side of blood vessels: often – excessive decrease in blood pressure, impaired orthostatic regulation of vascular tone (orthostatic hypotension), syncope; infrequently – flushes of blood to the skin of the face; rarely – the occurrence or intensification of circulatory disorders against the background of stenotic vascular lesions, vasculitis; frequency unknown – Raynaud’s syndrome.

From the side of the central nervous system: often – headache, feeling of lightness in the head; uncommon – dizziness, ageusia (loss of taste sensitivity), dysgeusia (impaired taste sensitivity), paresthesia (burning sensation); rarely – tremor, imbalance; frequency unknown – cerebral ischemia, including ischemic stroke and transient cerebrovascular accident, impaired psychomotor reactions, parosmia (impaired odor perception).

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

On the part of the hearing organ: rarely – hearing impairment, ringing in the ears.

From the psyche: infrequently – depressed mood, anxiety, nervousness, restlessness, sleep disturbances, including drowsiness; rarely – confusion; frequency unknown – impaired concentration.

From the respiratory system: often – dry cough (worsening at night and when lying down), bronchitis, sinusitis, shortness of breath; infrequently – bronchospasm, including worsening of bronchial asthma, nasal congestion.

From the digestive system: often – inflammatory reactions in the stomach and intestines, digestive disorders, discomfort in the abdominal area, dyspepsia, diarrhea, nausea, vomiting; uncommon – pancreatitis, incl. and 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 the blood plasma, intestinal angioedema, abdominal pain, gastritis, constipation, dry oral mucosa; rarely – glossitis; frequency unknown – aphthous stomatitis (inflammatory reaction of the oral mucosa).

From the hepatobiliary system: infrequently – increased activity of liver enzymes and the content of conjugated bilirubin in the blood plasma; rarely – cholestatic jaundice, hepatocellular lesions; frequency unknown – acute liver failure, cholestatic or cytolytic hepatitis (death was extremely rare).

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

From 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 red blood cells in the peripheral blood, a decrease in hemoglobin, thrombocytopenia; frequency unknown – suppression of bone marrow hematopoiesis, pancytopenia, hemolytic anemia.

From the skin and mucous membranes: often – skin rash, in particular maculopapular; uncommon – angioedema, incl. and with a fatal outcome (swelling of the larynx can cause obstruction of the airways, leading to death), itching, hyperhidrosis (increased sweating); rarely – exfoliative dermatitis, urticaria, onycholysis; very rarely – photosensitivity reactions; frequency unknown – toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, worsening of psoriasis, psoriasis-like dermatitis, pemphigoid or lichenoid (lichenoid) exanthema or enanthema, alopecia.

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

From the side of metabolism, nutrition and laboratory parameters: often – increased potassium content in the blood; infrequently – anorexia, loss of appetite; frequency unknown – decreased sodium concentration in the blood, syndrome of inappropriate ADH secretion.

From the immune system: frequency unknown – anaphylactic or anaphylactoid reactions (with ACE inhibition, the number of anaphylactic or anaphylactoid reactions to insect venoms increases), increased titer of antinuclear antibodies.

General disorders: often – chest pain, feeling tired; uncommon – increased body temperature; rarely – asthenia (weakness).

Interaction

Amlodipine

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

A simultaneous single dose 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 CCBs, no clinically significant interaction was found with amlodipine (III generation CCB) when used together with NSAIDs, especially indomethacin.

It is possible to enhance the antianginal and antihypertensive effect of CCBs when used together with thiazide and loop diuretics, verapamil, ACE inhibitors, beta-blockers and nitrates, as well as increase their antihypertensive effect when used together with alpha1-blockers, antipsychotics. Although a negative inotropic effect has not generally been observed in amlodipine studies, some CCBs may enhance the negative inotropic effects of antiarrhythmic drugs that cause QT prolongation (eg, amiodarone and quinidine).

When CCBs are used together with lithium preparations (no data are available for amlodipine), their neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus) may increase.

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

A single dose of aluminum/magnesium-containing antacids does not have a significant effect on the pharmacokinetics of amlodipine.

A single dose of 100 mg of sildenafil in patients with essential hypertension does not affect the pharmacokinetic parameters 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. With simultaneous use of amlodipine with digoxin in healthy volunteers, the content of digoxin in the serum and its renal clearance do not change. With single and repeated use at a dose of 10 mg, amlodipine does not have a significant effect on the pharmacokinetics of ethanol.

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

Combinations not recommended

Simultaneous use of dantrolene (iv administration), inducers of isoenzymes of the cytochrome CYP3A4 system (for example, rifampicin, preparations of St. John’s wort) and inhibitors of isoenzymes of the cytochrome CYP3A4 system (protease inhibitors, antifungals of the azole group, macrolides (for example, erythromycin or clarithromycin), verapamil or diltiazem).

Ramipril

Contraindicated combinations

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

Combinations not recommended

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

Combinations to use with caution

With antihypertensive drugs (especially diuretics) and other drugs that lower 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, narcotics and other painkillers, a more pronounced decrease in blood pressure is possible.

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

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

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

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

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

Combinations to Consider

With NSAIDs (indomethacin, acetylsalicylic acid) – the effect of ramipril may be weakened, the risk of renal dysfunction and increased potassium levels in the blood serum may be increased.

With heparin, an increase in potassium levels in the blood serum is possible.

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).

Desensitization therapy for hypersensitivity to insect venoms – ACE inhibitors, including ramipril, increase the likelihood of developing severe anaphylactic or anaphylactoid reactions to insect venoms.

Overdose

There is no information on overdose of the drug 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 the development of shock and death).

Treatment: administration of activated charcoal (especially in the first 2 hours after an overdose), gastric lavage, elevating the limbs, actively maintaining the functions of the cardiovascular system, monitoring heart and lung performance, monitoring blood volume and diuresis. To restore vascular tone and blood pressure, if there are no contraindications, the use of vasoconstrictor drugs may be useful. Use intravenous administration of calcium gluconate. Amlodipine is highly 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 disturbances, acute renal failure, stupor.

Treatment: gastric lavage, administration of adsorbents, sodium sulfate (if possible during the first 30 minutes). In case of a pronounced decrease in blood pressure, the patient should be laid down, legs raised, and cardiovascular functions actively supported; The administration of alpha1-adrenergic agonists (norepinephrine, dopamine) and angiotensinamide can additionally be added to therapy to replenish blood volume and restore electrolyte balance. In case of bradycardia refractory to drug treatment, installation of a temporary artificial pacemaker may be required. In case of overdose, it is necessary to monitor the content of creatinine and electrolytes in the blood serum. Ramiprilat is poorly removed from the blood by hemodialysis.

Storage conditions

At a temperature not exceeding 25 °C.

Shelf life

3 years.

Manufacturer

EGIS, Hungary