Ramipril-ACOS pills 10mg, 30pcs

Composition

Per tablet:

Active ingredient: ramipril – 10.0 mg.

Excipients: magnesium stearate, talc, sodium carboxymethyl starch (sodium starch glycolate), microcrystalline cellulose, iron oxide red dye (iron oxide red), lactose monohydrate (milk sugar).

Pharmacological action

Pharmacotherapy group: angiotensin converting enzyme (ACE) inhibitor.

ATX code: C 09 AA 05.

Pharmacological properties

Pharmacodynamics

The active metabolite of ramipril, ramiprilate, formed under the influence of “liver” enzymes, is a long –acting ACE inhibitor (ACE synonyms: kininase II, dipeptidyl carboxydipeptidase I). ACE in blood plasma and tissues catalyzes the conversion of angiotensin I to angiotensin II, which has a vasoconstrictive effect, and the breakdown of bradykinin, which has a vasodilating effect. Therefore, when taking ramipril orally, the formation of angiotensin II decreases and bradykinin accumulates, which leads to vasodilation and a decrease in blood pressure (BP). Ramipril causes an increase in the activity of the kallikrein-kinin system in blood and tissues with activation of the prostaglandin system and an increase in the synthesis of prostaglandins that stimulate the formation of nitric oxide in endotheliocytes, which determines its cardioprotective and endothelioprotective effects.

Angiotensin II stimulates the production of aldosterone, so taking ramipril leads to a decrease in aldosterone secretion and an increase in serum potassium ion concentrations.

With a decrease in the concentration 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 plasma renin activity.

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 arterial hypertension, taking ramipril leads to a decrease in blood pressure in the “lying” and “standing” positions, without a compensatory increase in heart rate (HR). Ramipril significantly reduces total peripheral vascular resistance (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 Ramipril-AKOS, the antihypertensive effect may gradually increase, usually stabilizing by 3-4 weeks 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 arterial hypertension, ramipril slows down the development and progression of myocardial and vascular wall hypertrophy.

In patients with chronic heart failure, ramipril reduces OPSS (reduces afterload on the heart), increases the capacity of the venous bed and reduces the filling pressure of the left ventricle, which, accordingly, leads to a decrease in preload on the heart. 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 and, therefore, reduces the need for hemodialysis or kidney transplantation. In the initial stages of diabetic or non-diabetic nephropathy, ramipril reduces the incidence of albuminuria.

In patients with a high risk of developing cardiovascular diseases due to vascular lesions (diagnosed coronary heart disease, a history of peripheral artery obliterating diseases, a history of stroke) or diabetes mellitus with at least one additional risk factor (microalbuminuria, arterial hypertension, increased total cholesterol (TC) concentrations, reduced high-density lipoprotein cholesterol (HDL-C) concentrations, smoking), the addition of ramipril to standard therapy significantly reduces the incidence of myocardial infarction, 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 chronic heart failure.

In patients with heart failure with clinical manifestations that developed in the first days of acute myocardial infarction (2-9 days), the use of ramipril, initiated from the 3rd to the 10th day of acute myocardial infarction, reduced mortality (by 27%), the risk of sudden death (by 30%), the risk of progression of heart failure to severe (NYHA functional class III-IV)/resistant to therapy (by 23%), the probability of subsequent hospitalization due to the development of heart failure (by 26%).

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

Pharmacokinetics

After oral use, ramipril is rapidly absorbed from the gastrointestinal tract (50-60%). Food intake slows down its absorption, but does not affect the completeness 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 glucuronated 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 the active metabolite, ramiprilate, after oral use of 2.5 mg and 5 mg of ramipril is approximately 45% (compared to its bioavailability after intravenous use at the same doses).

After oral use of ramipril, the maximum plasma concentrations of ramipril and ramiprilate are reached in 1 and 2-4 hours, respectively. Reduced plasma concentrations of ramiprilat occurs in several stages: phase distribution and excretion with a half-life (T_1/2) of ramiprilat approximately 3 h, and then the intermediate phase with a T_1/2 of ramiprilat approximately 15 h, and the final phase with very low concentrations of ramiprilat in plasma T_1/2 of ramiprilat 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 during the day, the equilibrium plasma concentration of ramiprilate is reached after approximately 4 days of treatment. With the course appointment of the drug “effective” T_1/2, depending on the dose, is 13-17 hours.

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

After intravenous use, the volume of distribution of ramipril and ramiprilate is approximately 90 L 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 are 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 animal studies, ramipril has been shown to be excreted in human milk.

In patients with impaired renal function with creatinine clearance (CC) less than 60 ml / min, the elimination of ramiprilate and its metabolites by the kidneys slows down. This leads to an increase in the plasma concentration of ramiprilate, 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 in patients with arterial hypertension after two weeks of treatment with ramipril at a daily dose of 5 mg. In patients with chronic heart failure, after two weeks of treatment with ramipril in a daily dose of 5 mg, there is a 1.5-1.8 fold increase in plasma concentrations of ramiprilate and the area under the pharmacokinetic curve “concentration-time” (AUC).

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 (in monotherapy or in combination with other antihypertensive drugs, for example, diuretics and slow calcium channel blockers).

– Chronic heart failure (as part of combination therapy, in particular, in combination with diuretics).

– Diabetic or non-diabetic nephropathy, preclinical and clinically expressed stages, including with pronounced proteinuria, especially in combination with arterial hypertension.

– Reducing the risk of myocardial infarction, stroke, or death from cardiovascular causes in patients with high cardiovascular risk:

– in patients with confirmed coronary heart disease, myocardial infarction in the anamnesis or without it, including patients undergoing percutaneous transluminal coronary angioplasty, coronary artery bypass grafting;

– patients with stroke in anamnesis;

– in patients with occlusive lesions of the peripheral arteries in history;

– in patients with diabetes with at least one additional risk factor (microalbuminuria, arterial hypertension, increased plasma concentrations of OH, the decline in plasma concentrations of HDL-C, Smoking).

– Heart failure with clinical manifestations that developed during the first few days (from day 2 to day 9) after acute myocardial infarction (see the section “Pharmacodynamics”).

Contraindications

-Hypersensitivity to ramipril, other ACE inhibitors or any of the components of the drug.

– Angioedema (hereditary or idiopathic, as well as after taking ACE inhibitors) in the anamnesis-the risk of rapid development of angioedema (see the section “Side effects”).

– Hemodynamically significant renal artery stenosis (bilateral or unilateral in the case of a single kidney).

– Arterial hypotension (systolic blood pressure (BP) less than 90 mm Hg) or conditions with unstable hemodynamic parameters.

– Concomitant use with aliskiren and drugs containing aliskiren in patients with diabetes mellitus and/or with moderate or severe renal impairment (glomerular filtration rate (GFR) less than 60 ml/min / 1.73 m2 of body surface area).

– Concomitant use with angiotensin II receptor antagonists (ARA II) in patients with diabetic nephropathy.

– Concomitant use with the combination therapy of sacubitril/valsartan (high risk of angioedema), see the sections “Interaction with |other drugs”, “Special instructions”.

– Hemodynamically significant aortic or mitral valve stenosis, or hypertrophic obstructive cardiomyopathy (HOCMP).

– Primary hyperaldosteronism.

– Severe renal insufficiency (GFR less than 20 ml / min/1.73 m2 of body surface area) (insufficient clinical experience).

– Hemodialysis (experience in clinical use is insufficient).

– Pregnancy.

– The period of breastfeeding.

– Nephropathy that is treated with glucocorticosteroids, nonsteroidal anti-inflammatory drugs, immunomodulators and/or other cytotoxic drugs (there is insufficient clinical experience, see the section “Interaction with other drugs”).

– Chronic heart failure in the stage of decompensation (clinical experience is insufficient).

– Age up to 18 years (experience in clinical use is insufficient).

– Hemodialysis or hemofiltration using certain membranes with a negatively charged surface, such as high-flow polyacrylonitrile membranes (risk of severe anaphylactoid reactions) (see sections “Interaction with other drugs”, “Special instructions”).

– Low-density lipoprotein apheresis using dextran sulfate (risk of severe anaphylactoid reactions) (see section “Special instructions”).

– Hyposensitizing therapy for hypersensitivity reactions to non-insect poisons, such as bees, wasps (see the section “Special instructions”).

– Lactose intolerance, lactase deficiency or glucose-galactose malabsorption (the drug contains lactose).

Additional contraindications when using the drug in the acute stage of myocardial infarction:

– severe heart failure (NYHA functional class IV);

– unstable angina;

– life-threatening ventricular arrhythmias;

– “pulmonary” heart.

With caution

-Simultaneous use of Ramipril-AKOS with drugs containing aliskiren or ARA II (with double blockade of the renin-angiotensin-aldosterone system (RAAS) – there is an increased risk of a sharp decrease in blood pressure, hyperkalemia and deterioration of renal function compared to monotherapy) (see the section “Special Instructions”).

– Conditions in which an excessive decrease in blood pressure is particularly dangerous (with atherosclerotic lesions of the coronary and cerebral arteries).

– Conditions accompanied by an increase in RAAS activity, in which ACE inhibition is associated with a risk of a sharp decrease in blood pressure with deterioration of renal function:

– severe hypertension, especially malignant arterial hypertension;

– chronic heart failure, especially heavy or about which to take other medications with a hypotensive effect;

– unilateral hemodynamically significant renal artery stenosis (in the presence of both kidneys) – in these patients, even a slight increase in the concentration of creatinine in the blood serum may be a manifestation of unilateral deterioration of renal function;

– prior to the use of diuretics;

– violations of water-electrolyte balance as a result of inadequate fluid intake and salt, diarrhoea, vomiting, sweating.

– Impaired liver function (lack of experience with the use of Ramipril-AKOS: it is possible to both increase and weaken the effects of Ramipril-AKOS; if patients with cirrhosis of the liver with ascites and edema, significant activation of RAAS is possible, see above “Conditions accompanied by increased RAAS activity”).

– Impaired renal function (GFR greater than 20 ml / min/1.73 m2 of body surface area) due to the risk of hyperkalemia and leukopenia.

– 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 (possible suppression of bone marrow hematopoiesis, development of neutropenia or agranulocytosis, see the section “Interaction with other drugs”).

– Diabetes mellitus (risk of hyperkalemia).

– Elderly age (risk of increased hypotensive effect).

– Hyperkalemia.

– Use during major surgical procedures or during general anesthesia (see the section “Special instructions”).

– Use in patients of the black race (see the section “Special instructions”).

Side effects

The undesirable effects listed below are given according to the following frequency gradations: very common (≥ 10%); common (≥ 1% – < 10%); infrequently (≥ 0,1% – < 1%); rarely (≥ 0,01% – < 0,1%); very rare (

Disorders of the blood and lymphatic system

Infrequently: eosinophilia.

Rare: leukopenia, including neutropenia and agranulocytosis; decreased number of red blood cells in the peripheral blood, decreased hemoglobin, thrombocytopenia.

Frequency unknown: inhibition of bone marrow hematopoiesis, pancytopenia, hemolytic anemia.

Immune system disorders

Frequency unknown: anaphylactic or anaphylactoid reactions (with ACE inhibition, the severity of anaphylactic or anaphylactoid reactions to insect poisons increases); increased titer of antinuclear antibodies.

Endocrine disorders

Frequency unknown: syndrome of inadequate secretion of antidiuretic hormone.

Metabolic and nutritional

disorders are common: increased blood potassium.

Infrequently: anorexia, decreased appetite.

Frequency unknown: decreased blood sodium.

Mental disorders

Infrequently: depressed mood, anxiety, nervousness, motor restlessness, sleep disorders, including drowsiness.

Rare: confusion.

Frequency unknown: attention disorder.

Disorders of the nervous system

Often: headache, dizziness (a feeling of “lightness” in the head).

Infrequently: vertigo, paresthesia, ageusia (loss of taste sensitivity), dysgeusia (violation of taste sensitivity).

Rare: tremor, balance disorder.

Frequency unknown: cerebral ischemia, including ischemic stroke and transient cerebrovascular accident, impaired psychomotor reactions, burning sensation, parosmia (impaired perception of odors).

Visual disturbances

Infrequently: visual disturbances, including blurred images.

Rare: conjunctivitis.

Hearing disorders

Rare: hearing loss, ringing in the ears.

Cardiac disorders

Infrequently: myocardial ischemia, including the development of an angina attack or myocardial infarction, tachycardia, arrhythmia, palpitation, peripheral edema.

Vascular disorders

Often: arterial hypotension, violation of orthostatic regulation of vascular tone (orthostatic hypotension), syncopal states.

Infrequently: “hot flashes” of blood to the skin of the face.

Rarely: vascular stenosis, hypoperfusion (increased circulatory disorders against the background of vascular stenosis), vasculitis.

Frequency unknown: Raynaud’s syndrome.

Disorders of the respiratory system, chest and mediastinal organs

Often: “dry” cough (worse at night and in the “lying” position), bronchitis, sinusitis, shortness of breath.

Infrequently: bronchospasm, including worsening of the course of bronchial asthma, nasal congestion.

Disorders of the gastrointestinal tract

Often: inflammatory reactions in the stomach and intestines, digestive disorders, abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting.

Infrequently: fatal pancreatitis (cases of pancreatitis with a fatal outcome when taking ACE inhibitors were observed extremely rarely), increased activity of pancreatic enzymes in blood plasma, angioedema of the small intestine, pain in the upper abdomen, including gastritis, constipation, dryness of the oral mucosa.

Rare: glossitis.

Frequency unknown: aphthous stomatitis (inflammatory reactions of the oral mucosa).

Liver and biliary tract disorders

Infrequently: increased activity of “liver” enzymes and the concentration of conjugated bilirubin in blood plasma.

Rare: cholestatic jaundice, hepatocellular lesions.

Frequency unknown: acute hepatic insufficiency, cholestatic or cytolytic hepatitis (extremely rare with fatal outcome).

Disorders of the skin and subcutaneous tissues

Often: skin rash, in particular maculopapular.

Infrequently: angioedema, including those with a fatal outcome (laryngeal edema can cause airway obstruction leading to death), itching of the skin, hyperhidrosis (increased sweating).

Rare: exfoliative dermatitis, urticaria, onycholysis.

Very rare: photosensitization reactions.

Frequency unknown: toxic epidermal necrolysis, 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 are common: muscle cramps, myalgia.

Infrequently: arthralgia.

Kidney and urinary tract disorders

Infrequently: impaired renal function, including the development of acute renal failure, increased urinary excretion, increased pre-existing proteinuria, increased blood urea and creatinine concentrations.

Disorders of the genitals and mammary glands

Infrequently: erectile dysfunction with transient impotence, decreased libido.

Frequency unknown: gynecomastia.

General disorders and disorders at the injection

site Often: chest pain, feeling tired.

Infrequently: increased body temperature.

Rare: asthenia (weakness).

Interaction

Contraindicated combinations

With sacubitril/valsartan combination therapy

Concomitant use of ACE inhibitors and a combination of ARA Ⅱ and a neutral endopeptidase inhibitor (synonym: NEP, neprilysin) – sacubitril/valsartan – is contraindicated due to the risk of angioedema. Treatment with Ramipril-AKOS should not be started until sacubitril and valsartan have been eliminated from the body. If you switch from Ramipril-ACOS therapy to sacubitril/valsartan combination therapy, you should not start therapy with this combination of drugs until ramipril is completely eliminated from the body.

The use of some high-flow membranes with a negatively charged surface (for example, polyacrylonitrile membranes) during hemodialysis or hemofiltration; the use of dextran sulfate in low-density lipoprotein apheresis

is a risk of developing severe anaphylactoid reactions. If the patient needs these procedures, then other types of membranes should be used (in the case of plasmapheresis and hemofiltration) or the patient should be transferred to antihypertensive drugs of other groups.

Simultaneous use of Ramipril-AKOS and drugs containing aliskiren

Concomitant use of Ramipril-AKOS with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or moderate to severe renal insufficiency (GFR less than 60 ml/min/1.73 m2 of body surface area) and is not recommended in other patients (see sections “Contraindications”, “With caution”, “Special instructions”).

Concomitant use with angiotensin II receptor antagonists (APA II)

Concomitant use of Ramipril-ACOS and APA II is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see section “Contraindications”, “With caution”, “Special instructions”).

Not recommended combinations

With potassium salts, potassium-sparing diuretics (for example, amiloride, spironolactone, triamterene, eplerenone (a derivative of spironolactone)), other drugs that can increase the content of potassium in the blood serum (including ARA II, tacrolimus, cyclosporine; trimethoprim, sulfamethoxazole, which are part of co-trimoxazole (a combined antibacterial agent containing sulfamethoxazole and trimethoprim)).

It is possible to increase the content of potassium in the blood serum, sometimes significantly pronounced (with simultaneous use, regular monitoring of the content of potassium in the blood serum is required).

Combinations that should be used with caution

With antihypertensive drugs (for example, diuretics) and other drugs that reduce blood pressure (nitrates, tricyclic antidepressants, general and local anesthesia, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin)

Potentiation of the antihypertensive effect; for combination with diuretics, see also the sections “Dosage and use”, “Side effects”, “Special instructions”, when combined with diuretics, the serum sodium content should be regularly monitored.

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

With vasopressor sympathomimetics (epinephrine (epinephrine), isoproterenol, dobutamine, dopamine)

Reducing the antihypertensive effect of ramipril, especially careful monitoring of blood pressure is recommended.

With allopurinol, procainamide, cytostatics, immunosuppressants, corticosteroids (glucocorticosteroids and mineralocorticosteroids) and other drugs that may affect hematological parameters

Combined use increases the risk of developing hematological reactions (see the section “Special instructions”).

With lithium salts

Increased serum lithium concentration and increased cardio-and neurotoxic effects of lithium. It is necessary to monitor the concentration of lithium in the blood serum.

With hypoglycemic agents (for example, insulin, hypoglycemic agents for oral use (sulfonylureas))

Due to the decrease in insulin resistance under the influence of ACE inhibitors, it is possible to increase the hypoglycemic effect of these drugs, up to the development of hypoglycemia. Especially careful monitoring of blood glucose concentrations is recommended at the beginning of their combined use with ACE inhibitors.

With dipeptidyl peptidase type IV (DPP-IV) inhibitors (gliptins), for example, sitagliptin, saxagliptin, vildagliptin, linagliptin

Increased risk of angioedema.

With mTOR inhibitors (mammalian Target of Rapamycin – target of rapamycin in mammalian cells), for example, temsirolimus, sirolimus, everolimus

Patients taking ACE inhibitors and mTOR inhibitors at the same time experienced an increase in the incidence of angioedema.

With racecadotril

An increased risk of angioedema has been reported with concomitant use of ACE inhibitors and neutral endopeptidase inhibitors (synonym: NEP, neprilysin), such as racecadotril (a treatment for diarrhea).

With estramustine

Increased risk of angioedema.

Combinations to take into account

With nonsteroidal anti-inflammatory drugs (indomethacin, acetylsalicylic acid)

It is possible to weaken the effect of Ramipril-AKOS, 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 chronic heart failure.

With ethanol-increased symptoms of vasodilation. The drug Ramipril-AKOS may increase the effect of ethanol on the body.

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

Desensitizing therapy in case of hypersensitivity to insect poisons, ACE inhibitors, including Ramipril-AKOS, increase the likelihood of developing severe anaphylactic or anaphylactoid reactions to insect poisons. It is assumed that this effect may also occur with the use of other allergens.

With gold preparations for parenteral use (sodium aurothiomalate)

The following reactions have been reported when ACE inhibitors (including ramipril) are co-administered with parenteral gold preparations (sodium aurothiomalate): flushing of the face, nausea, vomiting, and hypotension.

With tissue plasminogen activators

Observational studies revealed an increased incidence of angioedema in patients taking ACE inhibitors after the use of alteplase for thrombolytic therapy of ischemic stroke.

How to take, course of use and dosage

Tablets should be swallowed whole (not chewed) and washed down with a sufficient amount (1/2 cup) of water, regardless of the time of the meal (that is, tablets can be taken both before, during or after a meal). The dose is selected depending on the therapeutic effect and tolerability of the drug by the patient.

Treatment with the drug is usually long-term, and its duration in each specific case is determined by the doctor.

Unless otherwise prescribed, the following dosage regimens are recommended for normal renal and hepatic function.

Arterial hypertension

Usually, the initial dose is 2.5 mg once a day in the morning. If taking the drug at this dose for 3 weeks or more fails to normalize blood pressure, the dose can be increased to 5 mg ramipril per day. If the 5 mg dose is not effective enough, it can be doubled in 2-3 weeks to the maximum daily dose of 10 mg per day.

As an alternative to increasing the dose to 10 mg per day, if the hypotensive effectiveness of the daily dose of 5 mg is insufficient, it is possible to add other antihypertensive agents to the treatment, in particular, diuretics or slow calcium channel blockers.

Chronic heart failure

Recommended starting dose: 1.25 mg once a day (1/2 tablet of 2.5 mg). Depending on the patient’s response to the therapy, the dose may increase. It is recommended to double the dose at intervals of 1-2 weeks. If a daily dose of 2.5 mg or higher is required, it can be taken either once a day or divided into 2 doses.

The maximum recommended daily dose is 10 mg.

Diabetic or nondiabetic nephropathy

Recommended starting dose: 1.25 mg once a day (1/2 tablet of 2.5 mg). The dose can be increased to 5 mg once a day.

Reducing the risk of myocardial infarction, stroke, or cardiovascular mortality in patients at high cardiovascular risk

Recommended starting dose: 2.5 mg once a day.

Depending on the patient’s tolerance to the drug, the dose can be gradually increased. It is recommended to double the dose after 1 week of treatment, and during the next 3 weeks of treatment – increase it to the usual maintenance dose of 10 mg 1 time per day.

Heart failure with clinical manifestations that developed during the first few days (from day 2 to day 9) after acute myocardial infarction

Initial dose

Treatment can be initiated no earlier than 48 hours after the moment of myocardial infarction (preferably from the 2nd to the 9th day of the disease) in clinically and hemodynamically stable patients with clinical manifestations of heart failure. The recommended starting dose of ramipril is 2.5 mg twice daily (morning and evening).

After taking the first dose, the patient should be under medical supervision for at least two hours, or at least one hour after blood pressure stabilizes. In case of intolerance to the first dose of ramipril (excessive decrease in blood pressure), it is recommended to use ramipril at a dose of 1.25 mg 2 times a day for two days, followed by an increase in the dose to 2.5 mg 2 times a day. If it is not possible to increase the dose of ramipril to 2.5 mg 2 times a day, then the drug should be discontinued.

Titration and maintenance dose

In the future, depending on the patient’s response, the dose of ramipril is recommended to be doubled at intervals of 1-3 days to the target maintenance dose of 5 mg 2 times a day. The maximum recommended daily dose of ramipril is 10 mg (preferably dividing the daily dose into 2 doses).

Currently, the experience of treating patients with severe heart failure (NYHA functional class III-IV) that occurred immediately after acute myocardial infarction is insufficient. If these patients decide to start treatment with ramipril, it is recommended to start treatment with the lowest possible dose (1.25 mg 1 time per day) and take special care with each dose increase.

Use of the drug in certain groups of patients

Patients with impaired renal function

For GFR from 50 to 20 ml / min/1.73 m2 of body surface area, the initial daily dose is usually 1.25 mg (1/2 tablet of 2.5 mg). The maximum allowable daily dose is 5 mg.

Patients with incompletely corrected fluid and electrolyte loss, patients with severe arterial hypertension, as well as patients for whom an excessive decrease in blood pressure poses a certain risk (for example, with severe atherosclerotic damage to the coronary and cerebral arteries)

The initial dose is reduced to 1.25 mg once a day (1/2 tablet of 2.5 mg).

Patients with previous diuretic therapy

It is necessary, if possible, to cancel diuretics 2-3 days (depending on the duration of action of diuretics) before starting treatment with Ramipril-AKOS, or at least reduce the dose of diuretics taken. Treatment of such patients should begin with the lowest dose of 1.25 mg ramipril (1/2 tablet of 2.5 mg), taken once a day in the morning. After taking the first dose and each time after increasing the dose of ramipril and / or diuretics, especially “loop” diuretics, patients should be under medical supervision for at least 8 hours to avoid the development of an uncontrolled hypotensive reaction.

Elderly patients (over 65 years of age)

The initial dose is reduced to 1.25 mg per day (1/2 tablet of 2.5 mg).

Patients with impaired liver function

The blood pressure response to Ramipril-AKOS may either increase (due to slowing down the elimination of ramiprilate) or weaken (due to slowing down the conversion of low-level ramipril to active ramiprilate). Therefore, careful medical supervision is required at the beginning of treatment. The maximum allowable daily dose is 2.5 mg.

Overdose

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

Treatment: gastric lavage, intake of adsorbents, sodium sulfate (if possible during the first 30 minutes). In the case of a marked decrease in blood pressure, the use of alpha-1-adrenergic agonists (norepinephrine, dopamine) can be added to therapy to replenish the volume of circulating blood and restore the water-electrolyte balance. If bradycardia is refractory to medical treatment, it may be necessary to install a temporary pacemaker. In case of overdose, serum creatinine and electrolyte concentrations should be monitored. There is no experience with the use of forced diuresis, changes in the pH of urine, hemofiltration or hemodialysis to accelerate the elimination of ramipril and ramiprilat from the body in case of overdose of the drug.

Special instructions

Before starting treatment with Ramipril-AKOS, hyponatremia and hypovolemia should be eliminated. In patients who have previously taken diuretics, they should be discontinued or at least their dose reduced 2-3 days before starting ramipril (in this case, the condition of patients with chronic heart failure should be carefully monitored, due to the possibility of decompensation with an increase in the volume of circulating blood).

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 careful medical supervision of the patient for at least 8 hours in order to take timely appropriate measures in case of excessive decrease in blood pressure.

If Ramipril-AKOS is used for the first time or at a high dose in patients with increased RAAS activity, then their blood pressure should be carefully monitored, especially at the beginning of treatment, since these patients have an increased risk of excessive blood pressure reduction (see the section “With caution”).

In patients with malignant arterial hypertension and heart failure, especially in the acute stage of myocardial infarction, treatment with Ramipril-AKOS should be started only in a hospital setting.

In patients with chronic heart failure, 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, and it is recommended to monitor renal function indicators in the initial phase of treatment (see also the section “Dosage and use”).

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

Caution should be exercised during exercise and / or hot weather because of the risk of increased sweating and dehydration with the development of hypotension, due to a decrease in the volume of circulating blood and a decrease in the content of sodium in the blood.

During treatment with Ramipril-AKOS, it is not recommended to consume alcohol (ethanol).

A temporary excessive decrease in blood pressure is not a contraindication for continuing treatment after blood pressure stabilization. In case of repeated development of a pronounced decrease in blood pressure, the dose should be reduced or the drug should be discontinued.

Concomitant use of Ramipril-ACOS with drugs containing aliskiren or with ARA II, which leads to double blockade of the RAAS, is not recommended due to the risk of excessive blood pressure reduction, hyperkalemia and deterioration of renal function compared to monotherapy. Concomitant use of Ramipril-AKOS and drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or moderate to severe renal insufficiency (GFR less than 60 ml/min/ 1.73 m2 of body surface area) and is not recommended in other patients (see sections “Contraindications”, “Interaction with other drugs”).

Concomitant use with ARA II is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see sections “Contraindications” and “Interaction with other drugs”).

Angioedema

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 difficulty swallowing or breathing, the patient should immediately stop taking the drug. Angioedema, localized in the tongue, the pharynx or larynx (possible symptoms: impaired swallowing or breathing), may be life-threatening and requires urgent measures for its relief: subcutaneous use of 0.3-0.5 mg or intravenous drip of 0.1 mg of epinephrine (adrenaline) (under the control of blood pressure, heart rate and ECG), followed by the use of corticosteroids (intravenous, intramuscular or inside); also recommended intravenous antihistamines (antagonists of N₁and N₂-histamine receptors), and in the case of failure inactivators of the enzyme With₁-esterase, you can consider the necessity of introducing in addition to epinephrine (adrenaline) inhibitors of the enzyme With₁-esterase. 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.

When used concomitantly with other drugs that may cause the development of angioedema, the risk of angioedema increases (see the sections “Contraindications”, “Interaction with other drugs”).

Treatment aimed at desensitization to insect venom (such as bees, wasps) and simultaneous 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. Against the background of treatment with ACE inhibitors, hypersensitivity reactions to the venom of insects (such as bees, wasps) develop faster and are more severe. If desensitization to insect venom is necessary, then the ACE inhibitor should be temporarily replaced with an appropriate drug of another group.

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 the use of this type of membrane, for example, for urgent hemodialysis or hemofiltration. In this case, it is preferable to use other types of membranes or exclude the use of ACE inhibitors. Similar reactions were observed in low-density lipoprotein apheresis with dextran sulfate. Therefore, this method should not be used in patients receiving ACE inhibitors.

Liver function disorders

In patients with impaired liver function, the response to treatment with Ramipril-AKOS may be 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 (see also the section “Dosage and use”).

Surgical interventions

Before surgery (including dental surgery), the surgeon/anesthesiologist should be warned about taking ACE inhibitors.

Cough

When using Ramipril-AKOS, a dry, unproductive, prolonged cough may occur, which disappears after the use of ACE inhibitors is discontinued, which should be taken into account in the differential diagnosis of cough against the background of the use of an ACE inhibitor.

Ethnic features

Ramipril-AKOS, like other ACE inhibitors, has a less pronounced antihypertensive effect in patients of the black race compared to representatives of other races.

Ramipril-AKOS should be used with caution in black patients because of the higher risk of angioedema.

Patients after kidney transplantation

Experience with the use of Ramipril-AKOS in patients who have recently undergone kidney transplantation is insufficient.

Monitoring of laboratory parameters before and during treatment with Ramipril-AKOS (up to 1 time per month in the first 3-6 months of treatment)

Monitoring of renal function (determination of serum creatinine concentrations)

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 with acute and chronic heart failure, impaired renal function, after kidney transplantation, patients with renovascular diseases, including patients with hemodynamically significant unilateral renal artery stenosis with two kidneys (in such patients, even a slight increase in serum creatinine concentration can be an indicator of decreased renal function).

Monitoring of the electrolyte content

Regular monitoring of serum potassium and sodium levels is recommended. Especially careful monitoring of the potassium content in the blood serum is required in patients with impaired renal function, significant violations of the water-electrolyte balance, and chronic heart failure.

Monitoring of hematological parameters (hemoglobin, number of white blood cells, red blood cells, platelets, leukocyte formula)

It is recommended to monitor the indicators of a general blood test to detect possible leukopenia. More regular monitoring is recommended at the beginning of treatment and in patients with impaired renal function, as well as in patients with connective tissue diseases or in patients receiving other medications that can change the peripheral blood picture at the same time (see the section “Interaction with other medications”). Monitoring the number of white blood cells is necessary for early detection of leukopenia, which is especially important in patients with an increased risk of developing it, 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 ACE inhibitors is required.

If symptoms due to leukopenia appear (for example, fever, enlarged lymph nodes, tonsillitis), urgent monitoring of the peripheral blood picture is necessary. In case of signs of bleeding (small petechiae, red-brown rashes on the skin and mucous membranes), it is also necessary to monitor the number of platelets in the peripheral blood.

Determination of the activity of “liver” enzymes, 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 by a doctor.

Influence on the ability to drive vehicles and mechanisms

During treatment with Ramipril-AKOS, it is necessary to refrain from engaging in potentially dangerous activities, including driving vehicles that require increased concentration of attention and speed of psychomotor reactions, because against the background of its use, dizziness, decreased speed of psychomotor reactions, and attention may occur, especially after taking the first dose.

Storage conditions

At a temperature not exceeding 25 ° C in the original packaging (cardboard pack).

Keep out of reach of children.

Shelf

life is 2 years.

Do not use after the expiration date.

Active ingredient

Ramipril

Conditions of release from pharmacies

By prescription

Dosage form

Tablets