Hartil - instructions for use, doses, side effects, contraindications

Auxiliary substances: sodium bicarbonate 2.5 / 5/10 mg, lactose monohydrate 155/94 / 193.2 mg, pregelatinized starch 1500 30 / 19.5 / 39 mg, croscarmellose sodium 4 / 2.6 / 5.2 mg, sodium stearyl fumarate 2 (1,3 / 2,6 mg, Pigment Blend PB-24877 4 (- / - mg, Pigment Blend РВ-22960 - / 2,6 / - mg.

Pigment Blend PB-24877: lactose monohydrate 3.8 mg, iron oxide yellow 0.2 mg.

Pigment Blend PB-22960: lactose monohydrate 2.47 mg, iron oxide red 0.09 mg, iron oxide yellow 0.04 mg.

Description:

Tablets of 1.25 mg: White or almost white oval flat tablets with bevel.

Tablets 2.5 mg: Yellow or light yellow, perhaps with a marble surface, flat oval tablets with bevel.

Tablets 5 mg: Light pink or orange-pink, perhaps with a marble surface of flat oval tablets with a bevel.

Tablets 10 mg: White or almost white flat oval tablets with bevel.

Pharmacotherapeutic group:inhibitor of angiotensin-converting enzyme (ACE).

ATX: & nbsp

C.09.A.A ACE Inhibitors

C.09.A.A.05 Ramipril

Pharmacodynamics:

Ramipril inhibits angiotensin-converting enzyme (ACE), resulting in (regardless of plasma renin activity) an antihypertensive effect (in the patient's "lying and standing" position) without compensatory increase in the heart rate (HR).

The suppression of ACE activity reduces the level of angiotensin II, which leads, in turn, to a decrease in the secretion of aldosterone. As a result of a decrease in angiotensin II concentration, by eliminating negative feedback, the plasma renin activity increases. Ramipril It acts on ACE, circulating in the blood and located in the tissues, incl.vascular wall. Reduces the overall peripheral vascular resistance (OPSS) or postnagruzku, pressure in the pulmonary capillaries (preload); increases cardiac output and increases exercise tolerance.

With prolonged use ramipril promotes the reverse development of myocardial hypertrophy in patients with arterial hypertension.

Ramipril reduces the frequency of arrhythmias with myocardial reperfusion, improves the blood supply of the ischemic myocardium.

Ramipril inhibits the breakdown of bradykinin and stimulates the formation of nitric oxide (N0) in the endothelium.

Antihypertensive effect begins 1-2 hours after taking the drug inside, the maximum effect develops within 3-6 hours and persists for 24 hours. With daily use, the antihypertensive effect increases for 3-4 weeks and persists with long-term treatment (1-2 years). Antihypertensive efficacy does not depend on the sex, age and body weight of the patient. In patients with acute myocardial infarction ramipril limits the zone of the spread of necrosis, improves the prognosis of life; reduces mortality in the early and distant periods of myocardial infarction,frequency of recurrent myocardial infarction; reduces the severity of manifestations of heart failure, slows its progression.

With long-term admission (at least 6 months) reduces the degree of pulmonary hypertension in patients with congenital and acquired heart defects.

Ramipril lowers the pressure in the portal vein with portal hypertension; inhibits microalbuminuria (in the initial stages) and impairment of renal function in patients with severe diabetic nephropathy. With non-diabetic nephropathy, accompanied by proteinuria (more than 3 g / day) and kidney failure, slows down further deterioration in kidney function, reduces proteinuria, the risk of increased creatinine levels or the development of terminal renal failure.

Pharmacokinetics:

After oral administration, it is rapidly absorbed from the gastrointestinal tract. The maximum concentration in the blood plasma is reached within 1 hour. The degree of absorption is not less than 50-60% of the administered dose. Almost completely metabolized (mainly in the liver) with the formation of active and inactive metabolites. Its active metabolite, ramiprilat, suppresses ACE activity approximately 6-fold more than ramipril. The maximum concentration of ramiprilate in blood plasma is achieved in 2-4 hours. Among the known inactive metabolites are diketopiperazine ether, diketopiperazic acid, and also glucuronides of ramipril and ramiprilate. The binding of ramipril and ramiprilata with plasma proteins is approximately 73% and 56%, respectively. When taking usual doses 1 time per day, the equilibrium concentration of the drug in the blood plasma is reached by the 4th day of taking the drug.

The half-life (T1 / 2) for ramipril is 5.1 hours, T1 / 2 for ramiprilata 13-17 hours.

Ramipril has a multiphase pharmacokinetic profile. After ingestion, a 60% dose is excreted in the urine (mainly in the form of metabolites), and approximately 40% with feces. Approximately 2% of the administered dose is excreted unchanged in the urine.

Elimination of ramipril, ramiprilata and inactive metabolites with urine decreases with renal insufficiency (which increases the concentration of ramiprilate).

Decreased enzymatic activity in the liver in violation of its function leads to a slowdown in the conversion of ramipril to ramipril, which can cause an increase in the level of ramipril.

Indications:

Arterial hypertension.

Chronic heart failure.

Chronic heart failure after acute myocardial infarction in patients with stable hemodynamics.

Diabetic nephropathy and chronic diffuse kidney disease (nondiabetic nephropathy).

Reducing the risk of developing myocardial infarction, stroke, or "coronary death" in patients with coronary heart disease, including patients who underwent myocardial infarction, percutaneous transluminal coronary angioplasty, aorto-coronary bypass surgery.

Contraindications:

Hypersensitivity to ramipril or any other component of the drug. Angioedema in history, including those associated with previous therapy with ACE inhibitors.

Hemodynamically significant bilateral stenosis of the renal arteries and stenosis of the artery of a single kidney.

Arterial hypotension or unstable hemodynamics.

Pregnancy and lactation.

Primary hyperaldosteronism.

Renal failure (creatinine clearance below 20 ml / min)

Carefully:

Hemodynamically significant aortic or mitral stenosis (risk of excessive blood pressure lowering with subsequent renal dysfunction); severe primary malignantarterial hypertension; Severe lesions of coronary and cerebral arteries (risk of blood flow decrease with excessive decrease of blood pressure), unstable angina, severe ventricular rhythm disturbances, terminal stage of CHF, decompensated pulmonary heart, diseases requiring the appointment of glucocorticosteroids and immunosuppressants (lack of clinical experience) h. with systemic connective tissue diseases, severe renal and / or hepatic insufficiency, hyperkalemia, hyponatremia (including against a background of diuretics and a diet with reduced intake Na +), initial or severe manifestations of fluid and electrolyte deficiencies; conditions accompanied by a decrease in the volume of circulating blood (including diarrhea, vomiting), diabetes mellitus, oppression of bone marrow hematopoiesis, a condition after kidney transplantation, advanced age, and age of 18 years (efficacy and safety not established). There is only limited experience with ramipril in patients who are on dialysis.

Dosing and Administration:

Tablets should be swallowed whole, not liquid, squeezed with a lot of liquid (about 1 glass).Tablets can be taken regardless of the time of ingestion. Dosage should be established for each patient individually, taking into account the therapeutic effect and tolerability.

Arterial hypertension: the recommended initial dose is 2.5 mg once a day (daily 1 tablet Hartil 2.5 mg). Depending on the therapeutic effect, the dose can be increased by doubling the daily dose every 2-3 weeks. The usual maintenance dose is 2.5-5 mg per day (1 tablet Hartil 2.5 mg or 1 tablet 5 mg). The maximum daily dose should not exceed 10 mg. Chronic heart failure: the recommended initial dose is 1.25 mg once a day (daily 1 tablet Hartil 1.25 mg). Depending on the therapeutic effect, the dose can be increased by doubling the daily dose every 2-3 weeks. If you need more than 2.5 mg of the drug, this dose can be taken immediately or divided into 2 divided doses. The maximum daily dose should not exceed 10 mg.

Treatment after myocardial infarction: it is recommended to start taking the drug on the 3rd - 10th day after an acute myocardial infarction. The recommended initial dose, depending on the condition of the patient and the time elapsed after an acute myocardial infarction, is 2.5 mg twice a day (2 tablets of Hartil 1.25 mg or 1 tablet of Hartil 2.5 mg) 2 times a day.Depending on the therapeutic effect, the initial dose can be doubled to 5 mg (2 tablets Hartil 2.5 mg or 1 tablet Hartil 5 mg) 2 times a day. The maximum daily dose should not exceed 10 mg. When intolerance of the drug should reduce the dose.

Nondiabetic or diabetic nephropathy: the recommended initial dose is 1.25 mg 1 time per

day (daily, 1 tablet of Hartil 1.25 mg). Depending on the therapeutic effect, the dose can be increased by doubling the daily dose every 2-3 weeks. If you need more than 2,5

mg of the drug, this dose can be taken immediately or divided into two doses. The recommended maximum daily dose is 5 mg.

Prevention of myocardial infarction, stroke or death from cardiovascular disorders:

the recommended initial dose is 2.5 mg once a day. Depending on the tolerability of the drug, after one week of administration, the dose should be doubled compared to the initial dose. This dose should be doubled again after 3 weeks of admission. The recommended maintenance dose is 10 mg once a day. Special patient groups

Elderly patients: the use of ramipril in elderly patients taking diuretics and / or heart failure, as well as impaired liver or kidney function, requires special attention.Dosage should be set by individual selection of doses depending on the response to the drug.

Patients with renal insufficiency: with a moderate violation of kidney function (creatinine clearance from 20 to 50 ml / min, calculated at 1.73 m² body surface), the initial dose is usually 1.25 mg once a day (one Hartil 1.25 tablet per day). The maximum daily dose should not exceed 5 mg.

If the creatinine clearance is not measured, it can be calculated from the serum creatinine level using the Cockcroft equation (Cockroft):

For men: Creatinine clearance (ml / min) = [body weight in kg x (140 - age) / 72 x serum creatinine (mg / dL)].

For women: the result of the calculation by the above equation is multiplied by 0.85.

Dysfunction of the liver: if liver function is impaired, the effect of Hartil may be equally or often decreased, or, in the early stages of treatment, patients with impaired liver function need to be closely monitored. The maximum daily dose in such cases should not exceed 2.5 mg.

In patients receiving diuretic therapy, because of the risk of a significant reduction in blood pressure (BP), the possibility of temporary cancellation or even a reduction in the dose of diuretics should be considered,not less than 2-3 days (or longer, depending on the duration of the action of diuretics) before the start of Hartil. For patients who previously received diuretics, usually the initial dose is 1.25 mg.

Side effects:

From the side of the cardiovascular system: reduction of blood pressure, orthostatic hypotension, tachycardia, rarely - arrhythmia, increased circulatory disorders of the organs caused by narrowing of blood vessels. With excessive decrease in blood pressure, mainly in patients with coronary heart disease and clinically significant narrowing of cerebral vessels, myocardial ischemia (angina pectoris or myocardial infarction) and cerebral ischemia (possibly with a dynamic cerebrovascular accident or stroke) may develop.

From the genitourinary system: the development or strengthening of renal failure, the strengthening of existing proteinuria, a decrease in the volume of urine (at the beginning of the drug), a decrease in libido.

From the central nervous system: dizziness, headache, weakness, drowsiness, paresthesia, nervous excitability, anxiety, tremor, muscle spasm, mood disorders; when used in high doses - insomnia, anxiety, depression, confusion, fainting.

From the sense organs: vestibular disorders, taste disorders (eg, metallic taste), smell, hearing and vision, tinnitus.

From the digestive system: nausea, vomiting, diarrhea or constipation, epigastric pain, dry mouth, thirst, decreased appetite, stomatitis, hypersensitivity or inflammation of the cheek mucosa, pancreatitis, rarely - hepatitis, cholestatic jaundice, impaired liver function with the development of acute liver failure.

From the respiratory system: "dry" cough, bronchospasm (in patients with increased excitability of cough reflex), dyspnea, rhinorrhea, rhinitis, sinusitis, bronchitis.

Allergic reactions: skin rash, itching, hives, conjunctivitis, photosensitivity; rarely angioedema, swelling of the face, extremities, lips, tongue, throat or larynx, exfoliative dermatitis, multiforme exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), pemphigus (pemphigus), serositis, onycholysis , vasculitis, myositis, myalgia, arthralgia, arthritis, eosinophilia.

From the hematopoiesis: anemia, a decrease in the concentration of hemoglobin and hematocrit, thrombocytopenia,leukocytopenia, neutropenia, agranulocytosis, pancytopenia, hemolytic anemia. A decrease in the number of red blood cells can occur. Depression of the bone marrow.

Other: cramps, alopecia, hyperthermia, sweating.

Laboratory indicators: hyperkreatininemia, increased urea nitrogen levels, increased activity of "hepatic" transaminases, hyperbilirubinemia, hyperkalemia, hyponatremia, extremely rare - an increase in the antinuclear factor titer.

Influence on the fetus: impaired fetal kidney development, decreased fetal and newborn infants, impaired renal function, hyperkalemia, skull hypoplasia, oligohydramnion, limb contracture, skull deformity, lung hypoplasia.

Overdose:

Symptoms: marked decrease in blood pressure, bradycardia, shock, disturbance of water-electrolyte balance, acute renal failure.

Treatment: in case of an easy overdose - gastric lavage, the introduction of adsorbents and sodium sulfate (preferably within 30 minutes after administration).

In acute overdose: monitoring and support of vital functions in the intensive care unit; with a decrease in blood pressure - the introduction of catecholamines and angiotensin II.Patient to lay on his back with an elevated position of the legs, to introduce additional amounts of liquid and sodium.

It is not known whether precipitated diuresis, hemofiltration and urine pH correction accelerate the excretion of ramipril. This should be taken into account when considering the possibility of hemodialysis and hemofiltration (see also the section "Contraindications").

Interaction:

Allopurinol, corticosteroids, procainamide, cytostatics and other substances that cause blood changes: increased risk of violations by the hematopoiesis system. Antidiabetic drugs (insulin or derivatives of sulfo-urea): excessive reduction in blood sugar levels. This phenomenon may be due to the fact that ACE inhibitors can increase the sensitivity of tissues to insulin.

Antihypertensive drugs (eg, diuretics) or other drugs with antihypertensive action (eg nitrates, tricyclic antidepressants and anesthetics): possibly increased antihypertensive effect.

Potassium salts and potassium-sparing diuretics, heparin: It is not recommended simultaneous reception with ramipril because of the risk of developing hyperkalemia.

Lithium salts: increasing serum lithium levels increases the risk of cardio and nephrotoxicity.

Nonsteroidal anti-inflammatory drugs and salts (sodium): decrease in the effectiveness of ACE inhibitors.

Membranes with high hydraulic permeability and dextran sulfate: there are reports of life-threatening anaphylactoid reactions, sometimes turning into shock, in patients on hemodialysis using membranes with high hydraulic permeability (for example, polyacrylonitrile) with the simultaneous administration of ACE inhibitors. Anaphylactoid reactions have also been observed in patients subjected to low-density lipoprotein apheresis with dextran sulfate uptake.

When desensitizing therapy is conducted to reduce the allergic reaction to insect bites (eg, bees and wasps) during the administration of ACE inhibitors: a severe, life-threatening anaphylactoid reaction may occur (drop in blood pressure, respiratory failure, vomiting, skin reactions). Therefore, ACE inhibitors should not be given to patients receiving desensitizing therapy.

Alcohol: ramipril can enhance the effects of alcohol.

Special instructions:

During treatment with Hartil, regular medical supervision is necessary.

After taking the first dose, as well as increasing the dosage of the diuretic and / or Hartil, patients should stay for 8 hours under medical supervision in order to avoid the development of an uncontrolled hypotensive reaction, it is recommended to repeatedly read blood pressure.

If possible, adjust the dehydration, hypovolemia, reduce the number of red blood cells before starting the drug. If these disorders are severe, taking ramipril should not begin or continue until measures are taken to prevent excessive fall in blood pressure and impaired renal function.

Careful observation is required for patients with renal vascular disease (eg, clinically insignificant stenosis of the renal artery or hemodynamically significant stenosis of the artery of a single kidney), impaired renal function, with a marked decrease in blood pressure, mainly in patients with heart failure, and also after kidney transplantation.

Impaired renal function can be identified by elevated levels of urea and serum creatinine, especially if the patient takes diuretics.

Due to a decrease in the synthesis of angiotensin II and the secretion of aldosterone, serum levels of sodium can decrease and potassium levels may rise. Hyperkalemia is more common in patients with impaired renal function (eg, with diabetic nephropathy) or with simultaneous admission with potassium-sparing diuretics.

In case of excessive reduction in blood pressure, the patient should lay and raise his lower limbs; it may also be necessary to administer fluid and other measures.

Changes in blood are more likely in patients with impaired renal function and concomitant connective tissue disease (eg, systemic lupus erythematosus and scleroderma), and in the case of other agents affecting the hematopoietic and immune systems.

The level of sodium in serum should also be checked regularly in patients taking diuretics concomitantly with Hartil. It should also regularly check the number of white blood cells to avoid the development of leukopenia. Control should be more frequent at the beginning of therapy and in patients belonging to any risk group.

When lactase deficiency, galactosemia, or glucose / lactose absorption disorder should be considered,that each tablet of the drug Hartil contains the following amounts of lactose: tablets of 1.25 mg contain 79.5 mg of lactose, tablets of 2.5 mg to 158.8 mg, tablets of 5 mg to 96.47 mg, tablets of 10 mg - 193.2 mg.

Experience with ramipril in children, patients with severe renal insufficiency (creatinine clearance less than 20 ml / min / 1.73 m² surface of the body) and in patients during dialysis - limited

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

At the beginning of treatment, a decrease in blood pressure can affect the ability to concentrate. In this case, patients are advised to refrain from driving vehicles and engage in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.In the future, the degree of restriction is determined for each patient individually.

Form release / dosage:

Tablets of 1,25, 2,5, 5 and 10 mg. 7 tablets in a blister pack. 2 or 4 blisters (14 or 28 tablets each) in a cardboard box together with instructions for use.

Packaging:7 tablets in a blister pack. 2 or 4 blisters (14 or 28 tablets each) in a cardboard box together with instructions for use.

Storage conditions:

At temperatures below 25 ° C, out of the reach of children.

Shelf life:

Tablets of 1.25 mg: 18 months.

Tablets 2.5 mg, 5 mg and 10 mg: 2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LS-000346

Date of registration:02.04.2010

The owner of the registration certificate:EGIS ZAO Pharmaceutical Plant EGIS ZAO Pharmaceutical Plant Hungary

Manufacturer: & nbsp

EGIS PHARMACEUTICALS, Plc Hungary

Representation: & nbspEGIS ZAO Pharmaceutical Plant EGIS ZAO Pharmaceutical Plant Hungary

Information update date: & nbsp27.01.2015

Illustrated instructions

Instructions

Hartil® (Hartil®)