KHARTIL - instructions for medical use of the drug

Pharmacological properties of the drug Hartil

Ramipril inhibits the activity of angiotensin-converting enzyme (ACE, kininase II), causing vasodilation and a decrease in blood pressure. Inhibition of ACE activity is accompanied by an increase in renin activity in the blood plasma and reduces the level of angiotensin II and aldosterone. The antihypertensive effect is noted 1–2 hours after use of the drug, the maximum effect develops over 3–6 hours and lasts at least 24 hours. In cases of severe non-diabetic or diabetic nephropathy, ramipril slows down the progression of renal dysfunction and the development of end-stage renal failure, in which it is necessary kidney transplant or dialysis. In patients at risk of nondiabetic or diabetic nephropathy, ramipril reduces albuminuria. Pharmacokinetics. Ramipril is rapidly absorbed from the gastrointestinal tract (at least 50–60% of the administered dose), the maximum concentration in the blood plasma is achieved within 1 hour. Ramipril is almost completely metabolized (mainly in the liver) with the formation of active and inactive metabolites. Its active metabolite, ramiprilat, is approximately 6 times more active than ramipril. The maximum concentration of the active metabolite in the blood plasma is achieved after 2–4 hours. Among the known inactive metabolites are diketopiperazine ester, diketopiperazine acid, as well as the glucuronides of ramipril and ramiprilat. The binding of ramipril and ramiprilat to blood proteins is about 73 and 56%, respectively. When used in usual doses (1 time per day), the equilibrium concentration of the drug in the blood plasma is achieved on the 4th day of use of the drug. 60% of the dose is excreted in the urine (mainly in the form of metabolites), and about 40% in the feces. Almost 2% of the administered dose is excreted unchanged in the urine.

Instructions for use HARTIL AMLO

Ramipril

Patients at increased risk of hypotension

• Patients with increased RAAS activity: There is a significant risk of an acute fall in blood pressure and deterioration of renal function due to ACE inhibition, especially when ACE inhibitors or concomitant diuretics are prescribed for the first time, or their doses are increased for the first time.

If there is a risk of manifestations of increased activity of the RAAS, then, if necessary, medical supervision should be provided, incl. monitoring blood pressure in patients:

• with severe arterial hypertension;
• with decompensated congestive heart failure;
• with hemodynamically severe obstructed inflow or outflow from the left ventricle (for example, stenosis of the aorta or mitral valve);
• with unilateral renal artery stenosis with a functioning second kidney;
• with existing (or possible) water and electrolyte imbalances (including patients taking diuretics);
• with liver cirrhosis and/or ascites;
• undergoing complex surgery, or undergoing anesthesia using drugs that cause arterial hypotension.

In general, it is recommended to correct conditions of dehydration, hypovolemia or salt deficiency before starting treatment (in patients with heart failure, but the benefits and risks of such measures should be carefully assessed, taking into account the risk of volume overload).

Read also:  Ebastine has not only an antihistamine effect
• in patients with transient (transient) or permanent heart failure after myocardial infarction;
• in patients at risk of developing cardiac or cerebral ischemia or in cases of acute hypotension.

At the initial stage of treatment, special medical supervision is required.

Double blockade of the RAAS

Dual blockade of the RAAS using ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of arterial hypotension, hyperkalemia and renal dysfunction (including acute renal failure) compared with monotherapy. Dual blockade of the RAAS using ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended, especially in patients with diabetic nephropathy.

In some cases, when the combined use of ACE inhibitors and angiotensin II receptor blockers is absolutely indicated, careful medical supervision and mandatory monitoring of renal function, water and electrolyte balance, and blood pressure are necessary. This applies to the use of candesartan or valsartan as adjunctive therapy to ACE inhibitors in patients with chronic heart failure. Carrying out double blockade of the RAAS under the careful supervision of a specialist and mandatory monitoring of renal function, water-electrolyte balance and blood pressure is possible in patients with chronic heart failure with intolerance to aldosterone antagonists (spironolactone), who continue to have symptoms of chronic heart failure despite other adequate therapy .

Surgical intervention

It is recommended, if possible, to discontinue use of ACE inhibitors such as ramipril 1 day before surgery.

Monitoring kidney function

Renal function should be examined before and during treatment, and the dose of the drug should be adjusted, especially in the first weeks of treatment. In patients with renal failure, particularly careful monitoring is required. There is a risk of impaired renal function, especially in patients with congestive heart failure or after kidney transplantation.

Angioedema

The occurrence of angioedema has been reported in patients receiving ACE inhibitors, incl. ramipril

If angioedema occurs, use of ramipril should be discontinued and emergency treatment should be started immediately. The patient should be monitored for at least 12-24 hours until symptoms resolve completely.

The occurrence of intestinal angioedema has been reported in patients receiving ACE inhibitors, incl. ramipril

These patients complained of abdominal pain (with or without symptoms of nausea or vomiting).

Anaphylactic reactions

The use of ACE inhibitors increases the likelihood of anaphylactic and anaphylactoid reactions (and their severity) to insect venoms and other allergens. Temporary discontinuation of ramipril should be considered until desensitization is completed.

Hyperkalemia

In some patients taking ACE inhibitors, incl. ramipril, hyperkalemia was observed. Patients at increased risk of developing hyperkalemia include patients with renal failure, elderly patients (over 70 years of age), patients with uncontrolled diabetes mellitus, or patients taking potassium salts, potassium-containing diuretics and other active substances that increase plasma potassium levels blood, as well as patients with conditions such as dehydration, acute heart failure or metabolic acidosis. If the simultaneous use of the above-mentioned drugs is considered appropriate, then regular monitoring of serum potassium levels is recommended.

Hyponatremia

A syndrome of inappropriate ADH secretion with subsequent hyponatremia has been observed in some patients receiving ramipril. In elderly patients and in cases of increased risk of developing hyponatremia, regular monitoring of serum sodium levels is recommended.

Neutropenia/agranulocytosis

There have been rare reports of neutropenia/agranulocytosis, thrombocytopenia and anemia, as well as bone marrow depression. For possible earlier detection of leukopenia, it is recommended to monitor the number of leukocytes. More frequent monitoring is recommended during the initial phase of treatment and among patients with impaired renal function, as well as in patients with concomitant collagen diseases (for example, lupus erythematosus or scleroderma), and in all patients taking other drugs that could cause changes in the blood picture.

Ethnic differences

ACE inhibitors increase the incidence of angioedema in black patients compared to patients of other skin color.

Like other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black patients compared to patients of other races. This may be due to the high prevalence of low-renin hypertension in the black hypertensive population.

Cough

There are reports of cough occurring after taking ACE inhibitors. A characteristic feature of cough is its dryness and persistence, as well as the disappearance of its manifestations after cessation of therapy. Cough caused by ACE inhibitors should be considered in the differential diagnosis of cough.

Amlodipine

The safety and effectiveness of amlodipine in hypertensive crisis has not been established.

Use in patients with heart failure

The drug should be prescribed with caution to patients with heart failure. In a long-term, placebo-controlled study in patients with severe heart failure (NYHA class III and IV), cases of pulmonary edema were reported, the incidence of which was higher in the amlodipine group compared with the placebo group, but this was not associated with more severe heart failure.

Use in patients with liver dysfunction

In patients with impaired liver function, T1/2 of amlodipine is prolonged; There are no recommendations for dose changes. In this category of patients the drug should be used with caution.

Use in patients with impaired renal function

Patients with impaired renal function can take amlodipine in normal doses. Changes in plasma concentrations of amlodipine concentrations do not correlate with the degree of renal failure. Amlodipine is not excreted during dialysis.

Other instructions

Any effect of amlodipine on changes in laboratory test parameters has not been established.

Use in pediatrics

It is not recommended to prescribe Hartil® Amlo to children and adolescents under 18 years of age.

since the safety and effectiveness of the drug in this group of patients has not been determined.

Excipients

The shell of the 5 mg/5 mg and 10 mg/5 mg capsules contains charming red (allura red AC-FD&C Red 40 E129, and the shell of the 5 mg/10 mg and 10 mg/10 mg capsules contains azorubine (carmoisine) (E122) .These dyes may cause allergic reactions.

Impact on the ability to drive vehicles and operate machinery

Some side effects (eg, symptoms of low blood pressure such as dizziness) may impair the patient's ability to concentrate and respond in a timely manner, and therefore increase the risk in situations where these abilities are especially important (eg, when driving or servicing machinery). and mechanisms).

This can especially happen at the beginning of treatment or when changing other drugs. After taking the first dose of the drug or subsequent increase in its dosage, it is not recommended to drive vehicles or service machines and mechanisms for several hours.

Preclinical safety studies

Ramipril

When ramipril was administered orally to rodents and dogs, it was found that the drug does not cause acute toxicity in animals. Studies using chronic oral administration of the drug have been conducted in rats, dogs and monkeys. Shifts in plasma electrolyte concentrations and changes in blood patterns were recorded in all three animal species.

As evidence of the pharmacodynamic activity of ramipril, the development of hypertrophy of the renal juxtaglomerular complex in dogs and monkeys was noted at a daily dose of 250 mg/kg/day. Rats, dogs and monkeys tolerated daily doses of 2, 2.5 and 8 mg/kg (body weight)/day, respectively, without adverse effects.

Studies of the toxic effects of the drug on the reproductive system in rats, rabbits and monkeys did not reveal any teratogenic effects of ramipril. No changes in fertility were observed in either male or female rats.

Administration of ramipril to female rats during the fetal period and during lactation at a daily dose of 50 mg/kg body weight (or higher) was accompanied by irreversible kidney damage (enlargement of the renal pelvis) of the fetuses. In very young rats, a single dose of ramipril caused irreversible kidney damage.

In large-scale studies using several test systems, no evidence of mutagenicity or genotoxicity of ramipril was found.

Amlodipine

Carcinogenesis.

In rats and mice that were supplemented with amlodipine maleate in their feed for up to 2 years at concentrations that corresponded to daily dosing levels of 0.5, 1.25 and 2.5 mg amlodipine/kg (body weight)/day, no carcinogenic effect of the drug was noted. The highest dose in mice (in terms of mg/m2) was comparable to the maximum recommended human dose (MRDV) of 10 mg amlodipine per day. The highest dose in rats (in terms of mg/m2) was approximately 2 times the MRDC.

Mutagenesis.

During studies of amlodipine maleate, no signs of mutagenicity caused by the use of the drug were identified, either at the gene level or at the chromosome level.

Decreased fertility.

Fertility in rats receiving oral amlodipine maleate at doses up to 10 mg/kg/day (which, in mg/m2 terms, was 8 times the MRDI of 10 mg/day) was not impaired.

Use of the drug Hartil

The tablets should be swallowed whole without chewing, with plenty of liquid, regardless of meals. AH (arterial hypertension) . The recommended starting dose is 2.5 mg 1 time per day (1 tablet 2.5 mg). Depending on the patient’s condition, the daily dose can be doubled every 2–3 weeks. The usual maintenance dose is 2.5–5 mg/day (1 tablet 2.5 mg or 5 mg). The maximum daily dose is 10 mg. If it is necessary to use a dose of 5 mg, instead of further increasing the dose of Hartil, consider combining it with other antihypertensive agents, such as diuretics or calcium channel blockers. Congestive heart failure. The initial recommended dose is 1.25 mg 1 time per day (1 tablet 1.25 mg). Depending on the therapeutic effect, the daily dose can be increased, doubling it every 2-3 weeks. The maximum daily dose should not exceed 10 mg. Heart failure after acute myocardial infarction. It is recommended to start using the drug on days 2–9 after myocardial infarction. The initial dose is 1.25–2.5 mg 2 times a day (1 tablet 1.25 or 2.5 mg). Depending on the therapeutic effect, the initial dose can be doubled to 2.5–5 mg (1 tablet of 2.5 or 5 mg) 2 times a day. The maximum daily dose should not exceed 10 mg. Severe non-diabetic or diabetic nephropathy, as well as its initial stages. The recommended starting dose is 1.25 mg 1 time per day (1 tablet 1.25 mg). Depending on the therapeutic effect, the dose can be increased by doubling the daily dose every 2-3 weeks. The recommended maximum daily dose is 5 mg. Prevention of circulatory disorders of the myocardium and brain - myocardial infarction, stroke or threat of death due to cardiovascular disorders . The initial dose is 2.5 mg 1 time per day (1 tablet 2.5 mg). Depending on the tolerability of the drug, after 1 week of use the daily dose should be doubled (1 tablet 5 mg). This dose can be doubled again after 3 weeks of use. The recommended maintenance dose is 10 mg 1 time per day (1 tablet of 10 mg or 2 tablets of 5 mg). Elderly patients. The use of the drug in elderly patients taking diuretics and/or with signs of heart failure, as well as with impaired liver or kidney function requires special monitoring. Dosage should be set individually, depending on the response to the drug. Patients with renal failure. With a moderate decrease in renal function (creatinine clearance 20–50 ml/min per 1.73 m2 of body surface), the initial dose is 1.25 mg 1 time per day (1 tablet 1.25 mg). The maximum daily dose should not exceed 5 mg. If it is not possible to determine creatinine clearance in a laboratory, it can be calculated from the serum creatinine level using the Cockroft equation: For men. Creatinine clearance (ml/min) = [body weight in kg • (140 – age) : 72 • serum creatinine (mg/dl)]. For women. The calculation result for men is multiplied by 0.85. Patients with impaired liver function. At the beginning of treatment with Hartil, patients with impaired liver function require careful medical supervision. The maximum daily dose in such cases should not exceed 2.5 mg. In patients receiving diuretic therapy, the possibility of temporarily discontinuing or reducing the dose of diuretics should be considered for at least 2-3 days (or more depending on the duration of action of the diuretics) before starting to use Hartil. In patients recently treated with diuretics, the usual starting dose is 1.25 mg (1 tablet 1.25 mg). In patients with fluid and electrolyte imbalance, severe hypertension and in cases where a significant decrease in blood pressure cannot be allowed (for example, with stenosis of the coronary or cerebral arteries), low initial doses, for example 1.25 mg / day, should be given preference.

KHARTIL - instructions for medical use of the drug

Trade name: HARTIL ®

International nonproprietary name: ramipril Dosage form: tablets Composition per 1 tablet: Active ingredient: ramipril 2.5/5/10 mg. Excipients: 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 mixture PB-22960 yellow 4/-/- mg, pigment mixture PB-24877 pink -/2.6/- mg. Pigment mixture PB-22960 yellow: lactose monohydrate 3.8 mg, iron oxide yellow 0.2 mg. Pigment mixture PB-24877 pink: lactose monohydrate 2.47 mg, red iron oxide 0.09 mg, yellow iron oxide 0.04 mg. Description Tablets 2.5 mg: Yellow or light yellow, possibly marbled, flat oval tablets with a bevel, with a score and engraving R2 on one side of the tablet, and scores on the side surfaces. 5 mg tablets: Light pink or orange-pink, possibly with a marbled surface, flat oval tablets with a chamfer, with a score and engraving R3 on one side of the tablet, and scores on the side surfaces. 10 mg tablets: White or off-white flat oval tablets with a chamfer, with a score and engraving R4 on one side of the tablet, and scores on the side surfaces.

Pharmacotherapeutic group: angiotensin-converting enzyme (ACE) inhibitor ATC code: C09AA05

PHARMACOLOGICAL PROPERTIES

Pharmacodynamics Ramipril inhibits angiotensin-converting enzyme (ACE), as a result of which (regardless of plasma renin activity) a hypotensive effect develops (in the patient’s “lying and standing” position without a compensatory increase in heart rate (HR). Suppression of ACE activity reduces the level of angiotensin II, which in turn leads to a decrease in aldosterone secretion. As a result of a decrease in the concentration of angiotensin II, due to the elimination of negative feedback, an increase in plasma renin activity occurs. Ramipril acts on ACE, circulating in the blood and located in tissues, incl. vascular wall. Reduces total peripheral vascular resistance (TPVR) or afterload, pressure in the pulmonary capillaries (preload); increases cardiac output and increases exercise tolerance. With long-term use, ramipril promotes the reverse development of myocardial hypertrophy in patients with arterial hypertension. Ramipril reduces the frequency of arrhythmias during myocardial reperfusion and improves blood supply to ischemic myocardium. Ramipril prevents the breakdown of bradykinin and stimulates the formation of nitric oxide (NO) in the endothelium. The antihypertensive effect begins 1-2 hours after taking the drug orally, the maximum effect develops within 3-6 hours and lasts for 24 hours. With daily use, the antihypertensive effect increases within 3-4 weeks and persists with long-term treatment (1-2 years). Antihypertensive effectiveness does not depend on the gender, age and body weight of the patient. In patients with acute myocardial infarction, ramipril limits the area of ​​necrosis and improves life prognosis; reduces mortality in the early and late periods of myocardial infarction, the incidence of recurrent infarctions; reduces the severity of manifestations of heart failure and slows its progression. With long-term use (at least 6 months) it reduces the degree of pulmonary hypertension in patients with congenital and acquired heart defects. Ramipril lowers portal vein pressure in portal hypertension; inhibits microalbuminuria (in the initial stages) and deterioration of renal function in patients with severe diabetic nephropathy. For non-diabetic nephropathy, accompanied by proteinuria (over 3 g/day) and renal failure, it slows down further deterioration of renal function, reduces proteinuria, the risk of increased creatinine levels or the development of end-stage renal failure.

Pharmacokinetics: After oral administration, it is rapidly absorbed from the gastrointestinal tract. The maximum concentration in blood plasma is achieved within 1 hour. The degree of absorption is at least 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 times more strongly than ramipril. The maximum concentration of ramiprilat in blood plasma is achieved after 2-4 hours. Known inactive metabolites include diketopiperazine ester, diketopiperazine acid, and the glucuronides of ramipril and ramiprilat. The binding of ramipril and ramiprilat to plasma proteins is approximately 73% and 56%, respectively. When taking usual doses once a day, the equilibrium concentration of the drug in the blood plasma is achieved by the 4th day of taking the drug. The half-life (T1/2) for ramipril is 5.1 hours, T1/2 for ramiprilat is 13-17 hours. Ramipril has a multiphasic pharmacokinetic profile. After oral administration, 60% of the dose is excreted in the urine (mainly in the form of metabolites), and approximately 40% is excreted in the feces. Approximately 2% of the administered dose is excreted unchanged in the urine. Urinary excretion of ramipril, ramiprilat and inactive metabolites is reduced in renal failure (which increases ramiprilat concentrations). A decrease in enzymatic activity in the liver when its function is impaired leads to a slowdown in the conversion of ramipril to ramiprilat, which can cause an increase in ramipril levels.

INDICATIONS FOR USE Arterial hypertension. Chronic heart failure. Chronic heart failure after acute myocardial infarction in patients with stable hemodynamics. Diabetic nephropathy and chronic diffuse kidney disease (non-diabetic nephropathy). Reducing the risk of myocardial infarction, stroke or “coronary death” in patients with coronary heart disease, including patients who have had myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting.

CONTRAINDICATIONS Hypersensitivity to ramipril or any other component of the drug. History of angioedema, including that associated with previous therapy with ACE inhibitors. Hemodynamically significant bilateral renal artery stenosis and stenosis of the artery of a single kidney. Arterial hypotension or unstable hemodynamics. Pregnancy and lactation period. Primary hyperaldosteronism. Renal failure (creatinine clearance below 20 ml/min)

With caution: Hemodynamically significant aortic or mitral stenosis (risk of excessive reduction in blood pressure with subsequent impairment of renal function); severe primary malignant arterial hypertension; severe lesions of the coronary and cerebral arteries (danger of decreased blood flow with an excessive decrease in blood pressure), unstable angina, severe ventricular arrhythmias, end-stage CHF, decompensated “pulmonary” heart, diseases requiring the use of glucocorticosteroids and immunosuppressants (lack of clinical experience) - incl. h. with systemic connective tissue diseases, severe renal and/or liver failure, hyperkalemia, hyponatremia (including against the background of diuretics and a diet with limited Na+ intake), initial or severe manifestations of fluid and electrolyte deficiency; conditions accompanied by a decrease in circulating blood volume (including diarrhea, vomiting), diabetes mellitus, suppression of bone marrow hematopoiesis, condition after kidney transplantation, old age, age under 18 years (efficacy and safety have not been established). There is only limited experience with the use of ramipril in patients on dialysis.

DOSAGE AND ADMINISTRATION Tablets should be swallowed without chewing, washed down with plenty of liquid (about 1 glass). Tablets can be taken regardless of meal time. The dosage should be set for each patient individually, taking into account the therapeutic effect and tolerability. The tablets can be divided in half, breaking according to the risk.

Arterial hypertension: the recommended initial dose is 2.5 mg once a day (1 tablet of Hartil 2.5 mg daily). 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 Hartil 2.5 mg tablet or 1 5 mg tablet). The maximum daily dose should not exceed 10 mg.

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

Treatment after myocardial infarction: it is recommended to start taking the drug 3–10 days after acute myocardial infarction. The recommended initial dose, depending on the patient's condition and the time elapsed after acute myocardial infarction, is 2.5 mg 2 times a day (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 of Hartil 2.5 mg or 1 tablet of Hartil 5 mg) 2 times a day. The maximum daily dose should not exceed 10 mg. If the drug is intolerant, the dose should be reduced.

Non-diabetic or diabetic nephropathy: the recommended initial dose is 1.25 mg 1 time per day (1/2 Hartil 2.5 mg tablet daily). Depending on the therapeutic effect, the dose can be increased by doubling the daily dose every 2-3 weeks. If it is necessary to take more than 2.5 mg of the drug, this dose can be taken at once or divided into two doses. The recommended maximum daily dose is 5 mg.

Prevention of myocardial infarction, stroke, or cardiovascular death: The recommended starting dose is 2.5 mg once daily. Depending on the tolerability of the drug, after one week of use the dose should be doubled compared to the initial one. This dose should be doubled again after 3 weeks of use. The recommended maintenance dose is 10 mg once daily.

Special groups of patients Elderly patients: the use of ramipril in elderly patients taking diuretics and/or with heart failure, as well as impaired liver or kidney function, requires special attention. The dosage should be established by individual selection of doses depending on the response to the drug. Patients with renal failure: with moderate renal impairment (creatinine clearance from 20 to 50 ml/min per 1.73 m2 of body surface), the initial dose is usually 1.25 mg 1 time per day (1/2 tablet Hartil 2, 5 per day). The maximum daily dose should not exceed 5 mg. If creatinine clearance is not measured, it can be calculated from the serum creatinine level using the Cockroft equation: For men: creatinine clearance (ml/min) = [kg body weight x (140 - age)/72 x serum creatinine ( mg/dl)]. For women: multiply the result of the calculation using the above equation by 0.85. Liver dysfunction: in case of liver dysfunction, a reduced or increased effect on taking the drug Hartil can equally often be observed, therefore, in the early stages of treatment, patients with liver dysfunction require careful medical supervision. The maximum daily dose in such cases should not exceed 2.5 mg. In patients receiving diuretic therapy, due to the risk of a significant decrease in blood pressure (BP), the possibility of temporarily discontinuing or at least reducing the dose of diuretics should be considered for at least 2-3 days (or longer, depending on the duration of action of the diuretics) before starting to take Hartil. For patients previously treated with diuretics, the usual starting dose is 1.25 mg.

SIDE EFFECTS From the cardiovascular system: decreased blood pressure, orthostatic hypotension, tachycardia, rarely - arrhythmia, increased circulatory disorders of organs caused by narrowing of blood vessels. With an excessive decrease in blood pressure, mainly in patients with coronary heart disease and clinically significant narrowing of cerebral vessels, myocardial ischemia (angina or myocardial infarction) and cerebral ischemia (possibly with dynamic cerebrovascular accident or stroke) may develop. From the genitourinary system: development or worsening of renal failure, increased existing proteinuria, decreased urine volume (at the beginning of taking the drug), decreased libido. From the central nervous system: dizziness, headache, weakness, drowsiness, paresthesia, nervous excitability, anxiety, tremor, muscle spasms, mood disorders; when used in high doses - insomnia, anxiety, depression, confusion, fainting. From the senses: vestibular disorders, disturbances of taste (for example, metallic taste), smell, hearing and vision, tinnitus. From the digestive system: nausea, vomiting, diarrhea or constipation, pain in the epigastric region, dry mouth, thirst, loss of appetite, stomatitis, hypersensitivity or inflammation of the buccal mucosa, pancreatitis, rarely - hepatitis, cholestatic jaundice, impaired liver function with development of acute liver failure. From the respiratory system: “dry” cough, bronchospasm (in patients with increased excitability of the cough reflex), shortness of breath, rhinorrhea, rhinitis, sinusitis, bronchitis. Allergic reactions: skin rash, itching, urticaria, conjunctivitis, photosensitivity; rarely - angioedema of the face, extremities, lips, tongue, pharynx or larynx, exfoliative dermatitis, exudative erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), pemphigus (pemphigus), serositis, onycholysis , vasculitis, myositis, myalgia, arthralgia, arthritis, eosinophilia. From the hematopoietic organs: anemia, decreased concentration of hemoglobin and hematocrit, thrombocytopenia, leukocytopenia, neutropenia, agranulocytosis, pancytopenia, hemolytic anemia. A decrease in the number of red blood cells may occur. Bone marrow depression. Other: convulsions, alopecia, hyperthermia, sweating. Laboratory indicators: hypercreatininemia, increased levels of urea nitrogen, increased activity of “liver” transaminases, hyperbilirubinemia, hyperkalemia, hyponatremia, extremely rarely - increased titer of antinuclear factor. Effect on the fetus: impaired development of the fetal kidneys, decreased blood pressure in the fetus and newborns, impaired renal function, hyperkalemia, cranial hypoplasia, oligohydramnios, contracture of the limbs, cranial deformation, pulmonary hypoplasia.

Overdose: Symptoms: marked decrease in blood pressure, bradycardia, shock, water and electrolyte imbalance, acute renal failure. Treatment: in case of mild overdose - gastric lavage, administration of adsorbents and sodium sulfate (preferably within 30 minutes after administration). In case of acute overdose: control and support of vital functions in the intensive care unit; when blood pressure decreases, administer catecholamines and angiotensin II. Place the patient on his back with his legs elevated, and administer additional fluids and sodium. It is not known whether forced diuresis, hemofiltration, and adjustment of urine pH accelerate the elimination of ramipril. This should be taken into account when considering hemodialysis and hemofiltration (see also section “Contraindications”).

INTERACTION WITH OTHER MEDICINES Allopurinol, corticosteroids, procainamide, cytostatics and other substances that cause changes in the blood: increased risk of disorders of the hematopoietic system. Antidiabetic drugs (insulin or sulfourea derivatives): excessive decrease in blood sugar levels. This phenomenon may be due to the fact that ACE inhibitors may increase tissue sensitivity to insulin. Antihypertensive drugs (for example, diuretics) or other drugs that have antihypertensive effects (for example, nitrates, tricyclic antidepressants and anesthetics): the antihypertensive effect may be enhanced. Potassium salts and potassium-sparing diuretics, heparin: simultaneous use with ramipril is not recommended due to the risk of developing hyperkalemia. Lithium salts: Elevated serum lithium levels increase the risk of cardio- and nephrotoxicity. Nonsteroidal anti-inflammatory drugs and salts (sodium): decreased effectiveness of ACE inhibitors. High-fluid membranes and dextran sulfate: There have been reports of life-threatening anaphylactoid reactions, sometimes leading to shock, in hemodialysis patients using high-fluid membranes (eg, polyacrylonitrile) during concomitant administration of ACE inhibitors. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate. During desensitization therapy used to reduce allergic reactions to insect stings (for example, bees and wasps) while taking ACE inhibitors: a severe, life-threatening anaphylactoid reaction (drop in blood pressure, difficulty breathing, vomiting, skin reactions) may occur. Therefore, ACE inhibitors should not be given to patients receiving desensitization therapy. Alcohol: Ramipril may increase the effects of alcohol.

SPECIAL INSTRUCTIONS During treatment with Hartil, regular medical monitoring is required. After taking the first dose, as well as when increasing the dosage of the diuretic and/or Hartil, patients should be under medical supervision for 8 hours to avoid the development of an uncontrolled hypotensive reaction; multiple blood pressure measurements are recommended. If possible, dehydration, hypovolemia, and a decrease in the number of red blood cells should be corrected before starting the drug. If these disorders are severe, ramipril should not be started or continued until measures are taken to prevent an excessive fall in blood pressure and renal dysfunction. Careful monitoring is required for patients with damage to the renal vessels (for example, 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 serum urea and creatinine levels, especially if the patient is taking diuretics. Due to decreased angiotensin II synthesis and aldosterone secretion, serum sodium levels may decrease and potassium levels may increase. Hyperkalemia occurs more often with impaired renal function (for example, with diabetic nephropathy) or when taken concomitantly with potassium-sparing diuretics. In case of excessive decrease in blood pressure, the patient should be laid down and the lower limbs elevated; Fluids and other measures may also be required. Blood changes are more likely in patients with impaired renal function and concomitant connective tissue disease (for example, systemic lupus erythematosus and scleroderma), as well as in the case of the use of other drugs that affect the hematopoietic and immune systems. Serum sodium levels should also be checked regularly in patients taking diuretics concomitantly with Hartil. The white blood cell count should also be checked regularly to avoid the development of leukopenia. Monitoring should be more frequent at the beginning of therapy and in patients belonging to any risk group. In case of lactase deficiency, galactosemia or glucose/lactose malabsorption syndrome, it should be noted that each Hartil tablet contains the following amounts of lactose: 1.25 mg tablets contain 79.5 mg of lactose, 2.5 mg tablets - 158.8 mg, 5 mg tablets - 96.47 mg, 10 mg tablets - 193.2 mg. High-fluid membranes and dextran sulfate: There have been reports of life-threatening anaphylactoid reactions, sometimes leading to shock, in hemodialysis patients using high-fluid membranes (eg, polyacrylonitrile) during concomitant administration of ACE inhibitors. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate. Experience with the use of ramipril in children, patients with severe renal failure (creatinine clearance less than 20 ml/min/1.73 m2 of body surface) and in patients undergoing dialysis is limited. Effect on driving At the beginning of treatment, a decrease in blood pressure may affect the ability to concentrate. In this case, patients are advised to refrain from driving vehicles and engaging 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.

Release form Tablets 2.5 mg, 5 mg, 10 mg. 7 tablets in a blister made of al. foil/polyamide/PVC. 2 or 4 blisters in a cardboard box along with instructions for use.

Storage conditions At a temperature not exceeding 25 °C. Keep out of the reach of children!

Shelf life: 2 years. Do not use after the expiration date stated on the packaging.

Conditions for dispensing from pharmacies By prescription.

Registration certificate holder JSC "EGIS Pharmaceutical Plant", Hungary 1106 Budapest, Kereszturi ut 30-38, Hungary Phone: (36-1)803-5555, Fax: (36-1)803-5529 Names and actual addresses of drug manufacturing organizations drug ZAO "Pharmaceutical Plant EGIS", Hungary, 1165 Budapest, Bokenyfoldi ut 118-120, Hungary or Actavis Ltd, Malta, BLB 016, Bulebel Industrial Estate, Zejtun ZTN3000, Malta Consumer complaints should be sent to: LLC "EGIS-RUS" , 121108, Moscow, st. Ivana Franko, 8, phone: (495) 363-39-66

Contraindications to the use of the drug Hartil

• hypersensitivity (history of angioedema associated with previous therapy with ACE inhibitors, hereditary or idiopathic angioedema);
• systemic lupus erythematosus, scleroderma (increased risk of developing neutropenia or agranulocytosis); inhibition of bone marrow hematopoiesis;
• hyperkalemia;
• bilateral renal artery stenosis, renal artery stenosis of a solitary kidney, kidney transplantation, renal failure;
• hyponatremia (risk of dehydration, hypertension (arterial hypertension), renal failure);
• liver failure;
• primary hyperaldosteronism;
• During pregnancy and breastfeeding;
• age up to 15 years.

Hartil

After taking the first dose, as well as when increasing the dosage of the diuretic and/or ramipril, patients should be under medical supervision for 8 hours to avoid the development of an uncontrolled hypotensive reaction.

In patients with CHF, taking the drug can lead to the development of severe arterial hypotension, which in some cases is accompanied by oliguria or azotemia and rarely by the development of acute renal failure.

The lower limit of systolic blood pressure for therapy in the early stages of myocardial infarction is considered to be 100 mm Hg.

Patients with malignant arterial hypertension or concomitant decompensated CHF should begin treatment in a hospital setting.

Before starting and during ramipril therapy, it is necessary to count the total number of leukocytes and determine the leukocyte formula (up to 1 time per month in the first 3-6 months of treatment in patients with an increased risk of neutropenia - with impaired renal function, systemic connective tissue diseases, or those receiving high doses, as well as at the first signs of infection). If neutropenia is confirmed (the number of neutrophils is less than 2 thousand/μl), therapy with ACE inhibitors should be discontinued.

Before and during treatment, it is necessary to monitor blood pressure, kidney function (creatinine, urea), K+ and other electrolytes in plasma, Hb, and the activity of “liver” enzymes in the blood.

Based on the results of epidemiological studies, it is assumed that the simultaneous use of ACE inhibitors and insulin, as well as oral hypoglycemic drugs, 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, careful glycemic control is required, especially during the first month of ACE inhibitor therapy.

Caution must be exercised when prescribing ramipril to patients on a low-salt or salt-free diet (increased risk of developing arterial hypotension). In patients with reduced blood volume (as a result of diuretic therapy), with limited salt intake, during dialysis, with diarrhea and vomiting, symptomatic hypotension may develop.

Transient hypotension is not a contraindication for continuing treatment after stabilization of blood pressure. If severe hypotension reoccurs, the dose should be reduced or the drug discontinued.

The use of AN69 dialysis membranes in combination with ACE inhibitors is not recommended (due to the possibility of developing anaphylactoid reactions in patients). If there is a history of evidence of the development of angioedema not associated with taking ACE inhibitors, then such patients still have an increased risk of developing it when taking it.

Safety and efficacy in pediatric practice: Close monitoring for hypotension, oliguria and hyperkalemia is recommended for neonates exposed in utero to ACE inhibitors. With oliguria, it is necessary to maintain blood pressure and renal perfusion by administering appropriate fluids and vasoconstrictor drugs. In neonates and infants there is a risk of oliguria and neurological disorders, possibly due to decreased renal and cerebral blood flow due to the decrease in blood pressure caused by ACE inhibitors (received during pregnancy and postpartum); Lower initial doses and close monitoring are recommended.

Caution should be exercised during exercise or hot weather due to the risk of dehydration and hypotension due to decreased fluid volume. It is not recommended to consume ethanol.

Before surgery (including dentistry), the surgeon/anesthesiologist must be warned about the use of ACE inhibitors.

During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions (dizziness is possible, especially after the initial dose of an ACE inhibitor in patients taking diuretic drugs).

Side effects of the drug Hartil

from the cardiovascular system and blood system: hypotension, angina, syncope, heart failure, myocardial infarction, vertigo, chest pain; very rarely - arrhythmia, tachycardia, hemolytic anemia, myelodepression, pancytopenia, thrombocytopenia, eosinophilia, agranulocytosis; vasculitis; from the gastrointestinal tract: nausea, vomiting, diarrhea; very rarely - dry mouth, anorexia, dyspepsia, dysphagia, constipation, abdominal pain, gastroenteritis, pancreatitis, hepatitis, liver dysfunction, increased transaminase levels; from the nervous system and sensory organs: dizziness, headache, asthenia; very rarely - cerebrovascular disorders, amnesia, drowsiness, convulsions, depression, sleep disturbance, neuralgia, neuropathy, paresthesia, tremor, hearing loss, visual impairment; from the respiratory system: dry cough, infectious diseases of the upper respiratory tract; very rarely - dyspnea, pharyngitis, sinusitis, rhinitis, tracheobronchitis, laryngitis, bronchospasm; from the urinary system: renal dysfunction, proteinuria, oliguria, edema; allergic reactions: urticaria, skin rash, erythema multiforme, photosensitivity, angioedema; other: weight loss, anaphylactoid reactions, increased levels of urea nitrogen and creatinine, angioedema, arthralgia/arthritis, myalgia, chills, hyperkalemia, increased activity of liver enzymes, concentrations of bilirubin, uric acid, glucose in the blood serum.

Instructions for use HARTIL

• with severe primary malignant hypertension;
• with heart failure, especially severe, as well as in conditions of combined use of other antihypertensive drugs;
• after taking diuretics;
• with a deficiency of fluid and sodium (due to insufficient fluid or salt intake, as well as, for example, with diarrhea or increased sweating with insufficient replenishment of fluid and salt);
• with hemodynamically significant renal artery stenosis.

Circulatory disorders of organs associated with vascular stenosis may increase while taking ramipril.

With an extremely strong decrease in blood pressure, mainly in patients with coronary artery disease and clinically significant narrowing of cerebral vessels, myocardial ischemia (angina pectoris or myocardial infarction) and cerebral ischemia (possibly with dynamic cerebrovascular accident or stroke) may develop.

Ramipril can usually be continued after hypotension has normalized and blood pressure and fluid and electrolyte balance have been restored.

urinary system

Administration of ramipril may worsen kidney function and, in some conditions, even cause life-threatening kidney failure, especially in the following cases:

• damage to the renal vessels (for example, with hemodynamically significant stenosis of the renal artery),
• after kidney transplantation,
• with a pronounced decrease in blood pressure, mainly in patients with heart failure.

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

The patient's existing proteinuria may worsen; however, renal protein excretion may also be reduced, especially in diabetic nephropathy.

Due to decreased angiotensin II synthesis and aldosterone secretion, serum sodium levels may decrease and potassium levels may increase. The latter is more common in cases of impaired renal function (for example, in diabetic nephropathy) or when taken in combination with potassium-sparing diuretics.

At the beginning of taking the drug, the volume of urine excreted may decrease.

Skin, anaphylactic and anaphylactoid reactions

Angioedema may occur in rare cases while taking ramipril. In such cases, taking Hartil should be stopped immediately, and the use of any other ACE inhibitor is also contraindicated.

Angioedema of the tongue, pharynx and larynx can develop into a life-threatening condition and requires immediate intervention.

Weaker swelling (not of an angioedema nature) may also be observed, mainly on the legs.

The following phenomena on the skin and mucous membranes may also occur:

• flushing with a feeling of heat in some areas of the skin, conjunctivitis, itching, urticarial elements, maculopapular and lichenoid exanthema and enanthema, erythema multiforme, alopecia, recurrence or exacerbation of Raynaud's syndrome. Like other ACE inhibitors, ramipril can also cause psoriasis- and pemphigus-like exanthema and enanthema, skin photosensitivity and onycholysis.

Vasculitis, myalgia, arthralgia, fever, and eosinophilia may also occur. An increase in the titer of antinuclear antibodies has been described during the use of other ACE inhibitors.

Respiratory system

Presumably due to the suppression of endogenous bradykinin degradation, a dry cough often occurs with a persistent increase in the cough reflex. This cough is often worse at night and when lying down, and is more common in women and non-smokers. Rhinitis, sinusitis, bronchitis, and, in patients with increased excitability of the cough reflex, bronchospasm may also occur. This cough always disappears when you stop taking ramipril. Sometimes the cough may stop when the patient is switched to another ACE inhibitor.

Gastrointestinal tract

Side effects from the gastrointestinal tract can include dry mouth, increased sensitivity or inflammation of the buccal mucosa, indigestion, constipation, diarrhea, nausea and vomiting, gastritis-like pain in the stomach, discomfort in the upper abdomen (sometimes accompanied by increased pancreatic enzyme levels), pancreatitis, elevated liver enzymes and/or bilirubin, cholestatic jaundice, other forms of liver damage and (sometimes) life-threatening hepatitis.

Hematopoietic system and laboratory parameters

A decrease in the number of red blood cells and hemoglobin concentration may occur (sometimes due to hemolytic anemia), a decrease in the number of platelets and leukocytes (reaching neutropenia).

Agranulocytosis, bone marrow depression and pancytopenia have been described in patients taking other ACE inhibitors.

The above blood changes are more likely in patients with impaired renal function and concomitant collagenosis (for example, systemic lupus erythematosus and scleroderma), as well as in the case of the use of other drugs that act on the hematopoietic and immune systems. Hyperkalemia occurs rarely in patients with normal renal function, but can develop in patients with even mild renal failure.

Other side effects

There may also be disturbances in the sense of balance, headache, nervous irritability, restlessness, tremors, sleep disturbances, confusion, lack of appetite, mood disturbances, anxiety, paresthesia, taste disturbances (for example, metallic taste), decreased or loss of taste, muscle spasm, impotence, decreased libido.

Patients should be advised to seek immediate medical attention if urticaria and/or difficulty breathing occurs, and to report any other side effects of the drug to their physician.

Special instructions for the use of the drug Hartil

After taking the first dose, as well as when increasing the dose of a diuretic and/or ramipril, patients should be under medical supervision for 8 hours to avoid the development of an uncontrolled hypotensive reaction. In patients with heart failure, taking the drug can lead to the development of severe arterial hypotension, which is accompanied by oliguria or azotemia and rarely by the development of acute renal failure. The lower limit of systolic blood pressure during therapy in the early period of myocardial infarction is considered to be 100 mm Hg. Art. Patients with malignant hypertension (arterial hypertension) or concomitant severe heart failure should begin treatment in a hospital setting. Before and during therapy with ACE inhibitors, it is necessary to monitor the hemogram with determination of the absolute content of leukocytes and leukocyte form (at least once a month in the first 3-6 months of therapy) in patients with an increased risk of neutropenia - with impaired renal function, collagenosis, and also at the first signs of infection). If neutropenia is confirmed (neutrophil count ≤2000/μl), ACE inhibitor therapy should be discontinued. Before and during treatment, monitoring of blood pressure, renal function, K+, creatinine, urea in the blood plasma, control of hemoglobin in the peripheral blood, concentrations of electrolytes and liver enzymes is necessary. Caution must be exercised when prescribing the drug to patients on a low- or salt-free diet (increased risk of developing arterial hypotension). In patients with reduced blood volume (due to diuretic therapy) - limiting salt intake, dialysis, vomiting, diarrhea - symptomatic hypotension may develop. Transient hypotension is not a contraindication for continuing treatment after stabilization of blood pressure. If severe hypotension reoccurs, the dose should be reduced or the drug discontinued. The use of AN69 dialysis membranes in combination with ACE inhibitors is not recommended (due to the possibility of developing anaphylactoid reactions in patients). If there is a history of angioedema not associated with taking ACE inhibitors, these patients have an increased risk of developing it when taking the drug. The safety and effectiveness of the drug in children are not known. During pregnancy and breastfeeding. Taking the drug Hartil is contraindicated during pregnancy, therefore, before starting use, the patient should be excluded from pregnancy, and it is also necessary to protect against pregnancy by using an adequate method of contraception. In case of planned pregnancy, you must stop taking Hartil and switch to using an alternative drug. If pregnancy occurs while taking Hartil, it should be discontinued immediately (before the end of the first trimester) and replaced with a drug that does not contain an ACE inhibitor to avoid the risk of fetal damage. The drug Hartil is contraindicated during breastfeeding. Ramipril is excreted into breast milk, so if the mother needs to use the drug, breastfeeding should be stopped. The ability to influence reaction speed when driving vehicles or other mechanisms. During treatment, you should refrain from driving vehicles and activities that require increased concentration and speed of psychomotor reactions, since dizziness may occur, especially after the initial dose of an ACE inhibitor in patients taking diuretics. Caution should be exercised when performing physical exercise or during heat due to the risk of dehydration and hypotension due to decreased fluid volume in the body. It is not recommended to drink alcoholic beverages during treatment with the drug. Before surgery (including dentistry), you should warn the surgeon/anesthesiologist about the use of the drug.

Hartil®

Before starting treatment with ramipril, hyponatremia and hypovolemia must be corrected. In patients who have previously taken diuretics, it is necessary to 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 carefully monitored, due to the possibility of their developing decompensation when increase in BCC).

After taking the first dose of the drug, as well as when increasing its dose and/or the dose of diuretics (especially loop diuretics), it is necessary to ensure careful 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 the drug is used for the first time or in a high dose in patients with increased activity of the RAAS, their blood pressure should be carefully monitored, especially at the beginning of treatment, since these patients have an increased risk of an excessive decrease in blood pressure (see section "With caution").

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, as they may be particularly sensitive to ACE inhibitors; it is recommended to monitor renal function in the initial phase of treatment (see also section Dosage and Administration).

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 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 concentration in the blood.

During treatment with ramipril, it is not recommended to drink alcohol (ethanol).

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

The simultaneous use of ramipril with drugs containing aliskiren or with ARA II, leading to double blockade of the RAAS, is not recommended due to the risk of excessive reduction in blood pressure, the development of hyperkalemia and deterioration of renal function compared with monotherapy. The simultaneous use of ramipril with drugs containing aliskiren in patients with diabetes mellitus and/or moderate to severe renal failure with creatinine clearance <60 ml/min is contraindicated (see sections Contraindications, Interactions with other drugs).

Concomitant use with ARA II in patients with diabetic nephropathy is contraindicated (see sections Contraindications, Interaction with other drugs).

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 administration 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 glucocorticosteroids (iv, intramuscular or orally); Intravenous 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 (adrenaline) 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 (such as bees, wasps) and concomitant use of ACE inhibitors can initiate anaphylactic and anaphylactoid reactions (eg, 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 (such as bees, wasps) develop faster and are more severe. If desensitization to insect venom is necessary, the ACE inhibitor should be temporarily replaced with a corresponding drug from another group.

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

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 (see also section Dosage and Administration).

Before surgery (including dental surgery), it is necessary to warn the surgeon/anesthesiologist about taking ACE inhibitors.

It is recommended to closely monitor neonates exposed in utero to ACE inhibitors 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.

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

Monitoring kidney function (determining serum creatinine concentrations)

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 acute and chronic HF, 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 concentration may be an indicator decreased kidney function).

Electrolyte control

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

Monitoring of hematological parameters (hemoglobin, 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 (see section Interactions with other drugs). 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 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. 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 the activity of “liver” enzymes, the concentration of bilirubin in the blood

If jaundice or a significant increase in the activity of “liver” enzymes appears, treatment with the drug should be stopped and medical supervision of the patient should be provided.

Hartil® tablets 2.5 mg, 5 mg and 10 mg contain lactose.

If you are lactose intolerant, you should take into account its content in each tablet: Hartil® 2.5 mg - 158.8 mg, Hartil® 5 mg - 96.47 mg, Hartil® 10 mg - 193.2 mg.

This drug should not be used in patients with rare hereditary galactose intolerance, hereditary lactase deficiency, or glucose-galactose malabsorption syndrome.

Drug interactions Hartil

Antihypertensive, diuretic, opioid analgesics, anesthetics enhance the hypotensive effect of Hartil. NSAIDs (especially indomethacin), kitchen salt reduce the effect of Hartil, interfere with the antihypertensive effect by inhibiting the synthesis of prostaglandins in the kidneys and/or due to sodium and fluid retention in the body. Therefore, patients receiving combination therapy with Hartil and NSAIDs should be under strict supervision. Cyclosporine, potassium-sparing diuretics (amiloride, spironolactone, triamterene), milk, potassium supplements, potassium mixtures, salt substitutes increase the risk of hyperkalemia. The simultaneous use of myelosuppressive drugs and Hartil increases the risk of developing neutropenia and/or agranulocytosis, which can be fatal. When Hartil is taken simultaneously with lithium preparations, the concentration in the blood of the latter increases. Enhances the hypoglycemic effect of sulfonylurea derivatives and insulin. The risk of developing leukopenia increases when used simultaneously with alopurinol, cytostatic agents, immunosuppressants, and procainamide. Hartil enhances the inhibitory effect of ethanol on the central nervous system. Estrogens reduce the hypotensive effect of the drug (cause fluid retention).

Overdose of the drug Hartil, symptoms and treatment

Symptoms: severe hypotension, shock, electrolyte imbalance, renal failure. Treatment of overdose depends on how and when the drug is administered, as well as the type and severity of symptoms. Treatment: general measures - gastric lavage, use of sorbents, sodium sulfate (if possible during the first 30 minutes). It is necessary to monitor and support the vital functions of the patient’s body in intensive care conditions; for hypotension, you can also administer catecholamines and angiotensin II, place the patient on his back with the foot end of the bed elevated, and administer additional fluid and sodium. Hemodialysis is ineffective.

Hartil, 5 mg, tablets, 28 pcs.

Inside,

without chewing, with plenty of liquid (about 1 glass), regardless of the time of meal.

The dosage should be set individually for each patient, taking into account the therapeutic effect and tolerability. The tablets can be divided in half, breaking according to the risk.

Arterial hypertension.

The recommended starting dose is 2.5 mg once a day (1 tablet of Hartil® 2.5 mg daily). 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.

CHF.

The recommended starting dose is 1.25 mg once a day (1/2 tablet of Hartil® 2.5 mg daily). Depending on the therapeutic effect, the dose can be increased by doubling the daily dose every 2-3 weeks. If it is necessary to take more than 2.5 mg of the drug, this dose can be taken immediately or divided into 2 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 acute myocardial infarction. The recommended initial dose, depending on the patient’s condition and the time elapsed after acute myocardial infarction, is 2.5 mg 2 times a day (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 of Hartil® 2.5 mg or 1 tablet of Hartil® 5 mg) 2 times a day. The maximum daily dose should not exceed 10 mg. If the drug is intolerant, the dose should be reduced.

Non-diabetic or diabetic nephropathy.

The recommended starting dose is 1.25 mg 1 time per day (1/2 tablet of Hartil® 2.5 mg daily). Depending on the therapeutic effect, the dose can be increased by doubling the daily dose every 2-3 weeks. If it is necessary to take more than 2.5 mg of the drug, this dose can be taken at once 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 starting dose is 2.5 mg once a day. Depending on the tolerability of the drug, after 1 week of use the dose should be doubled compared to the initial one. This dose should be doubled again after 3 weeks of use. 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 with heart failure, as well as impaired liver or kidney function, requires special attention. The dosage should be established by individual selection of doses depending on the response to the drug.

Patients with renal failure.

For moderate renal impairment (creatinine Cl from 20 to 50 ml/min per 1.73 m2 body surface area), the initial dose is usually 1.25 mg 1 time per day (1/2 tablet Hartil® 2.5 mg per day). The maximum daily dose should not exceed 5 mg.

If creatinine clearance is not measured, it can be calculated from serum creatinine using Cockroft's equation:

For men:

creatinine clearance, ml/min = (body weight, kg · (140−age)/72 · serum creatinine, mg/dl).

For women:

multiply the result of the calculation using the above equation by 0.85.

Liver dysfunction.

In case of impaired liver function, a reduced or increased effect on taking the drug Hartil can equally often be observed, therefore, in the early stages of treatment, patients with impaired liver function require careful medical supervision. The maximum daily dose in such cases should not exceed 2.5 mg.

In patients receiving diuretic therapy,

due to the risk of a significant decrease in blood pressure, you should consider temporarily discontinuing or at least reducing the dose of diuretics at least 2-3 days (or longer, depending on the duration of action of the diuretics) before starting to take Hartil®. For patients previously treated with diuretics, the usual starting dose is 1.25 mg.