NAVELA 1.5

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HARTIL (HARTIL)

Composition

active substance: ramipril; 1 tablet contains ramipril 2.5 mg or 5 mg, or 10 mg; excipients: sodium hydrocarbonate, lactose monohydrate, sodium croscarmellose, pre-gelatinized starch, sodium stearyl fumarate, iron oxide red (E 172) (for 5 mg tablets), iron oxide yellow (E 172) (for 2.5 mg and 5 mg tablets).

Pharmaceutical Form

Tablets.

Main Physical and Chemical Properties

2.5 mg tablets – light yellow, flat, oval tablets without a coating, with a notch, with possible inclusions, with a score line on one side and on the side surfaces, with the marking R2, size 10.0 x 5.0 mm; 5 mg tablets – light pink, flat, oval tablets without a coating, with a notch, with possible inclusions, with a score line on one side and on the side surfaces, with the marking R3, size 8.8 x 4.4 mm; 10 mg tablets – white or almost white, flat, oval tablets without a coating, with a notch, with a score line on one side and on the side surfaces, with the marking R4, size 11.0 x 5.5 mm.

Pharmacotherapeutic Group

Drugs acting on the renin-angiotensin system. Angiotensin-converting enzyme inhibitors (ACE inhibitors). ATC code C09A A05.

Pharmacological Properties

Pharmacodynamics

Ramiprilat, the active metabolite of the drug ramipril, inhibits the enzyme dipeptidylcarboxypeptidase (synonyms: angiotensin-converting enzyme, kininase II). In plasma and tissues, this enzyme catalyzes the conversion of angiotensin I to the active vasoconstrictor substance angiotensin II, as well as the breakdown of the active vasodilator bradykinin. The decrease in the formation of angiotensin II and the inhibition of the breakdown of bradykinin lead to vasodilation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat contributes to a decrease in aldosterone secretion.

The appointment of ramipril causes a significant decrease in peripheral arterial resistance. In general, there are no significant changes in renal plasma flow and glomerular filtration rate. The appointment of ramipril to patients with arterial hypertension leads to a decrease in blood pressure in the horizontal and vertical positions, without compensatory increased heart rate.

In most patients, the antihypertensive effect after a single dose occurs within 1-2 hours after oral administration of the drug. The maximum effect after a single dose is usually achieved within 3-6 hours after oral administration. The antihypertensive effect lasts for 24 hours. The maximum antihypertensive effect with prolonged treatment with ramipril usually becomes apparent within 3-4 weeks. It has been shown that the antihypertensive effect is maintained during long-term therapy for 2 years. Sudden cessation of ramipril intake does not lead to rapid and excessive rebound hypertension.

Pharmacokinetics

Absorption. After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract: peak plasma concentrations are reached within one hour. Given the amount of substance found in the urine, the degree of absorption is at least 56%, and it is not significantly affected by the presence of food in the gastrointestinal tract. The bioavailability of the active metabolite ramiprilat after oral administration of ramipril at a dose of 2.5 mg and 5 mg is 45%.

Peak plasma concentrations of ramiprilat, the only active metabolite of ramipril, are reached within 2-4 hours after taking the drug.

Under conditions of usual dosing (once a day), the equilibrium concentration of the drug in plasma is reached on the 4th day of administration.

Distribution

The binding of ramipril to plasma proteins is approximately 73%, and ramiprilat is 56%.

Metabolism

Ramipril is almost completely metabolized to ramiprilat, a diketopiperazine ester, a diketopiperazine acid, and glucuronides of ramipril and ramiprilat.

Excretion

The excretion of metabolites is predominantly renal. The decrease in ramiprilat concentration in plasma occurs in several phases. Given the powerful saturable binding to ACE and slow dissociation from the enzyme, ramiprilat is characterized by a prolonged terminal elimination phase at very low plasma concentrations.

After repeated doses of ramipril once a day, the effective half-life is 13-17 hours for doses of 5-10 mg and longer for lower doses of 1.25-2.5 mg. The difference is due to the saturable capacity of the enzyme for binding ramiprilat.

After taking a single oral dose of ramipril, ramipril and its metabolite were not detected in breast milk. However, the effect of multiple doses is unknown.

Renal excretion of ramiprilat is reduced in patients with impaired renal function, and renal clearance of ramiprilat is proportional to creatinine clearance. This leads to an increase in plasma concentrations of ramiprilat, which decrease more slowly than in individuals with normal renal function.

In patients with liver damage, the metabolism of ramipril to ramiprilat is slowed down, which is due to the reduced activity of liver esterases, and the levels of ramipril in the plasma of these patients were elevated. However, the peak concentrations of ramiprilat in these patients did not differ from those in individuals with normal liver function.

Clinical Characteristics

Indications

Treatment of arterial hypertension.

Prevention of cardiovascular diseases: reduction of cardiovascular morbidity and mortality in patients with:

• expressed cardiovascular disease of atherothrombotic genesis (history of ischemic heart disease or stroke or peripheral vascular disease);
• diabetes, who have at least one cardiovascular risk factor (see section "Pharmacological properties").

Treatment of kidney disease:

• initial diabetic nephropathy, evidenced by the presence of microalbuminuria;
• expressed diabetic nephropathy, evidenced by the presence of macroproteinuria, in patients who have at least one cardiovascular risk factor (see section "Pharmacological properties");
• expressed non-diabetic nephropathy, evidenced by the presence of macroproteinuria ≥ 3 g/day (see section "Pharmacological properties").

Treatment of heart failure accompanied by clinical symptoms.

Secondary prevention after a myocardial infarction: reduction of mortality during the acute phase of myocardial infarction in patients with clinical signs of heart failure, provided that treatment is started more than 48 hours after the onset of acute myocardial infarction.

Contraindications

Increased sensitivity to the active substance or to any of the excipients that make up the drug, or to other ACE inhibitors (see section "Composition").

History of angioneurotic edema (hereditary, idiopathic, or previously experienced on the background of ACE inhibitors or angiotensin II receptor antagonists).

Concomitant use with sacubitril/valsartan (see sections "Special instructions" and "Interaction with other medicinal products and other types of interactions").

Significant bilateral stenosis of the renal arteries or unilateral stenosis of the renal artery in the presence of a single functioning kidney.

Pregnant or planning to become pregnant (see section "Use during pregnancy or breastfeeding").

Ramipril should not be used in patients with arterial hypotension or hemodynamically unstable conditions.

Concomitant use with drugs containing aliskiren in patients with diabetes or patients with moderate or severe renal impairment (glomerular filtration rate (GFR) <60 ml/min/1.73 m2) (see sections "Interaction with other medicinal products and other types of interactions" and "Pharmacodynamics").

It is necessary to avoid concomitant use of ACE inhibitors and extracorporeal treatments that lead to contact between blood and negatively charged surfaces, as such use can lead to severe anaphylactoid reactions. Such extracorporeal treatments include dialysis or hemofiltration using certain membranes with high hydraulic permeability (e.g., polyacrylonitrile) and low-density lipoprotein apheresis using dextran sulfate.

Interaction with Other Medicinal Products and Other Types of Interactions

Clinical data have shown that dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is associated with an increased risk of adverse events such as arterial hypotension, hyperkalemia, and worsening renal function (including acute renal failure), compared to the use of only one RAAS-affecting drug (see sections "Pharmacodynamics", "Contraindications", and "Special instructions").

Prohibited combinations. Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see sections "Contraindications" and "Special instructions"). Treatment with ramipril should be started only after 36 hours after the last dose of sacubitril/valsartan. Treatment with sacubitril/valsartan should be started only after 36 hours after the last dose of the drug Hartil.

Methods of extracorporeal therapy that result in contact between blood and negatively charged surfaces, such as dialysis or hemofiltration using certain membranes with high flow intensity (e.g., polyacrylonitrile membranes) and low-density lipoprotein apheresis using dextran sulfate, due to the increased risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is necessary, it is recommended to consider using a different dialysis membrane or using a different class of antihypertensive drugs.

Concomitant use of the drug Hartil with drugs containing aliskiren is contraindicated in patients with diabetes or patients with moderate or severe renal impairment and is not recommended for other categories of patients (see sections "Contraindications" and "Special instructions").

Combinations that require precautions.

Potassium salts, heparin, potassium-sparing diuretics, and other active substances that increase the potassium level in the blood (including angiotensin II antagonists, trimethoprim, and its fixed combinations with sulfamethoxazole, tacrolimus, cyclosporine). Hyperkalemia may occur, so it is necessary to carefully monitor the potassium level in the blood.

Antihypertensive drugs (e.g., diuretics) and other substances that can lower blood pressure (e.g., nitrates, tricyclic antidepressants, anesthetics, alcohol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin). It should be expected that the risk of arterial hypotension will increase (see section "Special instructions" regarding diuretics).

Vasopressor sympathomimetics and other substances (e.g., isoproterenol, dobutamine, dopamine, epinephrine) that can reduce the antihypertensive effect of the drug Hartil. It is recommended to carefully monitor blood pressure.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics, and other substances that can cause changes in the blood picture. The likelihood of hematological reactions increases (see section "Special instructions").

Lithium salts. ACE inhibitors can reduce lithium excretion, which can lead to an increase in lithium toxicity. It is necessary to carefully monitor the lithium level.

Antidiabetic drugs, including insulin. Hypoglycemic reactions may occur. It is recommended to carefully monitor blood glucose levels.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid. It is expected that the antihypertensive effect of the drug Hartil will decrease. Moreover, concomitant use of ACE inhibitors and NSAIDs can be accompanied by an increased risk of worsening renal function and increased potassium levels in the blood.

Salt. Excessive salt consumption can lead to a weakening of the hypotensive effect of the drug.

Trimethoprim or a combination of trimethoprim and sulfamethoxazole (co-trimoxazole).

In patients taking ACE inhibitors with a combination of trimethoprim and sulfamethoxazole, the risk of hyperkalemia increases.

Selective immunosuppressants or mTOR inhibitors (e.g., temsirolimus, everolimus, sirolimus) or vildagliptin. It is possible to increase the risk of angioedema in patients who concomitantly receive such drugs as mTOR inhibitors (e.g., temsirolimus, everolimus, sirolimus) or vildagliptin. It is recommended to start such therapy with caution (see section "Special instructions").

Neprilysin inhibitors (NEP). There have been reports of a potential increase in the risk of angioedema when using ACE inhibitors and NEP inhibitors (e.g., sacubitril) concomitantly (see section "Special instructions").

Special Instructions

Special Patient Categories

Pregnancy. Treatment with ACE inhibitors or angiotensin II receptor antagonists is contraindicated during pregnancy. Except in cases where continuation of ACE inhibitor/angiotensin II receptor antagonist therapy is considered absolutely necessary, patients who are planning to become pregnant should be switched to an alternative antihypertensive drug that is safe for use during pregnancy. As soon as pregnancy is diagnosed, treatment with ACE inhibitors/angiotensin II receptor antagonists should be stopped immediately and, if necessary, replaced with another drug (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Double blockade of the renin-angiotensin-aldosterone system (RAAS) using drugs containing aliskiren.

It has been found that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and worsening renal function (including acute renal failure). In connection with this, double blockade of RAAS by concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is not recommended (see sections "Interaction with other medicinal products and other types of interactions" and "Pharmacodynamics").

If such dual blockade therapy is considered absolutely necessary, it should be used only under the supervision of a specialist and with frequent and careful monitoring of renal function, electrolyte levels, and blood pressure.

ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.

Concomitant use of the drug Hartil and aliskiren is contraindicated in patients with diabetes or patients with renal impairment (glomerular filtration rate (GFR) <60 ml/min/1.73 m2) (see section "Contraindications").

Patients at risk of developing arterial hypotension.

Patients with significant activation of the renin-angiotensin-aldosterone system (RAAS). In patients with significant RAAS activation, there is a risk of sudden significant decrease in blood pressure and worsening renal function due to ACE inhibition, especially if an ACE inhibitor or a concomitant diuretic is prescribed for the first time or the dose is increased for the first time.

Significant RAAS activation, which requires medical supervision, including constant blood pressure monitoring, can be expected, for example, in patients:

• with severe arterial hypertension;
• with decompensated congestive heart failure;
• with hemodynamically significant obstruction of blood flow to or from the left ventricle (e.g., with aortic or mitral stenosis);
• with unilateral stenosis of the renal artery in the presence of a second functioning kidney;
• in whom there is or may develop a lack of fluid or electrolytes (including those receiving diuretics);
• with liver cirrhosis and/or ascites;
• undergoing extensive surgical interventions or during anesthesia using hypotensive drugs.

As a rule, it is recommended to correct dehydration, hypovolemia, or electrolyte deficiency before starting treatment (however, for patients with heart failure, such corrective measures should be carefully weighed against the risk of fluid overload).

In patients with liver function disorders, the response to treatment with the drug Hartil may be either enhanced or reduced. In addition, in patients with severe liver cirrhosis accompanied by edema and/or ascites, the activity of the renin-angiotensin system (RAS) may be significantly increased; therefore, when treating these patients, it is necessary to exercise particular caution.

Transient or persistent heart failure after myocardial infarction.

Patients at risk of developing cardiac or cerebral ischemia in case of acute arterial hypotension. In the initial phase of treatment, special medical supervision is required.

Elderly patients. See section "Method of administration and dosage".

Surgical intervention. If possible, treatment with ACE inhibitors, such as ramipril, should be stopped 1 day before surgery.

Renal function monitoring. Renal function should be evaluated before and during treatment, and the dose should be adjusted, especially in the first weeks of treatment. Particular careful monitoring is required for patients with impaired renal function (see section "Method of administration and dosage"). There is a risk of worsening renal function, especially in patients with congestive heart failure or after kidney transplantation.

Angioedema. In patients who received ACE inhibitors, including ramipril, angioedema has been observed (see section "Adverse reactions").

This risk is increased in patients who concomitantly receive such drugs as mTOR inhibitors (e.g., temsirolimus, everolimus, sirolimus) or vildagliptin or sacubitril. The combination of ramipril with sacubitril/valsartan is contraindicated due to the increased risk of angioedema (see sections "Contraindications" and "Interaction with other medicinal products and other types of interactions").

In case of angioedema, the use of the drug Hartil should be stopped. Emergency therapy should be started immediately. The patient should be under medical supervision for at least 12-24 hours and can be discharged after complete disappearance of symptoms.

In patients who received ACE inhibitors, including Hartil, cases of angioedema of the intestine have been observed (see section "Adverse reactions"). These patients complained of abdominal pain (with or without nausea/vomiting).

Anaphylactic reactions during desensitization. When using ACE inhibitors, the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens increase. Before desensitization, it is recommended to temporarily stop taking the drug Hartil.

Electrolyte balance control. Hyperkalemia. In some patients who received ACE inhibitors, including the drug Hartil, hyperkalemia has been observed. The risk group for hyperkalemia includes patients with renal failure, patients over 70 years old, patients with uncontrolled diabetes, patients taking potassium salts, potassium-sparing diuretics, and other active substances that increase potassium levels in the blood, or patients with conditions such as dehydration, acute heart failure, or metabolic acidosis. If concomitant use of the above-mentioned drugs is considered necessary, it is recommended to regularly monitor the potassium level in the blood (see section "Interaction with other medicinal products and other types of interactions").

Electrolyte balance control. Hyponatremia. In some patients who received ramipril, a syndrome of inadequate secretion of antidiuretic hormone with subsequent development of hyponatremia has been observed. It is recommended to regularly monitor serum sodium levels in elderly patients and in other patients who are at risk of developing hyponatremia.

Neutropenia/agramulocytosis. Cases of neutropenia/agramulocytosis, as well as thrombocytopenia and anemia, have been rarely observed. There have also been reports of bone marrow suppression.

In order to detect possible leukopenia, it is recommended to monitor the white blood cell count. More frequent monitoring is desirable at the beginning of treatment and in patients with impaired renal function, concomitant collagenosis (e.g., systemic lupus erythematosus or scleroderma), or those taking other drugs that can cause changes in the blood picture (see sections "Interaction with other medicinal products and other types of interactions" and "Adverse reactions").

Ethnic differences. ACE inhibitors more often cause angioedema in patients of the Negroid race than in representatives of other races. As with other ACE inhibitors, the antihypertensive effect of ramipril may be less pronounced in patients of the Negroid race compared to representatives of other races. This may be due to the fact that in patients of the Negroid race with arterial hypertension, renin-angiotensin system activation is more often low.

Cough. When using ACE inhibitors, there have been reports of coughing. Characteristically, the cough is non-productive, prolonged, and disappears after stopping therapy. When diagnosing cough, it is necessary to consider the possibility of coughing due to ACE inhibitors.

Patients with such rare hereditary diseases as galactose intolerance, lactase deficiency, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this drug.

Use During Pregnancy or Breastfeeding

Pregnancy

The drug should not be used in pregnant women or women planning to become pregnant.

Epidemiological data on the risk of teratogenicity after exposure to ACE inhibitors during the first trimester of pregnancy are not conclusive; however, a small increase in risk cannot be excluded. If ACE inhibitor therapy is continued, patients who are planning to become pregnant should be switched to alternative antihypertensive drugs that have an established safety profile for use during pregnancy.

If pregnancy is confirmed during treatment with this drug, its use should be stopped immediately and replaced with another drug approved for use in pregnant women.

It is known that therapy with ACE inhibitors/angiotensin II receptor antagonists (ARBs) in the second and third trimesters causes fetotoxicity in humans (reduced renal function, oligohydramnios, delayed ossification of the skull) and neonatal toxicity (renal failure, hypotension, hyperkalemia). In case of ACE inhibitor use in the second trimester, an ultrasound check of renal function and skull is recommended. In newborns whose mothers took ACE inhibitors, it is necessary to carefully monitor for hypotension, oliguria, and hyperkalemia (see sections "Contraindications" and "Special instructions").

Breastfeeding

Due to the lack of information on the use of ramipril during breastfeeding (see section "Pharmacological properties"), it is not recommended to prescribe this drug to breastfeeding women, and it is preferable to give priority to other drugs that are safer during lactation, especially during breastfeeding of newborns or premature infants.

Ability to Affect the Speed of Reaction When Driving Vehicles or Operating Other Mechanisms

Certain adverse effects (e.g., symptoms of decreased blood pressure, such as dizziness) can impair the patient's ability to concentrate and affect reaction speed, especially at the beginning of treatment or when switching from other drugs.

After taking the first dose or further increasing the dose, it is not recommended to drive a car or work with other mechanisms for several hours.

Method of Administration and Dosage

The drug is for oral administration.

The drug Hartil is recommended to be taken daily at the same time. The drug can be taken before, during, and after meals, as food intake does not affect the bioavailability of the drug. Hartil tablets should be swallowed whole, washed down with water. They should not be chewed or crushed. To ensure proper administration, the tablets can be divided into equal doses along the score line.

Patients taking diuretics. At the beginning of treatment with the drug Hartil, arterial hypotension may develop, which is more likely in patients who are also taking diuretics. In such cases, caution is recommended, as these patients may have decreased circulating blood volume and/or electrolyte levels.

It is desirable to stop taking diuretics 2-3 days before starting treatment with the drug Hartil, if possible (see section "Special instructions").

In patients with arterial hypertension who cannot stop taking diuretics, treatment with the drug Hartil should be started with a dose of 1.25 mg. It is necessary to carefully monitor renal function and potassium levels in the blood. Further dosing of the drug Hartil should be adjusted based on the target blood pressure level.

Arterial Hypertension

The dose should be selected individually, depending on the characteristics of the patient's condition (see section "Special instructions") and the results of blood pressure monitoring. Hartil can be used as monotherapy or in combination with other classes of antihypertensive drugs (see sections "Contraindications", "Special instructions", "Interaction with other medicinal products and other types of interactions", and "Pharmacodynamics").

Initial dose. Treatment with the drug Hartil should be started gradually, starting with the recommended initial dose of 2.5 mg per day.

In patients with significant activation of the renin-angiotensin-aldosterone system (RAAS), a significant decrease in blood pressure may occur after taking the initial dose. For such patients, the recommended initial dose is 1.25 mg, and their treatment should be started under medical supervision (see section "Special instructions").

Dose titration and maintenance dose. The dose can be doubled every 2-4 weeks until the target blood pressure level is reached; the maximum dose of the drug Hartil is 10 mg per day. The drug is recommended to be taken once a day.

Prevention of Cardiovascular Diseases

Initial dose. The recommended initial dose of the drug Hartil is 2.5 mg once a day.

Dose titration and maintenance dose. Depending on individual tolerance to the drug, the dose should be gradually increased. It is recommended to double the dose after 1-2 weeks of treatment, and then increase it to the target maintenance dose of 10 mg once a day.

(Also see the information above regarding dosing for patients taking diuretics).

Treatment of Kidney Disease

In patients with diabetes and microalbuminuria.

Initial dose. The recommended initial dose of the drug Hartil is 1.25 mg (in the corresponding dosage) once a day.

Dose titration and maintenance dose. Depending on individual tolerance to the drug, the dose should be increased during further treatment. After 2 weeks of treatment, the daily dose should be doubled to 2.5 mg, and then to 5 mg after another 2 weeks of treatment.

Patients with diabetes and at least one cardiovascular risk factor.

Initial dose. The recommended initial dose of the drug Hartil is 2.5 mg once a day.

Dose titration and maintenance dose. Depending on individual tolerance to the drug, the dose should be increased during further treatment. After 1-2 weeks of treatment, the daily dose of the drug Hartil should be doubled to 5 mg, and then to 10 mg after another 2-3 weeks of treatment. The target daily dose is 10 mg.

Patients with non-diabetic nephropathy, evidenced by the presence of macroproteinuria ≥ 3 g/day.

Initial dose. The recommended initial dose of the drug Hartil is 1.25 mg (in the corresponding dosage) once a day.

Dose titration and maintenance dose. Depending on individual tolerance to the drug, the dose should be increased during further treatment. After 2 weeks of treatment, the daily dose should be doubled to 2.5 mg, and then to 5 mg after another 2 weeks of treatment.

Heart Failure with Clinical Symptoms

Initial dose. For patients whose condition has stabilized after treatment with diuretics, the recommended initial dose is 1.25 mg per day.

Dose titration and maintenance dose. The dose of the drug Hartil should be titrated by doubling it every 1-2 weeks until the maximum daily dose of 10 mg is reached. It is desirable to divide the dose into 2 intakes.

Secondary Prevention After Myocardial Infarction

Initial dose. After 48 hours of myocardial infarction, patients whose condition is clinically and hemodynamically stable should be prescribed an initial dose of 2.5 mg twice a day for 3 days. If the initial dose of 2.5 mg is poorly tolerated, then a dose of 1.25 mg (in the corresponding dosage) should be used twice a day for 2 days, with a subsequent increase to 2.5 mg and 5 mg twice a day. If the dose cannot be increased to 2.5 mg twice a day, treatment should be discontinued.

(Also see the information above regarding dosing for patients taking diuretics).

Dose titration and maintenance dose. Further, the daily dose should be increased by doubling it with an interval of 1-3 days until the target maintenance dose of 5 mg twice a day is reached.

When possible, the maintenance daily dose should be divided into 2 intakes.

If the dose cannot be increased to 2.5 mg twice a day, treatment should be discontinued. There is currently insufficient experience with the treatment of patients with severe (IV NYHA class) heart failure immediately after myocardial infarction. If it is still decided to treat such patients with this drug, it is recommended to start therapy with a dose of 1.25 mg (in the corresponding dosage) once a day, and any increase in dose should be carried out with extreme caution.

Special Patient Categories

Patients with impaired renal function. The daily dose for patients with impaired renal function depends on the creatinine clearance rate (see section "Pharmacological properties"):

• if creatinine clearance is ≥ 60 ml/min, there is no need to adjust the initial dose (2.5 mg/day), and the maximum daily dose is 10 mg;
• if creatinine clearance is 30-60 ml/min, there is no need to adjust the initial dose (2.5 mg/day), and the maximum daily dose is 5 mg;
• if creatinine clearance is 10-30 ml/min, the initial daily dose is 1.25 mg (in the corresponding dosage)/day, and the maximum daily dose is 5 mg;
• patients with arterial hypertension on hemodialysis: during hemodialysis, ramipril is excreted to a negligible extent; the initial dose is 1.25 mg (in the corresponding dosage) per day, and the maximum daily dose is 5 mg; the drug should be taken a few hours after the hemodialysis session.

Patients with impaired liver function (see section "Pharmacological properties"). Treatment of patients with liver function disorders with the drug Hartil should be started under close medical supervision, and the maximum daily dose in such cases should be 2.5 mg.

Elderly patients. The initial dose should be lower, and further dose titration should be carried out more gradually, given the higher likelihood of adverse effects, especially in very elderly and frail patients. In such cases, a lower initial dose of 1.25 mg (in the corresponding dosage) of ramipril should be prescribed.

Children. The drug Hartil is not recommended for use in children (under 18 years old), as there is insufficient data on the safety and efficacy of this drug for such patients.

Currently available data on ramipril are described in the sections "Pharmacological properties" and "Adverse reactions".

Overdose

Symptoms of overdose with ACE inhibitors may include excessive peripheral vasodilation (with pronounced arterial hypotension, shock), bradycardia, electrolyte disturbances, renal failure. The patient's condition should be carefully monitored. Symptomatic and supportive treatment should be prescribed. Proposed measures include primary detoxification (gastric lavage, administration of sorbents) and means to restore hemodynamic stability, including the administration of alpha-1-adrenergic agonists or angiotensin II (angiotensinamide). Ramiprilat, the active metabolite of ramipril, is poorly excreted from the systemic circulation by hemodialysis.

Adverse Reactions

The safety profile of the drug Hartil includes data on persistent cough and reactions caused by arterial hypotension. Serious adverse reactions include angioedema, hyperkalemia, liver or kidney function disorders, pancreatitis, severe skin reactions, and neutropenia/agramulocytosis.

The frequency of adverse reactions is classified as follows: very common (≥ 1/10); common (from ≥ 1/100 to < 1/10); uncommon (from ≥ 1/1000 to < 1/100); rare (from ≥ 1/10000 to < 1/1000); very rare (< 1/10000), unknown (cannot be calculated from available data). In each group, adverse reactions are presented in order of decreasing frequency of their manifestation.

Shelf Life

2 years.

Storage Conditions

Store at a temperature not exceeding 25°C in a place inaccessible to children.

Packaging

7 tablets in a blister pack; 2 or 4 blister packs in a cardboard box.

Release Category

By prescription only.

Manufacturer

1. EGIS Pharmaceuticals Ltd., Hungary.

2. Actavis Ltd., Malta.

Manufacturer's Location and Address of the Place of Business

1. 1165, Budapest, Bökényföldi street 118-120, Hungary.

2. BLB015, BLB016, Bulebel Industrial Estate, Zejtun, ZTN3000, Malta.