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

Composition:

Active substance: ramipril;

1 tablet contains 2.5 mg, 5 mg, or 10 mg of ramipril;

Excipients: sodium hydrocarbonate, lactose monohydrate, sodium croscarmellose, pregelatinized 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 physicochemical properties:

2.5 mg tablets – light yellow, flat, oval uncoated tablets with bevelled edges, possible specks, with a score line on one side and on the side surfaces, marked R2, size 10.0 x 5.0 mm;

5 mg tablets – light pink, flat, oval uncoated tablets with bevelled edges, possible specks, with a score line on one side and on the side surfaces, marked R3, size 8.8 x 4.4 mm;

10 mg tablets – white or almost white, flat, oval uncoated tablets with bevelled edges, with a score line on one side and on the side surfaces, marked R4, size 11.0 x 5.5 mm.

Pharmacotherapeutic group. Agents acting on the renin-angiotensin system. Angiotensin-converting enzyme (ACE) inhibitors. ATC code C09AA05.

Pharmacological properties.

Pharmacodynamics.

Ramiprilat, the active metabolite of ramipril, inhibits the enzyme dipeptidyl carboxy peptidase (synonyms: angiotensin-converting enzyme, kininase II). In blood plasma and tissues, this enzyme catalyzes the conversion of angiotensin I into the active vasoconstrictor substance angiotensin II, as well as the breakdown of the active vasodilator bradykinin. Reduced formation of angiotensin II and inhibition of bradykinin degradation lead to vasodilation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat promotes a reduction in aldosterone secretion.

Administration of ramipril results in a significant decrease in arterial peripheral resistance. Generally, there are no significant changes in renal plasma flow or glomerular filtration rate. Administration of ramipril to patients with arterial hypertension leads to a reduction in blood pressure in both supine and upright positions, without compensatory increase in heart rate.

In most patients, the antihypertensive effect after a single dose begins 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 persists for 24 hours. The maximum antihypertensive effect during long-term ramipril therapy generally becomes evident within 3–4 weeks. It has been shown that the antihypertensive effect is maintained during prolonged therapy for up to 2 years. Sudden discontinuation of ramipril does not lead to rapid or excessive rebound increase in blood pressure.

In addition to standard therapy with diuretics and, if necessary, cardiac glycosides, ramipril has been shown to be effective in patients with NYHA functional classes II–IV. The drug exerts beneficial effects on cardiac hemodynamics (reduction in filling pressures of the left and right ventricles, total peripheral vascular resistance, increase in cardiac output, and improvement in cardiac index). It also reduces neuroendocrine activation.

Pharmacokinetics.

Absorption. After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract: peak plasma concentrations are reached within one hour. Based on the amount of substance detected in urine, the extent of absorption is at least 56%, and 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 doses of 2.5 mg and 5 mg is 45%.

Peak plasma concentrations of ramiprilat, the sole active metabolite of ramipril, are reached within 2–4 hours after drug administration.

With standard dosing (once daily), steady-state plasma concentrations of the drug are achieved by the 4th day of treatment.

Distribution.

Plasma protein binding of ramipril is approximately 73%, and of ramiprilat is 56%.

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

Elimination. Metabolite excretion is predominantly renal. The decline in ramiprilat plasma concentrations occurs in several phases. Due to strong 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 once-daily doses of ramipril, the effective elimination half-life is 13–17 hours for doses of 5–10 mg, and longer for lower doses of 1.25–2.5 mg. This difference is due to the enzyme's saturable capacity for binding ramiprilat.

After a single oral dose, 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 the renal clearance of ramiprilat is proportionally related to creatinine clearance. This leads to elevated plasma concentrations of ramiprilat, which decline more slowly than in individuals with normal renal function.

In patients with hepatic impairment, the metabolism of ramipril to ramiprilat is slowed due to reduced activity of hepatic esterases, resulting in elevated plasma levels of ramipril. However, peak ramiprilat concentrations 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:

• established atherosclerotic cardiovascular disease (history of ischemic heart disease, stroke, or peripheral vascular disease);
• diabetes mellitus and at least one cardiovascular risk factor (see section "Pharmacological properties").

Treatment of kidney disease:

• early diabetic glomerular nephropathy, indicated by presence of microalbuminuria;
• advanced diabetic glomerular nephropathy, indicated by presence of macroproteinuria, in patients with at least one cardiovascular risk factor (see section "Pharmacological properties");
• advanced non-diabetic glomerular nephropathy, indicated by presence of macroproteinuria
  ≥ 3 g/day (see section "Pharmacological properties").

Treatment of heart failure accompanied by clinical manifestations.

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

Contraindications.

Hypersensitivity to the active substance or to any of the excipients contained in the medicinal product, or to other ACE inhibitors (see section "Composition").

History of angioedema (hereditary, idiopathic, or previously experienced during treatment with ACE inhibitors or angiotensin II receptor antagonists).

Concomitant use with sacubitril/valsartan (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

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

Pregnancy or women planning to become pregnant (see section "Use during pregnancy or lactation").

Ramipril should not be administered to patients with arterial hypotension or hemodynamically unstable conditions.

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

Concomitant use of ACE inhibitors with extracorporeal treatment methods that involve blood contact with negatively charged surfaces should be avoided, as such use may lead to severe anaphylactoid reactions. Such extracorporeal treatment methods include dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile membranes) and low-density lipoprotein apheresis using dextran sulfate.

Interaction with other medicinal products and other forms of interaction.

Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is associated with an increased incidence of adverse events such as arterial hypotension, hyperkalemia, and worsening renal function (including acute renal failure), compared to treatment with a single RAAS-acting agent (see sections "Pharmacodynamics", "Contraindications", and "Special precautions for use").

Contraindicated combinations. Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Special precautions for use"). Ramipril therapy should be initiated only 36 hours after the last dose of sacubitril/valsartan. Sacubitril/valsartan therapy should be initiated only 36 hours after the last dose of Hartil®.

Extracorporeal treatment methods involving blood contact with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile membranes) and low-density lipoprotein apheresis using dextran sulfate, are contraindicated due to increased risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is necessary, consideration should be given to using an alternative dialysis membrane or another class of antihypertensive agents.

Concomitant use of Hartil® with medicinal products containing aliskiren is contraindicated in patients with diabetes or moderate to severe renal impairment and is not recommended for other patient categories (see sections "Contraindications" and "Special precautions for use").

Combinations requiring precautions.

Potassium salts, heparin, potassium-sparing diuretics, and other active substances that increase plasma potassium levels (including angiotensin II antagonists, trimethoprim and its fixed combinations with sulfamethoxazole, tacrolimus, cyclosporine). Hyperkalemia may occur; therefore, plasma potassium levels should be closely monitored.

Antihypertensive medicinal products (e.g., diuretics) and other substances capable of lowering blood pressure (e.g., nitrates, tricyclic antidepressants, anesthetics, alcohol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin). An increased risk of arterial hypotension should be anticipated (see section "Special precautions for use" regarding diuretics).

Vasopressor sympathomimetics and other substances (e.g., isoprenaline, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of Hartil®. Blood pressure should be closely monitored.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatic agents, and other substances that may cause blood count changes. Increased risk of hematological reactions (see section "Special precautions for use").

Lithium salts. ACE inhibitors may reduce lithium excretion, potentially leading to increased lithium toxicity. Lithium levels should be closely monitored.

Antidiabetic agents, including insulin. Hypoglycemic reactions may occur. Blood glucose levels should be closely monitored.

Non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid. A reduced antihypertensive effect of Hartil® is expected. Furthermore, concomitant use of ACE inhibitors and NSAIDs may be associated with an increased risk of worsening renal function and elevated blood potassium levels.

Salt. Excessive salt intake may reduce the antihypertensive effect of the medicinal product.

Trimethoprim or trimethoprim/sulfamethoxazole combination (co-trimoxazole). Patients receiving ACE inhibitors together with trimethoprim/sulfamethoxazole combination have an increased risk of hyperkalemia.

Selective immunosuppressants or mTOR inhibitors (e.g., temsirolimus, everolimus, sirolimus) or vildagliptin. Increased risk of angioedema may occur in patients receiving concomitant therapy with mTOR inhibitors (e.g., temsirolimus, everolimus, sirolimus) or vildagliptin. Such therapy should be initiated with caution (see section "Special precautions for use").

Neprilysin inhibitors (NEP). There have been reports of a potential increased risk of angioedema with concomitant use of ACE inhibitors and neprilysin (neutral endopeptidase) inhibitors, such as racecadotril (see section "Special precautions for use").

Special precautions for use.

Special patient categories.

Pregnancy. Treatment with ACE inhibitors or angiotensin II receptor antagonists is contraindicated during pregnancy. Except in cases where continued treatment with an ACE inhibitor/angiotensin II receptor antagonist is absolutely necessary, women planning pregnancy should be switched to an alternative antihypertensive agent considered safe for use during pregnancy. As soon as pregnancy is diagnosed, treatment with ACE inhibitors/angiotensin II receptor antagonists should be discontinued immediately and, if necessary, treatment with another agent should be initiated (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with medicinal products containing aliskiren.

Concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren has been associated with an increased risk of arterial hypotension, hyperkalemia, and worsening renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is not recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").

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

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

Combination therapy with Xarelto® and aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²) (see section "Contraindications").

Patients at particular risk of arterial hypotension.

Patients with significantly increased activity of the renin-angiotensin-aldosterone system (RAAS). In patients with markedly increased RAAS activity, there is a risk of sudden and pronounced reduction in blood pressure and worsening renal function due to ACE inhibition, particularly when initiating treatment with an ACE inhibitor or concomitant diuretic or increasing their dose for the first time.

Significant RAAS activation requiring medical supervision, including continuous blood pressure monitoring, may be expected, for example, in patients:

• with severe arterial hypertension;
• with decompensated congestive heart failure;
• with hemodynamically significant obstruction to inflow or outflow of blood from the left ventricle (e.g., aortic or mitral valve stenosis);
• with unilateral renal artery stenosis and a functioning contralateral kidney;
• who have or may develop fluid or electrolyte depletion (including those receiving diuretics);
• with liver cirrhosis and/or ascites;
• undergoing major surgery or anesthesia with agents that may cause arterial hypotension.

In general, dehydration, hypovolemia, or electrolyte depletion should be corrected prior to initiating treatment (however, such corrective measures should be carefully considered in patients with heart failure due to the risk of volume overload).

In patients with hepatic impairment, the response to treatment with Xarelto® may be either enhanced or reduced. Furthermore, in patients with severe liver cirrhosis associated with edema and/or ascites, renin-angiotensin system (RAS) activity may be markedly increased; therefore, particular caution is required when treating these patients.

Transient or persistent heart failure following myocardial infarction.

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

Elderly patients. See section "Dosage and administration".

Surgery. If possible, treatment with ACE inhibitors such as ramipril should be discontinued one day prior to surgery.

Monitoring of renal function. Renal function should be assessed before and during treatment, and dosage adjusted accordingly, especially during the first weeks of therapy. Close monitoring is particularly important in patients with impaired renal function (see section "Dosage and administration"). There is a risk of worsening renal function, particularly in patients with congestive heart failure or after kidney transplantation.

Angioedema. Angioedema has been observed in patients receiving ACE inhibitors, including ramipril (see section "Adverse reactions").

The risk is increased in patients receiving concomitant medicinal products such as mammalian target of rapamycin (mTOR) inhibitors (e.g., temsirolimus, everolimus, sirolimus) or vildagliptin or racecadotril. Combination of ramipril with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

In case of angioedema, treatment with Xarelto® should be discontinued immediately. Emergency therapy should be initiated promptly. The patient should remain under medical supervision for at least 12–24 hours and may be discharged only after complete resolution of symptoms.

Cases of intestinal angioedema have been reported in patients receiving ACE inhibitors, including Xarelto® (see section "Adverse reactions"). These patients presented with abdominal pain (with or without nausea/vomiting).

Anaphylactic reactions during desensitization. The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased when ACE inhibitors are used. Temporary discontinuation of Xarelto® is recommended prior to desensitization procedures.

Monitoring of electrolyte balance. Hyperkalemia. Hyperkalemia has been observed in some patients receiving ACE inhibitors, including Xarelto®. Patients at risk of hyperkalemia include those with renal impairment, patients aged 70 years or older, patients with uncontrolled diabetes mellitus, patients taking potassium salts, potassium-sparing diuretics, or other active substances that increase plasma potassium levels, and patients with conditions such as dehydration, acute heart failure, or metabolic acidosis. If concomitant use of the above-mentioned agents is considered necessary, regular monitoring of plasma potassium levels is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Monitoring of electrolyte balance. Hyponatremia. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) followed by hyponatremia has been observed in some patients receiving ramipril. Regular monitoring of serum sodium levels is recommended in elderly patients and in other patients at risk of developing hyponatremia.

Neutropenia/Agranulocytosis. Cases of neutropenia/agranulocytosis, as well as thrombocytopenia and anemia, have been reported rarely. Bone marrow suppression has also been reported. To detect possible leukopenia, monitoring of white blood cell count is recommended. More frequent monitoring is advisable at the beginning of treatment and in patients with impaired renal function, concomitant collagenosis (e.g., systemic lupus erythematosus or scleroderma), or those receiving other medicinal products that may affect blood counts (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Ethnic differences. ACE inhibitors cause angioedema more frequently in black patients than in other ethnic groups. As with other ACE inhibitors, the antihypertensive effect of ramipril may be less pronounced in black patients compared to other ethnic groups. This may be due to the higher prevalence of low-renin hypertension in black patients with arterial hypertension.

Cough. Cough has been reported during treatment with ACE inhibitors. The cough is typically non-productive, persistent, and resolves after discontinuation of therapy. When performing differential diagnosis of cough, the possibility of ACE inhibitor-induced cough should be considered.

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

Use during pregnancy or breastfeeding.

Pregnancy. This medicinal product should not be used in pregnant women or women planning pregnancy.

Epidemiological data on the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy are inconclusive; however, a small increased risk cannot be excluded. Women planning pregnancy who are receiving ACE inhibitor therapy should be switched to alternative antihypertensive agents with an established safety profile during pregnancy.

If pregnancy is confirmed during treatment with this medicinal product, its use must be discontinued immediately and replaced with another agent approved for use during pregnancy.

It is known that therapy with ACE inhibitors/angiotensin II receptor antagonists (ARBs) during the second and third trimesters causes fetotoxicity in humans (reduced renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia). If an ACE inhibitor has been used during the second trimester of pregnancy, ultrasound assessment of renal function and skull development is recommended. Newborns whose mothers received ACE inhibitors should be closely monitored for hypotension, oliguria, and hyperkalemia (see sections "Contraindications" and "Special precautions for use").

Breastfeeding. Due to lack of information on the use of ramipril during breastfeeding (see section "Pharmacological properties"), this medicinal product is not recommended for use in breastfeeding women. It is preferable to use other medicinal products considered safer during lactation, especially when breastfeeding newborns or preterm infants.

Ability to affect reaction speed when driving vehicles or operating machinery.

Some adverse effects (e.g., symptoms of low blood pressure such as dizziness) may impair a patient's ability to concentrate and affect reaction speed, particularly at the beginning of treatment or when switching from other antihypertensive therapies.

After taking the first dose or any subsequent dose increase, driving vehicles or operating machinery should be avoided for several hours.

Method of Administration and Dosage.

The drug is for oral use.

The drug Hartil® should be taken daily at the same time. Hartil® can be taken before, during, or after meals, as food intake does not affect the bioavailability of the drug. Hartil® tablets should be swallowed whole with water. They must not be chewed or crushed. To ensure proper administration, the tablet may be divided into equal doses along the break line.

Patients taking diuretics. Arterial hypotension may occur at the beginning of Hartil® treatment, and this is more likely in patients who are simultaneously receiving diuretics. In such cases, caution is recommended, as these patients may have reduced blood volume and/or electrolyte levels.

It is advisable to discontinue diuretic therapy 2–3 days before starting Hartil® treatment, if possible (see section "Special Precautions").

In patients with arterial hypertension who cannot discontinue diuretics, Hartil® treatment should be initiated at a dose of 1.25 mg. Renal function and serum potassium levels should be carefully monitored. Subsequent Hartil® dosage should be adjusted according to the target blood pressure level.

Arterial Hypertension.

The dose should be individually adjusted depending on the patient's condition (see section "Special Precautions") and results of blood pressure monitoring. Hartil® may be used as monotherapy or in combination with other classes of antihypertensive drugs (see sections "Contraindications", "Special Precautions", "Interaction with Other Medicinal Products and Other Forms of Interaction", and "Pharmacodynamics").

Initial Dose. Hartil® treatment should be initiated gradually, starting with the recommended initial dose of 2.5 mg once daily.

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

Dose Titration and Maintenance Dose. The dose may be doubled every 2–4 weeks until the target blood pressure level is achieved; the maximum dose of Hartil® is 10 mg once daily. The drug is recommended to be taken once daily.

Prevention of Cardiovascular Diseases.

Initial Dose. The recommended initial dose of Hartil® is 2.5 mg once daily.

Dose Titration and Maintenance Dose. Depending on individual tolerance, the dose should be gradually increased. It is recommended to double the dose after 1–2 weeks of treatment, and then again after 2–3 weeks to reach the target maintenance dose of 10 mg once daily.

(See also the above information on dosing for patients receiving diuretics.)

Treatment of Kidney Disease.

In Patients with Diabetes and Microalbuminuria.

Initial Dose. The recommended initial dose of Hartil® is 1.25 mg (in the appropriate dosage form) once daily.

Dose Titration and Maintenance Dose. Depending on individual tolerance during further treatment, the dose should be increased. 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 Hartil® is 2.5 mg once daily.

Dose Titration and Maintenance Dose. Depending on individual tolerance during further treatment, the dose should be increased. After 1–2 weeks of treatment, the daily dose of 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, Indicated by Macroproteinuria
≥ 3 g/day.

Initial Dose. The recommended initial dose of Hartil® is 1.25 mg (in the appropriate dosage form) once daily.

Dose Titration and Maintenance Dose. Depending on individual patient tolerance to the drug during further treatment, the dose should be increased. 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 Manifestations.

Initial Dose. For patients whose condition has been stabilized with diuretic therapy, the recommended initial dose is 1.25 mg once daily.

Dose Titration and Maintenance Dose. The dose of Hartil® should be titrated by doubling every 1–2 weeks up to the maximum daily dose of 10 mg. It is preferable to divide the dose into two administrations.

Secondary Prevention after Acute Myocardial Infarction in the Presence of Heart Failure.

Initial Dose. 48 hours after the onset of myocardial infarction, patients whose condition is clinically and hemodynamically stable should be given an initial dose of 2.5 mg twice daily for 3 days. If the initial dose of 2.5 mg is poorly tolerated, then a dose of 1.25 mg (in the appropriate dosage form) twice daily should be administered for 2 days, followed by an increase to 2.5 mg and then to 5 mg twice daily. If the dose cannot be increased to 2.5 mg twice daily, treatment should be discontinued.

(See also the above information on dosing for patients receiving diuretics.)

Dose Titration and Maintenance Dose. Subsequently, the daily dose should be increased by doubling every 1–3 days until the target maintenance dose of 5 mg twice daily is reached.

When possible, the maintenance daily dose should be divided into two administrations.

If the dose cannot be increased to 2.5 mg twice daily, treatment should be discontinued. Experience with treating patients with severe (NYHA Class IV) heart failure immediately after myocardial infarction is still limited. If treatment of such patients with this drug is nevertheless decided upon, therapy should be initiated at a dose of 1.25 mg (in the appropriate dosage form) once daily, and any dose increase should be made with extreme caution.

Special Patient Categories.

Patients with Renal Impairment. The daily dose for patients with renal impairment depends on creatinine clearance (see section "Pharmacological Properties"):

• if creatinine clearance is ≥ 60 mL/min, no adjustment of the initial dose (2.5 mg/day) is required, and the maximum daily dose is 10 mg;
• if creatinine clearance is 30–60 mL/min, no adjustment of the initial dose (2.5 mg/day) is required, 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 appropriate dosage form)/day, and the maximum daily dose is 5 mg;
• patients with arterial hypertension undergoing hemodialysis: ramipril is only minimally removed during hemodialysis; the initial dose is 1.25 mg once daily (in the appropriate dosage form), and the maximum daily dose is 5 mg; the drug should be taken several hours after a hemodialysis session.

Patients with Hepatic Impairment (see section "Pharmacological Properties"). Hartil® treatment in patients with hepatic impairment should be initiated under strict medical supervision, and the maximum daily dose in such cases should not exceed 2.5 mg.

Elderly Patients. The initial dose should be lower, and subsequent dose titration should be performed more gradually due to the higher risk of adverse effects, especially in very old and frail patients. In such cases, a lower initial dose of 1.25 mg (in the appropriate dosage form) of ramipril should be prescribed.

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

Current data on ramipril are described in the sections "Pharmacological Properties" and "Adverse Reactions".

Overdose.

Symptoms of angiotensin-converting enzyme (ACE) inhibitor overdose may include excessive peripheral vasodilation (with marked arterial hypotension, shock), bradycardia, electrolyte disturbances, and renal failure. The patient's condition should be closely monitored. Symptomatic and supportive treatment should be administered. Proposed measures include primary detoxification (gastric lavage, administration of sorbents) and interventions to restore hemodynamic stability, including administration of alpha-1-adrenergic agonists or angiotensin II (angiotensinamide). Ramiprilat, the active metabolite of ramipril, is poorly removed from 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 angioneurotic edema, hyperkalemia, hepatic or renal dysfunction, pancreatitis, severe skin reactions, and neutropenia/agranulocytosis.

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); not known (cannot be estimated from the available data). Within each group, adverse events are listed in order of decreasing severity.

Shelf life. 2 years.

Storage conditions. Store at a temperature not exceeding 25 ºC in a place inaccessible to children.

Packaging. 7 tablets per blister; 2 or 4 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

1. Egis Pharmaceuticals Ltd., Hungary.
2. Actavis Ltd., Malta.

Manufacturer's address and address of its business operation.

1. 118-120 Bekenyfelti Street, Budapest 1165, Hungary.
2. BLB015, BLB016, Bulebel Industrial Building, Zejtun, ZTN3000, Malta.