INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Ramipril-Teva (Ramipril-Teva)

Composition:

Active substance: ramipril;

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

Excipients: lactose monohydrate, pregelatinized starch, sodium croscarmellose, sodium hydrogen carbonate, sodium stearyl fumarate; tablets of 2.5 mg — iron oxide yellow (E 172); tablets of 5 mg — iron oxide red (E 172), iron oxide yellow (E 172).

Pharmaceutical form. Tablets.

Main physicochemical properties:

tablets of 2.5 mg: light yellow, round, biconvex tablets with specks ranging from yellow to yellow-orange, with a score line on one side, approximately 8.0 mm in diameter and 3.5 mm in height ± 0.5 mm;

tablets of 5 mg: pink, round, biconvex tablets with irregularly shaped reddish-brown specks, with a score line on one side, approximately 6.5 mm in diameter and 3.3 mm in height ± 0.5 mm;

tablets of 10 mg: white or almost white, round, biconvex tablets with a score line on one side, approximately 9.0 mm in diameter and 3.55 mm in height ± 0.5 mm.

Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors. Single-component ACE inhibitors. Ramipril. ATC code C09A A05.

Pharmacological properties.

Mechanism of action. Ramiprilat, the active metabolite of the prodrug ramipril, is an inhibitor of the enzyme dipeptidyl carboxypeptidase I (synonyms: ACE, kininase II). In blood plasma and tissues, this enzyme catalyzes the conversion of angiotensin I to angiotensin II (an active vasoconstrictor substance) and the breakdown of the active vasodilator bradykinin. Reduced formation of angiotensin II and inhibition of bradykinin breakdown lead to vasodilation. Since angiotensin II also stimulates the release of aldosterone, ramiprilat reduces aldosterone secretion. The response to monotherapy with ACE inhibitors has generally been less pronounced in patients of non-Caucasian race (African-Caribbean origin) with arterial hypertension (a population typically characterized by low renin levels in hypertension) compared to patients of other racial groups.

Pharmacodynamics.

Antihypertensive properties. Administration of ramipril causes a significant reduction in peripheral arterial resistance. Generally, no major changes in renal plasma flow or glomerular filtration rate occur. Administration of ramipril to patients with arterial hypertension reduces blood pressure in both supine and upright positions, without compensatory increase in heart rate.

After a single oral dose, the antihypertensive effect occurs within 1–2 hours in most patients, with maximum effect usually achieved within 3–6 hours. The antihypertensive effect typically persists for 24 hours.

During long-term treatment with ramipril, the maximum antihypertensive effect develops within 3–4 weeks. It has been demonstrated that the antihypertensive effect is maintained for up to 2 years with prolonged therapy. Abrupt discontinuation of ramipril does not cause rapid or excessive rebound increase in blood pressure (rebound phenomenon).

Heart failure. Ramipril, when used as an addition to conventional therapy with diuretics and, if necessary, cardiac glycosides, has been proven effective in patients with NYHA (New York Heart Association) functional class II–IV heart failure. 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. Maximum plasma concentrations are reached within 1 hour. Based on the amount of substance recovered 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%.

Maximum plasma concentrations of ramiprilat, the sole active metabolite of ramipril, are reached 2–4 hours after ramipril administration. After repeated daily doses of ramipril, steady-state plasma concentrations of ramiprilat are achieved by approximately day 4 of treatment.

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

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

Elimination. Metabolites are primarily eliminated via renal excretion. The decline in ramiprilat plasma concentration is multiphasic. Due to strong saturable binding to ACE and slow dissociation from the enzyme complex, ramiprilat exhibits a prolonged terminal elimination phase at very low plasma concentrations.

After repeated once-daily doses of ramipril, the effective half-life is 13–17 hours for doses of 5–10 mg and higher, and longer for lower doses (1.25–2.5 mg). This difference is due to the saturable binding capacity of the enzyme for ramiprilat.

Patients with renal impairment (see section "Dosage and administration"). In patients with impaired renal function, renal excretion of ramiprilat is reduced, and the renal clearance of ramiprilat is proportional to creatinine clearance. This results in elevated plasma concentrations of ramiprilat, which decline more slowly than in individuals with normal renal function.

Patients with hepatic impairment (see section "Dosage and administration"). In patients with impaired liver function, the metabolism of ramipril to ramiprilat is slowed due to reduced activity of hepatic esterases, and plasma levels of ramipril are elevated. However, maximum concentrations of ramiprilat in these patients do not differ from those in individuals with normal liver function.

Lactation period. After a single oral dose, neither ramipril nor its metabolites were detected in breast milk. However, the effect of multiple dosing is unknown.

Pediatric population. The pharmacokinetic profile of ramipril was studied in 30 children aged 2–16 years with arterial hypertension and body weight >10 kg. After administration of doses ranging from 0.05 to 0.2 mg/kg, ramipril was rapidly and extensively metabolized to ramiprilat. Maximum plasma concentrations of ramiprilat were achieved within 2–3 hours. Ramiprilat clearance was significantly correlated with the logarithm of body weight (p < 0.01) and with the administered dose (p < 0.001). Clearance and volume of distribution increased proportionally with age within each dose group. Administration of a dose of 0.05 mg/kg in children achieved exposure levels comparable to those in adults receiving a 5 mg dose of ramipril. Administration of a 0.2 mg/kg dose in children resulted in exposure levels higher than those achieved with the maximum recommended adult dose of 10 mg/day.

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

Treatment of symptomatic heart failure.

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 of the medicinal product, or to other ACE inhibitors.

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

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

Pregnancy and planned pregnancy (see section "Use during pregnancy or breast-feeding").

Arterial hypotension or hemodynamically unstable conditions.

Concomitant use of Ramipril-Teva with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal dysfunction (eGFR < 60 mL/min/1.73 m²) (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use with sacubitril/valsartan is contraindicated. Treatment with Ramipril-Teva may be initiated only 36 hours after the last dose of sacubitril/valsartan (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ACE inhibitors and extracorporeal treatment methods leading to blood contact with negatively charged surfaces must be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Contraindicated combinations.

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 switching to another class of antihypertensive agents.

Medicinal products that increase the risk of angioedema. 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 treatment should be initiated only 36 hours after the last dose of sacubitril/valsartan. Sacubitril/valsartan treatment should be initiated only 36 hours after the last dose of ramipril.

Concomitant use of ACE inhibitors with racecadotril, mammalian target of rapamycin (mTOR) inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin may increase the risk of angioedema (see section "Special precautions for use").

Combinations requiring precautions.

Potassium-sparing diuretics, potassium-containing dietary supplements, or potassium-containing salt substitutes. Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients receiving this medicinal product. Potassium-sparing diuretics (such as spironolactone, triamterene, or amiloride), potassium-containing dietary supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium levels. Caution is also required when Ramipril-Teva is used concomitantly with other medicinal products that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic, similar to amiloride. Therefore, combination of Ramipril-Teva with the above-mentioned medicinal products is not recommended. If concomitant use is indicated, treatment should be administered with caution and serum potassium levels should be monitored frequently (see section "Special precautions for use").

Cyclosporine. Hyperkalemia may occur when ACE inhibitors are used concomitantly with cyclosporine. Monitoring of serum potassium levels is recommended.

Heparin. Hyperkalemia may occur when ACE inhibitors are used concomitantly with heparin. Monitoring of serum potassium levels is recommended.

Tacrolimus. 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 "Dosage and administration" regarding diuretics).

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

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics, 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. Serum 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 Ramipril-Teva is expected. Additionally, concomitant use of ACE inhibitors and NSAIDs may be associated with an increased risk of worsening renal function and elevated serum potassium levels.

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

Special precautions for use.

Special patient groups.

Pregnancy. Treatment with ACE inhibitors (such as ramipril) or angiotensin II receptor antagonists should not be initiated during pregnancy. ACE inhibitors or angiotensin II receptor antagonists should be used during pregnancy only if absolutely necessary. Patients planning pregnancy should be switched to an alternative antihypertensive agent considered safe during pregnancy. As soon as pregnancy is diagnosed, treatment with ACE inhibitors/angiotensin II receptor antagonists should be discontinued immediately and, if necessary, therapy with another agent should be initiated (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Patients at risk of developing arterial hypotension.

Patients with markedly increased RAAS activity

Patients with markedly increased RAAS activity are at risk of sudden, marked reduction in blood pressure and worsening of renal function due to ACE inhibition, particularly when the ACE inhibitor or concomitant diuretic is used for the first time or the dose is increased for the first time.

Markedly increased RAAS activity requiring medical supervision, including continuous monitoring of blood pressure, 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 receiving anesthetics that may cause arterial hypotension.

In general, correction of dehydration, hypovolemia, or electrolyte depletion is recommended prior to initiating treatment (however, for patients with heart failure, such corrective measures should be carefully weighed against the risk of volume overload).

Dual blockade of the RAAS

Concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren has been associated with increased risk of arterial hypotension, hyperkalemia, and worsening of 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 "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction").

If therapy involving such dual blockade 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.

Transient or persistent heart failure following myocardial infarction
Patients at risk of 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, particularly during the first weeks of therapy. Close monitoring is especially 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, as well as in cases of renal vascular disease, including patients with hemodynamically significant unilateral renal artery stenosis.

Hypersensitivity/angioedema. Angioedema has been observed in patients receiving ACE inhibitors, including ramipril (see section "Adverse reactions"). If angioedema develops, treatment with Ramipril-Teva should be discontinued immediately and emergency therapy initiated. 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 ramipril (see section "Adverse reactions"). Patients presented with abdominal pain (with or without nausea/vomiting).

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Treatment with sacubitril/valsartan may be initiated only 36 hours after the last dose of Ramipril-Teva. Treatment with Ramipril-Teva may be initiated only 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (mammalian target of rapamycin) (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin may increase the risk of angioedema (e.g., airway or tongue swelling, with or without respiratory compromise) (see section "Interaction with other medicinal products and other forms of interaction").

Caution should be exercised when initiating racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin in patients already receiving an ACE inhibitor.

Anaphylactic reactions during desensitization. The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased during ACE inhibitor therapy. Therefore, temporary discontinuation of Ramipril-Teva is recommended prior to desensitization.

Monitoring of electrolyte balance: serum potassium levels. Hyperkalemia has been observed in some patients receiving ACE inhibitors, including ramipril. Patients at risk of hyperkalemia include those with renal impairment, patients aged 70 years or older, patients with uncontrolled diabetes mellitus, and patients with conditions such as dehydration, acute heart decompensation, or metabolic acidosis.

ACE inhibitors may cause hyperkalemia because they inhibit aldosterone release. This effect is usually minor in patients with normal renal function. However, hyperkalemia may occur in patients with impaired renal function and/or in patients taking potassium-containing dietary supplements (including salt substitutes), potassium-sparing diuretics, other agents that increase serum potassium levels (e.g., heparin, trimethoprim or co-trimoxazole, also known as trimethoprim/sulfamethoxazole), and particularly aldosterone antagonists or angiotensin receptor antagonists. Caution is advised when using potassium-sparing diuretics or angiotensin receptor antagonists in patients taking ACE inhibitors. Serum potassium levels and renal function should be monitored in such patients (see section "Interaction with other medicinal products and other forms of interaction").

If concomitant use of the above-mentioned agents is considered appropriate, 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 with subsequent 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 careful monitoring is recommended 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 cause blood count abnormalities (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 patients of other races. The antihypertensive effect of ramipril, as with other ACE inhibitors, may be less pronounced in black patients compared to patients of other races. This may be due to the higher prevalence of low-renin hypertension in black patients.

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.

Ramipril-Teva contains lactose monohydrate and therefore should not be used in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Sodium content. This medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy. This medicinal product is contraindicated in pregnant women or women who may become pregnant. If pregnancy occurs during treatment, the drug should be discontinued immediately and, if necessary, replaced with another medicinal product approved for use during pregnancy (see section "Contraindications").

Breastfeeding. Due to lack of information on the use of ramipril during breastfeeding (see section "Pharmacological properties"), this drug is not recommended for breastfeeding women; preference should be given to other medicinal products considered safer during lactation, especially when breastfeeding newborns or preterm infants.

Ability to affect reaction speed when driving or operating machinery.

Some adverse effects (e.g., symptoms of low blood pressure such as dizziness) may impair the patient's ability to concentrate and reduce reaction speed, which may be hazardous in situations where these abilities are particularly important (e.g., driving vehicles or operating machinery).

This is usually possible at the beginning of treatment or when switching from therapy with other drugs to Ramipril-Teva. 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 medicinal product is for oral use.

Ramipril-Teva should be taken daily at the same time each day. The product can be taken before, during, or after meals, as food does not affect the bioavailability of the drug. Ramipril-Teva tablets should be swallowed whole with water. Tablets may be divided into equal doses but must not be chewed or crushed.

To divide a tablet, place it on a flat, hard surface (e.g., a table) and press with the index or thumb fingers of both hands on either side of the break line on the outer surface of the tablet.

If the prescribed dose cannot be administered, ramipril in the appropriate dosage strength should be used instead.

Adults

Patients receiving diuretics
At the beginning of treatment with Ramipril-Teva, arterial hypotension may occur, particularly in patients concurrently receiving diuretics. Caution is advised in such cases, as these patients may have reduced blood volume and/or electrolyte levels.

If possible, it is recommended to discontinue diuretic therapy 2–3 days before initiating treatment with Ramipril-Teva (see section "Special Warnings and Precautions for Use").

In hypertensive patients in whom diuretic discontinuation is not feasible, treatment with Ramipril-Teva should be initiated at a dose of 1.25 mg. Renal function and serum potassium levels should be closely monitored. The dosage of Ramipril-Teva should then be adjusted based on the target blood pressure level.

Arterial Hypertension

Dosage should be individualized according to the patient's clinical condition (see section "Special Warnings and Precautions for Use") and blood pressure monitoring results. Ramipril-Teva may be used as monotherapy or in combination with other classes of antihypertensive medicinal products (see sections "Pharmacodynamics", "Contraindications", "Interaction with Other Medicinal Products and Other Forms of Interaction", "Special Warnings and Precautions for Use").

Initial Dose
Treatment with Ramipril-Teva 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), marked reduction in arterial 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 Warnings and Precautions for Use").

Dose Titration and Maintenance Dose
The dose may be doubled every 2–4 weeks until the target blood pressure is achieved. The maximum daily dose of Ramipril-Teva is 10 mg. The drug is generally administered once daily.

Prevention of Cardiovascular Diseases

Initial Dose
The recommended initial dose of Ramipril-Teva is 2.5 mg once daily.

Dose Titration and Maintenance Dose
Depending on individual tolerability, the dose should be gradually increased. It is recommended to double the dose after 1–2 weeks of treatment, then increase to the target maintenance dose of 10 mg once daily after another 2–3 weeks (also see above regarding dosing in patients receiving diuretics).

Treatment of Kidney Disease

In Patients with Diabetes and Microalbuminuria

Initial Dose
The recommended initial dose of Ramipril-Teva is 1.25 mg once daily.

Dose Titration and Maintenance Dose
Depending on individual tolerability, the dose should be increased during continued treatment. After 2 weeks of treatment, the daily dose should be doubled to 2.5 mg, and then increased to 5 mg after another 2 weeks of treatment.

In Patients with Diabetes and at Least One Cardiovascular Risk Factor

Initial Dose
The recommended initial dose of Ramipril-Teva is 2.5 mg once daily.

Dose Titration and Maintenance Dose
Depending on individual tolerability, the dose should be increased during continued treatment. After 1–2 weeks of treatment, the daily dose should be doubled to 5 mg, and then increased to 10 mg after another 2–3 weeks of treatment. The target daily dose is 10 mg.

In Patients with Non-Diabetic Nephropathy, Indicated by Macroproteinuria ≥ 3 g/day

Initial Dose
The recommended initial dose of Ramipril-Teva is 1.25 mg once daily.

Dose Titration and Maintenance Dose
Depending on individual patient tolerability, the dose should be increased during continued treatment. After 2 weeks of treatment, the daily dose should be doubled to 2.5 mg, and then increased to 5 mg after another 2 weeks of treatment.

Heart Failure with Clinical Manifestations

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

Dose Titration and Maintenance Dose
The dose of Ramipril-Teva should be titrated by doubling every 1–2 weeks until the maximum daily dose of 10 mg is reached. The dose should preferably be divided into two daily doses.

Secondary Prevention Following Acute Myocardial Infarction in the Presence of Heart Failure

Initial Dose
Starting 48 hours after the onset of myocardial infarction, patients with clinically and hemodynamically stable conditions 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, a dose of 1.25 mg 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.

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

Whenever 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 medicinal product is considered necessary, therapy should be initiated at a dose of 1.25 mg once daily, and any dose escalation should be performed with extreme caution (also see above regarding dosing in patients receiving diuretics).

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 once daily) is required; the maximum daily dose is 10 mg;
If creatinine clearance is 30–60 mL/min, no adjustment of the initial dose (2.5 mg once daily) is required; the maximum daily dose is 5 mg;
If creatinine clearance is 10–30 mL/min, the initial daily dose is 1.25 mg once daily, and the maximum daily dose is 5 mg;
Patients with arterial hypertension undergoing hemodialysis: Ramipril is only minimally removed by hemodialysis; the initial dose is 1.25 mg, and the maximum daily dose is 5 mg; the product should be taken several hours after a hemodialysis session.

Patients with Hepatic Impairment (see section "Pharmacological Properties")
Treatment with Ramipril-Teva in patients with hepatic impairment should be initiated under close 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 increased risk of adverse effects, especially in very elderly and frail patients. In such cases, a lower initial dose of 1.25 mg of ramipril should be prescribed.

Children

Ramipril-Teva is not recommended for use in children (under 18 years of age), as there is insufficient data on efficacy and safety in this patient population.

Overdose

Symptoms associated with angiotensin-converting enzyme (ACE) inhibitor overdose may include excessive peripheral vasodilation (with marked hypotension and shock), bradycardia, electrolyte imbalances, and renal failure. Close monitoring of the patient is required, along with symptomatic and supportive therapy. Recommended treatment measures include primary decontamination (gastric lavage, administration of adsorbents) and interventions aimed at restoring 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.

Side effects.

The safety profile of the medicinal product Ramipril-Teva includes data on persistent cough and reactions caused by arterial hypotension. Serious adverse reactions include angioedema, hyperkalemia, hepatic or renal function impairment, pancreatitis, severe skin reactions, and neutropenia/agranulocytosis.

The frequency of adverse reactions is classified as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Within each category, adverse reactions are listed in order of decreasing clinical severity.

Cardiac disorders. Uncommon: myocardial ischemia (including angina or myocardial infarction), tachycardia, arrhythmia, palpitations, peripheral edema.

Blood and lymphatic system disorders. Uncommon: eosinophilia. Rare: decreased leukocyte count (including neutropenia or agranulocytosis), decreased erythrocyte count, decreased hemoglobin levels, thrombocytopenia. Not known: bone marrow failure, pancytopenia, hemolytic anemia.

Nervous system disorders. Common: headache, dizziness. Uncommon: vertigo, paresthesia, ageusia, dysgeusia. Rare: tremor, loss of balance. Not known: cerebral ischemia (including ischemic stroke and transient ischemic attack), psychomotor disturbances, burning sensation, parosmia.

Eye disorders. Uncommon: visual disturbances, including blurred vision. Rare: conjunctivitis.

Ear and labyrinth disorders. Rare: hearing disturbances, tinnitus.

Respiratory, thoracic and mediastinal disorders. Common: non-productive irritating cough, bronchitis, sinusitis, dyspnea. Uncommon: bronchospasm, including asthma exacerbation; nasal congestion.

Gastrointestinal disorders. Common: gastrointestinal inflammation, digestive disorders, abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting. Uncommon: pancreatitis (in isolated cases fatal outcomes have been reported with ACE inhibitors); increased pancreatic enzyme levels, angioedema of the small intestine, upper abdominal pain including gastritis, constipation, dry mouth. Rare: glossitis. Not known: aphthous stomatitis.

Renal and urinary disorders. Uncommon: renal function impairment, including acute renal failure, increased diuresis, worsening of background proteinuria, increased blood urea levels, increased serum creatinine levels.

Skin and subcutaneous tissue disorders. Common: skin rashes, particularly maculopapular. Uncommon: angioedema; in very rare cases — airway obstruction due to angioedema, which may be fatal; pruritus, hyperhidrosis. Rare: exfoliative dermatitis, urticaria, onycholysis. Very rare: photosensitivity reaction. Not known: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, exacerbation of psoriasis, psoriatic dermatitis, pemphigoid or lichenoid exanthema or enanthema, alopecia.

Musculoskeletal and connective tissue disorders. Common: muscle spasms, myalgia. Uncommon: arthralgia.

Endocrine disorders. Not known: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders. Common: increased blood potassium levels. Uncommon: anorexia, decreased appetite. Not known: decreased blood sodium levels.

Vascular disorders. Common: arterial hypotension, orthostatic hypotension, syncope. Uncommon: sensation of flushing. Rare: vascular stenosis, hypoperfusion, vasculitis. Not known: Raynaud's syndrome.

General disorders and administration site conditions. Common: chest pain, fatigue. Uncommon: pyrexia. Rare: asthenia.

Immune system disorders. Not known: anaphylactic and anaphylactoid reactions, increased levels of antinuclear antibodies.

Hepatobiliary disorders. Uncommon: increased levels of liver enzymes and/or conjugated bilirubin. Rare: cholestatic jaundice, hepatocellular damage. Not known: acute liver failure, cholestatic or cytolytic hepatitis (in very rare cases with fatal outcome).

Reproductive system and breast disorders. Uncommon: transient erectile dysfunction, decreased libido. Not known: gynecomastia.

Psychiatric disorders. Uncommon: depressed mood, anxiety, nervousness, restlessness, sleep disturbances, including somnolence. Rare: confusion. Not known: attention disturbances.

Pediatric population. The safety of ramipril has been evaluated in 325 children and adolescents aged 2–16 years in two clinical trials. According to the results, the type and severity of adverse reactions in children were similar to those observed in adults, but the frequency of certain reactions was higher in children than in adults, namely:

Tachycardia, nasal congestion, and rhinitis: common (≥ 1/100 to < 1/10) in pediatric population vs. uncommon (≥ 1/1,000 to < 1/100) in adults;
Conjunctivitis: common (≥ 1/100 to < 1/10) in pediatric population vs. rare (≥ 1/10,000 to < 1/1,000) in adults;
Tremor and urticaria: uncommon (≥ 1/1,000 to < 1/100) in pediatric population vs. rare (≥ 1/10,000 to < 1/1,000) in adults.

Overall, the safety profile of ramipril in children does not differ significantly from that in adults.

Reporting of suspected adverse reactions. All suspected adverse reactions and cases of lack of drug efficacy should be reported via the following link: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C. Keep in the original packaging to protect from moisture. Keep out of reach and sight of children.

Packaging. 10 tablets per blister, 3 or 6 blisters per carton.

Prescription status. Prescription only.

Manufacturer. Merckle GmbH.

Manufacturer's address and place of business.

Ludwig-Merckle-Straße 3, 89143 Blaubeuren, Germany.

Ramipril-teva