Ramises

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RАМІZЕS® (RAMiZES)

Composition:

Active substance: ramipril;

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

Excipients:

tablets of 2.5 mg: sodium hydrocarbonate, monohydrate lactose, sodium croscarmellose, pregelatinized starch 1500, magnesium stearate, yellow iron oxide (E 172);

tablets of 5 mg: sodium hydrocarbonate, monohydrate lactose, sodium croscarmellose, pregelatinized starch 1500, magnesium stearate, yellow iron oxide (E 172), red iron oxide (E 172);

tablets of 10 mg: sodium hydrocarbonate, monohydrate lactose, sodium croscarmellose, pregelatinized starch 1500, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

tablets of 2.5 mg: flat cylindrical tablets, light yellow in color, with beveled edges and a score line, with a weak specific odor or odorless. Slight specks and marbling on the tablet surface are permissible;

tablets of 5 mg: flat cylindrical tablets, light pink in color, with beveled edges and a score line, with a weak specific odor or odorless. Slight specks and marbling on the tablet surface are permissible;

tablets of 10 mg: flat cylindrical tablets, white or almost white in color, with beveled edges and a score line, with a weak specific odor or odorless. Slight marbling on the tablet surface is permissible.

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

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Ramiprilat, the active metabolite of the prodrug ramipril, is an inhibitor of the enzyme dipeptidyl carboxypeptidase I (synonyms: angiotensin-converting enzyme; 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. The reduction in angiotensin II formation and inhibition of bradykinin breakdown lead to vasodilation. Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a reduction in aldosterone secretion. The response to monotherapy with ACE inhibitors has generally been less pronounced in non-Caucasian (Afro-Caribbean origin) patients with arterial hypertension (a population characterized by low renin levels in arterial hypertension) compared to patients of other racial groups.

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

In most patients, the antihypertensive effect occurs within 1–2 hours after oral administration of a single dose. The maximum effect after a single oral dose usually occurs within 3–6 hours. The antihypertensive effect after a single dose generally 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 a rapid and excessive increase in blood pressure (rebound phenomenon).

Heart failure. Ramipril, when used as an adjunct to conventional therapy with diuretics and, if necessary, cardiac glycosides, has been shown to be effective in patients with heart failure of 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.

Clinical efficacy and safety.

Prevention of cardiovascular diseases/nephroprotection.

A preventive, placebo-controlled study (the HOPE study) involving over 9,200 patients who received ramipril in addition to standard therapy was conducted. This study included patients at high risk of developing cardiovascular disease following a history of atherothrombotic cardiovascular disease (presence of ischemic heart disease, stroke, or peripheral vascular disease) or patients with diabetes mellitus who had at least one additional risk factor (documented microalbuminuria, arterial hypertension, elevated total cholesterol, low-density lipoprotein cholesterol, or smoking).

This study demonstrated that ramipril significantly reduces the incidence of myocardial infarction, cardiovascular mortality, and stroke, both individually and in combination (primary composite endpoint).

The MICRO-HOPE study, a pre-planned substudy of the HOPE study, evaluated the effect of adding ramipril 10 mg to existing treatment regimens compared to placebo in patients aged 55 years and older (no upper age limit) with normal or elevated blood pressure, most of whom had type 2 diabetes mellitus (and at least one cardiovascular risk factor).

The primary analysis results showed that overt nephropathy developed in 6.5% of participants receiving ramipril and in 8.4% receiving placebo, representing a 24% relative risk reduction; 95% CI [3–40], p = 0.027.

The REIN study, a multicenter, randomized, double-blind, placebo-controlled, parallel-group study, was conducted to evaluate the effect of ramipril treatment on the rate of decline in glomerular filtration rate (GFR) in patients with normal or elevated blood pressure (aged 18–70 years) who had mild (urinary protein excretion > 1 and < 3 g/day) or severe proteinuria (≥ 3 g/day) due to chronic non-diabetic nephropathy. Both subgroups were prospectively stratified.

The main analysis results in patients with the most severe proteinuria (a subgroup that prematurely discontinued participation in the study because benefit from treatment in the ramipril group was proven) demonstrated that the mean rate of decline in GFR per month was lower with ramipril than with placebo. The between-group difference was 0.34 [0.03–0.65] mL/min/month, approximately 4 mL/min/year; 23.1% of patients in the ramipril group reached the combined secondary endpoint – doubling of plasma creatinine concentration and/or end-stage renal disease (requirement for hemodialysis or kidney transplantation) – compared to 45.5% in the placebo group.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Two large-scale randomized controlled trials [ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (Veterans Affairs Nephropathy in Diabetes trial)] evaluated the use of a combination of an ACE inhibitor with an angiotensin II receptor antagonist.

The ONTARGET trial included patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with associated target organ damage. The VA NEPHRON-D trial included patients with type 2 diabetes and diabetic nephropathy.

These studies did not show significant advantages of combination therapy regarding renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalemia, acute renal failure, and/or arterial hypotension was observed compared to monotherapy. Given the similar pharmacodynamic characteristics of these drugs, these results are also applicable to other ACE inhibitors and angiotensin II receptor antagonists.

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

The ALTITUDE trial (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints) evaluated the benefits of adding aliskiren to standard therapy with an ACE inhibitor or angiotensin II receptor antagonist in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. This trial was terminated prematurely due to an increased risk of adverse clinical outcomes. In the aliskiren group compared to the placebo group, there was a higher incidence of cardiovascular mortality and stroke, as well as an increased frequency of serious adverse events of special interest (hyperkalemia, arterial hypotension, and renal dysfunction).

Secondary prevention after acute myocardial infarction. The AIRE study included patients with transient/persistent symptoms of heart failure after myocardial infarction. Ramipril treatment was initiated 3–10 days after the onset of acute myocardial infarction. This study demonstrated that after a mean follow-up period of 15 months, mortality in the ramipril group was 16.9%, compared to 22.6% in the placebo group. This represents an absolute reduction in mortality of 5.7% and a relative risk reduction of 27%.

Pediatric population. In a randomized, double-blind, placebo-controlled clinical trial involving pediatric patients with arterial hypertension (73% of whom had primary arterial hypertension), aged 6–16 years, participants received low, medium, or high doses of ramipril to achieve plasma concentrations of ramiprilat corresponding to adult dose ranges of 1.25 mg, 5 mg, and 20 mg, adjusted for body weight. After completion of the 4-week period, ramipril was found to be ineffective regarding the primary endpoint – reduction in systolic blood pressure – but it reduced diastolic pressure when the highest dose in the studied range was used. It was shown that both medium and high doses of ramipril significantly reduced systolic and diastolic blood pressure in children with confirmed arterial hypertension.

This effect was not observed in a 4-week, randomized, double-blind, dose-escalation trial evaluating the effect of drug withdrawal, involving pediatric patients aged 6–16 years (75% of whom had primary arterial hypertension). In this trial, after discontinuation of the drug, a moderate rebound increase in both diastolic and systolic pressure was observed, but it was not statistically significant for returning pressure to baseline levels in all dose groups of the studied ramipril range [low doses (0.625–2.5 mg), medium doses (2.5–10 mg), or high doses (5–20 mg)] adjusted for body weight. In the studied pediatric population, ramipril did not exhibit a linear dose-dependent effect.

Pharmacokinetics.

Absorption. After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract. Maximum plasma concentration is reached within 1 hour. Based on the amount of substance found in urine, the extent 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 doses of 2.5 mg and 5 mg is 45%.

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

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

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

Excretion. Metabolite excretion occurs predominantly 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 has a prolonged terminal elimination phase at very low plasma concentrations.

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

After oral administration of a single dose, neither ramipril nor its metabolite was detected in breast milk. However, the effect of repeated dosing is unknown.

Patients with impaired renal function (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 leads to elevated plasma concentrations of ramiprilat, which decline more slowly than in individuals with normal renal function.

Patients with impaired hepatic function (see section "Dosage and administration"). In patients with impaired hepatic 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.

Breastfeeding. After administration of a single oral dose of ramipril, its level in breast milk was below the limit of detection. However, the effect of multiple dosing is unknown.

Pediatric population. The pharmacokinetic profile of ramipril was studied in 30 pediatric patients with arterial hypertension aged 2–16 years with 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 concentration of ramiprilat was achieved within 2–3 hours. Ramiprilat clearance correlated significantly with the logarithm of body weight (p < 0.01) and with the dose of the drug (p < 0.001). Clearance and volume of distribution increased proportionally with age in each dosing 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 achieved exposure levels higher than those achieved with the maximum recommended adult dose of 10 mg daily.

Preclinical safety data. Oral administration of ramipril to rodents and dogs did not cause acute toxic effects. Long-term oral administration studies were conducted in rats, dogs, and monkeys. In all three species, changes in electrolyte balance and blood parameters were observed. In dogs and monkeys receiving the drug at a dose of 250 mg/kg body weight per day, a marked increase in the juxtaglomerular apparatus was observed, which is a manifestation of the pharmacodynamic activity of ramipril. Rats, dogs, and monkeys tolerated daily doses of the drug of 2, 2.5, and 8 mg/kg body weight per day, respectively, without adverse effects.

Reproductive toxicity studies conducted in rats, rabbits, and monkeys did not reveal any teratogenic properties of the drug. No adverse effects on fertility were observed in either male or female rats.

Administration of ramipril to female rats during pregnancy and lactation resulted in irreversible kidney damage (renal pelvis dilation) in offspring at doses of 50 mg/kg body weight per day and higher.

Numerous mutagenicity tests using various test systems did not reveal mutagenic or genotoxic properties of ramipril.

Clinical characteristics.

Indications.

Treatment of arterial hypertension.

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

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

Treatment of heart failure with 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 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 (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 renal artery stenosis in a single functioning kidney.

Pregnancy and planned pregnancy (see section "Use in pregnancy and lactation").

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

Concomitant use of ramipril with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal dysfunction (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 and extracorporeal treatment methods that involve blood contact with negatively charged surfaces should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Clinical trial data have shown that dual blockade of the RAAS pathway 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 agent affecting the RAAS (see sections "Contraindications", "Special precautions for use", and "Pharmacodynamics").

Contraindicated combinations.

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an 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 ramipril.

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 an 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.

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 reducing arterial 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 ramipril. Careful monitoring of arterial pressure is recommended.

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. Lithium levels should be closely monitored.

Antidiabetic agents, including insulin. Hypoglycemic reactions may occur. Close monitoring of blood glucose levels is recommended.

Non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid. A reduced antihypertensive effect of ramipril is expected. Moreover, 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 drug.

Specific allergen immunotherapy. Due to ACE inhibition, the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom may increase. This effect is also considered possible with other allergens.

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

Racecadotril. There have been reports of a potential increased risk of angioedema when ACE inhibitors are used concomitantly with neutral endopeptidase (NEP) inhibitors, such as racecadotril (see section "Special precautions for use").

Special precautions for use.

Special patient groups

Pregnancy. Treatment with ACE inhibitors or angiotensin II receptor antagonists should not be initiated 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 another 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").

Dual blockade of the RAAS. Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of arterial hypotension, hyperkalaemia, and impaired renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combined use of 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, 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.

Patients at particular risk of arterial hypotension.

Patients with markedly increased RAAS activity. In patients with markedly increased RAAS activity, there is a risk of sudden, significant reduction in blood pressure and worsening of renal function due to ACE inhibition, especially when the ACE inhibitor or a 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 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 receiving anaesthetics that may cause arterial hypotension.

In general, correction of dehydration, hypovolaemia, 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).

Transient or persistent heart failure after myocardial infarction.

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

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

Surgery. If possible, treatment with ACE inhibitors such as ramipril should be discontinued one day before 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 required in patients with impaired renal function (see section "Method of administration and dosage"). 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.

Angioedema. Angioedema has been observed in patients receiving ACE inhibitors, including ramipril (see section "Adverse reactions"). This risk is increased in patients receiving concomitant medicinal products such as mammalian target of rapamycin (mTOR) inhibitors (e.g., temsirolimus, everolimus, sirolimus), vildagliptin, or racecadotril.

The 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").

If angioedema occurs, administration of Ramises**®** should be discontinued immediately. Emergency treatment must 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 Ramises**®** (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 during ACE inhibitor therapy. Ramipril (Ramises**®**) should be temporarily discontinued prior to desensitization procedures.

Monitoring electrolyte balance. Hyperkalaemia. Hyperkalaemia has been observed in some patients receiving ACE inhibitors, including Ramises**®**. Patients at risk of hyperkalaemia include those with renal impairment, patients aged 70 years or older, patients with uncontrolled diabetes mellitus, patients receiving potassium supplements or potassium-sparing diuretics, patients receiving other active substances that increase plasma potassium levels, or patients with conditions such as dehydration, acute heart decompensation, or metabolic acidosis. 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 electrolyte balance. Hyponatraemia. The syndrome of inappropriate antidiuretic hormone secretion with subsequent hyponatraemia has been observed in some patients receiving ramipril. Regular monitoring of serum sodium levels is recommended, particularly in elderly patients and other patients at risk of hyponatraemia.

Neutropenia/agranulocytosis. Cases of neutropenia/agranulocytosis, as well as thrombocytopenia and anaemia, have been reported rarely. Bone marrow suppression has also been reported. To detect possible leucopenia, monitoring of white blood cell counts 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 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 patients of black race than in other racial groups. As with other ACE inhibitors, the antihypertensive effect of ramipril may be less pronounced in patients of black race compared to other racial 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 ACE inhibitor therapy. 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.

The medicinal product contains lactose; therefore, patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

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

Use during pregnancy or breastfeeding.

Pregnancy. The drug is contraindicated in pregnant women or women planning pregnancy. 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 medicinal product is not recommended for breastfeeding women. Alternative medicinal products with a more favourable safety profile during lactation should be preferred, 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 a patient's ability to concentrate and reduce reaction speed, posing a risk in situations where these abilities are particularly important (e.g., when driving vehicles or operating machinery).

This is generally possible at the beginning of treatment or when switching from another therapy to Ramises**®**. 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.

RamiZES® should be taken daily at the same time each day. RamiZES® can be taken before, during, or after meals, as food intake does not affect its bioavailability. RamiZES® tablets should be swallowed whole with water. They must not be chewed or crushed.

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

Adults.

Patients receiving diuretics. At the beginning of ramipril therapy, arterial hypotension may occur, and this is more likely in patients concurrently receiving diuretics. In such cases, caution is recommended, as these patients may have reduced circulating blood volume and/or electrolyte depletion.

If possible, it is advisable to discontinue diuretic therapy 2–3 days before starting treatment with RamiZES® (see section "Special Warnings and Precautions for Use").

In patients with arterial hypertension who cannot discontinue diuretic therapy, ramipril treatment should be initiated at a dose of 1.25 mg (use ramipril in the corresponding dosage strength). Renal function and serum potassium levels should be closely monitored. Subsequent ramipril dosing should be adjusted according to the target blood pressure level.

Arterial Hypertension.

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

Initial Dose. Treatment with RamiZES® 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 (use ramipril in the corresponding dosage strength), 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 level is achieved; the maximum dose of RamiZES® is 10 mg once daily. The drug is generally taken once daily.

Prevention of Cardiovascular Diseases.

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

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

Treatment of Kidney Disease.

Patients with Diabetes and Microalbuminuria.

Initial Dose. The recommended initial dose of ramipril is 1.25 mg (use ramipril in the corresponding dosage strength) once daily.

Dose Titration and Maintenance Dose. Depending on individual tolerance during continued treatment, the dose should be increased. 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.

Patients with Diabetes and at Least One Cardiovascular Risk Factor.

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

Dose Titration and Maintenance Dose. Depending on individual tolerance during continued treatment, the dose should be increased. After 1–2 weeks of treatment, the daily dose of ramipril 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.

Patients with Non-Diabetic Nephropathy Characterized by Macroproteinuria ≥ 3 g/day.

Initial Dose. The recommended initial dose of ramipril is 1.25 mg (use ramipril in the corresponding dosage strength) once daily.

Dose Titration and Maintenance Dose. Depending on individual patient tolerance during continued treatment, the dose should be increased. 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 with diuretic therapy, the recommended initial dose is 1.25 mg (use ramipril in the corresponding dosage strength) once daily.

Dose Titration and Maintenance Dose. Ramipril dose should be titrated by doubling every 1–2 weeks until the maximum daily dose of 10 mg is reached. It is preferable to divide the daily 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, in patients whose condition is clinically and hemodynamically stable, initiate treatment with an initial dose of 2.5 mg twice daily for 3 days. If the initial dose of 2.5 mg is poorly tolerated, then administer 1.25 mg (use ramipril in the corresponding dosage strength) twice daily for 2 days, followed by escalation to 2.5 mg and then 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. Subsequently, increase the daily dose by doubling at intervals of 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 functional class IV) heart failure immediately after myocardial infarction is still limited. If treatment of such patients is nevertheless initiated, therapy should start at a dose of 1.25 mg (use ramipril in the corresponding dosage strength) 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/day (use ramipril in the corresponding dosage strength), and the maximum daily dose is 5 mg;
• patients with arterial hypertension undergoing hemodialysis: ramipril is removed to a negligible extent during hemodialysis; the initial dose is 1.25 mg (use ramipril in the corresponding dosage strength), 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"). Ramipril therapy in patients with hepatic impairment should be initiated 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 subsequent dose titration should be performed more gradually due to the higher risk of adverse effects, especially in very elderly and frail patients. In such cases, a lower initial dose of 1.25 mg ramipril (use ramipril in the corresponding dosage strength) should be prescribed.

(see also the information above regarding dosing for patients receiving diuretics).

Children.

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

Overdose.

Symptoms associated with angiotensin-converting enzyme (ACE) inhibitor overdose may include excessive peripheral vasodilation (with marked hypotension, shock), bradycardia, electrolyte imbalances, and renal failure. The patient should be closely monitored and symptomatic and supportive therapy should be administered. Proposed therapeutic measures include primary detoxification (gastric lavage, administration of adsorbents), as well as interventions aimed at restoring stable hemodynamics, 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 ramipril includes data on persistent cough and reactions due to 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 frequency group, adverse events are listed in order of decreasing severity.

Pediatric population. The safety of ramipril was evaluated in 325 children and adolescents aged 2–16 years in two clinical trials. According to the results, the nature and severity of adverse reactions in children were similar to those observed in adults; however, 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 the pediatric population and uncommon (≥ 1/1000 to < 1/100) in adult patients.

Conjunctivitis: common (≥ 1/100 to < 1/10) in the pediatric population and rare (≥ 1/10,000 to < 1/1000) in adult patients.

Tremor and urticaria: uncommon (≥ 1/1000 to < 1/100) in the pediatric population and rare (≥ 1/10,000 to < 1/1000) in adult patients.

The overall safety profile of ramipril in children and adults does not differ significantly.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product.

Healthcare professionals should report any adverse reactions via the pharmacovigilance system of Ukraine.

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. Store in the original packaging at a temperature not exceeding 25°C.

Keep out of reach and sight of children.

Packaging. 10 tablets in a blister. 1 or 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's name and address of the place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.