Ramimed

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RАMIMED® (RAMIMED)

Composition:

Active substance: ramipril;

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

Excipients: pregelatinized starch (starch 1500); sodium hydrocarbonate; lactose monohydrate; sodium croscarmellose; sodium stearyl fumarate;

Colorants:
tablelets 2.5 mg – colorant PB22960 yellow (lactose monohydrate; iron oxide yellow (E 172));
tablets 5 mg – colorant PB24877 pink (lactose monohydrate; iron oxide red (E 172); iron oxide yellow (E 172)).

Pharmaceutical form. Tablets.

Main physicochemical properties:

2.5 mg tablets – pale yellow, capsule-shaped, flat uncoated tablets with bevelled edges, with a score line on one side and inscriptions "R 2" on both sides, approximately 10.0 × 5.0 mm in size;

5.0 mg tablets – pale pink, capsule-shaped, flat uncoated tablets with bevelled edges, with a score line on one side and inscriptions "R 3" on both sides, approximately 8.8 × 4.4 mm in size;

10 mg tablets – white or almost white, capsule-shaped, flat uncoated tablets with bevelled edges, with a score line on one side and inscriptions "R 4" on both sides, approximately 11.0 × 5.5 mm in size.

Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors. Single-component ACE inhibitors. 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 (also known as angiotensin-converting enzyme; kinase 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 bradykin inflamm degradation 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 patients of non-Caucasian race (African-Caribbean origin) with arterial hypertension (a population typically characterized by low renin levels in arterial hypertension) compared to patients of other racial groups.

Antihypertensive properties. Administration of ramipril results in significant reduction of peripheral arterial pressure. Generally, no substantial changes in renal plasma flow or glomerular filtration rate occur. Administration of ramipril to patients with arterial hypertension leads to reduction in arterial pressure both in the supine and upright positions, without compensatory increase in heart rate (HR).

In most patients, the antihypertensive effect begins 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 during prolonged therapy.

Abrupt discontinuation of ramipril does not cause a rapid or excessive increase in arterial pressure (rebound phenomenon).

Heart failure. Ramipril has been proven effective as an adjunct to conventional therapy with diuretics and, if necessary, cardiac glycosides in patients with NYHA 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.

Clinical efficacy and safety.

Prevention of cardiovascular diseases/nephroprotection.

A preventive, placebo-controlled trial (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 cardiovascular disease due to prior atherothrombotic cardiovascular disease (history of ischemic heart disease, stroke, or peripheral vascular disease) or diabetic patients with at least one additional risk factor (documented microalbuminuria, arterial hypertension, elevated total cholesterol, low-density lipoprotein cholesterol (LDL-C), 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).

HOPE study: key results

In the MICRO-HOPE study, which was prospectively planned as part of the HOPE study, the effect of adding ramipril at a dose of 10 mg to existing treatment regimens was compared with placebo in 3577 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 had at least one cardiovascular risk factor).

The primary analysis results demonstrated that overt nephropathy developed in 117 (6.5%) participants receiving ramipril and in 149 (8.4%) receiving placebo, corresponding to a 24% relative risk reduction; 95% CI [3–40], p = 0.027.

The REIN study, a multicenter, randomized, double-blind, placebo-controlled parallel-group trial, was conducted to evaluate the effect of ramipril treatment on the rate of decline in glomerular filtration rate (GFR) in 352 patients aged 18–70 years with normal or elevated blood pressure, who had mild (urinary protein excretion >1 to <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 ramipril treatment was proven) demonstrated that the mean rate of decline in GFR was lower with ramipril than with placebo: −0.54 (0.66) vs −0.88 (1.03) mL/min/month, p = 0.038. Thus, the between-group difference was 0.34 [0.03–0.65] mL/min/month, approximately 4 mL/min/year. A total of 23.1% of patients in the ramipril group reached the combined secondary endpoint—doubling of plasma creatinine concentration and/or end-stage renal disease (requiring hemodialysis or kidney transplantation)—compared with 45.5% in the placebo group (p = 0.02).

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)] 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 evidence of target organ damage. The VA NEPHRON-D trial included patients with type 2 diabetes and diabetic nephropathy.

These studies did not demonstrate significant benefits of combination therapy regarding renal and/or cardiovascular outcomes or mortality, while an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was observed compared to monotherapy. Given the similar pharmacodynamic characteristics of these drugs, these findings 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, hypotension, and renal dysfunction).

Secondary prevention after acute myocardial infarction. The AIRE study included over 2000 patients with transient/persistent symptoms of heart failure following acute 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 was 16.9% in the ramipril group and 22.6% in the placebo group. This represents an absolute reduction in mortality of 5.7% and a relative risk reduction of 27% (95% CI [11–40%]).

Pediatric population. In a randomized, double-blind, placebo-controlled clinical trial involving 244 pediatric patients with hypertension (73% of whom had primary 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 a 4-week period, ramipril was found to be ineffective regarding the primary endpoint—reduction in systolic blood pressure—although diastolic blood pressure was reduced with the highest dose in the studied range. It was shown that both medium and high doses of ramipril significantly reduced systolic and diastolic blood pressure in children with confirmed hypertension.

This effect was not observed in a 4-week randomized, double-blind, dose-escalation trial assessing the effect of drug withdrawal, involving 218 pediatric patients aged 6–16 years (75% of whom had primary hypertension). In this study, moderate rebound increases in both diastolic and systolic blood pressure were observed after drug discontinuation, but these were not statistically significant for return to baseline blood pressure levels across all dose groups in the studied ramipril range [low doses (0.625 mg–2.5 mg), medium doses (2.5 mg–10 mg), or high doses (5 mg–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 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 administration of usual doses of ramipril once daily, 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, the diketopiperazine ester, diketopiperazine acid, and glucuronides of ramipril and ramiprilat.

Elimination. 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 exhibits 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 for ramiprilat.

After single oral doses, neither ramipril nor its metabolites were detected in breast milk. However, the effect of repeated dosing is unknown.

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 leads to 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. After a single oral dose of ramipril, levels in breast milk were 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 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 concentrations of ramiprilat were achieved within 2–3 hours. Ramiprilat clearance correlated significantly with the logarithm of body weight (p<0.01) and with drug dose (p<0.001). Clearance and volume of distribution increased proportionally with age within each dosing group. Administration of a 0.05 mg/kg dose 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.

Preclinical safety data. After oral administration in rodents and dogs, ramipril was found not to cause acute toxic effects. Long-term oral administration studies were conducted in rats, dogs, and monkeys. Electrolyte imbalances and hematological changes were observed in all three species. In dogs and monkeys receiving 250 mg/kg/day, marked increases in the juxtaglomerular apparatus were observed, which is a manifestation of the pharmacodynamic activity of ramipril. Rats, dogs, and monkeys tolerated daily doses of 2, 2.5, and 8 mg/kg body weight, respectively, without adverse effects.

Reproductive toxicity studies in rats, rabbits, and monkeys revealed no teratogenic properties of the drug. No adverse effects on fertility were observed in either male or female rats. Administration of ramipril to pregnant and lactating female rats resulted in irreversible kidney damage (renal pelvis dilation) in offspring at doses of 50 mg/kg/day and above. Multiple 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 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 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 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 angiotensin-converting enzyme (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 patient with a single functioning kidney.

Pregnancy and planned pregnancy (see section "Use during pregnancy or breastfeeding").

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

Concomitant use of Ramimed**®** with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or moderate to severe renal impairment (eGFR < 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 demonstrated 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 "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"). Treatment with ramipril should be initiated only 36 hours after the last dose of sacubitril/valsartan. Treatment with sacubitril/valsartan 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.

Concomitant use of Ramimed**®** with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or moderate to severe renal impairment and is not recommended for other patient groups (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, 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 Ramimed**®**.* Blood pressure should be closely monitored.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics, and other substances that may cause blood count alterations. 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 Ramimed**®** 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 medicinal product.

Specific allergen immunotherapy (hyposensitization). 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 therapy 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 with concomitant use of ACE inhibitors and neutral endopeptidase (NEP) inhibitors, such as racecadotril (see section "Special precautions for use").

Sacubitril/valsartan. Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema.

Special precautions for use.

Special patient categories.

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 to become pregnant should be switched to another 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, therapy with another agent should be initiated (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Dual blockade of the RAAS with medicinal products containing aliskiren. Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and impaired 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.

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 and significant reduction in blood pressure and worsening of renal function due to ACE inhibition, especially when an 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 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 causing arterial hypotension.

In general, correction of dehydration, hypovolemia, or electrolyte deficiency 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 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 planned surgical procedures.

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 "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.

Angioedema. Angioedema has been observed in patients receiving ACE inhibitors, including ramipril (see section "Adverse reactions"). This risk is increased in patients concurrently receiving 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 development, administration of Ramimed**®** 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.

Angioedema of the intestine has been reported in patients receiving ACE inhibitors, including Ramimed**®** (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. Administration of Ramimed**®** should be temporarily discontinued prior to desensitization procedures.

Monitoring of electrolyte balance. Hyperkalemia. Hyperkalemia has been observed in some patients receiving ACE inhibitors, including Ramimed**®**. 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 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 of electrolyte balance. Hyponatremia. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) 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 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 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 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.

Since the medicinal product contains lactose, patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this product.

Use during pregnancy or breastfeeding.

Pregnancy. The product is contraindicated in pregnant women or women planning to become pregnant. If pregnancy occurs during therapy, treatment 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 product is not recommended for breastfeeding women. Alternative medicinal products with a more favorable safety profile during lactation should be preferred, especially when breastfeeding newborns or preterm infants.

Ability to influence the ability to drive and use machines. Some adverse effects (e.g., symptoms of low blood pressure such as dizziness) may impair a patient's concentration and reduce reaction speed, posing a risk in situations where these abilities are particularly important (e.g., driving vehicles or operating machinery).

This is generally possible at the beginning of treatment or when switching from therapy with other drugs to Ramimed**®**. After taking the first dose or after 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.

RamiMed**®** is recommended to be taken daily at the same time each day. RamiMed**®** may be taken before, during, or after meals, as food intake does not affect the bioavailability of the drug. RamiMed**®** tablets should be swallowed whole with water. They must not be chewed or crushed. If the prescribed dose cannot be administered, ramipril in the appropriate dosage strength should be used to ensure treatment regimens where the recommended initial dose is 1.25 mg.

Adults

Patients receiving diuretics. At the beginning of treatment with RamiMed**®**, arterial hypotension may occur, and its development is more likely in patients concurrently receiving diuretics. Caution is recommended in such cases, as these patients may have reduced circulating blood volume and/or electrolyte depletion.

It is advisable to discontinue diuretic therapy 2–3 days before initiating treatment with RamiMed**®**, if possible (see section "Special Warnings and Precautions for Use").

In hypertensive patients in whom discontinuation of diuretics is not feasible, treatment with RamiMed**®** should be initiated at a dose of 1.25 mg. Renal function and serum potassium levels should be closely monitored. Subsequent dosing of RamiMed**®** should be adjusted according to 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. RamiMed**®** 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 RamiMed**®** 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 blood pressure may occur after administration of 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 level is achieved; the maximum daily dose of RamiMed**®** is 10 mg. The drug is generally administered once daily.

Prevention of Cardiovascular Diseases.

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

Dose Titration and Maintenance Dose. Depending on individual tolerability, 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.

(See also the above information regarding dosing in patients receiving diuretics.)

Treatment of Kidney Disease.

In patients with diabetes and microalbuminuria.

Initial Dose. The recommended initial dose of RamiMed**®** 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 RamiMed**®** 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 of RamiMed**®** 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 characterized by macroproteinuria ≥ 3 g/day.

Initial Dose. The recommended initial dose of RamiMed**®** 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.

Clinically Manifest Heart Failure.

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 RamiMed**®** should be titrated by doubling every 1–2 weeks until the maximum daily dose of 10 mg is reached. It is advisable 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 clinical and hemodynamic status is stable, initiate treatment with an initial dose of 2.5 mg twice daily for 3 days. If the initial dose of 2.5 mg twice daily is poorly tolerated, administer 1.25 mg 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.

(See also the above information regarding dosing in patients receiving diuretics.)

Dose Titration and Maintenance Dose. Thereafter, 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 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.

Special Patient Populations.

Patients with Renal Impairment. The daily dose in 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, and the maximum daily dose is 5 mg;
• hypertensive patients undergoing hemodialysis: ramipril is only minimally removed during hemodialysis; the initial dose is 1.25 mg, and the maximum daily dose is 5 mg; the drug should be administered several hours after a hemodialysis session.

Patients with Hepatic Impairment (see section "Pharmacological Properties"). Treatment with RamiMed**®** 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. RamiMed**®** is not recommended for use in children, as there is insufficient data on efficacy and safety of this medicinal product in this patient population.

Overdose. Symptoms associated with overdose of ACE inhibitors may include excessive peripheral vasodilation (with marked arterial hypotension and shock), bradycardia, electrolyte imbalances, and renal failure. Close monitoring of the patient is required, along with symptomatic and supportive therapy. Recommended management measures include primary detoxification (gastric lavage, administration of adsorbents), and 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-containing medicinal products includes data on persistent cough and reactions due to 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 frequency category, adverse reactions are listed in order of decreasing 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, angioneurotic edema 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 pre-existing proteinuria, increased blood urea levels, increased serum creatinine levels.

Skin and subcutaneous tissue disorders:
Common – skin rash, 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 cramps, 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 phenomenon.

General disorders:
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 bilirubin conjugates;
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.

Paediatric 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, specifically:

Tachycardia, nasal congestion, and rhinitis: common (i.e., ≥ 1/100 to < 1/10) in the paediatric population and uncommon (i.e., ≥ 1/1,000 to < 1/100) in adult patients;
Conjunctivitis: common (i.e., ≥ 1/100 to < 1/10) in the paediatric population and rare (i.e., ≥ 1/10,000 to < 1/1,000) in adult patients.

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

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

Reporting of suspected adverse reactions.
Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any adverse reactions via the pharmacovigilance system of Ukraine.

Shelf life. 2 years.

Storage conditions. Store at temperatures not exceeding 25 °C in the original packaging, in a place inaccessible to children.

Packaging. 10 tablets in a blister. 3 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

1. Medochimie Ltd (Central Plant) / Medochemie Ltd (Central Factory).
2. Actavis Ltd.

Manufacturer's address.

1. 1-10 Constantinoupoleos Street, Limassol, 3011, Cyprus.
2. BLB015, BLB016, Bulebel Industrial Estate, Zejtun ZTN3000, Malta.