Ramipril-darnitsa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RAMIPRIL-DARNITSA (RAMIPRIL-DARNITSA)

Composition:

Active substance: ramipril;

One tablet contains ramipril 5 mg;

Excipients: hypromellose, pregelatinized starch, microcrystalline cellulose, sodium stearyl fumarate, iron oxide red;

One tablet contains ramipril 10 mg;

Excipients: hypromellose, pregelatinized starch, microcrystalline cellulose, sodium stearyl fumarate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

5 mg tablets: flat cylindrical tablets, with a score line and bevel, light pink in color. Slight speckles of pink color of varying intensity may be present on the surface of the tablets;

10 mg tablets: flat cylindrical tablets, with a score line and bevel, white or almost white in color.

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 (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. Reduced formation of angiotensin II and inhibition of bradykinin 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 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 ramipiltril to patients with arterial hypertension leads to a reduction in arterial blood pressure both in the supine and upright positions, without being accompanied by a compensatory increase in heart rate.

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 lasts 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.

Sudden discontinuation of ramipril does not cause a rapid and excessive increase in blood pressure (rebound phenomenon).

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

Clinical efficacy and safety.

Prevention of cardiovascular disease/nephroprotection.

A preventive, placebo-controlled study (the HOPE study) was conducted involving over 9,200 patients who received ramipril in addition to standard therapy. This study included patients at high risk of cardiovascular events due to established atherothrombotic cardiovascular disease (history 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 death, and stroke, both individually and in combination (primary composite endpoint).

Table 1

HOPE Study: Main Results

Parameter	Ramipril	Placebo	Relative risk (95% confidence interval)	p value
	%	%
All patients	n=4,645	N=4,652
Primary combined endpoint	14	17.8	0.78 (0.7–0.86)	<0.001
Myocardial infarction	9.9	12.3	0.80 (0.7–0.9)	<0.001
Cardiovascular death	6.1	8.1	0.74 (0.64–0.87)	<0.001
Stroke	3.4	4.9	0.68 (0.56–0.84)	<0.001
Secondary endpoints
Fatal outcome from any cause	10.4	12.2	0.84 (0.75–0.95)	0.005
Need for revascularization	16.0	18.3	0.85 (0.77–0.94)	0.002
Hospitalization due to unstable angina	12.1	12.3	0.98 (0.87–1.1)	not significant
Hospitalization due to heart failure	3.2	3.5	0.88 (0.7–1.1)	0.25
Complications related to diabetes	6.4	7.6	0.84 (0.72–0.98)	0.03

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 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 study, was conducted to evaluate the effect of ramipril treatment on the rate of decline in glomerular filtration rate (GFR) in 352 patients with normal or elevated blood pressure (aged 18–70 years) who had mild (mean 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 ramipril treatment had been demonstrated) showed 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; 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).

Double blockade of the renin-angiotensin-aldosterone system (RAAS). The combination of an ACE inhibitor with an angiotensin II receptor antagonist was evaluated in 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)].

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 arterial hypotension was observed compared to monotherapy. Given the similar pharmacodynamic characteristics of these medicinal products, 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 prematurely terminated due to an increased risk of adverse clinical outcomes. In the aliskiren group compared to the placebo group, there was a higher incidence of fatal cardiovascular events 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 over 2000 patients with transient or ongoing 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 mortality reduction 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 ineffective regarding the primary endpoint—reduction in systolic blood pressure—although it reduced diastolic pressure when the highest dose in the studied range was administered. 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% with primary hypertension). In this study, moderate rebound increases in both diastolic and systolic pressure were observed after drug discontinuation, but these were not statistically significant for return to baseline 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 concentration is reached within 1 hour. Based on the amount of substance detected in urine, the absorption rate 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 concentration of ramiprilat, the sole active metabolite of ramipril, is reached 2–4 hours after ramipril administration. After repeated daily doses of ramipril, steady-state plasma concentrations of ramiprilat are achieved by approximately the 4th day of treatment.

Distribution. 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.

Excretion. Metabolite excretion occurs predominantly via renal excretion. The decline in plasma concentration of ramiprilat 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 daily doses of ramipril, 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.

Following 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 concentration of ramiprilat was reached 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 dose of 0.05 mg/kg in children achieved exposure levels comparable to those in adults receiving 5 mg ramipril. Administration of 0.2 mg/kg in children resulted in exposure levels higher than those achieved with the maximum recommended adult dose of 10 mg/day.

Preclinical safety data. Oral administration of ramipril to rodents and dogs did not reveal 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 ramipril at 250 mg/kg body weight per day, marked enlargement of the juxtaglomerular apparatus was noted, reflecting the pharmacodynamic activity of ramipril. Rats, dogs, and monkeys tolerated daily doses 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 pregnant and lactating female rats 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.

Treatment of kidney disease:

• Early diabetic glomerular nephropathy, indicated by presence of microalbuminuria;
• Overt diabetic glomerular nephropathy, indicated by presence of macroproteinuria, in patients with at least one cardiovascular risk factor;
• Overt non-diabetic glomerular nephropathy, indicated by presence of macroproteinuria ≥ 3 g/day.

Treatment of heart failure associated with clinical symptoms.

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.
• History of angioedema (hereditary, idiopathic, or previously occurring during treatment with ACE inhibitors or angiotensin II receptor antagonists).
• Concomitant use with sacubitril/valsartan.
• Significant bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney.
• Ramipril should not be administered to patients with arterial hypotension or hemodynamically unstable conditions.
• Concomitant use of Ramipril-Darnitsa 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).
• Concomitant use of ACE inhibitors with extracorporeal treatment methods leading to blood contact with negatively charged surfaces should be avoided.
• Pregnancy and planned pregnancy.

Interaction with other medicinal products and other forms of interaction.

Clinical studies 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 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 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). May increase the risk of hyperkalemia; 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). 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-Darnitsa. Careful monitoring of blood pressure is recommended.

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

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

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

Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid. Reduced antihypertensive effect of Ramipril-Darnitsa is expected. Moreover, concomitant use of ACE inhibitors and NSAIDs may be associated with 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 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").

Neprilysin inhibitors. There have been reports of potential increased risk of angioedema with concomitant use of ACE inhibitors and neprilysin (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 increased risk of angioedema.

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 medicinal product considered safe during pregnancy. As soon as pregnancy is diagnosed, treatment with ACE inhibitors/angiotensin II receptor antagonists should be stopped immediately and, if necessary, therapy with another medicinal product 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, 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 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 anesthesia with agents that may cause arterial hypotension.

In general, it is recommended to correct dehydration, hypovolemia, or electrolyte depletion prior to starting 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 method of administration».

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, especially during the first weeks of therapy. Particular care is required in patients with impaired renal function (see section «Dosage and method of 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 stenock.

Angioedema. Angioedema has been observed in patients receiving ACE inhibitors, including ramipril (see section «Adverse reactions»). The risk of angioedema is increased in patients receiving concomitant medicinal products that may cause angioedema, such as mammalian target of rapamycin (mTOR) inhibitors (e.g., temsirolimus, everolimus, sirolimus), vildagliptin, or neprilysin inhibitors (NEP) (such as racecadotril).

The combination of ramipril with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see sections «Contraindications» and «Interaction with other medicinal products and other forms of interaction»).

If angioedema occurs, administration of Ramipril-Darnitsya should be discontinued immediately. Emergency treatment should be initiated promptly. The patient should remain under medical supervision for at least 12–24 hours and may be discharged only after complete resolution of symptoms.

Angioedema of the intestine has been reported in patients receiving ACE inhibitors, including Ramipril-Darnitsya (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 treatment with ACE inhibitors. Administration of Ramipril-Darnitsya should be temporarily discontinued prior to desensitization procedures.

Monitoring of electrolyte balance. Hyperkalemia. Hyperkalemia has been observed in some patients receiving ACE inhibitors, including Ramipril-Darnitsya. Patients at risk of hyperkalemia include those with renal impairment, patients aged 70 years or older, patients with uncontrolled diabetes mellitus, patients receiving 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 medicinal products 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 development of 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 changes (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. As with other ACE inhibitors, the antihypertensive effect of ramipril 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 with arterial hypertension.

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

Important information on excipients.

This medicinal product contains sodium stearyl fumarate. Caution is advised when administering to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy. This medicinal product is contraindicated in pregnant women or women planning to become pregnant. If pregnancy occurs during treatment, the medicinal product should be discontinued immediately and, if necessary, replaced with another medicinal product approved for use during pregnancy.

Breastfeeding. Due to lack of information on the use of ramipril during breastfeeding, this medicinal product is not recommended for nursing mothers. It is preferable to use other medicinal products considered safer during lactation, especially when breastfeeding newborns or preterm infants.

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

Some adverse effects (e.g., symptoms of low blood pressure such as dizziness) may impair a patient's ability to concentrate and 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 other medicinal products to Ramipril-Darnitsya. After taking the first dose or subsequent dose increase, driving vehicles or operating machinery should be avoided for several hours.

Dosage and Administration

The medicinal product is for oral use.

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

If the prescribed dose is unavailable, ramipril in the corresponding dosage strength should be used.

Adults

Patients on diuretics. At the beginning of treatment with Ramipril-Darnitsya, arterial hypotension may occur, particularly 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 prior to initiating treatment with Ramipril-Darnitsya (see section "Special Warnings and Precautions for Use").

In patients with arterial hypertension who cannot discontinue diuretic therapy, treatment with Ramipril-Darnitsya 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 dosing of Ramipril-Darnitsya should be adjusted according to the target blood pressure level.

Arterial hypertension.

Dosage should be individualized according to patient-specific factors (see section "Special Warnings and Precautions for Use") and blood pressure monitoring results. The medicinal product 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 Ramipril-Darnitsya should be initiated gradually, starting with the recommended initial dose of 2.5 mg (use ramipril in the corresponding dosage strength) once daily.

In patients with significant activation of the renin-angiotensin-aldosterone system (RAAS), marked reduction in arterial 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 daily dose of Ramipril-Darnitsya is 10 mg. The medicinal product is generally taken once daily.

Prevention of cardiovascular disease.

Initial dose. The recommended initial dose of Ramipril-Darnitsya is 2.5 mg (use ramipril in the corresponding dosage strength) 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.

Treatment of kidney disease.

Patients with diabetes and microalbuminuria.

Initial dose. The recommended initial dose of Ramipril-Darnitsya is 1.25 mg (use ramipril in the corresponding dosage strength) 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 (use ramipril in the corresponding dosage strength), 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-Darnitsya is 2.5 mg (use ramipril in the corresponding dosage strength) 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.

Patients with non-diabetic nephropathy, indicated by macroproteinuria ≥ 3 g/day.

Initial dose. The recommended initial dose of Ramipril-Darnitsya is 1.25 mg (use ramipril in the corresponding dosage strength) 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 (use ramipril in the corresponding dosage strength), 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 (use ramipril in the corresponding dosage strength) daily.

Dose titration and maintenance dose. The dose of Ramipril-Darnitsya 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, patients whose condition is clinically and hemodynamically stable should be given an initial dose of 2.5 mg (use ramipril in the corresponding dosage strength) twice daily for 3 days. If the initial dose of 2.5 mg (use ramipril in the corresponding dosage strength) is poorly tolerated, a dose of 1.25 mg (use ramipril in the corresponding dosage strength) twice daily should be administered for 2 days, followed by an increase to 2.5 mg (use ramipril in the corresponding dosage strength) and then to 5 mg twice daily. If the dose cannot be increased to 2.5 mg (use ramipril in the corresponding dosage strength) twice daily, treatment should be discontinued.

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

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

If the dose cannot be increased to 2.5 mg (use ramipril in the corresponding dosage strength) twice daily, treatment should be discontinued. Experience with treating patients with severe heart failure (NYHA functional class IV) 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 (use ramipril in the corresponding dosage strength) once daily, and any dose increase should be performed with extreme caution.

Special patient populations.

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 (use ramipril in the corresponding dosage strength)) 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 (use ramipril in the corresponding dosage strength)) 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 only minimally removed 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 medicinal product should be taken several hours after a hemodialysis session.

Patients with hepatic impairment (see section "Pharmacological Properties"). Treatment with Ramipril-Darnitsya 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 (use ramipril in the corresponding dosage strength).

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 (use ramipril in the corresponding dosage strength) should be prescribed.

The above information regarding dosage also applies to patients receiving diuretics.

Children

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

Overdose

Symptoms associated with angiotensin-converting enzyme (ACE) inhibitor overdose may include excessive peripheral vasodilation (with marked arterial hypotension, shock), bradycardia, electrolyte imbalances, and renal failure. The patient should be closely monitored, and symptomatic and supportive therapy should be administered. Recommended therapeutic 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.

Side effects.

The safety profile of the medicinal product Ramipril-Darnitsia includes data on persistent cough and reactions caused by arterial hypotension. Serious adverse reactions include angioedema, hyperkalemia, impairment of liver or kidney function, 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 events are listed in order of decreasing severity.

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 – inflammatory conditions in the gastrointestinal tract, digestive disorders, abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting; uncommon – pancreatitis (in isolated cases fatal outcomes have been reported, exclusively with ACE inhibitors), increased levels of pancreatic enzymes, angioedema of the small intestine, upper abdominal pain, including that associated with gastritis, constipation, dry mouth; rare – glossitis; not known – aphthous stomatitis.

Hepatobiliary disorders: Uncommon – increased levels of liver enzymes and/or conjugated bilirubin; rare – cholestatic jaundice, hepatic cell injury; not known – acute liver failure, cholestatic or cytolytic hepatitis (in very rare cases with fatal outcome).

Renal and urinary disorders: Uncommon – renal function impairment, including acute renal failure, increased urine output, worsening of underlying proteinuria, increased blood urea nitrogen, increased serum creatinine.

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.

Nervous system disorders: Common – headache, dizziness; uncommon – vertigo, paresthesia, ageusia, dysgeusia; rare – tremor, balance disorder; not known – cerebral ischemia, including ischemic stroke and transient ischemic attack, psychomotor disturbances, burning sensation, parosmia.

Psychiatric disorders: Uncommon – depressed mood, anxiety, nervousness, restlessness, sleep disturbances, including somnolence; rare – confusion; not known – attention disturbance.

Cardiac and vascular disorders: Common – arterial hypotension, orthostatic hypotension, syncope; uncommon – myocardial ischemia, including angina or myocardial infarction, tachycardia, arrhythmia, palpitations, peripheral edema, flushing sensation; rare – vascular stenosis, hypoperfusion, vasculitis; not known – Raynaud's phenomenon.

Blood and lymphatic system disorders: Uncommon – eosinophilia; rare – decreased leukocyte count (including neutropenia or agranulocytosis), decreased erythrocyte count, decreased hemoglobin levels, decreased platelet count; not known – bone marrow failure, pancytopenia, hemolytic anemia.

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

Skin and subcutaneous tissue disorders: Common – rash, including maculopapular; uncommon – angioedema, including 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 exanthem or enanthem, alopecia.

Musculoskeletal and connective tissue disorders: Common – muscle spasms, myalgia; uncommon – arthralgia.

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

General disorders: Common – chest pain, fatigue; uncommon – pyrexia; rare – asthenia.

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, specifically:

tachycardia, nasal congestion, and rhinitis: common (i.e., ≥1/100 to <1/10) in the pediatric 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 pediatric 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 pediatric population and rare (i.e., ≥1/10,000 to <1/1,000) in adult patients.

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

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report any suspected adverse reactions and/or lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

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; 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnitsya".

Manufacturer's address and location of business activity.

13, Borispilska Street, Kyiv, 02093, Ukraine.