INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BARTON® (BARATON®)

Composition:

Active substance: ramipril (ramipril);

each tablet contains 5 mg or 10 mg of ramipril;

Excipients: low-substituted hydroxypropyl cellulose, mannite (E 421), calcium carbonate, sodium stearyl fumarate, iron oxide yellow (E 172).

Pharmaceutical form. Tablets.

Main physico-chemical properties:

5 mg tablets: yellow or light-yellow tablets with a characteristic yellow pigment, round, flat, with a score line on one side and smooth on the other side;

10 mg tablets: yellow or light-yellow tablets with a characteristic yellow pigment, oval, biconvex, smooth on both sides.

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 ramipril, inhibits the enzyme dipeptidyl carboxypeptidase I (synonyms: ACE; kininase II). In blood plasma and tissues, this enzyme catalyzes the conversion of angiotensin I into the active vasoconstrictor substance angiotensin II, as well as the breakdown of the active vasodilator bradykinin. Reduction in angiotensin II formation and inhibition of bradykinin breakdown lead to vasodilation.

Since angiotensin II also stimulates the release of aldosterone, ramipril promotes a reduction in aldosterone secretion. The response to monotherapy with ACE inhibitors has generally been less pronounced in patients of non-Caucasian (Afro-Caribbean) descent with arterial hypertension (a population typically characterized by low renin levels in arterial hypertension) compared to individuals of other racial backgrounds.

Pharmacokinetics.

Antihypertensive properties

Administration of ramipril results in a significant reduction in peripheral arterial resistance. Typically, no substantial changes in renal plasma flow or glomerular filtration rate (GFR) occur. Administration of ramipril to patients with arterial hypertension leads to a reduction in blood pressure in both supine and upright positions, without compensatory increases in heart rate.

In most patients, the antihypertensive effect begins within 1–2 hours after a single dose. The maximum effect of a single dose is usually achieved within 3–6 hours. The antihypertensive effect after a single dose generally persists for 24 hours.

The maximum antihypertensive effect during long-term ramipril therapy is generally observed after 3–4 weeks. It has been demonstrated that the antihypertensive effect is maintained for up to 2 years with prolonged therapy.

Abrupt discontinuation of ramipril does not cause a rapid or excessive increase in blood 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 heart failure classified as NYHA functional classes II–IV. The drug exerts beneficial effects on cardiac hemodynamics (reduction in filling pressures of the left and right ventricles, total peripheral vascular resistance, and improvement in cardiac output and cardiac index). It also reduces neuroendocrine activation.

Clinical efficacy and safety

Prevention of cardiovascular diseases/nephroprotection

A preventive, placebo-controlled study (the HOPE study) involving over 9,200 patients who received ramipril in addition to standard therapy was conducted. This study included patients at high risk of cardiovascular events due to prior atherothrombotic cardiovascular disease (with documented 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, elevated 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).

HOPE study: key results

Parameter	Ramipril	Placebo	Relative risk (95% confidence interval (CI))	p value
Parameter	%	%
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
Death 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 10 mg to existing treatment 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 (and at least one cardiovascular risk factor).

The primary analysis results showed 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 was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study 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 (mean urinary protein excretion >1 and <3 g/day) or severe (mean urinary protein excretion ≥3 g/day) proteinuria 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 the study because benefit from ramipril treatment was demonstrated) showed that the mean monthly rate of decline in GFR was lower with ramipril than with placebo: −0.54 (0.66) versus −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, or approximately 4 mL/min/year; 23.1% of patients in the ramip rue group reached the combined secondary endpoint—doubling of plasma creatinine concentration and/or end-stage renal disease (requiring hemodialysis or kidney transplantation)—compared to 45.5% in the placebo group (p=0.02).

Double blockade of the renin-angiotensin-aldosterone system (RAAS)

Two large-scale randomized controlled trials [ONTARGET (a study of telmisartan as monotherapy and in combination with ramipril on a primary composite endpoint) and VA NEPHRON-D (a study of diabetic nephropathy in veterans)] evaluated the use of a combination of an ACE inhibitor with an angiotensin II receptor antagonist.

The ONTARGET study included patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. The VA NEPHRON-D study 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 drug classes, 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 study (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and 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 study was terminated prematurely due to an increased risk of adverse clinical outcomes. In the aliskiren group compared to placebo, 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, hypotension, and renal dysfunction).

Secondary prevention after acute myocardial infarction

The AIRE study included over 2000 patients with transient or persistent signs 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, representing 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 patients aged 6 to 16 years with hypertension (73% of whom had primary hypertension), patients 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 4 weeks, ramipril was ineffective on the primary endpoint—reduction in systolic blood pressure—but reduced diastolic blood pressure at the highest dose tested. 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 withdrawal study evaluating the effect of drug discontinuation, involving 218 pediatric patients aged 6–16 years (75% with primary hypertension). In this study, moderate rebound increases in both diastolic and systolic blood pressure were observed after drug withdrawal, but these were not statistically significant in returning blood pressure to baseline levels across all dose groups tested [low doses (0.625–2.5 mg), medium doses (2.5–10 mg), or high doses (5–20 mg)] adjusted for body weight. In the studied pediatric population, ramipril did not demonstrate a linear dose-response relationship.

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 drug 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 once-daily doses of ramipril, steady-state plasma concentrations of ramiprilat are reached by approximately day 4 of treatment.

Distribution

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

Metabolism

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

Elimination

Metabolite excretion occurs predominantly via renal excretion. The decline in plasma ramiprilat concentration is multiphasic. Due to strong saturable binding to ACE and slow dissociation from the enzyme, ramiprilat exhibits a prolonged terminal elimination phase at very low plasma concentrations.

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

Patients with renal impairment (see section "Dosage and administration")

In patients with impaired renal function, renal excretion of ramiprilat is reduced, and the renal clearance of ramiprilat is proportional to creatinine clearance. This 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, the maximum concentration of ramiprilat in these patients does not differ from that in individuals with normal liver function.

Lactation

After a single oral dose of ramipril, its concentration in breast milk was below the limit of detection. However, the effect of repeated administration is unknown.

Pediatric population

The pharmacokinetic profile of ramipril was studied in 30 pediatric patients aged 2–16 years with hypertension and body weight >10 kg. After administration of doses ranging from 0.05 to 0.2 mg/kg, ramipril was rapidly and extensively metabolized to ramiprilat. Maximum plasma concentrations of ramiprilat were reached within 2–3 hours. Ramiprilat clearance correlated significantly with body weight (p<0.01) and 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 5 mg 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

Oral administration of ramipril to animals (rodents and dogs) showed no acute toxic effects. Long-term oral toxicity studies were conducted in rats, dogs, and monkeys. Electrolyte 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, reflecting the pharmacodynamic activity of ramipril. Rats, dogs, and monkeys tolerated daily doses of 2, 2.5, and 8 mg/kg/day, respectively, without adverse effects.

Reproductive toxicity studies in rats, rabbits, and monkeys revealed no teratogenic properties of ramipril. No adverse effects on fertility were observed in either male or female rats.

Administration of ramipril to pregnant and lactating rats resulted in irreversible kidney damage (renal pelvis dilation) in offspring at doses of 50 mg/kg/day and higher.

Multiple mutagenicity tests using various test systems showed no 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 who have 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 who have at least one cardiovascular risk factor (see section "Pharmacological properties");
- overt non-diabetic glomerular nephropathy, indicated by the presence of macroproteinuria ≥ 3 g per 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 ACE inhibitors.
History of angioedema (hereditary, idiopathic, or previously occurred during treatment with ACE inhibitors or angiotensin II receptor antagonists).
Concomitant use with sacubitril/valsartan (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").
Concomitant use of extracorporeal treatment methods leading to blood contact with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction").
Severe bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney.
Pregnancy and planned pregnancy (see section "Use during pregnancy or breast-feeding").
Ramipril should not be used in patients with arterial hypotension or hemodynamically unstable conditions.
Concomitant use of ramipril with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60 mL/min/1.73 m²) (see sections "Pharmacodynamics" and "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 renal dysfunction (including acute renal failure), compared to treatment with a single agent acting on the RAAS (see sections "Pharmacodynamics", "Contraindications", and "Special precautions for use").

Contraindicated combinations

Sacubitril/valsartan

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

Extracorporeal therapy

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 medicinal products.

Combinations requiring precautions

Potassium salts, heparin, potassium-sparing diuretics, and other active substances that increase plasma potassium levels (including angiotensin II antagonists, trimethoprim and its fixed combinations with sulfamethoxazole, tacrolimus, cyclosporine)

Hyperkalemia may occur; therefore, plasma potassium levels should be closely monitored.

Antihypertensive medicinal products (e.g., diuretics) and other substances capable of lowering blood pressure (e.g., nitrates, tricyclic antidepressants, anesthetics, alcohol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin)

An increased risk of arterial hypotension should be anticipated (see section "Special precautions for use" regarding diuretics).

Vasopressor sympathomimetics and other substances (e.g., isoprenaline, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of ramipril Close monitoring of blood pressure is recommended.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatic agents, and other substances that may affect the blood picture

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. Plasma lithium levels should be closely monitored.

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

Non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid

A reduced antihypertensive effect of ramipril is expected. Additionally, concomitant use of ACE inhibitors and NSAIDs may be associated with an increased risk of renal dysfunction and elevated blood potassium levels.

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

Specific allergen immunotherapy Due to ACE inhibition, the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom are increased. This effect may also occur with other allergens.

mTOR inhibitors or DPP-4 inhibitors

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

Neprilysin inhibitors (NEP)

A potential increase in the risk of angioedema has been reported with concomitant use of ACE inhibitors and neprilysin 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 groups

Pregnancy

Treatment with ACE inhibitors or angiotensin II receptor antagonists should not be initiated during pregnancy. If continuation of ACE inhibitor therapy is considered necessary, women planning pregnancy should switch to an alternative antihypertensive agent with an established safety profile during pregnancy. If pregnancy is diagnosed, treatment with ACE inhibitors/angiotensin II receptor antagonists should be stopped immediately and, if necessary, alternative therapy should be initiated (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Patients at particular risk of arterial hypotension

Patients with significantly increased RAAS activity

The risk of sudden symptomatic lowering of blood pressure with renal function impairment due to ACE inhibition is increased in patients with pronounced RAAS activation, especially when the ACE inhibitor or concomitant diuretic is administered for the first time or during initial dose titration.

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

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

Correction of dehydration, hypovolemia, or electrolyte deficiency is generally recommended prior to starting treatment (however, for patients with heart failure, such corrective measures should be carefully weighed against the risk of volume overload).

Dual blockade of the RAAS

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

If 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.

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 "Posology and method of administration".

Surgery

It is recommended to discontinue treatment with ACE inhibitors such as ramipril, if possible, one day prior to surgery.

Monitoring of renal function

Renal function should be assessed before and during treatment, and dosage adjusted accordingly, especially during the first weeks of therapy. Particular care is required in patients with pre-existing renal impairment (see section "Posology and method of administration"). There is a risk of renal function deterioration, particularly in patients with congestive heart failure or after kidney transplantation, as well as in those with renal vascular disease, including patients with hemodynamically significant unilateral renal artery stenosis.

Angioedema

Cases of angioedema have been reported in patients receiving ACE inhibitors, including ramipril (see section "Adverse reactions"). The risk of angioedema (symptoms may include swelling of the airways or tongue, with or without respiratory distress) may be increased in patients concurrently receiving medicinal products such as mammalian target of rapamycin (mTOR) inhibitors (e.g., temsirolimus, everolimus, sirolimus), vildagliptin, or neprilysin inhibitors (such as 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, the drug should be discontinued immediately and emergency treatment initiated. Patients should remain under medical supervision for at least 12–24 hours until complete resolution of symptoms.

Intestinal angioedema has been observed during treatment with ACE inhibitors (see section "Adverse reactions"). These patients presented with abdominal pain (with or without nausea/vomiting).

Anaphylactic reactions during desensitization

The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased during ACE inhibitor therapy. Temporary discontinuation of ramipril should be considered prior to desensitization.

Monitoring of electrolyte balance. Hyperkalemia

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

Monitoring of electrolyte balance. Hyponatremia

The syndrome of inappropriate antidiuretic hormone secretion leading to hyponatremia has been observed in some patients receiving ramipril. Serum sodium levels should be monitored regularly, particularly in elderly patients and 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 in plasma is recommended. More frequent monitoring is advisable at the beginning of treatment and in patients with renal impairment, concomitant collagenosis (e.g., systemic lupus erythematosus or scleroderma), or those receiving other medicinal products that may affect blood counts (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Ethnic differences

ACE inhibitors cause angioedema more frequently in patients of black race than in those of Caucasian race. As with other ACE inhibitors, ramipril may be less effective in lowering blood pressure in patients of black race. This may be due to the higher prevalence of low-renin hypertension in black patients with arterial hypertension.

Cough

Cough has been reported with ACE inhibitor use. The cough is typically non-productive, persistent, and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Excipients.

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

Use during pregnancy or breastfeeding.

Pregnancy

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

Breastfeeding

Due to lack of information on the use of ramipril during breastfeeding (see section "Pharmacological properties"), this medicinal product is not recommended for breastfeeding women. Alternative medicinal products with a more favorable safety profile during lactation should preferably be used, especially when breastfeeding newborns or premature infants.

Ability to affect reaction speed when driving or operating machinery.

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

This is usually possible at the beginning of treatment or when switching from other medications to ramipril. After taking the first dose or any subsequent dose increase, driving vehicles or operating machinery should be avoided for several hours.

Dosage and Administration.

The drug is administered orally.

Ramipril is recommended to be taken daily at the same time. The drug can be taken independently of food intake, as food does not affect its bioavailability (see section "Pharmacological Properties"). The 5 mg tablets are intended to be split in half to obtain a 2.5 mg dose. They must not be chewed or crushed. In cases where a dose of 1.25 mg is required, ramipril preparations allowing such dosing should be used.

Adults

Patients receiving diuretics

Arterial hypotension may occur at the beginning of treatment with the drug, and this is more likely in patients concurrently receiving diuretics. In such cases, caution is advised, as these patients may have reduced circulating blood volume and/or electrolyte depletion.

It is advisable to discontinue diuretic therapy 2–3 days before starting ramipril treatment, if possible (see section "Special Warnings and Precautions for Use"). In hypertensive patients for whom discontinuation of diuretics is not feasible, treatment should be initiated at a dose of 1.25 mg. Renal function and serum potassium levels must be closely monitored. Subsequent ramipril dosing should be adjusted according to the target blood pressure level.

Arterial hypertension

The dose should be individually adjusted according to the patient's condition (see section "Special Warnings and Precautions for Use") and blood pressure monitoring results. Ramipril can be used as monotherapy or in combination with antihypertensive drugs of other classes (see sections "Pharmacodynamics", "Contraindications", "Interaction with Other Medicinal Products and Other Forms of Interaction", and "Special Warnings and Precautions for Use").

Initial dose

Treatment should be initiated gradually, starting with the recommended initial dose of 2.5 mg once daily.

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