Hartil®

INSTRUCTIONS FOR MEDICINAL USE OF THE MEDICINAL PRODUCT HARTIL® (HARTIL®)

Composition:

Active substance: ramipril;

1 tablet contains ramipril 5 mg or 10 mg;

Excipients: sodium hydrocarbonate, lactose monohydrate, sodium croscarmellose, pregelatinized starch, sodium stearyl fumarate, iron oxide red (E 172) (for 5 mg tablets), iron oxide yellow (E 172) (for 5 mg tablets).

Pharmaceutical form. Tablets.

Main physicochemical properties:

5 mg tablets – light pink, flat, oval uncoated tablets with bevelled edges, possible speckles, with a score line on one side and on the lateral surfaces, marked with R3, size 8.8 x 4.4 mm.

10 mg tablets – white or almost white, flat, oval uncoated tablets with bevelled edges, with a score line on one side and on the lateral surfaces, marked with R4, size 11.0 x 5.5 mm.

Pharmacotherapeutic group. Agents acting on the renin-angiotensin system. Angiotensin-converting enzyme (ACE) inhibitors. ATC code C09A A05.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Ramiprilat, the active metabolite of ramipril, inhibits the enzyme dipeptidyl carboxy peptidase (synonyms: angiotensin-converting enzyme, 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. Reduced formation of angiotensin II and inhibition of bradykinin degradation lead to vasodilation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat promotes a reduction in aldosterone secretion. The response to monotherapy with ACE inhibitors has generally been less pronounced in patients of Black race (Afro-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 causes a significant reduction in peripheral arterial resistance. Generally, there are no significant changes in renal plasma flow or glomerular filtration rate. Administration of ramipril to patients with arterial hypertension results in a reduction of arterial blood pressure in both supine and upright positions, without compensatory increase in heart rate.

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

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

Sudden discontinuation of ramipril does not lead to rapid or excessive rebound increase in blood pressure (rebound phenomenon).

Heart failure. In addition to standard therapy with diuretics and, if necessary, cardiac glycosides, ramipril has been shown to be effective in patients with NYHA functional classes II–IV. The drug exerts favorable effects on cardiac hemodynamics (reduction in filling pressure of the left and right ventricles, total peripheral vascular resistance, increase in cardiac output, and improvement in cardiac index). It also reduces neuroendocrine activation.

Clinical efficacy and safety.

Prevention of cardiovascular diseases / nephroprotection.

A preventive, placebo-controlled study (the HOPE study) involving more than 9,200 patients who received ramipril in addition to standard therapy was conducted. This study included patients at high risk of developing cardiovascular disease due to prior 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 levels of 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

* Note: The table content was not provided in the original text.

Parameter	Ramipril	Placebo	Relative risk (95% confidence interval)	p value
	%	%
All patients	n=4,645	N=4,652
Primary composite 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 for unstable angina	12.1	12.3	0.98 (0.87−1.1)	not significant
Hospitalization for 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 trial, the effect of adding ramipril at a dose of 10 mg to existing treatment was evaluated versus 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, representing 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 trial designed 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 to <3 g/day) or severe (≥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 participation in the study because benefit from ramipril treatment was demonstrated) showed that the mean 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, approximately equivalent to 4 mL/min/year; 23.1% of patients in the ramipril group reached the combined secondary endpoint—doubling of plasma creatinine concentration and/or end-stage renal disease (requirement for hemodialysis or kidney transplantation)—compared to 45.5% in the placebo group (p = 0.02).

Double 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)] investigated 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 advantages of combination therapy regarding renal and/or cardiovascular outcomes or mortality, while an increased risk of hyperkalemia, acute renal failure, and/or arterial hypotension was observed compared to monotherapy. Given the similar pharmacodynamic characteristics of these drugs, these 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 death 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 acute or chronic symptoms of heart failure following myocardial infarction. Ramipril treatment was initiated 3–10 days after the 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 (73% of whom had primary arterial hypertension) aged 6–16 years with arterial hypertension, 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 4 weeks, ramipril was ineffective on the primary endpoint—reduction in systolic blood pressure—but it reduced diastolic blood pressure when the highest dose in the tested 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 arterial 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 arterial hypertension). In this study, after drug withdrawal, a moderate rebound increase in both diastolic and systolic blood pressure was observed, but it was not statistically significant for return to baseline levels across all dose groups in the tested 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-response relationship.

Pharmacokinetics.

Absorption. After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract: peak plasma concentrations are reached within one 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%.

Peak plasma concentrations of ramiprilat, the sole active metabolite of ramipril, are reached 2–4 hours after drug administration.

Under conditions of regular dosing (once daily), steady-state plasma concentrations are achieved by 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 is predominantly renal. The decline in plasma ramiprilat concentration occurs in several phases. 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 elimination half-life is 13–17 hours for doses of 5–10 mg and longer for lower doses of 1.25–2.5 mg. This difference is due to the enzyme's saturable binding capacity for ramiprilat.

After a single oral dose, ramipril and its metabolite were not detected in breast milk. However, the effect of multiple doses is unknown.

Patients with renal impairment (see section "Dosage and administration"). Renal excretion of ramiprilat is reduced in patients with impaired renal function, and the renal clearance of ramiprilat is proportionally related to creatinine clearance. This leads to higher 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 liver disease, the metabolism of ramipril to ramiprilat is slowed due to reduced hepatic esterase activity, resulting in elevated plasma levels of ramipril. However, peak concentrations of ramiprilat in these patients did 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 repeated dosing is unknown.

Pediatric population. The pharmacokinetic profile of ramipril was studied in 30 pediatric patients with arterial hypertension aged 2–16 years with body weight >10 kg. After administration of doses ranging from 0.05 to 0.2 mg/kg, ramipril was rapidly and extensively metabolized to ramiprilat. Maximum plasma concentrations of ramiprilat were reached within 2–3 hours. Ramiprilat clearance was strongly correlated 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 dose group. Administration of a dose of 0.05 mg/kg 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 dose of 10 mg/day in adults.

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. Electrolyte imbalances and hematological changes were observed in all three species. In dogs and monkeys receiving ramipril at 250 mg/kg/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/day, respectively, without adverse effects.

Reproductive toxicity studies 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 rats resulted in irreversible kidney damage (renal pelvis dilation) in offspring at doses of 50 mg/kg/day and higher.

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

Clinical characteristics.

Indications.

Treatment of arterial hypertension.

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

• Established atherothrombotic cardiovascular disease (history of ischemic heart disease, stroke, or peripheral vascular disease);
• Diabetes mellitus and at least one cardiovascular risk factor (see section "Pharmacological properties").

Treatment of kidney disease:

• Early diabetic glomerular nephropathy, indicated by the presence of microalbuminuria;
• Advanced diabetic glomerular nephropathy, indicated by the presence of macroproteinuria, in patients with at least one cardiovascular risk factor (see section "Pharmacological properties");
• Advanced 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 warnings and 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 lactation").

Ramipril should not be administered to patients with arterial hypotension or hemodynamically unstable conditions.

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

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

Interaction with other medicinal products and other forms of interaction.

Clinical trial data have shown that dual blockade of the 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 of renal function (including acute renal failure), compared to treatment with a single RAAS-acting agent (see sections "Pharmacodynamics", "Contraindications", and "Special warnings and precautions for use").

Contraindicated combinations. Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see sections "Contraindications" and "Special warnings and 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 Hartil®.

Extracorporeal therapies 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 Hartil® with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or moderate to severe renal impairment and is not recommended in other patient populations (see sections "Contraindications" and "Special warnings and 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 and its fixed combinations with sulfamethoxazole, tacrolimus, cyclosporine). Hyperkalemia may occur; therefore, plasma potassium levels should be closely monitored.

Antihypertensive medicinal products (e.g., diuretics) and other substances capable of reducing 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 warnings and precautions for use" regarding diuretics).

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

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

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

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

Non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid. A reduced antihypertensive effect of Hartil® is expected. Furthermore, 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. 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.

Trimethoprim or trimethoprim/sulfamethoxazole combination (co-trimoxazole). In patients receiving ACE inhibitors together with trimethoprim/sulfamethoxazole combination, the risk of hyperkalemia is increased.

Selective immunosuppressants or mTOR inhibitors (e.g., temsirolimus, everolimus, sirolimus) or vildagliptin. The risk of angioedema may be increased 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 warnings and precautions for use").

Neprilysin inhibitors (NEP). There have been reports of a potential increased risk of angioedema with concomitant use of ACE inhibitors and neprilysin (neutral endopeptidase) inhibitors, such as racecadotril (see section "Special warnings and 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 is contraindicated during pregnancy. Except in cases where continued treatment with an ACE inhibitor/angiotensin II receptor antagonist is absolutely necessary, patients who are planning to become pregnant should be switched to another antihypertensive agent considered safe during pregnancy. As soon as pregnancy is diagnosed, treatment with ACE inhibitors/angiotensin II receptor antagonists should be discontinued immediately and, if necessary, therapy with another agent should be initiated (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with medicinal products containing aliskiren.

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

If such dual blockade therapy is considered absolutely necessary, it should be administered only under specialist supervision and with frequent and careful monitoring of renal function, electrolyte levels, and blood pressure.

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

Patients at particular risk of arterial hypotension.

Patients with markedly increased activity of the renin-angiotensin-aldosterone system (RAAS). 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, particularly when initiating or increasing the dose of an ACE inhibitor or concomitant diuretic therapy.

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 haemodynamically 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 anaesthesia with agents that may cause arterial hypotension.

Dehydration, hypovolaemia, or electrolyte depletion should generally be corrected prior to initiating treatment (however, for patients with heart failure, such corrective measures should be carefully weighed against the risk of volume overload).

In patients with hepatic impairment, the response to treatment with Hartil® may be either enhanced or diminished. Furthermore, in patients with severe liver cirrhosis associated with oedema and/or ascites, activity of the renin-angiotensin system (RAS) may be markedly increased; therefore, particular caution is required during treatment of these patients.

Transient or persistent heart failure following myocardial infarction.

Patients at risk of cardiac or cerebral ischaemia in the event 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. If possible, treatment with ACE inhibitors such as ramipril should be discontinued one day prior to surgery.

Monitoring of renal function. Renal function should be assessed before and during treatment, and dosage adjusted accordingly, particularly during the first weeks of therapy. Close monitoring is especially required in patients with impaired renal function (see section "Posology and method of administration"). There is a risk of worsening renal function, particularly in patients with congestive heart failure or after kidney transplantation.

Angioedema. Angioedema has been observed in patients receiving ACE inhibitors, including ramipril (see section "Adverse reactions").

The risk of angioedema is increased in patients who are concomitantly receiving medicinal products that may induce angioedema, such as mammalian target of rapamycin (mTOR) inhibitors (e.g., temsirolimus, everolimus, sirolimus), vildagliptin, or neprilysin inhibitors (NEP) (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").

If angioedema occurs, Hartil® 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 Hartil® (see section "Adverse reactions"). These patients presented with abdominal pain (with or without nausea/vomiting).

Anaphylactic reactions during desensitisation. The use of ACE inhibitors increases the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens. Hartil® should be temporarily discontinued prior to desensitisation procedures.

Monitoring of electrolyte balance. Hyperkalaemia. Hyperkalaemia has been observed in some patients receiving ACE inhibitors, including Hartil®. Patients at risk of hyperkalaemia include those with renal impairment, patients aged 70 years or older, patients with uncontrolled diabetes mellitus, patients taking potassium supplements, 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 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. Hyponatraemia. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) leading to hyponatraemia 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 hyponatraemia.

Neutropenia/Agranulocytosis. Cases of neutropenia/agranulocytosis, as well as thrombocytopenia and anaemia, have been reported rarely. Bone marrow suppression has also been reported.
To detect possible leucopenia, monitoring of white blood cell 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 are more likely to cause angioedema in black patients than in those of other races. As with other ACE inhibitors, the antihypertensive effect of ramipril may be less pronounced in black patients compared to other racial groups. This may be due to the higher prevalence of low-renin hypertension in black patients with arterial hypertension.

Cough. Cough has been reported with the use of 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.

Lactose. In patients with lactose intolerance, it should be noted that each 5 mg tablet contains 96.47 mg and each 10 mg tablet contains 193.2 mg of lactose monohydrate.

Patients with rare hereditary disorders such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

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

Use during pregnancy or breastfeeding.

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

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

Ability to 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 antihypertensive therapies to Hartil®. 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 product is for oral use.

Hartil® should be taken daily at the same time each day. Hartil® can be taken before, during, or after meals, as food intake does not affect the bioavailability of the drug. Hartil® tablets should be swallowed whole with water. They must not be chewed or crushed. For proper administration, the tablet may be divided into equal doses along the score line.

Additional Information

Since a dose of 1.25 mg of ramipril cannot be achieved with Hartil® tablets, another ramipril-containing medicinal product should be used for this purpose.

Patients taking diuretics

At the beginning of Hartil® treatment, arterial hypotension may occur, particularly in patients who are simultaneously 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 starting Hartil®, if possible (see section "Special Warnings and Precautions for Use").

In hypertensive patients for whom diuretic discontinuation is not feasible, ramipril therapy should be initiated at a dose of 1.25 mg ramipril (in the appropriate formulation). Renal function and serum potassium levels should be closely monitored. Subsequent ramipril dosing should be adjusted according to the target blood pressure level.

Arterial Hypertension

Dosage should be individualized according to patient characteristics (see section "Special Warnings and Precautions for Use") and blood pressure monitoring results. Hartil® 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 Hartil® should be initiated gradually, starting with the recommended initial dose of 2.5 mg once daily (by dividing the 5 mg tablet).

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

Dose Titration and Maintenance Dose

The dose may be doubled every 2–4 weeks until the target blood pressure level is achieved; the maximum dose of Hartil® is 10 mg once daily. The drug should be taken once daily.

Prevention of Cardiovascular Diseases

Initial Dose

The recommended initial dose of Hartil® is 2.5 mg (by dividing the 5 mg tablet) 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 information above regarding dosing in patients receiving diuretics.)

Treatment of Kidney Disease

In patients with diabetes and microalbuminuria

Initial Dose

The recommended initial dose is 1.25 mg ramipril (in the appropriate formulation) 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 (by dividing the 5 mg tablet), and then 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 Hartil® is 2.5 mg (by dividing the 5 mg tablet) 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 Hartil® should be doubled to 5 mg, and then 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 is 1.25 mg ramipril (in the appropriate formulation) 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 (by dividing the 5 mg tablet), and then 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 ramipril (in the appropriate formulation) once daily.

Dose Titration and Maintenance Dose

The dose of Hartil® should be titrated by doubling every 1–2 weeks until the maximum daily dose of 10 mg is reached. The dose is preferably divided 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, a starting dose of 2.5 mg (by dividing the 5 mg tablet) twice daily should be administered for 3 days to patients whose condition is clinically and hemodynamically stable. If the initial dose of 2.5 mg (by dividing the 5 mg tablet) is poorly tolerated, a dose of 1.25 mg ramipril (in the appropriate formulation) twice daily should be administered for 2 days, followed by an increase to 2.5 mg (by dividing the 5 mg tablet) and then to 5 mg twice daily. If the dose cannot be increased to 2.5 mg (by dividing the 5 mg tablet) twice daily, treatment should be discontinued.

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

Dose Titration and Maintenance Dose

The daily dose should subsequently 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 (by dividing the 5 mg tablet) 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 nevertheless decided upon, therapy should be initiated at a dose of 1.25 mg ramipril (in the appropriate formulation) once daily, and any dose increase should be made 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) 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 ramipril (in the appropriate formulation)/day, 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 ramipril (in the appropriate formulation) per day, and the maximum daily dose is 5 mg; the drug should be taken several hours after a hemodialysis session.

Patients with Hepatic Impairment (see section "Pharmacological Properties"). Treatment with Hartil® in patients with hepatic impairment should be initiated under close medical supervision, and the maximum daily dose in such cases should be 2.5 mg.

Elderly Patients
The initial dose should be lower, and subsequent dose titration should be performed more gradually due to the increased risk of adverse effects, especially in very elderly and frail patients. In such cases, a lower initial dose of 1.25 mg ramipril (in the appropriate formulation) should be prescribed.

Children
Hartil® is not recommended for use in children (under 18 years of age) due to insufficient data on safety and efficacy in this patient population.

Current data on ramipril are described in the sections "Pharmacological Properties" and "Adverse Reactions".

Overdose

Symptoms of angiotensin-converting enzyme (ACE) inhibitor overdose may include excessive peripheral vasodilation (with marked arterial hypotension, shock), bradycardia, electrolyte disturbances, and renal failure. The patient's condition should be closely monitored. Symptomatic and supportive treatment should be administered. Recommended measures include primary detoxification (gastric lavage, administration of adsorbents) and interventions to restore hemodynamic stability, including administration of alpha-1 adrenergic agonists or angiotensin II (angiotensinamide). Ramiprilat, the active metabolite of ramipril, is poorly removed from the systemic circulation by hemodialysis.

Adverse reactions.

The safety profile of the Hartil® medicinal product includes data on persistent cough and reactions due to arterial hypotension. Serious adverse reactions include angioneurotic edema, hyperkalemia, hepatic or renal dysfunction, pancreatitis, severe skin reactions, and neutropenia/agranulocytosis.

The frequency of adverse reactions is classified as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000), not known (cannot be estimated from the available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

System organ class	Adverse reactions by frequency
	Common	Uncommon	Rare	Very rare	Not known
Blood and lymphatic system disorders		Eosinophilia	Decreased white blood cell count (including neutropenia or agranulocytosis), decreased red blood cell count, decreased hemoglobin levels, decreased platelet count		Bone marrow failure, pancytopenia, hemolytic anemia
Immune system disorders					Anaphylactic and anaphylactoid reactions, increased levels of antinuclear antibodies
Endocrine disorders					Inappropriate antidiuretic hormone secretion syndrome (SIADH)
Metabolism and nutrition disorders	Increased blood potassium levels	Anorexia, decreased appetite			Decreased blood sodium levels
Psychiatric disorders		Depressed mood, anxiety, nervousness, restlessness, sleep disturbances including somnolence	Confusional state		Attention disturbance
Nervous system disorders	Headache, dizziness	Vertigo, paraesthesia, ageusia, dysgeusia	Tremor, loss of balance		Cerebral ischemia, including ischemic stroke and transient ischemic attack; psychomotor function disturbances; burning sensation; parosmia
Eye disorders		Visual disturbances, including blurred vision	Conjunctivitis
Ear and labyrinth disorders			Hearing impairment, tinnitus
Cardiac disorders		Myocardial ischemia, including angina or myocardial infarction; tachycardia; arrhythmia; palpitations; peripheral edema
Vascular disorders	Arterial hypotension, orthostatic hypotension, syncope	Flushing	Vascular stenosis, hypoperfusion, vasculitis		Raynaud's phenomenon
Respiratory, thoracic and mediastinal disorders	Non-productive irritating cough, bronchitis, sinusitis, dyspnea	Bronchospasm, including asthma exacerbation; nasal congestion
Gastrointestinal disorders	Inflammatory conditions of the gastrointestinal tract, digestive disorders, abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting	Pancreatitis (in isolated cases fatal outcomes have been reported with ACE inhibitors), increased levels of pancreatic enzymes, angioneurotic edema of the small intestine, upper abdominal pain including gastritis, constipation, dry mouth	Glossitis		Aphthous stomatitis
Hepatobiliary disorders		Elevated liver enzymes and/or conjugated bilirubin	Cholestatic jaundice, hepatic cell damage		Acute liver failure, cholestatic or cytolytic hepatitis (in very rare cases with fatal outcome)
Skin and subcutaneous tissue disorders	Rash, including maculopapular	Angioedema; in very rare cases airway obstruction due to angioedema which may be fatal; pruritus, hyperhidrosis	Exfoliative dermatitis, urticaria, onycholysis	Photosensitivity reaction	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	Muscle spasms, myalgia	Arthralgia
Renal and urinary disorders		Renal dysfunction, including acute renal failure; increased urine output, worsening of pre-existing proteinuria, increased blood urea levels, increased blood creatinine levels
Reproductive system and breast disorders		Transient erectile impotence, decreased libido			Gynecomastia
General disorders	Chest pain, fatigue	Pyrexia	Asthenia

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

Tachycardia, nasal congestion, and rhinitis: common (i.e. from ≥ 1/100 to < 1/10) in the pediatric population and uncommon (i.e. from ≥ 1/1000 to < 1/100) in adult patients.

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

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

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

Reporting of suspected adverse reactions.
Reporting suspected adverse reactions after drug approval is an important step. It enables continuous monitoring of the benefit-risk balance of the medicinal product.

Healthcare professionals are required to report any cases of adverse reactions through the pharmacovigilance system of Ukraine.

Shelf life. 2 years.

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

Packaging. 7 tablets per blister; 2 or 4 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Egis Pharmaceuticals Ltd., Hungary.

Manufacturer's address and location of its business operations.

1165 Budapest, Bekásvölgyi Street 118–120, Hungary.