Laceran

INSTRUCTION for medical use of the medicinal product LACERAN (LACERAN)

Composition:

Active substance: ramipril;

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

Excipients:

tablets of 2.5 mg: hypromellose, microcrystalline cellulose (PH 112), microcrystalline cellulose (PH 101), pregelatinized starch, iron oxide red (E 172), sodium stearyl fumarate;

tablets of 5 mg: hypromellose, microcrystine cellulose (PH 112), microcrystalline cellulose (PH 101), pregelatinized starch, iron oxide yellow (E 172), sodium stearyl fumarate;

tablets of 10 mg: hypromellose, microcrystalline cellulose (PH 112), microcrystalline cellulose (PH 101), pregelatinized starch, iron oxide yellow (E 172), sodium stearyl fumarate;

Pharmaceutical form. Tablets.

Main physicochemical properties:

tablets of 2.5 mg: mottled tablets ranging from pink to red in color, elongated in shape, with the marking R and 18 on both sides of the break line on one side of the tablet and with a break line on the other.

tablets of 5 mg: mottled tablets ranging from light yellow to yellow in color, elongated in shape, with the marking R and 19 on both sides of the break line on one side of the tablet and with a break line on the other.

tablets of 10 mg: mottled tablets ranging from light yellow to yellow in color, elongated in shape, with the marking R and 20 on both sides of the break line on one side of the tablet and with a break line on the other.

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

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Ramiprilat, the active metabolite of the prodrug ramipril, is an inhibitor of the enzyme dipeptidyl carboxypeptidase I (synonyms: angiotensin-converting enzyme; kininase II). In blood plasma and tissues, this enzyme catalyzes the conversion of angiotensin I to angiotensin II (an active vasoconstrictor substance) and the breakdown of the active vasodilator bradykinin. Reduced formation of angiotensin II and inhibition of bradykin combust 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 (Afro-Caribbean origin) with arterial hypertension (a population typically characterized by low renin levels in arterial hypertension) compared to patients of other races.

Antihypertensive properties. Administration of ramipril leads to a significant reduction in peripheral arterial resistance. Generally, no significant changes in renal plasma flow or glomerular filtration rate occur. Administration of ramipril to patients with arterial hypertension results in a reduction of arterial pressure in both 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 is usually achieved within 3–6 hours. The antihypertensive effect after a single dose generally persists for 24 hours.

With long-term treatment using ramipril, the maximum antihypertensive effect develops within 3–4 weeks. It has been demonstrated that during prolonged therapy, the antihypertensive effect is maintained for up to 2 years.

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

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

Clinical efficacy and safety.

Prevention of cardiovascular diseases / nephroprotection.

A preventive, placebo-controlled study (the HOPE study) was conducted involving over 9,200 patients who received ramipril in addition to standard therapy. This study included patients at high risk of cardiovascular disease due to prior atherothrombotic cardiovascular disease (history of ischemic heart disease, stroke, or peripheral vascular disease) or 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 reduced, in a statistically reliable manner, the incidence of myocardial infarction, cardiovascular death, and stroke, both individually and in combination (primary combined endpoint).

Table 1. HOPE study: main results

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 regimens was evaluated compared to 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 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 to <3 g/day) or severe proteinuria (≥3 g/day) due to chronic non-diabetic nephropathy. Both subgroups were prospectively stratified.

The main analysis results in patients with the most severe proteinuria (a subgroup that prematurely discontinued 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, or 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 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 (the Telmisartan Randomized Trial to Evaluate Cardiovascular Outcomes) 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 arterial hypotension was observed compared to monotherapy. Given the similar pharmacodynamic characteristics of these drugs, these results are also applicable to other ACE inhibitors and angiotensin II receptor antagonists.

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

The ALTITUDE study (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 study 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 transient or ongoing symptoms of heart failure following acute 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 in the ramipril group was 16.9% compared to 22.6% in the placebo group. This corresponds to 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 study 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 4 weeks, ramipril was ineffective on the primary endpoint—reduction in systolic blood pressure—but it reduced diastolic blood pressure at the highest dose in the studied range. It was shown that both medium and high doses of ramipril significantly reduced systolic and diastolic blood pressure in children with confirmed hypertension.

This effect was not observed in a 4-week randomized, double-blind, dose-escalation study assessing the effect of drug withdrawal, involving 218 pediatric patients aged 6–16 years (75% of whom had primary 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 returning blood pressure to baseline levels in all dose groups of 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 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 concentration of ramiprilat, the sole active metabolite of ramipril, is reached 2–4 hours after ramipril administration. After administration of usual daily doses of ramipril once daily, steady-state plasma concentrations of ramiprilat are achieved by approximately day 4 of treatment.

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

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

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

After repeated 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 enzyme's binding capacity for ramiprilat being saturable.

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

Patients with renal impairment (see section "Posology and method of 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 higher plasma concentrations of ramiprilat, which decline more slowly than in individuals with normal renal function.

Patients with hepatic impairment (see section "Posology and method of administration"). In patients with impaired liver function, metabolism of ramipril to ramiprilat is slowed due to reduced activity of hepatic esterases, and plasma levels of ramipril are elevated. However, maximum concentrations of ramiprilat in these patients do not differ from those in individuals with normal liver function.

Breastfeeding. After 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 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 concentration of ramiprilat was reached within 2–3 hours. Ramiprilat clearance correlated significantly with the logarithm of body weight (p<0.01) and with dose (p<0.001). Clearance and volume of distribution increased proportionally with age in each dose group. Administration of a 0.05 mg/kg dose in children achieved exposure levels comparable to those in adults receiving a 5 mg dose of ramipril. Administration of a 0.2 mg/kg dose in children resulted in exposure levels higher than those achieved with the maximum recommended adult dose of 10 mg/day.

Preclinical safety data. 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 250 mg/kg/day, marked increases in the juxtaglomerular apparatus were noted, reflecting the pharmacodynamic activity of ramipril. Rats, dogs, and monkeys tolerated daily doses of 2, 2.5, and 8 mg/kg body weight, respectively, without adverse effects.

Reproductive toxicity studies 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/day and higher.

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

Clinical characteristics.

Indications.

Treatment of arterial hypertension.

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

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

Treatment of kidney disease:

• early diabetic glomerular nephropathy, indicated by the presence of microalbuminuria;
• 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 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 in pregnancy and lactation").

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

Concomitant use of the medicinal product Laceren 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 leading to blood contact with negatively charged surfaces should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Clinical trial data have demonstrated that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is associated with an increased frequency of adverse events such as arterial hypotension, hyperkalemia, and worsening of renal function (including acute renal failure), compared to using a single agent acting on the RAAS (see sections "Contraindications", "Special precautions for use", and "Pharmacodynamics").

Contraindicated combinations.

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

Extracorporeal therapeutic methods involving blood contact with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile membranes) and low-density lipoprotein apheresis using dextran sulfate, are contraindicated due to an increased risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is necessary, consideration should be given to using an alternative dialysis membrane or another class of antihypertensive agents.

Combinations requiring precautions.

Potassium salts, heparin, potassium-sparing diuretics, and other active substances that increase plasma potassium levels (including angiotensin II antagonists, trimethoprim and its fixed combinations with sulfamethoxazole, tacrolimus, cyclosporine). Hyperkalemia may occur; therefore, plasma potassium levels should be closely monitored.

Antihypertensive medicinal products (e.g., diuretics) and other substances capable of reducing 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 Laceren. Blood pressure should be closely monitored.

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

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

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

Non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid. A reduced antihypertensive effect of Laceren is expected. Moreover, concomitant use of ACE inhibitors and NSAIDs may be associated with an increased risk of worsening renal function and elevated blood potassium levels.

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

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

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

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

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

Special precautions for use.

Special patient 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, patients who are planning to become pregnant should be switched to an alternative antihypertensive agent considered safe for use during pregnancy. As soon as pregnancy is diagnosed, treatment with ACE inhibitors/angiotensin II receptor antagonists should be discontinued immediately and, if necessary, therapy with another medication should be initiated (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of hypotension, hyperkalaemia, and deterioration of 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 activity of the renin-angiotensin-aldosterone system. In patients with markedly increased activity of the renin-angiotensin-aldosterone system, 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 concomitant diuretic is initiated or its dose is increased for the first time. Markedly increased activity of the renin-angiotensin-aldosterone system requiring medical supervision, including continuous blood pressure monitoring, may be expected, for example, in patients:

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

In general, correction of dehydration, hypovolaemia, or electrolyte depletion is recommended 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 ischaemia in case of acute arterial hypotension. Special medical supervision is required during the initial phase of treatment.

Elderly patients. See section "Dosage and administration".

Surgery. If possible, treatment with ACE inhibitors such as ramipril should be discontinued one day before surgery.

Monitoring of renal function. Renal function should be assessed before and during treatment, and dosage adjusted accordingly, particularly during the first weeks of therapy. Close monitoring is especially required in patients with impaired renal function (see section "Dosage and administration"). There is a risk of worsening renal function, particularly in patients with congestive heart failure or after kidney transplantation, as well as in cases of renal vascular disease, including patients with hemodynamically significant unilateral renal artery stenosis.

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

Combination of ramipril with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

If angioedema develops, administration of the drug Laceren should be discontinued. Immediate emergency treatment should be initiated. The patient should remain under medical supervision for at least 12–24 hours and may be discharged only after complete resolution of symptoms.

Cases of intestinal angioedema have been observed in patients receiving ACE inhibitors, including Laceren (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. Treatment with Laceren should be temporarily discontinued prior to desensitization procedures.

Monitoring of electrolyte balance. Hyperkalaemia. Hyperkalaemia has been observed in some patients receiving ACE inhibitors, including Laceren. 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 or potassium-sparing diuretics, patients receiving other active substances that increase plasma potassium levels, or patients with conditions such as dehydration, acute heart decompensation, or metabolic acidosis. If concomitant use of the above-mentioned agents is considered 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. The 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 hyponatraemia.

Neutropenia/agranulocytosis. Cases of neutropenia/agranulocytosis, as well as thrombocytopenia and anaemia, have been reported rarely. Bone marrow suppression has also been reported. To detect possible leucopenia, monitoring of white blood cell counts is recommended. More frequent monitoring is advisable at the beginning of treatment and in patients with impaired renal function, concomitant collagenosis (e.g., systemic lupus erythematosus or scleroderma), or those receiving other medicinal products that may 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 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 ACE inhibitor therapy. 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.

Use during pregnancy or breastfeeding.

Pregnancy. The drug is contraindicated in pregnant women or women who are planning to become pregnant. If pregnancy occurs during therapy, 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 drug is not recommended for breastfeeding women. It is preferable to use alternative medicinal products considered safer during lactation, especially when breastfeeding newborns or premature infants.

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

This is generally possible at the beginning of treatment or when switching from therapy with other drugs to treatment with Laceren. After taking the first dose or any subsequent dose increase, driving or operating machinery should be avoided for several hours.

Method of Administration and Dosage

For oral use.

Laceran should be taken daily at the same time. Laceran may be taken before, during, or after meals, as food intake does not affect the bioavailability of the drug. Laceran tablets should be swallowed whole with water. They must not be chewed or crushed.

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

Adults.

Patients receiving diuretics. At the beginning of treatment with Laceran, arterial hypotension may occur, particularly in patients who are simultaneously receiving diuretics. In such cases, caution is recommended, as these patients may have reduced circulating blood volume and/or electrolyte depletion.

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

In hypertensive patients in whom discontinuation of diuretics is not feasible, treatment with Laceran should be initiated at a dose of 1.25 mg (use ramipril in the corresponding dosage). Renal function and serum potassium levels should be closely monitored. Subsequent dosage adjustments of Laceran should be based on 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. Laceran 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 Laceran should be initiated gradually, starting with the recommended initial dose of 2.5 mg (use ramipril in the corresponding dosage) once daily.

In patients with significant activation of the renin-angiotensin-aldosterone system, marked reduction in blood pressure may occur after the initial dose. For such patients, the recommended initial dose is 1.25 mg (use ramipril in the corresponding dosage), 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 Laceran is 10 mg once daily. The drug is generally administered once daily.

Cardiovascular Disease Prevention.

Initial Dose. The recommended initial dose of Laceran is 2.5 mg (use ramipril in the corresponding dosage) once daily.

Dose Titration and Maintenance Dose. Depending on individual tolerability, the dose should be gradually increased. It is recommended to double the dose after 1–2 weeks of treatment, and then increase it 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 Laceran is 1.25 mg (use ramipril in the corresponding dosage) 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), 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 Laceran is 2.5 mg (use ramipril in the corresponding dosage) 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 Laceran should be doubled to 5 mg, and then increased to 10 mg after another 2–3 weeks of treatment. The target daily dose is 10 mg.

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

Initial Dose. The recommended initial dose of Laceran is 1.25 mg (use ramipril in the corresponding dosage) 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), and then increased to 5 mg after another 2 weeks of treatment.

Heart Failure with Clinical Manifestations.

Initial Dose. For patients whose condition has been stabilized with diuretic therapy, the recommended initial dose is 1.25 mg (use ramipril in the corresponding dosage) once daily.

Dose Titration and Maintenance Dose. The dose of Laceran 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 dose into two administrations.

Secondary Prevention Following Acute Myocardial Infarction in the Presence of Heart Failure.

Initial Dose. 48 hours after the onset of myocardial infarction, patients whose clinical and hemodynamic status is stable are given an initial dose of 2.5 mg (use ramipril in the corresponding dosage) twice daily for 3 days. If the initial dose of 2.5 mg (use ramipril in the corresponding dosage) is poorly tolerated, a dose of 1.25 mg (use ramipril in the corresponding dosage) twice daily should be administered for 2 days, followed by an increase to 2.5 mg (use ramipril in the corresponding dosage) and then to 5 mg twice daily. If the dose cannot be increased to 2.5 mg (use ramipril in the corresponding dosage) 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 reached.

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) twice daily, treatment should be discontinued. Experience with treatment of patients with severe (NYHA functional 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 (use ramipril in the corresponding dosage) 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)) 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)) is required, but 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), and the maximum daily dose is 5 mg;
• hypertensive patients undergoing hemodialysis: ramipril is only minimally removed during hemodialysis; the initial dose is 1.25 mg (use ramipril in the corresponding dosage), and the maximum daily dose is 5 mg; the drug should be administered several hours after a hemodialysis session.

Patients with Hepatic Impairment (see section "Pharmacological Properties"). Treatment with Laceran 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 (use ramipril in the corresponding dosage).

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

Also refer to the information above regarding dosage for patients receiving diuretics.

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

Overdose.

Symptoms associated with overdose of ACE inhibitors may include excessive peripheral vasodilation (with marked arterial hypotension, shock), bradycardia, electrolyte disturbances, and renal failure. Close monitoring of the patient is required, and symptomatic and supportive therapy should be administered. Recommended treatment measures include initial decontamination (gastric lavage, administration of adsorbents), as well as interventions aimed at restoring stable hemodynamics, including administration of alpha-1 adrenergic agonists or angiotensin II (angiotensinamide). Ramiprilat, the active metabolite of ramipril, is poorly removed from systemic circulation by hemodialysis.

Adverse reactions.

The safety profile of the drug Lacernan includes data on persistent cough and reactions caused by arterial hypotension. Serious adverse reactions include angioneurotic edema, hyperkalemia, hepatic or renal dysfunction, pancreatitis, severe skin reactions, and neutropenia/agranulocytosis.

The frequency of adverse reactions is classified as follows: very common (≥ 1/10); common (from ≥ 1/100 to < 1/10); uncommon (from ≥ 1/1,000 to < 1/100); rare (from ≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). Within each group, adverse reactions are listed in order of decreasing severity.

Table 2.

Pediatric population.
The safety of ramipril has been 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: frequent (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: frequent (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 marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product.

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

Shelf life. 2 years.

Storage conditions.
Store in the original packaging at a temperature 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.
Sun Pharmaceutical Industries Limited.

Sun Pharmaceutical Industries Limited.

Manufacturer's address and place of business.
V. Ganguwala, Paonta Sahib, District Sirmour, Himachal Pradesh 173025, India.