Ampril

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Amprilâ (Amprilâ)

Composition:

Active substance: ramipril;

1 tablet contains ramipril 1.25 mg or 2.5 mg or 5 mg or 10 mg;

Excipients:

tablets of 1.25 mg and 10 mg: sodium hydrocarbonate, lactose monohydrate, sodium croscarmellose, pregelatinized starch, sodium stearyl fumarate;

tablets of 2.5 mg: sodium hydrocarbonate, lactose monohydrate, sodium croscarmellose, pregelatinized starch, sodium stearyl fumarate, Pigment Blend PB 22886 Yellow (contains lactose monohydrate, yellow iron oxide (E 172));

tablets of 5 mg: sodium hydrocarbonate, lactose monohydrate, sodium croscarmellose, pregelatinized starch, sodium stearyl fumarate, Pigment blend PB 24899 Pink (contains lactose monohydrate, yellow iron oxide (E 172), red iron oxide (E 172)).

Pharmaceutical form. Tablets.

Main physicochemical properties:

tablets of 1.25 mg – oval, flat, uncoated tablets, white or almost white in color;

tablets of 2.5 mg – oval, flat, uncoated tablets, yellow in color;

tablets of 5 mg – oval, flat, uncoated tablets, pink in color;

tablets of 10 mg – oval, flat, uncoated tablets, white or almost white in color.

Pharmacotherapeutic group. Agents acting on the renin-angiotensin system. Angiotensin-converting enzyme (ACE) inhibitors. Ramipril. ATC code C09AA05.

Pharmacological properties.

Pharmacodynamics.

Ramipril belongs to prodrugs; after absorption, it is hydrolyzed in the liver to form ramiprilat. Ramiprilat is a potent, long-acting angiotensin-converting enzyme (ACE) inhibitor. ACE catalyzes the conversion of angiotensin I into the vasoconstrictive substance angiotensin II. ACE is also kininase II, an enzyme responsible for the degradation of bradykinin. Inhibition of ACE activity leads to reduced concentrations of angiotensin II, increased plasma renin activity, potentiation of bradykinin effects, and decreased aldosterone secretion. The latter may lead to increased serum potassium levels.

In patients with arterial hypertension, the antihypertensive and hemodynamic effects of ramipril are due to the dilation of resistance vessels and reduction in total peripheral vascular resistance, resulting in a gradual decrease in arterial pressure. Heart rate usually remains unchanged. During long-term treatment, left ventricular hypertrophy is reduced without affecting cardiac function. The antihypertensive effect after a single dose begins within 1–2 hours, reaches its maximum within 3–6 hours, and typically lasts for 24 hours. Ramipril is also effective in the treatment of congestive heart failure. In patients with clinical signs of chronic heart failure following acute myocardial infarction, ramipril reduces the risk of sudden death, progression to severe or persistent heart failure, and decreases hospitalization rates due to heart failure.

According to published data, ramipril significantly reduces the incidence of myocardial infarction and stroke, and decreases cardiovascular mortality in patients at high risk due to cardiovascular disease (e.g., active stage of ischemic heart disease, previous stroke, or peripheral vascular disease) or due to diabetes mellitus with at least one additional risk factor (microalbuminuria, arterial hypertension, elevated total cholesterol, low high-density lipoprotein levels, smoking). The drug also reduces overall mortality, the need for revascularization procedures, and delays the onset and progression of congestive heart failure. In patients with diabetes mellitus, as well as in other patients, ramipril significantly reduces the likelihood of developing microalbuminuria and the risk of nephropathy. These effects are observed in patients with normal or elevated blood pressure.

Pharmacokinetics.

Ramipril is rapidly absorbed from the gastrointestinal tract. Its bioavailability is 50–60% and is not affected by food intake. Maximum serum concentration (Cmax) is reached within 1 hour. The elimination half-life of ramipril is approximately 1 hour.

Ramipril is metabolized in the liver. The main metabolite is ramiprilat, which is six times more potent as an ACE inhibitor than ramipril. In addition to ramiprilat, inactive metabolites have also been identified (diketopiperazine ester and acid, as well as their conjugates).

Maximum serum concentration of ramiprilat is achieved 2–4 hours after administration. Steady-state concentrations in serum are reached after 4 days.

Approximately 73% of ramipril and 56% of ramiprilat are bound to serum proteins.

Ramipril and ramiprilat are primarily excreted via the kidneys (about 60%), mostly as metabolites, and less than 2% of the administered dose is excreted unchanged as ramipril.

Ramiprilat is eliminated in a multi-phase manner. After administration of ramipril at therapeutic doses, the terminal elimination half-life of ramiprilat ranges from 13 to 17 hours.

Animal studies have shown that this drug passes into breast milk.

Studies in healthy volunteers aged 65 to 76 years have shown that the pharmacokinetics of ramipril and ramiprilat in this group are similar to those in younger healthy volunteers.

In patients with renal impairment, elimination of ramipril, ramiprilat, and their metabolites is delayed; therefore, ramipril dosage must be adjusted according to renal function (see section "Dosage and administration").

In patients with hepatic impairment (possibly due to reduced activity of hepatic esterases), the metabolic conversion of ramipril to ramiprilat may be slowed, and serum concentrations of ramipril may be increased (see section "Dosage and administration").

Clinical characteristics.

Indications.

• Treatment of arterial hypertension.

• Prevention of cardiovascular diseases: reduction in the incidence of cardiovascular events and cardiovascular mortality in patients with:

• established atherosclerotic cardiovascular disease (history of ischemic heart disease, stroke, or peripheral vascular disease), or

• diabetes mellitus, and at least one additional cardiovascular risk factor (see section "Pharmacodynamics").

• Treatment of kidney disease:

• early diabetic nephropathy, indicated by the presence of microalbuminuria;

• overt diabetic nephropathy, indicated by the presence of macroproteinuria, in patients with at least one cardiovascular risk factor (see section "Pharmacodynamics");

• overt non-diabetic glomerular nephropathy, indicated by the presence of macroproteinuria ≥ 3 g per day (see section "Pharmacodynamics").

• Treatment of symptomatic heart failure.

• Secondary prevention following acute myocardial infarction: reduction in mortality during the acute phase of myocardial infarction in patients with clinical signs of heart failure, provided 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 (see section "Composition").
• History of angioedema (hereditary, idiopathic, or previously induced by ACE inhibitors or angiotensin II receptor antagonists).
• Significant bilateral renal artery stenosis or stenosis of the renal artery in a patient with a single functioning kidney.
• Pregnancy or women planning pregnancy (see section "Use in pregnancy or lactation").
• Ramipril should not be used in patients with arterial hypotension or hemodynamically unstable conditions.
• Concomitant use with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73m²) (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with sacubitril/valsartan due to increased risk of angioedema. The medicinal product must not be administered within 36 hours of switching to or from sacubitril/valsartan – a drug containing a neprilysin inhibitor (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").
• Concomitant use of ACE inhibitors with extracorporeal treatment methods involving blood contact with negatively charged surfaces should be avoided, as such use may lead to severe anaphylactoid reactions (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 frequency of adverse events such as arterial hypotension, hyperkalemia, and renal dysfunction (including acute renal failure), compared to use of a single RAAS-acting agent (see sections "Pharmacodynamics", "Contraindications", and "Special precautions for use").

Contraindicated combinations

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Special precautions for use").

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

Combined use of ramipril 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 groups (see sections "Contraindications" and "Special precautions for use").

Combinations requiring precautions

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

Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients receiving ramipril. Concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium-containing dietary supplements, or salt substitutes may lead to a significant increase in serum potassium. Caution should also be exercised when ramipril is used concomitantly with other agents that increase serum potassium, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Therefore, combination of ramipril with the above-mentioned agents is not recommended. If these agents are indicated due to hypokalemia, they should be used with caution and serum potassium levels should be monitored regularly (see section "Special precautions for use").

Cyclosporine

Hyperkalemia may occur when ACE inhibitors are used concomitantly with cyclosporine. Monitoring of serum potassium levels is recommended.

Heparin

Hyperkalemia may occur with concomitant use of ACE inhibitors and heparin. Monitoring of serum potassium levels is recommended.

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 Ampril®

Careful monitoring of blood pressure is recommended.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics, and other substances that may cause blood count abnormalities

Increased risk of hematological reactions (see section "Special precautions for use").

Salts of lithium

ACE inhibitors may reduce lithium excretion, potentially leading to increased lithium toxicity. Serum 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 Ampril® is expected. Concomitant use of ACE inhibitors and NSAIDs may also be associated with an increased risk of renal dysfunction and elevated blood potassium levels.

mTOR inhibitors or DPP-IV inhibitors

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

Neprilysin inhibitors (NEP)

An increased risk of angioedema has been reported with concomitant use of ACE inhibitors and NEP inhibitors such as racecadotril (see section "Special precautions for use").

Co-trimoxazole (trimethoprim/sulfamethoxazole)

In patients receiving co-trimoxazole (trimethoprim/sulfamethoxazole) concomitantly, the risk of hyperkalemia may be increased (see section "Special precautions for use").

Salt

Excessive salt intake may reduce the antihypertensive effect of the drug.

Specific allergen immunotherapy

Due to ACE inhibition, the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom are increased. This effect is also considered possible with other allergens.

Special precautions for use.

Special patient groups

Pregnancy

Treatment with angiotensin-converting enzyme (ACE) inhibitors, such as ramipril, or angiotensin II receptor antagonists (AIIAs) should not be initiated during pregnancy. If antihypertensive therapy is considered necessary, women planning pregnancy should switch to alternative treatments with established safety profiles during pregnancy. If pregnancy is confirmed during treatment with the medicinal product, ACE inhibitors/AIIAs should be discontinued immediately and, if necessary, alternative therapy should be initiated (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Dual blockade of the RAAS

Evidence shows that concomitant use of ACE inhibitors, AIIAs, or aliskiren increases the risk of arterial hypotension, hyperkalaemia, and impaired renal function (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 only be administered under specialist supervision and with frequent and careful monitoring of renal function, electrolyte levels, and arterial blood pressure.

ACE inhibitors and AIIAs must not be used concomitantly in patients with diabetic nephropathy.

Concomitant use of aliskiren and Ampril® is contraindicated in patients with diabetes mellitus or impaired renal function (eGFR < 60 mL/min/1.73 m²) (see section "Contraindications").

Patients at high risk of arterial hypotension

Patients with markedly increased RAAS activity

In patients with markedly increased RAAS activity, there is a risk of sudden and significant reduction in arterial blood pressure and impaired renal function due to ACE inhibition, particularly when initiating or increasing the dose of an ACE inhibitor or concomitant diuretic for the first time. Markedly increased RAAS activity requiring medical supervision, including continuous monitoring of arterial 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 receiving anaesthetics that may cause arterial hypotension.

Dehydration, hypovolaemia, or electrolyte depletion should generally be corrected before initiating treatment (however, in patients with heart failure, such corrective measures should be applied with caution due to the risk of volume overload).

In patients with hepatic impairment, the response to Ampril® may be either enhanced or reduced. Furthermore, in patients with severe liver cirrhosis associated with oedema and/or ascites, RAAS activity 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 case of acute arterial hypotension

Special medical supervision is required at the beginning of therapy.

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, especially during the first weeks of therapy. Particular careful monitoring is required in patients with impaired renal function (see section "Dosage and administration"). There is a risk of impaired 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.

Increased sensitivity/angioedema

Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients receiving ACE inhibitors, including ramipril (see section "Adverse reactions").

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Initiation of sacubitril/valsartan must not occur within 36 hours of the last dose of ramipril. Ramipril therapy must not be initiated within 36 hours of the last dose of sacubitril/valsartan (see sections "Contraindications" and "Special precautions for use").

Concomitant use of ACE inhibitors with racécadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and vildagliptin increases the risk of angioedema (e.g., airway or tongue swelling, with or without respiratory distress); therefore, special caution is required at the beginning of therapy in such patients (see section "Interaction with other medicinal products and other forms of interactions").

If angioedema develops, ramipril 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.

Intestinal angioedema has been observed in patients receiving ACE inhibitors, including ramipril (see section "Adverse reactions"). These patients reported 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. Ramipril should be temporarily discontinued prior to desensitization procedures.

Monitoring of electrolyte balance. Hyperkalaemia

ACE inhibitors may cause hyperkalaemia as they inhibit aldosterone release. This effect is usually mild in patients with normal renal function. Patients at risk of hyperkalaemia include those with renal impairment, patients aged 70 years or older, patients with uncontrolled diabetes mellitus, patients taking potassium salts, potassium-sparing diuretics, or other active substances that increase plasma potassium levels (e.g., heparin, trimethoprim, or co-trimoxazole, also known as trimethoprim/sulfamethoxazole, particularly aldosterone antagonists or angiotensin receptor antagonists), or patients with conditions such as dehydration, acute cardiac decompensation, or metabolic acidosis. If concomitant use of the above-mentioned medicinal products is considered appropriate, regular monitoring of serum potassium levels and renal function 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) with subsequent development of hyponatraemia has been observed in some patients receiving ramipril. Regular monitoring of serum sodium levels is recommended, particularly in elderly patients and 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 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 taking 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 frequently associated with angioedema 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 explained by the lower plasma renin levels in these patients.

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.

Excipients

The medicinal product contains lactose and therefore should not be administered to patients with rare hereditary problems of galactose intolerance or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Pregnancy

The medicinal product should not be used in pregnant women or women planning pregnancy.

If pregnancy is confirmed during ramipril treatment, therapy should be discontinued immediately and, if necessary, treatment with another medicinal product approved for use in pregnancy should be initiated.

Period of breastfeeding

Due to insufficient information on the use of ramipril (see section "Pharmacokinetics"), the medicinal product is not recommended for administration to breastfeeding women; alternative medicinal products considered safe should preferably be used, especially when breastfeeding newborns or preterm infants.

Ability to influence reaction speed when driving or operating machinery.

Some adverse reactions (certain symptoms of low blood pressure, such as dizziness or vertigo) may affect the ability to drive or operate machinery. Patients should be advised not to drive or operate machinery until they know how they react to the treatment.

Method of Administration and Dosage

Dosage and duration of treatment depend on the patient's condition, need for concomitant therapy, and are always determined by the physician.

The drug 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 "Pharmacokinetics").

Tablets should be swallowed whole with water (approximately ½ glass). They must not be chewed or crushed.

Adults

Patients taking diuretics

At the beginning of treatment with the drug, arterial hypotension may occur, which is more likely in patients concurrently taking diuretics. In such cases, caution is recommended, since 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 Instructions").

In patients with arterial hypertension who cannot discontinue diuretics, ramipril therapy should be initiated at a dose of 1.25 mg. Renal function and serum potassium levels must be carefully monitored. Further dosage adjustments should be made depending on the target blood pressure level.

Arterial hypertension

Dosage should be individually adjusted depending on the patient's condition (see section "Special Instructions") and results of blood pressure monitoring. Ramipril can be used as monotherapy or in combination with other classes of antihypertensive drugs (see sections "Pharmacodynamics", "Contraindications", "Special Instructions", and "Interaction with Other Medicinal Products and Other Forms of Interaction").

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

In patients with significant activation of the RAAS, marked reduction 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 Instructions").

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 the drug is 10 mg per day. The drug is usually taken once daily.

Prevention of cardiovascular diseases

Initial dose. The recommended initial dose is 2.5 mg once daily.

Dose titration and maintenance dose. Depending on the individual response to treatment, the dose should be gradually increased. It is recommended to double the dose after 1–2 weeks of treatment, and then increase it to the target maintenance dose of 10 mg once daily after another 2–3 weeks.

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

Treatment of kidney disease

Patients with diabetes mellitus and microalbuminuria

Initial dose. The recommended initial dose is 1.25 mg once daily.

Dose titration and maintenance dose. Depending on the individual response to treatment, the dose should be gradually increased. After 2 weeks of treatment, the once-daily dose should be doubled to 2.5 mg, and then to 5 mg after another 2 weeks of treatment.

Patients with diabetes mellitus and at least one cardiovascular risk factor

Initial dose. The recommended initial dose is 2.5 mg once daily.

Dose titration and maintenance dose. Depending on the individual response to treatment, the dose should be gradually increased. After 1–2 weeks of treatment, the daily dose 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 per day

Initial dose. The recommended initial dose is 1.25 mg once daily.

Dose titration and maintenance dose. Depending on the individual response to treatment, the dose should be gradually increased. After 2 weeks of treatment, the once-daily dose should be doubled to 2.5 mg, 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 after diuretic therapy, the recommended initial dose is 1.25 mg per day.

Dose titration and maintenance dose. The dose should be titrated by doubling every 1–2 weeks until the maximum daily dose of 10 mg is reached. It is advisable to divide the dose into two administrations.

Secondary prevention after acute myocardial infarction in the presence of heart failure

Initial dose. 48 hours after the onset of myocardial infarction, patients whose condition is clinically and hemodynamically stable should be given an initial dose of 2.5 mg twice daily for 3 days. If the initial dose of 2.5 mg is poorly tolerated, a dose of 1.25 mg twice daily should be used for 2 days, followed by an increase to 2.5 mg and then 5 mg twice daily. If the dose cannot be increased to 2.5 mg twice daily, treatment should be discontinued.

Also see the above information regarding dosage for patients receiving diuretics.

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.

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

If the dose cannot be increased to 2.5 mg twice daily, treatment should be discontinued. Experience in treating patients with severe (NYHA functional class IV) heart failure immediately after myocardial infarction is still limited. If treatment of such patients is nevertheless decided upon, therapy should be initiated with a dose of 1.25 mg once daily, and any dose increase should be performed with extreme caution.

Special patient groups

Patients with impaired renal function

The daily dose for patients with impaired renal function depends on creatinine clearance (see section "Pharmacokinetics"):

• if creatinine clearance is ≥ 60 mL/min, no adjustment of the initial dose (2.5 mg per day) is necessary, 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 per day) is necessary, and the maximum daily dose is 5 mg;
• if creatinine clearance is 10–30 mL/min, the initial daily dose is 1.25 mg, and the maximum daily dose is 5 mg;
• hypertensive patients undergoing hemodialysis: ramipril is only slightly removed during hemodialysis; the initial dose is 1.25 mg, and the maximum daily dose is 5 mg; the drug should be taken several hours after hemodialysis.

Patients with impaired liver function (see section "Pharmacokinetics")

Therapy should be initiated under close medical supervision, and the maximum daily dose should not exceed 2.5 mg.

Elderly patients

The initial dose should be lower, and further dose titration should be performed more gradually due to the higher likelihood of adverse effects, especially in very elderly and frail patients. In such cases, a lower initial dose of 1.25 mg of ramipril should be prescribed.

Children.

Ramipril is not recommended for use in children (under 18 years of age), as the safety and efficacy of ramipril in such patients have not been established.

Overdose.

Overdose may cause excessive peripheral vasodilation (accompanied by pronounced arterial hypotension, shock), bradycardia, electrolyte imbalance, and renal failure.

In case of hypotension, the patient should be placed in a horizontal position with the head lowered and legs elevated. If necessary, plasma volume should be expanded by infusion of 0.9% sodium chloride solution. After ingestion of a large number of tablets, gastric lavage should be performed, and adsorbents and sodium sulfate should be administered (within the first 30 minutes, if possible). Blood pressure, renal function, and serum potassium levels should be carefully monitored. In addition to volume and salt replacement, administration of alpha-1 adrenergic agonists (e.g., noradrenaline, dopamine) and angiotensin II (angiotensinamide) may be considered for hypotension.

The effectiveness of dialysis in intoxication has not been proven.

Adverse reactions.

The safety profile of ramipril 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.

Adverse reactions are classified by system organ classes and frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); unknown (cannot be estimated from available data). Within each group, adverse events are listed in order of decreasing severity.

Table.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions following authorization of the medicinal product is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are obliged to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C in the original packaging to protect from moisture. Keep out of reach of children.

Packaging. 10 tablets per blister; 1, 3, 6, 9 blisters per cardboard box;

7 tablets per blister; 2, 4, 8, 12, or 14 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and place of business.
Smarjeska cesta 6, 8501 Novo mesto, Slovenia.