Cardipril 2.5

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CАRDIPRIL 2.5 CАRDIPRIL 5 CАRDIPRIL 10 (CАRDIPRIL 2.5 CАRDIPRIL 5 CАRDIPRIL 10)

Composition:

Active ingredient: ramipril;

1 capsule contains ramipril 2.5 mg or 5 mg or 10 mg;

Excipient: pregelatinized starch.

Dosage form. Capsules.

Main physicochemical properties:

Cardipril 2.5: hard gelatin capsules size 2, blue/white in color, capsule content – white or almost white powder;

Cardipril 5: hard gelatin capsules size 4, red-brown/white in color, capsule content – white or almost white powder;

Cardipril 10: hard gelatin capsules size 4, blue/white in color, capsule content – white or almost white powder.

Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors. Single-component ACE inhibitors. Ramipril.

ATC code C09A A05.

Pharmacological Properties

Ramiprilat, the active metabolite of ramipril, inhibits the enzyme dipeptidyl carboxypeptidase I (synonyms: angiotensin-converting enzyme (ACE); kininase II). In plasma and tissues, this enzyme catalyzes the conversion of angiotensin I to angiotensin II, an active vasoconstrictor substance, and also inhibits the degradation of the active vasodilator bradykinin. Reduced formation of angiotensin II and inhibition of bradykinin breakdown lead to vasodilation. Since angiotensin II also stimulates the release of aldosterone, ramiprilat reduces aldosterone secretion.

ACE inhibitors are effective even in patients with arterial hypertension who have low plasma renin concentrations. The average response to monotherapy with an ACE inhibitor is lower in non-black patients (typically in populations with arterial hypertension and low renin levels) compared to individuals of other races.

Pharmacodynamics

Administration of ramipril results in a marked reduction in peripheral arterial resistance. Overall, renal plasma flow and glomerular filtration rate are not significantly altered.

Administration of ramipril to patients with arterial hypertension leads to a reduction in arterial blood pressure in both supine and standing positions, without compensatory increases in heart rate.

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

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

No rapid or marked increase in arterial blood pressure occurs upon abrupt discontinuation of ramipril.

In patients with significant non-diabetic or diabetic nephropathy, ramipril reduces the rate of progression of renal failure and the onset of end-stage renal disease, thereby reducing the need for dialysis or kidney transplantation. In patients with early signs of non-diabetic or diabetic nephropathy, ramipril reduces albumin excretion.

Clinical studies have shown that ramipril significantly reduces the incidence of myocardial infarction (by 20%), stroke (by 32%), and cardiovascular mortality (by 26%). Additionally, ramipril reduces overall mortality, the need for revascularization procedures, and delays the onset and progression of congestive heart failure. Ramipril reduces the risk of developing nephropathy in both the general population and in patients with diabetes mellitus. Ramipril also significantly reduces the incidence of microalbuminuria. These effects have been observed in patients both with and without arterial hypertension.

Pharmacokinetics

In the liver, presystemic metabolism of the prodrug ramipril occurs, resulting in the formation of the single active metabolite ramiprilat (via hydrolysis, primarily in the liver). In addition to this activation, ramipril undergoes glucuronidation and is converted into ramipril diketopiperazine (ester). Ramiprilat is also glucuronidated and converted into ramiprilat diketopiperazine (acid).

As a result of this prodrug activation and metabolism, approximately 20% of orally administered ramipril is bioavailable. The bioavailability of ramiprilat after oral administration of 2.5 and 5 mg ramipril is approximately 45%, compared to its availability after intravenous administration of the same doses.

After oral administration of 10 mg radiolabeled ramipril, approximately 40% of the total radioactivity is excreted in feces and about 60% in urine. After oral administration of 5 mg ramipril to patients with biliary drainage, approximately equal amounts of ramipril and its metabolites were excreted in urine and bile within the first 24 hours.

Approximately 80–90% of metabolites in urine and bile are ramiprilat or metabolites of ramiprilat. Ramipril glucuronide and ramipril diketopiperazine account for approximately 10–20% of the total, while unchanged ramipril accounts for about 2%.

Animal studies have shown that ramipril is excreted in milk.

Ramipril is rapidly absorbed after oral administration. Based on measurements of urinary excretion of radiolabeled material, which reflects only one elimination pathway, absorption of ramipril is at least 56%. Co-administration of ramipril with food does not significantly affect absorption.

Peak plasma concentration of ramipril is reached within 1 hour after oral administration. The elimination half-life of ramipril is approximately 1 hour. Peak plasma concentration of ramiprilat occurs between 2 and 4 hours after oral administration of ramipril.

The decline in ramiprilat plasma concentration occurs in several phases. The half-life of the initial distribution and elimination phase is approximately 3 hours. This is followed by a transitional phase (with a half-life of approximately 15 hours) and then a terminal phase, during which plasma concentrations of ramiprilat are very low, with a half-life of approximately 4–5 days.

The prolonged terminal phase is due to the slow dissociation of ramiprilat from a tight, but saturable, binding to ACE.

Despite the long terminal elimination phase, steady-state plasma concentrations of ramiprilat are achieved within approximately 4 days after single doses of ramipril of 2.5 mg or higher. After multiple dosing, the "effective" elimination half-life ranges from 13 to 17 hours, depending on the dose.

In vitro studies have shown that the inhibition constant of ramiprilat is 7 mmol/L, and the half-dissociation time of ramiprilat from ACE is 10.7 hours, indicating high activity.

Protein binding of ramipril and ramiprilat to plasma proteins is approximately 73% and 56%, respectively.

In healthy individuals aged 65 to 76 years, the pharmacokinetics of ramipril and ramiprilat are similar to those in younger healthy individuals.

In patients with impaired renal function, renal excretion of ramiprilat is reduced, and the renal clearance of ramiprilat decreases proportionally to creatinine clearance. This leads to elevated plasma concentrations of ramiprilat, which decline more slowly than in individuals with normal renal function.

With administration of high doses (10 mg) in patients with impaired liver function, the conversion of ramipril to ramiprilat is delayed, plasma concentrations of ramipril increase, and elimination of ramiprilat is slowed.

Similarly to healthy individuals and hypertensive patients, after oral administration of 5 mg ramipril once daily for 2 weeks in patients with congestive heart failure, no significant accumulation of ramipril or ramiprilat was observed.

Clinical characteristics.

Indications.

• Treatment of arterial hypertension.
• Prevention of cardiovascular diseases: reduction of cardiovascular morbidity and mortality in patients with:
  • established atherosclerotic cardiovascular disease (history of ischemic heart disease, stroke, or peripheral vascular disease);
  • diabetes mellitus who have at least one cardiovascular risk factor.
• Treatment of kidney disease:
  • early diabetic glomerular nephropathy, indicated by the presence of microalbuminuria;
  • overt diabetic glomerular nephropathy, indicated by the presence of macroproteinuria, in patients who have at least one cardiovascular risk factor;
  • overt non-diabetic glomerular nephropathy, indicated by the presence of macroproteinuria ≥ 3 g per day.
• 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.

The drug is not recommended for use in children (under 18 years of age).

Hypersensitivity to the active substance or to any of the excipients contained in the drug, 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); significant renal artery stenosis (bilateral stenosis or stenosis of the artery of a solitary kidney); hypotensive or hemodynamically unstable conditions; systemic lupus erythematosus; scleroderma (increased risk of neutropenia or agranulocytosis); bone marrow suppression; hyperkalemia; kidney transplantation; renal insufficiency; hyponatremia (risk of dehydration, arterial hypotension, renal failure); hepatic insufficiency; primary hyperaldosteronism.

Pregnant women or women planning pregnancy (see section "Use during pregnancy and breastfeeding").

The combination with drugs containing aliskiren is contraindicated in patients with diabetes mellitus or moderate to severe renal impairment (GFR < 60 mL/min).

Avoid using ramipril or other ACE inhibitors in combination with extracorporeal therapies that involve contact of blood with negatively charged surfaces, due to the risk of severe anaphylactoid reactions, which may sometimes lead to severe anaphylactic shock. Therefore, when taking ramipril, dialysis or hemofiltration using polyacrylonitrile membranes with high ultrafiltration activity and sodium-2-methylsulfonate membranes (e.g., "AN 69") or LDL apheresis using dextran sulfate should not be performed.

Interaction with other medicinal products and other types of interactions.

Contraindicated combinations.

Extracorporeal therapies involving contact of blood with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile membranes) and LDL 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.

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 for other patient categories (see sections "Contraindications" and "Special precautions for use").

Combinations requiring precautions.

Not recommended combinations.

Potassium salts, heparin, potassium-sparing diuretics, and other active substances that increase plasma potassium levels (including angiotensin II antagonists, trimethoprim, tacrolimus, cyclosporine): increased potassium concentration in blood serum is expected. Careful monitoring of serum potassium concentration is required during concomitant treatment with ramipril and potassium-sparing diuretics (e.g., spironolactone) or potassium salts.

Use with caution.

Antihypertensive medicinal products (e.g., diuretics) and other agents capable of lowering blood pressure (e.g., nitrates, tricyclic antidepressants, anesthetics, alcohol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): enhanced hypotensive effect of ramipril is expected. Regular monitoring of serum sodium concentration is recommended in patients receiving concomitant diuretic therapy (see section "Special precautions for use" regarding diuretics).

Vasopressor sympathomimetics and other substances (e.g., isoprenaline, dobutamine, dopamine, epinephrine). These may reduce the blood pressure-lowering effect. Careful monitoring of blood pressure is recommended.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics, and other medicinal products that may cause changes in hemogram may increase the likelihood of hematological reactions when used concomitantly with ramipril.

Lithium salts. Excretion of lithium may be reduced under the influence of ACE inhibitors. This reduction may lead to increased serum lithium concentration and increased lithium toxicity. Therefore, careful monitoring of lithium concentration is required.

Antidiabetic agents (e.g., insulin and sulfonylurea derivatives).

ACE inhibitors may enhance the effect of insulin. In some cases, this may lead to hypoglycemic reactions in patients receiving antidiabetic agents concomitantly. Close monitoring of blood glucose levels is recommended at the beginning of treatment.

Food.

Food does not significantly affect ramipril absorption.

To be considered.

Non-steroidal anti-inflammatory drugs (NSAIDs), e.g., indomethacin and acetylsalicylic acid. Possible reduction of the blood pressure-lowering effect of ramipril. In addition, concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function and elevated serum potassium levels.

Heparin. Possible increase in serum potassium concentration.

Alcohol. Vascular dilation is increased. Ramipril may enhance the effect of alcohol.

Salt. High salt intake may reduce the antihypertensive effect of Cardipril.

Specific hyposensitization. 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.

Ramipril should be used under constant medical supervision.

Special patient groups.

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

Dual blockade of the renin-angiotensin-aldosterone system by combining ramipril with aliskiren is not recommended, as this increases the risk of developing arterial hypotension, hyperkalaemia, and changes in renal function.

The combination of ramipril and aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (eGFR <60 mL/min) (see section "Contraindications").

Angioedema of the face, extremities, lips, tongue, larynx, or pharynx has been observed in patients treated with ACE inhibitors. Emergency treatment of life-threatening angioedema requires immediate administration of epinephrine (subcutaneously or slowly intravenously); ECG and blood pressure monitoring should be performed simultaneously. If angioedema occurs, ramipril should be discontinued immediately. Emergency therapy should be initiated promptly. Hospitalization is recommended, with patient observation for at least 12–24 hours. Discharge is permitted only after symptoms have completely resolved.

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

Intestinal angioedema has been observed in patients treated with ACE inhibitors. These patients complained of abdominal pain (with or without nausea or vomiting); in some cases, facial angioedema also occurred. Symptoms of intestinal angioedema resolved after discontinuation of the ACE inhibitor.

There is insufficient appropriate therapeutic experience with use in patients with severe renal impairment (creatinine clearance below 20 mL/min per 1.73 m² body surface area).

Patients with increased activity of the renin-angiotensin system.

Particular caution is required when treating patients with increased activity of the renin-angiotensin system. Such patients are at 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 administered for the first time or at a higher dose. Careful monitoring of blood pressure is required at the beginning of treatment or during dose escalation, as long as there is a risk of a sharp drop in blood pressure.

Increased activity of the renin-angiotensin system requiring medical supervision, including continuous blood pressure monitoring, may be expected, in particular:

• in patients with severe, and especially malignant hypertension. Special medical supervision is required during the initial phase of treatment;
• in patients with heart failure, especially with severe heart failure or heart failure previously treated with other drugs that may lower blood pressure. In cases of severe heart failure, special medical supervision is required during the initial phase of treatment;
• in patients with hemodynamically significant inflow or outflow obstruction of the left ventricle (e.g., due to aortic stenosis, mitral valve stenosis, or hypertrophic cardiomyopathy). Special medical supervision is required during the initial phase of treatment;
• in patients with hemodynamically significant renal artery stenosis. Close medical supervision is required during the initial phase of treatment. Discontinuation of diuretic therapy may be necessary;
• in patients previously treated with diuretics. If discontinuation or dose reduction of diuretics is not possible, special medical supervision is required during the initial phase of treatment;
• in patients who have or may develop fluid or salt depletion (due to inadequate fluid or salt intake, or, for example, due to diarrhea, vomiting, or excessive sweating, when compensation for fluid and salt depletion is inadequate);
• in patients undergoing major surgery or anesthesia with agents causing arterial hypotension.

In general, correction of dehydration, hypovolemia, or salt depletion is recommended before starting treatment (however, for patients with heart failure, such corrective measures should be carefully evaluated regarding the risk of volume overload). In clinically significant conditions, treatment may be initiated or continued only if appropriate measures to prevent excessive reduction in blood pressure and worsening of renal function are simultaneously taken.

Patients with liver disease.

In patients with impaired liver function, the response to treatment may be either increased or decreased. In addition, in patients with severe cirrhosis of the liver with edema and/or ascites, activity of the renin-angiotensin system may be significantly increased; therefore, special caution is required during treatment of these patients.

Patients with significant reduction in blood pressure are at particular risk. Special medical supervision during the initial phase of treatment is required for patients for whom a significant drop in blood pressure poses a particular risk (e.g., patients with hemodynamically significant stenosis of coronary arteries or cerebral blood vessels).

Elderly patients.

In elderly patients, the response to ACE inhibitors may be more pronounced. At the beginning of treatment, renal function should be assessed.

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 monitored before and during treatment, and dosage adjusted accordingly, especially during the first weeks of ACE inhibitor therapy. Particularly careful monitoring is required in patients with:

• heart failure;
• renovascular disease, including patients with hemodynamically significant unilateral renal artery stenosis. In this group of patients, even a slight increase in serum creatinine may indicate unilateral deterioration of renal function;
• reduced renal function;
• transplanted kidney.

Monitoring of electrolyte balance.

Regular monitoring of serum potassium concentration is recommended. More frequent monitoring of serum potassium levels is required in patients with impaired renal function.

Hyperkalaemia. Hyperkalaemia has been observed in some patients receiving ACE inhibitors, including ramipril. Patients at risk of hyperkalaemia include those with renal impairment, patients aged 70 years and older, patients with uncontrolled diabetes mellitus, patients taking potassium supplements or potassium-sparing diuretics, as well as 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 drugs is considered appropriate, regular monitoring of plasma potassium levels is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Monitoring of electrolyte balance. Hyponatraemia. The syndrome of inappropriate antidiuretic hormone secretion with subsequent development of 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 changes in blood counts (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Haematological monitoring.

Monitoring of white blood cell count is recommended to detect possible leucopenia early. More frequent monitoring is recommended during the initial phase of treatment in patients with impaired renal function, concomitant connective tissue disease (e.g., lupus erythematosus or scleroderma), or those treated with other drugs that may cause changes in blood counts. Cases of neutropenia/agranulocytosis, as well as thrombocytopenia and anaemia, have been observed rarely. Bone marrow suppression has also been reported.

Ethnic differences. ACE inhibitors cause angioedema more frequently in patients of Black race than in those of other races. As with other ACE inhibitors, the antihypertensive effect of ramipril may be less pronounced in patients of Black race compared to other races. This may be due to the fact that arterial hypertension with low renin activity is more common in patients of Black race.

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

Use during pregnancy or breastfeeding.

Pregnancy.

Ramipril is contraindicated in pregnant women or women planning to become pregnant. If pregnancy occurs during treatment, ramipril 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, the drug is not recommended for nursing mothers. It is preferable to use other medicinal products that are safer during lactation, especially when breastfeeding newborns or premature infants.

Ability to affect reaction speed when driving or operating machinery.

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

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

Administration and Dosage

For oral use.

The medication should be taken daily at the same time each day. It may be taken before, during, or after meals, as food intake does not affect the drug's bioavailability. Capsules should be swallowed whole with water. They must not be chewed or crushed.

Adults.

Patients receiving diuretics. Arterial hypotension may occur at the beginning of treatment with this medication, and the risk is higher in patients concurrently receiving diuretics. Caution is advised 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 initiating ramipril treatment, if possible (see section "Special precautions for use").

In patients with arterial hypertension who cannot discontinue diuretics, treatment should be initiated at a dose of 1.25 mg (administered in the appropriate dosage form). Renal function and serum potassium levels should be closely monitored. Subsequent dosage adjustments should be based on the target blood pressure level.

Arterial hypertension.

Dosage should be individualized according to patient characteristics (see section "Special precautions for use") and blood pressure monitoring results. Ramipril may be used as monotherapy or in combination with other classes of antihypertensive agents.

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

In patients with significant activation of the renin-angiotensin-aldosterone system, marked reduction in blood pressure may occur after the first dose. For such patients, the recommended initial dose is 1.25 mg (administered in the appropriate dosage form), and treatment should be initiated under medical supervision (see section "Special precautions for use").

Dose titration and maintenance dose. The dose may be doubled every 2–4 weeks until the target blood pressure is achieved; the maximum daily dose of ramipril is 10 mg. The drug is generally taken once daily.

(See also the dosage recommendations above for patients receiving diuretics.)

Prevention of cardiovascular disease.

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

Dose titration and maintenance dose. Depending on individual tolerance, 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 dosage recommendations above for patients receiving diuretics.)

Treatment of kidney disease

For patients with diabetes mellitus and microalbuminuria.

Initial dose. The recommended initial dose is 1.25 mg once daily (administered in the appropriate dosage form).

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

(See also the dosage recommendations above for patients receiving diuretics.)

For patients with diabetes mellitus and at least one cardiovascular risk factor.

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

Dose titration and maintenance dose. Depending on individual tolerance, the dose should be increased during continued treatment. After 1–2 weeks of treatment, the daily dose should be doubled to 5 mg, and then increased to 10 mg after another 2–3 weeks. The target daily dose is 10 mg.

(See also the dosage recommendations above for patients receiving diuretics.)

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

Initial dose. The recommended initial dose of ramipril is 1.25 mg once daily (administered in the appropriate dosage form).

Dose titration and maintenance dose. Depending on individual patient tolerance, the dose should be increased during continued treatment. After 2 weeks of treatment, the daily dose should be doubled to 2.5 mg, and then increased to 5 mg after another 2 weeks.

Heart failure with clinical symptoms.

Initial dose. For patients whose condition has been stabilized with diuretic therapy, the recommended initial dose is 1.25 mg daily (administered in the appropriate dosage form).

Dose titration and maintenance dose. The ramipril dose 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.

(See also the dosage recommendations above for patients receiving diuretics.)

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 (administered in the appropriate dosage form) twice daily should be used for 2 days, followed by an increase to 2.5 mg and then to 5 mg twice daily. If the dose cannot be increased to 2.5 mg twice daily, treatment should be discontinued.

(See also the dosage recommendations above 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 with treating patients with severe (NYHA Class IV) heart failure immediately after myocardial infarction is still limited. If treatment of such patients with this drug is nevertheless decided upon, therapy should be initiated at a dose of 1.25 mg (administered in the appropriate dosage form) 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:

• if creatinine clearance is ≥ 60 mL/min, no adjustment of the initial dose (2.5 mg daily) 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 daily) 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 (administered in the appropriate dosage form), 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 (administered in the appropriate dosage form), and the maximum daily dose is 5 mg; the drug should be taken several hours after a hemodialysis session.

Patients with hepatic impairment. Ramipril therapy in patients with hepatic impairment should be initiated under close medical supervision, and the maximum daily dose in such cases should not exceed 2.5 mg.

Elderly patients. The initial dose should be lower, and subsequent dose titration should be more gradual due to the increased risk of adverse effects, especially in very old and frail patients. In such cases, a lower initial dose of 1.25 mg ramipril (administered in the appropriate dosage form) should be prescribed.

Children.

The drug is not recommended for use in children (under 18 years of age), as there is insufficient data on efficacy and safety in this patient population.

Overdose.

Symptoms. Overdose may cause excessive peripheral vasodilation (with marked arterial hypotension, shock), bradycardia, electrolyte imbalance, and renal failure.

Treatment. Close monitoring of the patient is required, along with symptomatic and supportive therapy. Recommended therapeutic measures include initial decontamination (gastric lavage, administration of adsorbents), as well as interventions aimed at restoring hemodynamic stability, 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.

Since ramipril is an antihypertensive agent, many of its adverse effects are secondary to its ability to lower blood pressure, resulting in adrenergic counter-regulation or organ hypoperfusion. Numerous other effects (e.g., effects on electrolyte balance, certain anaphylactoid reactions, or mucosal inflammatory reactions) are caused by ACE inhibition or other pharmacological effects of this class of drugs. Serious adverse reactions include angioneurotic edema, persistent cough, hyperkalemia, hepatic or renal dysfunction, pancreatitis, severe skin reactions, and neutropenia/agranulocytosis.

Cardiac disorders: myocardial ischemia, including angina or myocardial infarction; tachycardia; arrhythmia; palpitations; peripheral edema.

Blood and lymphatic system disorders: eosinophilia; decreased white blood cell count (including neutropenia or agranulocytosis), decreased red blood cell count, decreased hemoglobin levels, thrombocytopenia; bone marrow failure, pancytopenia, hemolytic anemia.

Hematological reactions to ACE inhibitors occur more frequently in patients with impaired renal function, those with concomitant collagen vascular disease (e.g., systemic lupus erythematosus or scleroderma), or those receiving other drugs that may affect blood counts.

Nervous system disorders: headache, dizziness; vertigo, paresthesia, ageusia, dysgeusia; tremor, loss of balance; cerebral ischemia, including ischemic stroke and transient ischemic attack; psychomotor disturbances; burning sensation; parosmia.

Eye disorders: visual disturbances, including blurred vision; conjunctivitis.

Ear and labyrinth disorders: hearing disturbances, tinnitus.

Respiratory system disorders: non-productive, irritating cough, bronchitis, sinusitis, dyspnea; bronchospasm, including asthma exacerbation; nasal congestion.

Gastrointestinal disorders: inflammatory events in the gastrointestinal tract, digestive disturbances, abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting; pancreatitis (in isolated cases, fatal outcomes have been reported with ACE inhibitors), elevated pancreatic enzyme levels, angioneurotic edema of the small intestine, upper abdominal pain including gastritis, constipation, dry mouth; glossitis; aphthous stomatitis.

Renal and urinary disorders: renal dysfunction, including acute renal failure; increased urine output, worsening of pre-existing proteinuria, elevated blood urea levels; elevated serum creatinine.

Skin and subcutaneous tissue disorders: rash, particularly maculopapular; angioedema; 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 exanthem or enanthem, alopecia.

Musculoskeletal and connective tissue disorders: muscle cramps, myalgia; arthralgia.

Endocrine disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders: increased blood potassium levels; anorexia, decreased appetite; decreased blood sodium levels.

Vascular disorders: arterial hypotension, orthostatic hypotension, syncope; flushing sensation; vascular stenosis, hypoperfusion, vasculitis; Raynaud's phenomenon.

General disorders: chest pain, fatigue; pyrexia; asthenia.

Immune system disorders: anaphylactic and anaphylactoid reactions, increased levels of antinuclear antibodies.

Hepatobiliary disorders: elevated liver enzymes and/or bilirubin conjugates; cholestatic jaundice, hepatocellular injury; acute liver failure, cholestatic or cytolytic hepatitis (in rare cases, with fatal outcome).

Reproductive system and breast disorders: transient erectile dysfunction, decreased libido; gynecomastia.

Psychiatric disorders: depressed mood, anxiety, nervousness, restlessness, sleep disturbances, including somnolence; confusion; attention disturbances.

Pediatric population. The nature and severity of adverse reactions in children were similar to those observed in adults, but the frequency of certain reactions was higher in children than in adults, specifically:

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 the adult population.

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 the adult population.

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 the adult population.

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

Shelf life. 3 years.

Storage conditions. Keep out of reach of children. Store in the original packaging at a temperature not exceeding 30 °C.

Packaging.

Cardipril 2.5: 10 capsules in a blister, 1 or 3 blisters per carton.

Cardipril 5 or Cardipril 10: 10 capsules in a blister; 3 blisters per carton.

Prescription category. Prescription only.

Manufacturer.

Flamingo Pharmaceuticals Ltd.

Manufacturer's name and address of the place of business.

E-28, Opp. Fire Brigade, M.I.D.C., Talodha, Raigad District, Maharashtra, IN–410208, India.

Marketing authorization holder.

Ananta Medicare Ltd.

Address of the marketing authorization holder and/or its representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.

INSTRUCTIONS

for medical use of the medicinal product

CARDIPRIL 2.5

CARDIPRIL 5

CARDIPRIL 10

(CАRDIPRIL 2.5

CАRDIPRIL 5

CАRDIPRIL 10)

Composition:

Active substance: ramipril;

1 capsule contains ramipril 2.5 mg or 5 mg or 10 mg;

Excipient: pregelatinized starch.

Pharmaceutical form. Capsules.

Main physicochemical properties:

Cardipril 2.5: hard gelatin capsules size 2, blue/white, contents of capsules – white or almost white powder;

Cardipril 5: hard gelatin capsules size 4, red-brown/white, contents of capsules – white or almost white powder;

Cardipril 10: hard gelatin capsules size 4, blue/white, contents of capsules – white or almost white powder.

Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors. Single-component ACE inhibitors. Ramipril.

ATC code C09A A05.

Pharmacological Properties

Ramiprilat, the active metabolite of ramipril, inhibits the enzyme dipeptidyl carboxypeptidase I (synonyms: angiotensin-converting enzyme (ACE); kininase II). In blood plasma and tissues, this enzyme catalyzes the conversion of angiotensin I into angiotensin II, an active vasoconstrictor substance, and also prevents 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 reduces aldosterone secretion.

ACE inhibitors are effective even in patients with arterial hypertension who have low plasma renin concentrations. The average response to monotherapy with an ACE inhibitor in non-black patients (typically in populations with arterial hypertension and low renin levels) is lower than in individuals of other races.

Pharmacodynamics

Administration of ramipril results in a marked reduction in peripheral arterial resistance. Overall, renal plasma flow and glomerular filtration rate remain essentially unchanged.

Administration of ramipril to patients with arterial hypertension leads to a reduction in blood pressure in both supine and standing positions, without a compensatory increase in heart rate.

In most patients, the antihypertensive effect after a single oral dose appears within 1–2 hours. The maximum effect of a single dose is usually achieved within 3–6 hours and typically lasts for 24 hours.

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

Abrupt discontinuation of ramipril does not lead to a rapid or significant increase in blood pressure.

In patients with significant non-diabetic or diabetic nephropathy, ramipril slows the progression of renal failure and the onset of end-stage renal disease, thereby reducing the need for dialysis or kidney transplantation. In patients with early signs of non-diabetic or diabetic nephropathy, ramipril reduces albumin excretion.

Clinical studies have demonstrated that ramipril significantly reduces the incidence of myocardial infarction (by 20%), stroke (by 32%), and cardiovascular mortality (by 26%) with high statistical significance. Additionally, ramipril reduces overall mortality and the need for revascularization procedures, and delays the onset and progression of congestive heart failure. Ramipril also reduces the risk of developing nephropathy in both the general population and in patients with diabetes. Furthermore, ramipril significantly reduces the incidence of microalbuminuria. These effects have been observed in patients both with and without arterial hypertension.

Pharmacokinetics

Presystemic metabolism of the prodrug ramipril occurs in the liver, resulting in the formation of the single active metabolite ramiprilat (via hydrolysis, primarily in the liver). In addition to this activation to ramiprilat, ramipril undergoes glucuronidation and is converted into ramipril diketopiperazine (ester). Ramiprilat is also glucuronidated and converted into ramiprilat diketopiperazine (acid).

As a result of this activation/metabolism of the prodrug, approximately 20% of orally administered ramipril is bioavailable. The bioavailability of ramiprilat after oral administration of 2.5 and 5 mg of ramipril is approximately 45%, compared to its availability after intravenous administration of the same doses.

After oral administration of 10 mg of radiolabeled ramipril, approximately 40% of the total radioactivity is excreted in feces and about 60% in urine. After oral administration of 5 mg of ramipril to patients with biliary drainage, approximately equal amounts of ramipril and its metabolites were excreted in urine and bile within the first 24 hours.

Approximately 80–90% of metabolites in urine and bile are ramiprilat or ramiprilat metabolites. Ramipril glucuronide and ramipril diketopiperazine account for approximately 10–20% of total excreted material, and unchanged ramipril accounts for about 2%.

Animal studies have shown that ramipril is excreted in milk.

Ramipril is rapidly absorbed after oral administration. Absorption, assessed by measuring urinary excretion of radiolabeled material (which reflects only one elimination pathway), is at least 56%. Co-administration of ramipril with food does not significantly affect absorption.

Peak plasma concentration of ramipril is reached within 1 hour after oral administration. The elimination half-life of ramipril is approximately 1 hour. Peak plasma concentration of ramiprilat occurs between 2 and 4 hours after oral administration of ramipril.

The decline in ramiprilat plasma concentration occurs in several phases. The half-life of the initial distribution and elimination phase is approximately 3 hours. This is followed by a transitional phase (with a half-life of about 15 hours), and then a terminal phase during which plasma concentrations of ramiprilat are very low, with a half-life of approximately 4–5 days.

The terminal phase is due to the slow dissociation of ramiprilat from its tight, but saturable, binding to ACE.

Despite the prolonged terminal elimination phase, steady-state plasma concentrations of ramiprilat are achieved within approximately 4 days after single doses of 2.5 mg or higher. After multiple dosing, the "effective" elimination half-life, depending on dose, ranges from 13 to 17 hours.

In vitro studies have shown that the inhibition constant of ramiprilat is 7 mmol/L, and the half-dissociation time of ramiprilat from ACE is 10.7 hours, indicating high activity.

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

In healthy individuals aged 65 to 76 years, the pharmacokinetics of ramipril and ramiprilat are similar to those in younger healthy subjects.

In patients with impaired renal function, renal excretion of ramiprilat is reduced, and the renal clearance of ramiprilat decreases proportionally to creatinine clearance. This leads to elevated plasma concentrations of ramiprilat, which decline much more slowly than in individuals with normal renal function.

With administration of high doses (10 mg) in patients with impaired liver function, conversion of ramipril to ramiprilat is delayed, plasma concentrations of ramipril increase, and elimination of ramiprilat is slowed.

Similarly to healthy individuals and hypertensive patients, after oral administration of 5 mg ramipril once daily for 2 weeks in patients with congestive heart failure, no significant accumulation of ramipril or ramiprilat was observed.

Clinical characteristics.

Indications.

• Treatment of arterial hypertension.
• Prevention of cardiovascular diseases: reduction of cardiovascular morbidity and mortality in patients with:
  • established atherosclerotic cardiovascular disease (history of ischemic heart disease, stroke, or peripheral vascular disease);
  • diabetes mellitus who have at least one cardiovascular risk factor.
• Treatment of kidney disease:
  • early diabetic glomerular nephropathy, indicated by the presence of microalbuminuria;
  • overt diabetic glomerular nephropathy, indicated by the presence of macroproteinuria, in patients who have at least one cardiovascular risk factor;
  • overt non-diabetic glomerular nephropathy, indicated by the presence of macroproteinuria ≥ 3 g per day.
• 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.

The drug is not recommended for use in children (under 18 years of age).

Hypersensitivity to the active substance or to any of the excipients listed in the composition, 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); significant renal artery stenosis (bilateral stenosis or stenosis of the artery of a single kidney); hypotensive or hemodynamically unstable conditions; systemic lupus erythematosus; scleroderma (increased risk of neutropenia or agranulocytosis); bone marrow suppression; hyperkalemia; kidney transplantation; renal insufficiency; hyponatremia (risk of dehydration, arterial hypotension, renal failure); hepatic insufficiency; primary hyperaldosteronism.

Pregnant women or women planning to become pregnant (see section "Use during pregnancy and breastfeeding").

Concomitant use with drugs containing aliskiren is not recommended in patients with diabetes mellitus or moderate to severe renal impairment (GFR < 60 mL/min).

Ramipril or other ACE inhibitors should not be used in combination with extracorporeal therapies that involve contact of blood with negatively charged surfaces, due to the risk of severe anaphylactoid reactions, which may sometimes lead to severe anaphylactic shock. Therefore, dialysis or hemofiltration using polyacrylonitrile, sodium-2-methylsulfonate membranes with high ultrafiltration activity (e.g., "AN 69") and LDL apheresis using dextran sulfate should not be performed during ramipril treatment.

Interaction with other medicinal products and other types of interactions.

Contraindicated combinations.

Extracorporeal therapies involving contact of blood with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile membranes) and LDL-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.

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 for other patient categories (see sections "Contraindications" and "Special precautions for use").

Combinations requiring precautions.

Not recommended combinations.

Potassium salts, heparin, potassium-sparing diuretics, and other active substances that increase plasma potassium levels (including angiotensin II antagonists, trimethoprim, tacrolimus, cyclosporine): increased potassium concentration in blood serum is expected. Careful monitoring of serum potassium concentration is required during concomitant treatment with ramipril and potassium-sparing diuretics (e.g., spironolactone) or potassium salts.

Use with caution.

Antihypertensive medicinal products (e.g., diuretics) and other agents capable of lowering blood pressure (e.g., nitrates, tricyclic antidepressants, anesthetics, alcohol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): enhanced hypotensive effect of ramipril is expected. Regular monitoring of serum sodium concentration is recommended in patients receiving concomitant diuretic therapy (see section "Special precautions for use" regarding diuretics).

Vasopressor sympathomimetics and other substances (e.g., isoprenaline, dobutamine, dopamine, epinephrine). These may reduce the blood pressure-lowering effect. Careful monitoring of blood pressure is recommended.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics, and other medicinal products that may cause changes in hemogram may increase the likelihood of hematological reactions when used concomitantly with ramipril.

Lithium salts. Excretion of lithium may be reduced under the influence of ACE inhibitors. This reduction may lead to increased serum lithium concentration and increased lithium toxicity. Therefore, serum lithium concentration must be closely monitored.

Antidiabetic agents (e.g., insulin and sulfonylurea derivatives).

ACE inhibitors may enhance the effect of insulin. In individual cases, this may lead to hypoglycemic reactions in patients receiving antidiabetic agents concomitantly. Close monitoring of blood glucose levels is recommended at the beginning of treatment.

Food.

Food does not significantly affect the absorption of ramipril.

To be considered.

Non-steroidal anti-inflammatory drugs (NSAIDs), e.g., indomethacin and acetylsalicylic acid. Possible reduction of the blood pressure-lowering effect of ramipril. In addition, concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function and elevated serum potassium levels.

Heparin. Possible increase in serum potassium concentration.

Alcohol. Vascular dilation is increased. Ramipril may enhance the effect of alcohol.

Salt. High salt intake may reduce the antihypertensive effect of Cardipril.

Specific hyposensitization. Due to ACE inhibition, the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom are increased. This effect is considered to possibly extend to other allergens as well.

Special precautions for use.

Ramipril should be used under constant medical supervision.

Special patient categories.

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

Dual blockade of the renin-angiotensin-aldosterone system by concomitant use of ramipril and aliskiren is not recommended, as it increases the risk of developing arterial hypotension, hyperkalaemia, and renal function impairment.

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

Angioedema of the face, extremities, lips, tongue, glottis or larynx has been observed in patients treated with ACE inhibitors. Life-threatening angioedema requires immediate treatment with epinephrine (subcutaneously or slowly intravenously), while ECG and blood pressure should be monitored simultaneously. If angioedema develops, ramipril should be discontinued immediately. Immediate emergency treatment should be initiated. Hospitalization is recommended, with patient monitoring for at least 12–24 hours, and discharge is permitted only after complete resolution of symptoms.

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

Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases, facial angioedema was also observed. Symptoms of intestinal angioedema resolved after discontinuation of the ACE inhibitor.

There is insufficient therapeutic experience with use in patients with severe renal impairment (creatinine clearance below 20 mL/min per 1.73 m² body surface area).

Patients with increased renin-angiotensin system activity.

Particular caution is required when treating patients with increased renin-angiotensin system activity. Such patients are at 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 increased for the first time. Close monitoring of blood pressure is required at the beginning of treatment or after dose escalation, as long as a sharp drop in blood pressure remains possible.

Increased renin-angiotensin system activity requiring medical supervision, including continuous blood pressure monitoring, may be expected, in particular:

• in patients with severe, especially malignant hypertension. Close medical supervision is required during initial treatment;
• in patients with heart failure, particularly severe or treated with other drugs that may lower blood pressure. In cases of severe heart failure, close medical supervision is required during initial treatment;
• in patients with hemodynamically significant inflow or outflow obstruction of the left ventricle (e.g., due to aortic stenosis, mitral valve stenosis, or hypertrophic cardiomyopathy). Close medical supervision is required during initial treatment;
• in patients with hemodynamically significant renal artery stenosis. Close medical supervision is required during initial treatment. Discontinuation of concomitant diuretic therapy may be necessary;
• in patients previously treated with diuretics. If diuretic discontinuation or dose reduction is not possible, close medical supervision is required during initial treatment;
• in patients with existing or potential fluid or salt depletion (due to inadequate fluid or salt intake, or, for example, diarrhea, vomiting, or excessive sweating, especially when compensation for fluid and salt loss is inadequate);
• in patients undergoing major surgery or anesthesia with agents that may cause arterial hypotension.

In general, dehydration, hypovolemia, or salt depletion should be corrected before starting treatment (however, for patients with heart failure, such corrective measures should be carefully evaluated regarding the risk of volume overload). In clinically significant conditions, treatment may be initiated or continued only if appropriate measures are taken simultaneously to prevent excessive blood pressure reduction and worsening of renal function.

Patients with liver disease.

In patients with impaired liver function, the response to treatment may be either increased or decreased. In addition, in patients with severe cirrhosis with edema and/or ascites, renin-angiotensin system activity may be markedly increased; therefore, particular caution is required when treating these patients.

Patients with marked reduction in blood pressure are at particular risk. Patients for whom a significant drop in blood pressure poses a particular risk (e.g., patients with hemodynamically significant coronary artery stenosis or stenosis of vessels supplying blood to the brain) require close medical supervision during initial treatment.

Elderly patients.

In elderly patients, the response to ACE inhibitors may be more pronounced. Renal function should be assessed at the beginning of treatment.

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

Monitoring of renal function.

Monitoring of renal function before and during treatment is recommended, with dose adjustment, especially during the first weeks of ACE inhibitor therapy. Particularly careful monitoring is required in patients with:

• heart failure;
• renovascular disease, including patients with hemodynamically significant unilateral renal artery stenosis. In this group of patients, even a slight increase in serum creatinine may indicate unilateral deterioration of renal function;
• impaired renal function;
• transplanted kidney.

Monitoring of electrolyte balance.

Regular monitoring of serum potassium concentration is recommended. More frequent monitoring of serum potassium levels is required in patients with impaired renal function.

Hyperkalaemia. Hyperkalaemia has been observed in some patients receiving ACE inhibitors, including ramipril. 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 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 drugs is considered necessary, regular monitoring of plasma potassium levels is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Electrolyte balance monitoring. Hyponatraemia. The syndrome of inappropriate antidiuretic hormone secretion, followed by 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 blood leukocyte count is recommended. More frequent monitoring is advisable at the beginning of treatment and in patients with impaired renal function, concomitant collagenosis (e.g., systemic lupus erythematosus or scleroderma), or those receiving other medicinal products that may cause blood count changes (see sections "Interaction with other medicinal products and other forms of interaction" and "Side effects").

Haematological monitoring.

Monitoring of leukocyte count is recommended to detect possible leucopenia early. More frequent monitoring is recommended during initial treatment of patients with impaired renal function, concomitant collagen disease (e.g., lupus erythematosus or scleroderma), or those treated with other drugs that may cause blood count changes. Cases of neutropenia/agranulocytosis, as well as thrombocytopenia and anaemia, have been reported rarely. Bone marrow suppression has also been reported.

Ethnic differences. ACE inhibitors cause angioedema more frequently in patients of Black race than in other racial groups. As with other ACE inhibitors, the antihypertensive effect of ramipril may be less pronounced in patients of Black race 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 during ACE inhibitor therapy. The cough is typically non-productive, persistent, and resolves after discontinuation of treatment. When performing differential diagnosis of cough, the possibility of ACE inhibitor-induced cough should be considered.

Use during pregnancy or breastfeeding.

Pregnancy.

Ramipril is contraindicated in pregnant women or women planning to become pregnant. If pregnancy is diagnosed during treatment, ramipril 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, the drug is not recommended for breastfeeding women. It is preferable to use other medicinal products considered safer during lactation, especially when breastfeeding newborns or preterm infants.

Ability to affect reaction speed when driving or operating machinery.

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

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

Administration and Dosage.

For oral use.

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

Adults.

Patients receiving diuretics. Arterial hypotension may occur at the beginning of treatment with the medicine, and this is more likely in patients who are concurrently receiving diuretics. Caution is recommended in such cases, as these patients may have reduced blood volume and/or electrolyte levels.

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 diuretic therapy, treatment with the medicine should be initiated at a dose of 1.25 mg (use appropriate dosage form). Renal function and serum potassium levels should be closely monitored. Subsequent dosing should be adjusted according to the target blood pressure level.

Arterial Hypertension.

Dosage should be individualized according to the patient's condition (see section "Special Instructions") and blood pressure monitoring results. Ramipril may be used as monotherapy or in combination with other classes of antihypertensive medicinal products.

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

In patients with significant activation of the renin-angiotensin-aldosterone system, a marked decrease in blood pressure may occur after the initial dose. For such patients, the recommended initial dose is 1.25 mg (use appropriate dosage form), 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 ramipril is 10 mg daily. The medicine is generally taken once daily.

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

Prevention of Cardiovascular Diseases.

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

Dose titration and maintenance dose. Depending on individual tolerance, 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.

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

Treatment of Kidney Disease

For patients with diabetes mellitus and microalbuminuria.

Initial dose. The recommended initial dose of the medicine is 1.25 mg once daily (use appropriate dosage form).

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

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

In patients with diabetes mellitus and at least one cardiovascular risk factor.

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

Dose titration and maintenance dose. Depending on individual tolerance during further treatment, the dose should be 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.

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

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

Initial dose. The recommended initial dose of ramipril is 1.25 mg once daily (use appropriate dosage form).

Dose titration and maintenance dose. Depending on individual patient tolerance during further treatment, the dose should be increased. After 2 weeks of treatment, the 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 with diuretic therapy, the recommended initial dose of the medicine is 1.25 mg daily (use appropriate dosage form).

Dose titration and maintenance dose. The dose of ramipril 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.

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

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, then a dose of 1.25 mg (use appropriate dosage form) twice daily should be administered for 2 days, followed by an increase to 2.5 mg and then to 5 mg twice daily. If the dose cannot be increased to 2.5 mg twice daily, treatment should be discontinued.

(See also the information above regarding dosing 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 with treating patients with severe (NYHA Class IV) heart failure immediately after myocardial infarction is still limited. If treatment of such patients with this medicine is nevertheless decided upon, therapy should be initiated at a dose of 1.25 mg (use appropriate dosage form) 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:

• if creatinine clearance is ≥ 60 mL/min, no adjustment of the initial dose (2.5 mg daily) 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 daily) 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 daily (use appropriate dosage form), 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 appropriate dosage form), and the maximum daily dose is 5 mg; the medicine should be taken several hours after a hemodialysis session.

Patients with impaired liver function. Treatment with ramipril in patients with impaired liver function should be initiated under close medical supervision, and the maximum daily dose in such cases should not exceed 2.5 mg.

Elderly patients. The initial dose should be lower, and subsequent 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 ramipril (use appropriate dosage form) should be prescribed.

Children.

The medicine is not recommended for use in children (under 18 years of age), as there is insufficient data on efficacy and safety of this medicine in such patients.

Overdose.

Symptoms. Overdose may cause excessive peripheral vasodilation (with marked arterial hypotension, shock), bradycardia, electrolyte imbalance, and renal failure.

Treatment. Close monitoring of the patient is required, along with symptomatic and supportive therapy. Proposed therapeutic measures include primary detoxification (gastric lavage, administration of adsorbents), as well as measures aimed at restoring stable hemodynamics, including administration of alpha-1 adrenergic agonists or angiotensin II (angiotensinamide). Ramiprilat, the active metabolite of ramipril, is poorly removed from systemic circulation by hemodialysis.

Side effects.

Since ramipril is an antihypertensive agent, many of its adverse effects are secondary to its ability to reduce blood pressure, resulting in adrenergic counter-regulation or organ hypoperfusion. Numerous other effects (e.g., effects on electrolyte balance, certain anaphylactoid reactions, or mucosal inflammatory reactions) are caused by ACE inhibition or other pharmacological effects of this class of drugs. Serious adverse reactions include angioedema, persistent cough, hyperkalemia, liver or kidney dysfunction, pancreatitis, severe skin reactions, and neutropenia/agranulocytosis.

Cardiac disorders: myocardial ischemia, including angina or myocardial infarction; tachycardia; arrhythmia; palpitations; peripheral edema.

Blood and lymphatic system disorders: eosinophilia; decreased white blood cell count (including neutropenia or agranulocytosis), decreased red blood cell count, decreased hemoglobin levels, thrombocytopenia; bone marrow failure, pancytopenia, hemolytic anemia.

Hematological reactions to ACE inhibitors occur more frequently in patients with impaired renal function, those with concomitant collagen vascular disease (e.g., systemic lupus erythematosus or scleroderma), or those taking other medications that may affect blood composition.

Nervous system disorders: headache, dizziness; vertigo, paresthesia, ageusia, dysgeusia; tremor, loss of balance; cerebral ischemia, including ischemic stroke and transient ischemic attack; psychomotor disturbances; burning sensation; parosmia.

Eye disorders: visual disturbances, including blurred vision; conjunctivitis.

Ear and labyrinth disorders: hearing disturbances, tinnitus.

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), elevated pancreatic enzyme levels, angioedema of the small intestine, upper abdominal pain including gastritis, constipation, dry mouth; glossitis; aphthous stomatitis.

Renal and urinary disorders: renal dysfunction, including acute renal failure; increased urine output, worsening of pre-existing proteinuria, elevated blood urea levels; elevated serum creatinine levels.

Skin and subcutaneous tissue disorders: skin rashes, particularly maculopapular; angioedema; 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 exanthem or enanthem, alopecia.

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

Endocrine disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolic and nutritional disorders: increased blood potassium levels; anorexia, decreased appetite; decreased blood sodium levels.

Vascular disorders: arterial hypotension, orthostatic hypotension, syncope; flushing; vascular stenosis, hypoperfusion, vasculitis; Raynaud's phenomenon.

General disorders and administration site conditions: chest pain, fatigue; pyrexia; asthenia.

Immune system disorders: anaphylactic and anaphylactoid reactions, increased levels of antinuclear antibodies.

Hepatobiliary disorders: elevated liver enzymes and/or bilirubin conjugates; cholestatic jaundice, hepatic cell damage; acute liver failure, cholestatic or cytolytic hepatitis (in rare cases, with fatal outcome).

Reproductive system and breast disorders: transient erectile dysfunction, decreased libido; gynecomastia.

Psychiatric disorders: depression, anxiety, nervousness, restlessness, sleep disturbances, including somnolence; confusion; attention disturbances.

Pediatric population. The nature and severity of adverse reactions in children were similar to those observed in adults, but the frequency of certain reactions was higher in children than in adults, specifically:

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

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

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

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

Shelf life. 3 years.

Storage conditions. Keep out of reach of children. Store in the original packaging at a temperature not exceeding 30 °C.

Packaging.

Cardipril 2.5: 10 capsules in a blister, 1 or 3 blisters per carton.

Cardipril 5 or Cardipril 10: 10 capsules in a blister; 3 blisters per carton.

Prescription category. Prescription only.

Manufacturer.

Arthura Pharmaceuticals Pvt. Ltd.

Manufacturer's address and location of its business operations.

1505 Portia Road, Sri City SEZ, Sedyavedu Mandal, Chittoor District – 517 588, Andhra Pradesh State, India.

Marketing authorization holder.

Ananta Medikear Ltd.

Address of the marketing authorization holder and/or its representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.

INSTRUCTION

for medical use of the medicinal product

CARDIPRIL 2.5

CARDIPRIL 5

CARDIPRIL 10

(CАRDIPRIL 2.5

CАRDIPRIL 5

CАRDIPRIL 10)

Composition:

Active substance: ramipril;

1 capsule contains ramipril 2.5 mg or 5 mg or 10 mg;

Excipient: pregelatinized starch.

Dosage form. Capsules.

Main physicochemical properties:

Cardipril 2.5: hard gelatin capsules size 2, blue/white, contents of capsules – white or almost white powder;

Cardipril 5: hard gelatin capsules size 4, red-brown/white, contents of capsules – white or almost white powder;

Cardipril 10: hard gelatin capsules size 4, blue/white, contents of capsules – white or almost white powder.

Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors. Single-component ACE inhibitors. Ramipril.

ATC code C09A A05.

Pharmacological properties.

Ramiprilat, the active metabolite of ramipril, inhibits the enzyme dipeptidyl carboxypeptidase I (synonyms: angiotensin-converting enzyme (ACE); kininase II). In blood plasma and tissues, this enzyme catalyzes the conversion of angiotensin I into angiotensin II – an active vasoconstrictor substance – and also inhibits 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 reduces aldosterone secretion.

ACE inhibitors are effective even in patients with arterial hypertension who have low plasma renin concentrations. The average response to monotherapy with an ACE inhibitor in non-black patients (typically in populations with hypertension and low renin levels) is lower than in individuals of other races.

Pharmacodynamics.

Administration of ramipril causes a marked reduction in peripheral arterial resistance. Overall, renal plasma flow and glomerular filtration rate remain essentially unchanged.

Administration of ramipril to patients with arterial hypertension results in reduced arterial blood pressure in both supine and standing positions, without compensatory increases in heart rate.

In most patients, the antihypertensive effect after a single oral dose becomes apparent within 1–2 hours. The maximum effect of a single dose is usually achieved within 3–6 hours and typically lasts for 24 hours.

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

Abrupt discontinuation of ramipril does not result in a rapid or significant increase in blood pressure.

In patients with significant non-diabetic or diabetic nephropathy, ramipril reduces the rate of progression of renal impairment and the onset of end-stage renal disease, thereby reducing the need for dialysis or kidney transplantation. In patients with early signs of non-diabetic or diabetic nephropathy, ramipril reduces albumin excretion.

Clinical studies have demonstrated that ramipril significantly reduces the incidence of myocardial infarction (by 20%), stroke (by 32%), and cardiovascular mortality (by 26%) with high statistical significance. Furthermore, ramipril reduces overall mortality and the need for revascularization procedures, and delays the onset and progression of congestive heart failure. Ramipril reduces the risk of developing nephropathy in both the general population and in patients with diabetes mellitus. Ramipril also significantly reduces the incidence of microalbuminuria. These effects have been observed in patients both with and without arterial hypertension.

Pharmacokinetics.

In the liver, presystemic metabolism of the prodrug ramipril occurs, resulting in the formation of the single active metabolite ramiprilat (via hydrolysis, primarily occurring in the liver). In addition to this activation to ramiprilat, ramipril undergoes glucuronidation and is converted into ramipril diketopiperazine (ester). Ramiprilat is also glucuronidated and converted into ramiprilat diketopiperazine (acid).

As a result of this prodrug activation/metabolism, approximately 20% of orally administered ramipril is bioavailable. The bioavailability of ramiprilat after oral administration of 2.5 and 5 mg of ramipril is approximately 45%, compared to its availability after intravenous administration of the same doses.

After oral administration of 10 mg of radiolabeled ramipril, approximately 40% of the total radioactivity is excreted in feces and approximately 60% in urine. After oral administration of 5 mg of ramipril to patients with biliary drainage, similar amounts of ramipril and its metabolites were excreted in urine and bile within the first 24 hours.

Approximately 80–90% of metabolites in urine and bile are ramiprilat or ramiprilat metabolites. Ramipril glucuronide and ramipril diketopiperazine account for approximately 10–20% of the total, while unchanged ramipril accounts for approximately 2%.

Animal studies have shown that ramipril is excreted into milk.

Ramipril is rapidly absorbed after oral administration. Based on measurements of urinary excretion of radiolabeled material, which reflects only one elimination pathway, absorption of ramipril is at least 56%. Co-administration of ramipril with food does not significantly affect absorption.

Peak plasma concentration of ramipril is reached within 1 hour after oral administration. The elimination half-life of ramipril is approximately 1 hour. Peak plasma concentration of ramiprilat occurs between 2 and 4 hours after oral administration of ramipril.

The decline in ramiprilat plasma concentration occurs in several phases. The half-life of the initial distribution and elimination phase is approximately 3 hours. This is followed by a transitional phase (with a half-life of approximately 15 hours), and then a terminal phase during which plasma concentrations of ramiprilat are very low, with a half-life of approximately 4–5 days.

The terminal phase is due to the slow dissociation of ramiprilat from its tight, but saturable, binding to ACE.

Despite the prolonged terminal elimination phase, after a single dose of ramipril of 2.5 mg or higher, steady-state conditions – where plasma concentrations of ramiprilat remain constant – are achieved within approximately 4 days. After multiple dosing, the "effective" elimination half-life, depending on dose, ranges from 13 to 17 hours.

In vitro studies have shown that the inhibition constant of ramiprilat is 7 mmol/L, and the half-dissociation time of ramiprilat from ACE is 10.7 hours, indicating its high activity.

Protein binding of ramipril and ramiprilat to plasma proteins is approximately 73% and 56%, respectively.

In healthy individuals aged 65 to 76 years, the kinetics of ramipril and ramiprilat are similar to those in younger healthy individuals.

In patients with impaired renal function, renal excretion of ramiprilat is reduced, and the renal clearance of ramiprilat decreases proportionally to creatinine clearance. This leads to elevated plasma concentrations of ramiprilat, which decline significantly more slowly than in individuals with normal renal function.

With administration of high doses (10 mg) in patients with impaired liver function, the conversion of ramipril to ramiprilat is delayed, plasma concentrations of ramipril increase, and elimination of ramiprilat is slowed.

Similarly to healthy individuals and hypertensive patients, after oral administration of 5 mg ramipril once daily for 2 weeks in patients with congestive heart failure, no significant accumulation of ramipril or ramiprilat was observed.

Clinical characteristics.

Indications.

• Treatment of arterial hypertension.
• Prevention of cardiovascular diseases: reduction of cardiovascular morbidity and mortality in patients with:
  • established atherosclerotic cardiovascular disease (history of ischemic heart disease, stroke, or peripheral vascular disease);
  • diabetes mellitus who have at least one cardiovascular risk factor.
• Treatment of kidney disease:
  • early diabetic glomerular nephropathy, indicated by the presence of microalbuminuria;
  • overt diabetic glomerular nephropathy, indicated by the presence of macroproteinuria, in patients who have at least one cardiovascular risk factor;
  • overt non-diabetic glomerular nephropathy, indicated by the presence of macroproteinuria ≥ 3 g per day.
• Treatment of symptomatic heart failure.
• 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.

The drug is not recommended for use in children (under 18 years of age).

Hypersensitivity to the active substance or to any of the excipients contained in the 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); significant renal artery stenosis (bilateral stenosis or stenosis of the artery of a solitary kidney); hypotensive or hemodynamically unstable conditions; systemic lupus erythematosus; scleroderma (increased risk of neutropenia or agranulocytosis); bone marrow suppression; hyperkalemia; kidney transplantation; renal insufficiency; hyponatremia (risk of dehydration, arterial hypotension, renal failure); hepatic insufficiency; primary hyperaldosteronism.

Pregnant women or women who are planning to become pregnant (see section "Use during pregnancy and breastfeeding").

Concomitant use with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or moderate to severe renal impairment (GFR < 60 mL/min).

Ramipril or other ACE inhibitors should be avoided in combination with extracorporeal therapies that involve contact of blood with negatively charged surfaces, due to the risk of severe anaphylactoid reactions, which may occasionally lead to severe anaphylactic shock. Therefore, dialysis or hemofiltration using polyacrylonitrile, sodium-2-methylsulfonate membranes with high ultrafiltration activity (e.g., "AN 69") and LDL apheresis using dextran sulfate must not be performed during ramipril treatment.

Interaction with other medicinal products and other forms of interaction.

Contraindicated combinations.

Extracorporeal therapies involving contact of blood with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile membranes) and LDL-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.

Combination of ramipril with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or moderate to severe renal impairment and is not recommended for other patient groups (see sections "Contraindications" and "Special precautions for use").

Combinations requiring precautions.

Not recommended combinations.

Potassium salts, heparin, potassium-sparing diuretics, and other active substances that increase plasma potassium levels (including angiotensin II antagonists, trimethoprim, tacrolimus, cyclosporine): increased potassium concentration in blood plasma is expected. Careful monitoring of serum potassium concentration is required during concomitant treatment with ramipril and potassium-sparing diuretics (e.g., spironolactone) or potassium salts.

Use with caution.

Antihypertensive medicinal products (e.g., diuretics) and other agents capable of reducing blood pressure (e.g., nitrates, tricyclic antidepressants, anesthetics, alcohol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): enhanced hypotensive effect of ramipril is expected. Regular monitoring of serum sodium concentration is recommended in patients receiving concomitant diuretic therapy (see section "Special precautions for use" regarding diuretics).

Vasopressor sympathomimetics and other substances (e.g., isoprenaline, dobutamine, dopamine, epinephrine). May attenuate the blood pressure-lowering effect. Careful monitoring of blood pressure is recommended.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics, and other medicinal products that may cause changes in hemogram may increase the likelihood of hematological reactions when used concomitantly with ramipril.

Lithium salts. Excretion of lithium may be reduced under the influence of ACE inhibitors. This reduction may lead to increased serum lithium concentration and increased lithium toxicity. Therefore, careful monitoring of lithium concentration is required.

Antidiabetic agents (e.g., insulin and sulfonylurea derivatives).

ACE inhibitors may enhance the effect of insulin. In some cases, this may lead to hypoglycemic reactions in patients receiving antidiabetic agents concomitantly. Close monitoring of blood glucose levels is recommended at the beginning of treatment.

Food.

Food does not significantly affect the absorption of ramipril.

To be considered.

Non-steroidal anti-inflammatory drugs (NSAIDs), e.g., indomethacin and acetylsalicylic acid. Possible attenuation of the blood pressure-lowering effect of ramipril. In addition, concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function and elevated serum potassium levels.

Heparin. Possible increase in serum potassium concentration.

Alcohol. Vasodilation is increased. Ramipril may potentiate the effect of alcohol.

Salt. High salt intake may attenuate the antihypertensive effect of Cardipril.

Specific hyposensitization. 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 regard to other allergens.

Special precautions for use.

Ramipril should be used under constant medical supervision.

Special patient groups.

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

Dual blockade of the renin-angiotensin-aldosterone system by combining ramipril with aliskiren is not recommended, as this increases the risk of developing arterial hypotension, hyperkalemia, and renal function impairment.

Combination therapy with ramipril and aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (eGFR <60 mL/min) (see section "Contraindications").

Angioedema of the face, extremities, lips, tongue, glottis, or pharynx has been observed in patients treated with ACE inhibitors. Emergency treatment of life-threatening angioedema requires immediate administration of epinephrine (subcutaneously or slowly intravenously), along with continuous ECG and blood pressure monitoring. If angioedema occurs, ramipril should be discontinued immediately. Emergency therapy should be initiated promptly. Hospitalization is recommended, with patient observation for at least 12–24 hours, and discharge permitted only after complete resolution of symptoms.

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

Angioedema of the intestine has been observed in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases, facial angioedema also occurred. Symptoms of intestinal angioedema resolved after discontinuation of the ACE inhibitor.

There is insufficient therapeutic experience with use in patients with severe renal impairment (creatinine clearance below 20 mL/min per 1.73 m² body surface area).

Patients with increased activity of the renin-angiotensin system.

Particular caution is required when treating patients with increased activity of the renin-angiotensin system. These patients are at risk of sudden and significant reduction in blood pressure and worsening renal function due to ACE inhibition, especially when initiating ACE inhibitor therapy or concomitant diuretic therapy, or increasing the dose. Close monitoring of blood pressure is required at the beginning of treatment or after dose escalation, due to the possibility of a sudden drop in blood pressure.

Increased activity of the renin-angiotensin system requiring medical supervision, including continuous blood pressure monitoring, may be expected particularly in:

• patients with severe, and especially malignant hypertension. Special medical supervision is required during the initial phase of treatment;
• patients with heart failure, particularly severe heart failure or heart failure previously treated with other medications that may lower blood pressure. In cases of severe heart failure, special medical supervision is required during the initial phase of treatment;
• patients with hemodynamically significant inflow or outflow obstruction of the left ventricle (e.g., due to aortic stenosis, mitral valve stenosis, or hypertrophic cardiomyopathy). Special medical supervision is required during the initial phase of treatment;
• patients with hemodynamically significant renal artery stenosis. Close medical supervision is required during the initial phase of treatment. Discontinuation of concomitant diuretic therapy may be necessary;
• patients previously treated with diuretics. If diuretic discontinuation or dose reduction is not possible, special medical supervision is required during the initial phase of treatment;
• patients who have or may develop fluid or salt depletion (due to inadequate fluid or salt intake, or, for example, diarrhea, vomiting, or excessive sweating, particularly when compensation for fluid and salt depletion is inadequate);
• patients undergoing major surgery, or anesthesia with agents that may cause arterial hypotension.

In general, correction of dehydration, hypovolemia, or salt depletion is recommended prior to initiating treatment (however, for patients with heart failure, such corrective measures should be carefully evaluated regarding the risk of volume overload). In clinically significant conditions, treatment may be initiated or continued only if appropriate measures to prevent excessive hypotension and worsening renal function are simultaneously implemented.

Patients with liver disease.

In patients with impaired liver function, the response to treatment may be either increased or decreased. Additionally, in patients with severe cirrhosis with edema and/or ascites, activity of the renin-angiotensin system may be markedly increased; therefore, special caution is required when treating these patients.

Patients at risk of significant blood pressure reduction are particularly vulnerable. Special medical supervision during the initial phase of treatment is required for patients in whom a marked reduction in blood pressure poses a particular risk (e.g., patients with hemodynamically significant coronary artery stenosis or stenosis of vessels supplying blood to the brain).

Elderly patients.

In elderly patients, the response to ACE inhibitors may be more pronounced. Renal function should be assessed at the beginning of treatment.

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 monitored before and during treatment, and dosage adjusted accordingly, particularly during the first weeks of ACE inhibitor therapy. Especially careful monitoring is required in patients with:

• heart failure;
• renovascular disease, including patients with hemodynamically significant unilateral renal artery stenosis. In the latter group, even a slight increase in serum creatinine may indicate unilateral deterioration of renal function;
• impaired renal function;
• transplanted kidney.

Monitoring of electrolyte balance.

Regular monitoring of serum potassium concentration is recommended. More frequent monitoring of serum potassium levels is required in patients with impaired renal function.

Hyperkalemia. Hyperkalemia has been observed in some patients receiving ACE inhibitors, including ramipril. Patients at risk of hyperkalemia include those with renal impairment, patients aged 70 years or older, patients with uncontrolled diabetes mellitus, patients taking potassium salts or potassium-sparing diuretics, patients receiving 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 medications is considered necessary, regular monitoring of plasma potassium levels is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Electrolyte balance monitoring. Hyponatremia. The syndrome of inappropriate antidiuretic hormone secretion with subsequent development of hyponatremia has been observed in some patients receiving ramipril. Regular monitoring of serum sodium levels is recommended in elderly patients and in other patients at risk of developing hyponatremia.

Neutropenia/Agranulocytosis. Cases of neutropenia/agranulocytosis, as well as thrombocytopenia and anemia, have been reported rarely. Bone marrow suppression has also been reported. To detect possible leukopenia, monitoring of white blood cell count is recommended. More frequent monitoring is advisable at the beginning of treatment and in patients with impaired renal function, concomitant collagenosis (e.g., systemic lupus erythematosus or scleroderma), or those receiving other medicinal products that may cause blood count abnormalities (see sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects").

Hematological monitoring.

Monitoring of white blood cell count is recommended to detect possible leukopenia early. More frequent monitoring is recommended during the initial phase of treatment in patients with impaired renal function, concomitant collagen disease (e.g., lupus erythematosus or scleroderma), or those treated with other medications that may cause blood count changes. Cases of neutropenia/agranulocytosis, as well as thrombocytopenia and anemia, have been observed rarely. Bone marrow suppression has also been reported.

Ethnic differences. ACE inhibitors cause angioedema more frequently in patients of Black race than in patients of other races. As with other ACE inhibitors, the antihypertensive effect of ramipril may be less pronounced in patients of Black race compared to patients of other races. This may be due to the higher prevalence of low-renin hypertension in Black patients with arterial hypertension.

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

Use during pregnancy or breastfeeding.

Pregnancy.

The drug is contraindicated in pregnant women or women planning pregnancy. If pregnancy is diagnosed 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, the drug is not recommended for nursing mothers. It is preferable to use other medicinal products considered safer during lactation, especially when breastfeeding newborns or preterm infants.

Ability to influence reaction speed when driving 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 medications to ramipril. After taking the first dose or after any subsequent dose increase, driving vehicles or operating machinery should be avoided for several hours.

Dosage and Administration

For oral use.

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

Adults.

Patients receiving diuretics. Arterial hypotension may occur at the beginning of treatment with the drug, and this is more likely 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 levels.

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 diuretic therapy, treatment with the drug should be initiated at a dose of 1.25 mg (administered at the corresponding dosage strength). Renal function and serum potassium levels should be closely monitored. Subsequent dosing should be adjusted according to the target blood pressure level.

Arterial Hypertension.

The dose should be individually adjusted according to the patient's condition (see section "Special Instructions") and results of blood pressure monitoring. Ramipril may be used as monotherapy or in combination with other classes of antihypertensive drugs.

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

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

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

Prevention of Cardiovascular Diseases.

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

Dose titration and maintenance dose. Depending on individual tolerance, 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.

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

Treatment of Kidney Disease

For patients with diabetes mellitus and microalbuminuria.

Initial dose. The recommended initial dose of the drug is 1.25 mg once daily (administered at the corresponding dosage strength).

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

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

In patients with diabetes mellitus and at least one cardiovascular risk factor.

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

Dose titration and maintenance dose. Depending on individual tolerance during further treatment, the dose should be 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.

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

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

Initial dose. The recommended initial dose of ramipril is 1.25 mg once daily (administered at the corresponding dosage strength).

Dose titration and maintenance dose. Depending on individual patient tolerance during further treatment, the dose should be increased. After 2 weeks of treatment, the 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 with diuretic therapy, the recommended initial dose of the drug is 1.25 mg once daily (administered at the corresponding dosage strength).

Dose titration and maintenance dose. The dose of ramipril 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.

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

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 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 is poorly tolerated, then a dose of 1.25 mg (administered at the corresponding dosage strength) twice daily should be used for 2 days, followed by an increase to 2.5 mg and then to 5 mg twice daily. If the dose cannot be increased to 2.5 mg twice daily, treatment should be discontinued.

(See also the above information regarding dosing 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 Class IV) heart failure immediately after myocardial infarction is still limited. If treatment of such patients with this drug is nevertheless decided upon, it is recommended to initiate therapy at a dose of 1.25 mg (administered at the corresponding dosage strength) once daily, and any dose increase should be performed with extreme caution.

Special patient populations.

Patients with impaired renal function. The daily dose for patients with impaired renal function depends on creatinine clearance:

• if creatinine clearance is ≥ 60 mL/min, no adjustment of the initial dose (2.5 mg daily) 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 daily) 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 daily (administered at the corresponding dosage strength), and the maximum daily dose is 5 mg;
• patients with arterial hypertension undergoing hemodialysis: ramipril is only minimally removed during hemodialysis; the initial dose is 1.25 mg (administered at the corresponding dosage strength), and the maximum daily dose is 5 mg; the drug should be taken several hours after a hemodialysis session.

Patients with impaired liver function. Treatment with ramipril in patients with impaired liver function should be initiated under close medical supervision, and the maximum daily dose in such cases should not exceed 2.5 mg.

Elderly patients. The initial dose should be lower, and subsequent dose titration should be performed more gradually due to the higher risk of adverse effects, especially in very elderly and frail patients. In such cases, a lower initial dose of 1.25 mg ramipril (administered at the corresponding dosage strength) should be prescribed.

Children.

The drug is not recommended for use in children (under 18 years of age), as there is insufficient data on efficacy and safety of this drug in such patients.

Overdose.

Symptoms. Overdose may cause excessive peripheral vasodilation (with marked arterial hypotension, shock), bradycardia, electrolyte imbalance, and renal failure.

Treatment. Close monitoring of the patient is required, along with symptomatic and supportive therapy. Recommended therapeutic measures include primary detoxification (gastric lavage, administration of adsorbents), and measures 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.

Since ramipril is an antihypertensive agent, many of its adverse effects are secondary to its ability to lower blood pressure, resulting in adrenergic counter-regulation or organ hypoperfusion. Numerous other effects (e.g., effects on electrolyte balance, certain anaphylactoid reactions, or mucosal inflammatory reactions) are caused by ACE inhibition or other pharmacological effects of this class of drugs. Serious adverse reactions include angioedema, persistent cough, hyperkalemia, hepatic or renal dysfunction, pancreatitis, severe skin reactions, and neutropenia/agranulocytosis.

Cardiac disorders: myocardial ischemia, including angina or myocardial infarction; tachycardia; arrhythmia; palpitations; peripheral edema.

Blood and lymphatic system disorders: eosinophilia; decreased white blood cell count (including neutropenia or agranulocytosis), decreased red blood cell count, decreased hemoglobin levels, thrombocytopenia; bone marrow failure, pancytopenia, hemolytic anemia.

Hematological reactions to ACE inhibitors occur more frequently in patients with impaired renal function, those with concomitant collagen vascular diseases (e.g., systemic lupus erythematosus or scleroderma), or those receiving other drugs that may affect blood counts.

Nervous system disorders: headache, dizziness; vertigo, paresthesia, ageusia, dysgeusia; tremor, loss of balance; cerebral ischemia, including ischemic stroke and transient ischemic attack; psychomotor disturbances; burning sensation; parosmia.

Eye disorders: visual disturbances, including blurred vision; conjunctivitis.

Ear and labyrinth disorders: hearing disturbances, tinnitus.

Respiratory system disorders: non-productive, irritating cough, bronchitis, sinusitis, dyspnea; bronchospasm, including asthma exacerbation; nasal congestion.

Gastrointestinal disorders: inflammatory events in the gastrointestinal tract, digestive disorders, abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting; pancreatitis (in isolated cases, fatal outcomes have been reported with ACE inhibitors), increased pancreatic enzyme levels, angioedema of the small intestine, upper abdominal pain including gastritis, constipation, dry mouth; glossitis; aphthous stomatitis.

Renal and urinary disorders: renal dysfunction, including acute renal failure; increased urination, worsening of pre-existing proteinuria, increased blood urea nitrogen; elevated serum creatinine.

Skin and subcutaneous tissue disorders: skin rashes, particularly maculopapular; angioedema; 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 exanthem or enanthem, alopecia.

Musculoskeletal and connective tissue disorders: muscle cramps, myalgia; arthralgia.

Endocrine disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders: increased blood potassium levels; anorexia, decreased appetite; decreased blood sodium levels.

Vascular disorders: arterial hypotension, orthostatic hypotension, syncope; flushing; vascular stenosis, hypoperfusion, vasculitis; Raynaud's phenomenon.

General disorders: chest pain, fatigue; pyrexia; asthenia.

Immune system disorders: anaphylactic and anaphylactoid reactions, increased levels of antinuclear antibodies.

Hepatobiliary disorders: elevated liver enzymes and/or bilirubin conjugates; cholestatic jaundice, hepatic cell damage; acute liver failure, cholestatic or cytolytic hepatitis (in rare cases, with fatal outcome).

Reproductive system and breast disorders: transient erectile impotence, decreased libido; gynecomastia.

Psychiatric disorders: depressed mood, anxiety, nervousness, restlessness, sleep disturbances, including somnolence; confusion; attention disturbances.

Pediatric population. The nature and severity of adverse reactions in children were similar to those observed in adults, but 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 the adult population.

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 the adult population.

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 the adult population.

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

Shelf life. 3 years.

Storage conditions. Keep out of reach of children. Store in the original packaging at a temperature not exceeding 30 °C.

Packaging.

Cardipril 2.5: 10 capsules in a blister, 1 or 3 blisters per carton.

Cardipril 5 or Cardipril 10: 10 capsules in a blister; 3 blisters per carton.

Prescription category. Prescription only.

Manufacturer.

Ananta Medicare Limited.

Manufacturer's address and place of business.

Chak 17 ML, Agro Food Park Road, RIICO Industrial Area, Udaig Nagar, Sri Ganganagar-335002 (Rajasthan), India.

Marketing authorization holder.

Ananta Medicare Ltd.

Address of the marketing authorization holder and/or its representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.