INSTRUCTION

for medical use of the medicinal product

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.

Basic physical and chemical properties:

Cardipril 2.5: 2 size, blue/white, hard gelatine capsules. The capsule contains white or almost white powder;

Cardipril 5: 4 size, red and brown/white, hard gelatine capsules. The capsule contains white or almost white powder;

Cardipril 10: 4 size, blue/white, hard gelatine capsules. The capsule contains white or almost white powder.

Pharmacotherapeutic group. Inhibitors of angiotensin converting enzyme (ACE). Monocomponent of ACE inhibitors. Ramipril.

ATC code C09AA05.

Pharmacological properties.
Pharmacodynamics.
Mechanism of action. Ramiprilat, the active metabolite of the prodrug ramipril, is an inhibitor of the enzyme dipeptidyl carboxypeptidase I (synonyms: angiotensin-converting enzyme (ACE); kinase II). In blood plasma and tissues, this enzyme catalyses the conversion of angiotensin I to angiotensin II (an active vasoconstrictor substance) and the cleavage of the active vasodilator bradykinin. A decrease in the formation of angiotensin II and inhibition of the cleavage of bradykinin lead to vasodilation. Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a decrease in aldosterone secretion. The response to monotherapy with ACE inhibitors was on average less pronounced in patients of the Negroid race (of Afro-Caribbean origin) with arterial hypertension (a population characterised by a low renin level in arterial hypertension) than in patients who are representatives of other races.
Antihypertensive properties. Administration of ramipril leads to a significant decrease in peripheral arterial resistance. As a rule, no significant changes in renal plasma flow or glomerular filtration rate (GFR) occur. Prescription of ramipril to patients with arterial hypertension leads to a decrease in blood pressure both in the horizontal and in the vertical position of the patient, which is not accompanied by a compensatory increase in heart rate.
In most patients, the antihypertensive effect occurs 1−2 hours after oral administration of a single dose of the medicinal product. The maximum effect after oral administration of a single dose usually occurs after 3−6 hours. The antihypertensive effect after administration of a single dose usually persists for 24 hours.
With long-term treatment with the use of ramipril, the maximum antihypertensive effect develops after 3−4 weeks. It has been proven that with long-term therapy the antihypertensive effect persists for 2 years.
Sudden discontinuation of ramipril does not cause a rapid and excessive increase in blood pressure (rebound phenomenon).
Heart failure. It has been proven that used as an addition to traditional therapy with diuretics and, if necessary, cardiac glycosides, ramipril is effective for patients with heart failure of NYHA functional classes II−IV. The medicinal product exhibits a favourable effect on cardiac haemodynamics (decrease in left and right ventricular filling pressure, total peripheral vascular resistance, increase in cardiac output and improvement of cardiac index). It also reduces neuroendocrine activation.
Clinical efficacy and safety
Prevention of cardiovascular diseases / nephroprotection
A preventive placebo-controlled study (the HOPE study) was conducted involving more than 9200 patients who, in addition to standard therapy, received ramipril. This study involved patients at high risk of developing a cardiovascular disease after suffering an atherothrombotic cardiovascular disease (presence in the anamnesis of ischaemic heart disease, stroke or peripheral vascular disease) or patients with diabetes mellitus who had at least one additional risk factor (documented microalbuminuria, arterial hypertension, elevated levels of total cholesterol, low-density lipoprotein cholesterol or smoking).
This study demonstrated that ramipril statistically significantly reduces the incidence of myocardial infarction, cardiovascular death and stroke both separately and in combination (primary combined endpoint).

HOPE study: main results

During the MICRO-HOPE study, the conduct of which was pre-planned within the framework of the HOPE study, the effect that occurred when adding ramipril at a dose of 10 mg to the existing treatment regimen was studied compared with placebo in 3577 patients aged 55 years and older (there was no upper age limit) with normal or elevated blood pressure, most of whom had type 2 diabetes mellitus (and had at least one cardiovascular risk factor).
The results of the primary analysis demonstrated that in 117 (6.5 %) study participants who received ramipril and in 149 (8.4 %) who received placebo, pronounced nephropathy developed, corresponding to a relative risk reduction of 24 %; 95 % CI [3–40], p = 0,027.
The REIN study, a multicentre randomised double-blind placebo-controlled study in parallel groups, was conducted with the aim of assessing the effect of treatment with ramipril on the intensity of GFR decline in 352 patients with normal or elevated blood pressure (aged 18−70 years), who had mild (mean amount of protein excreted in urine > 1 and < 3 g/day) or severe (≥ 3 g/day) proteinuria due to chronic non-diabetic nephropathy. Both subgroups were prospectively stratified.
The results of the main analysis of the condition of patients with the most severe proteinuria (the subgroup that prematurely terminated participation in the study, since the benefit of treatment in the ramipril group was proven) demonstrated that the mean intensity of GFR decline per month was lower with the use of ramipril than with the use of placebo: − 0.54 (0.66) compared with – 0.88 (1.03) mL/min/month, p = 0.038. Thus, the between-group difference was 0.34 [0.03−0.65] mL/min/month and approximately 4 mL/min/year; 23.1 % of patients in the ramipril group achieved the combined secondary endpoint – doubling of the creatinine concentration in blood plasma and/or end-stage kidney disease (need for haemodialysis or kidney transplantation) – compared with 45.5 % in the placebo group (p = 0.02).
Dual blockade of the renin-angiotensin-aldosterone system (RAAS). In two large randomised controlled studies [ONTARGET (study of the effect of telmisartan as monotherapy and in combination with ramipril on the total endpoint) and VA NEPHRON-D (study of diabetic nephropathy in veterans)], the use of a combination of an ACE inhibitor with an angiotensin II receptor antagonist was studied.
The ONTARGET study was conducted with the participation of patients with cardiovascular or cerebrovascular diseases in the anamnesis or with type 2 diabetes mellitus with concomitant signs of target organ damage. The VA NEPHRON-D study involved patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies did not show significant advantages of combination therapy regarding renal and/or cardiovascular outcomes and mortality, while at the same time an increased risk of hyperkalaemia, acute renal failure and/or arterial hypotension was observed compared with monotherapy. Given the similar pharmacodynamic characteristics of these medicinal products, these results are also applicable to other ACE inhibitors and angiotensin II receptor antagonists.
Therefore, ACE inhibitors and angiotensin II receptor antagonists must not be used simultaneously in patients with diabetic nephropathy.
The ALTITUDE study (study of the effect of aliskiren on the condition of patients with type 2 diabetes mellitus using cardiovascular and renal endpoints) evaluated the benefits of adding aliskiren to standard therapy with an ACE inhibitor or an angiotensin II receptor antagonist for patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease or both pathologies. This study was terminated prematurely due to an increased risk of undesirable clinical outcomes. In the aliskiren group compared with the placebo group, a higher incidence of deaths from cardiovascular causes and stroke was noted, as well as an increase in the frequency of serious adverse events that were of special interest (hyperkalaemia, arterial hypotension and renal dysfunction).
Secondary prevention after suffering acute myocardial infarction. The AIRE study involved more than 2000 patients with transient/permanent symptoms of heart failure after suffering myocardial infarction. Treatment with ramipril was started 3–10 days after the occurrence of acute myocardial infarction. This study demonstrated that after the end of the follow-up period, which averaged 15 months, mortality in the group receiving ramipril was 16.9 %, and in the placebo group – 22.6 %. This means an absolute reduction in mortality of 5.7 % and a relative risk reduction of 27 % (95 % CI [11−40 %]).
Paediatric population. During a randomised double-blind placebo-controlled clinical study involving 244 paediatric patients with arterial hypertension (73 % of whom had primary arterial hypertension) aged 6−16 years, participants received low, medium or high doses of ramipril with the aim of achieving in them plasma concentrations of ramiprilat that correspond to the dose range for adults of 1.25 mg, 5 mg and 20 mg calculated by body weight. After the end of a 4-week period, it was found that ramipril was ineffective regarding the endpoint – reduction of systolic blood pressure, however it reduced diastolic blood pressure with the use of the highest dose of the studied range. It was shown that both medium and high doses of ramipril reduce systolic and diastolic blood pressure by a statistically significant amount in children with confirmed arterial hypertension.
Such an effect was not observed during a 4-week randomised double-blind dose-escalation study, where the effect of discontinuation of the medicinal product was evaluated and in which 218 paediatric patients aged 6−16 years participated (75 % of whom had primary arterial hypertension). During this study, after discontinuation of the medicinal product, a moderate rebound increase in both diastolic and systolic blood pressure was observed, however it was not statistically significant for the return of pressure to the initial level in all dose groups of the studied range of ramipril [low doses (0,625–2.5 mg), medium doses (2.5–10 mg) or high doses (5–20 mg)] calculated by body weight. In the studied paediatric population, ramipril did not exhibit a linear dose-dependent effect.
Pharmacokinetics.
Absorption. After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract. The maximum concentration in blood plasma is reached within 1 hour. Given the amount of substance detected in urine, the degree of absorption is at least 56 % and it is not significantly affected by the presence of food in the gastrointestinal tract. The bioavailability of the active metabolite ramiprilat after oral administration of ramipril at a dose of 2.5 mg and 5 mg is 45 %.
The maximum concentration in blood plasma of ramiprilat, the only active metabolite of ramipril, is reached 2−4 hours after administration of ramipril. After administration of usual doses of ramipril once daily, the steady-state concentration of ramiprilat in blood plasma is reached approximately on the 4th day of treatment.
Distribution. The binding of ramipril to blood plasma proteins is approximately 73 %, and of ramiprilat – 56 %.
Metabolism. Ramipril is almost completely metabolised to ramiprilat, diketopiperazine ester, diketopiperazine acid and glucuronides of ramipril and ramiprilat.
Elimination. The elimination of metabolites occurs mainly by renal excretion. The decrease in the concentration of ramiprilat in blood plasma is multiphasic. Due to the potent saturable binding to ACE and slow dissociation from the bond with the enzyme, ramiprilat has a prolonged terminal elimination phase at very low plasma concentrations.
After administration of repeated doses of ramipril once daily, the effective half-life is 13−17 hours for doses of 5−10 mg and more for lower doses (1,25−2,5 mg). The difference is due to the fact that the ability of the enzyme to bind to ramiprilat is saturable.
With oral administration of a single dose of the medicinal product, neither ramipril nor its metabolite was detected in breast milk. However, it is unknown what effect repeated doses have.
Patients with renal impairment (see section "Method of administration and dosage"). In patients with renal impairment, the renal excretion of ramiprilat is reduced, and the renal clearance of ramiprilat is proportional to creatinine clearance. This leads to an increase in the concentration of ramiprilat in blood plasma, which decreases more slowly than in persons with normal renal function.
Patients with hepatic impairment (see section "Method of administration and dosage"). In patients with hepatic impairment, the metabolism of ramipril with the formation of ramiprilat was slowed down due to a decrease in the activity of hepatic esterases, and the level of ramipril in blood plasma in these patients was elevated. However, the maximum concentration of ramiprilat in these patients did not differ from that in persons with normal hepatic function.
Breastfeeding. After administration of a single dose of ramipril orally, its levels in breast milk were below the limit of detection. However, the effect with multiple administrations is unknown.
Paediatric population. The pharmacokinetic profile of ramipril was studied in 30 paediatric patients with arterial hypertension aged 2−16 years with a body weight > 10 kg. After administration of doses from 0.05 to 0.2 mg/kg, ramipril was rapidly and to a significant extent metabolised to ramiprilat. The maximum concentration of ramiprilat in blood plasma was reached after 2−3 hours. The clearance of ramiprilat significantly correlated with the logarithm of body weight (p < 0.01), as well as with the dose of the medicinal product (p < 0.001). Clearance and volume of distribution increased in direct proportion to the age of the children in each dosing group. With the use of a dose of 0.05 mg/kg in children, exposure levels were achieved that were comparable to the exposure in adults with the use of a dose of 5 mg of ramipril. As a result of the use of a dose of 0.2 mg/kg in children, exposure levels were achieved that were higher than with the use of the maximum recommended dose of 10 mg per day in adults.
Preclinical safety data. With oral administration to rodents and dogs, it was found that ramipril does not cause acute toxic phenomena. Studies with long-term oral administration of the medicinal product were conducted on rats, dogs and monkeys. In all these three animal species, changes in electrolyte balance and blood picture were observed. In dogs and monkeys that received the medicinal product at a dose of 250 mg/kg body weight per day, a significant increase in the juxtaglomerular apparatus was noted, which is a manifestation of the pharmacodynamic activity of ramipril. Rats, dogs and monkeys tolerated daily doses of the medicinal product that amounted to 2, 2.5 and 8 mg/kg body weight per day, respectively. At the same time, undesirable effects did not occur in them.
Reproductive toxicity studies conducted on rats, rabbits and monkeys did not reveal any teratogenic properties of the medicinal product. A negative effect on fertility was not observed in either male or female rats.
Administration of ramipril to female rats during pregnancy and lactation led to irreversible kidney damage (dilation of the renal pelvis) in the offspring with the use of doses of 50 mg/kg body weight per day and higher.
Numerous mutagenicity tests with the use of various test systems did not reveal mutagenic or genotoxic properties of ramipril.

Clinical particulars.
Indications.
• Treatment of arterial hypertension.
• Prevention of cardiovascular diseases: reduction of cardiovascular morbidity and mortality in patients with:
− pronounced cardiovascular disease of atherothrombotic origin (presence in the anamnesis of ischaemic heart disease or stroke or peripheral vascular disease);
− diabetes mellitus who have at least one cardiovascular risk factor (see section "Pharmacological properties").
• Treatment of kidney disease:
− initial glomerular diabetic nephropathy, as evidenced by the presence of microalbuminuria;
− pronounced glomerular diabetic nephropathy, as evidenced by the presence of macroproteinuria, in patients who have at least one cardiovascular risk factor (see section "Pharmacological properties");
− pronounced glomerular non-diabetic nephropathy, as evidenced by the presence of macroproteinuria ≥ 3 g per day (see section "Pharmacological properties").
• Treatment of heart failure accompanied by clinical manifestations.
• Secondary prevention after suffering acute myocardial infarction: reduction of mortality during the acute stage of myocardial infarction in patients with clinical signs of heart failure provided that treatment is started more than 48 hours after the occurrence of acute myocardial infarction.

Contraindications.
Hypersensitivity to the active substance or to any of the excipients included in the composition of the medicinal product, or to other ACE (angiotensin-converting enzyme) inhibitors (see section "Composition").
Presence in the anamnesis of angioedema (hereditary, idiopathic or previously suffered against the background of the use of ACE inhibitors or angiotensin II receptor antagonists).
Co-administration with sacubitril/valsartan (see sections "Interaction with other medicinal products and other forms of interaction" and "Precautions for use").
Significant bilateral renal artery stenosis or renal artery stenosis in the presence of a single functioning kidney.
Pregnancy and planning of pregnancy (see section "Use during pregnancy or breastfeeding").
Ramipril should not be used in patients with arterial hypotension or a haemodynamically unstable condition.
Co-administration of the medicinal product Cardipril with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal dysfunction (GFR < 60 mL/min/1,73 m2) (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction").
It is necessary to avoid simultaneous use of ACE inhibitors and extracorporeal treatment methods that lead to contact of blood with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.
Data from clinical studies have demonstrated that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is associated with an increased incidence of such undesirable phenomena as arterial hypotension, hyperkalaemia and deterioration of renal function (including acute renal failure), compared with the use of only one medicinal product affecting the RAAS (see sections "Pharmacodynamics", "Contraindications" and "Precautions for use").
Contraindicated combinations
Co-administration of ACE inhibitors with sacubitril/valsartan is contraindicated due to the increased risk of developing angioedema (see sections "Contraindications" and "Precautions for use"). Treatment with ramipril should be started only 36 hours after taking the last dose of sacubitril/valsartan. Treatment with sacubitril/valsartan should be started only 36 hours after taking the last dose of ramipril.
Methods of extracorporeal therapy, as a result of which contact of blood with negatively charged surfaces occurs, such as dialysis or haemofiltration with the use of certain high-flux membranes (for example, polyacrylonitrile membranes) and low-density lipoprotein apheresis with the use of dextran sulfate, given the increased risk of developing severe anaphylactoid reactions (see section "Contraindications"). If such treatment is necessary, the use of another dialysis membrane or the use of antihypertensive agents of another class should be considered.
Combinations requiring precautionary measures
Potassium salts, heparin, potassium-sparing diuretics and other active substances that increase the level of potassium in blood plasma (including angiotensin II antagonists, trimethoprim and its fixed combinations with sulfamethoxazole, tacrolimus, cyclosporine). Hyperkalaemia may occur, therefore the level of potassium in blood plasma must be carefully monitored.
Antihypertensive medicinal products (for example, diuretics) and other substances capable of lowering blood pressure (for example, nitrates, tricyclic antidepressants, anaesthetics, alcohol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin). An increase in the risk of occurrence of arterial hypotension should be expected (see section "Precautions for use" regarding diuretics).
Vasopressor sympathomimetics and other substances (for example, isoproterenol, dobutamine, dopamine, epinephrine) that can reduce the antihypertensive effect of the medicinal product Cardipril. It is recommended to carefully monitor blood pressure.
Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that can cause changes in the blood picture. Increased probability of occurrence of haematological reactions (see section "Precautions for use").
Lithium salts. ACE inhibitors can reduce the excretion of lithium, which can lead to an increase in lithium toxicity. The level of lithium must be carefully monitored.
Antidiabetic agents, including insulin. Hypoglycaemic reactions may occur. It is recommended to carefully monitor the level of glucose in the blood.
Non-steroidal anti-inflammatory medicinal products (NSAIDs) and acetylsalicylic acid. A decrease in the antihypertensive effect of the medicinal product Cardipril is expected. Simultaneous use of ACE inhibitors and NSAIDs may be accompanied by an increased risk of deterioration of renal function and an increase in the level of potassium in the blood.
Salt. With excessive consumption of salt, a weakening of the hypotensive effect of the medicinal product is possible.
Specific hyposensitisation. As a result of ACE inhibition, the probability of occurrence and severity of anaphylactic and anaphylactoid reactions to insect venom increases. It is believed that such an effect may also be observed regarding other allergens.
Inhibitors of the mammalian target of rapamycin (mTOR) or vildagliptin. A possible increase in the risk of developing angioedema in patients who simultaneously receive such medicinal products as mTOR inhibitors (for example, temsirolimus, everolimus, sirolimus) or vildagliptin. Such therapy should be started with caution (see section "Precautions for use").
Neprilysin inhibitors. An increase in the risk of developing angioedema has been reported with simultaneous use of ACE inhibitors and a neutral endopeptidase (NEP) inhibitor, for example racecadotril (see section "Precautions for use").
Sacubitril/valsartan. Co-administration of ACE inhibitors with sacubitril/valsartan is contraindicated due to the increased risk of developing angioedema.

Precautions for use.
Special groups of patients
Pregnancy. Treatment with ACE inhibitors or angiotensin II receptor antagonists should not be started during pregnancy. Except in cases where continuation of treatment with an ACE inhibitor / angiotensin II receptor antagonists is absolutely necessary, patients who plan to become pregnant must be transferred to another antihypertensive medicinal product, the use of which during pregnancy is recognised as safe. As soon as pregnancy is diagnosed, treatment with ACE inhibitors / angiotensin II receptor antagonists should be immediately discontinued and, if necessary, treatment with another medicinal product should be started (see sections "Contraindications" and "Use during pregnancy or breastfeeding").
Dual blockade of the renin-angiotensin-aldosterone system (RAAS).
There are evidentiary data in favour of the fact that simultaneous use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren increases the risk of arterial hypotension, hyperkalaemia and deterioration of renal function (including the development of acute renal failure). In this regard, dual blockade of the RAAS by combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is not recommended (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction").
If therapy in the form of such a dual blockade is regarded as absolutely necessary, it should be used only under the supervision of a specialist and subject to frequent and careful monitoring of renal function, electrolyte content and blood pressure level.
ACE inhibitors and angiotensin II receptor antagonists must not be used simultaneously in patients with diabetic nephropathy.
Patients in whom there is a special risk of occurrence of arterial hypotension
Patients with a significant increase in the activity of the renin-angiotensin-aldosterone system (RAAS)
In patients with a significant increase in the activity of the RAAS, there is a risk of a sudden significant decrease in blood pressure and deterioration of renal function as a result of ACE inhibition, especially if the ACE inhibitor or concomitant diuretic is prescribed for the first time or the dose is increased for the first time. A significant increase in the activity of the RAAS, which requires medical supervision, including constant monitoring of blood pressure, can be expected, for example, in patients:

• - with severe arterial hypertension;
• - with decompensated congestive heart failure;
• - with a haemodynamically significant obstacle to the inflow or outflow of blood from the left ventricle (for example, with stenosis of the aortic or mitral valve);
• - with unilateral renal artery stenosis in the presence of a second functioning kidney;
• - in whom there is or may develop a deficiency of fluid or electrolytes (including those receiving diuretics);
• - with cirrhosis of the liver and/or ascites;
• - who undergo major surgical interventions or during anaesthesia with the use of medicinal products that cause arterial hypotension.

It is recommended to carry out correction of dehydration, hypovolaemia or electrolyte deficiency before starting treatment (however, for patients with heart failure, such corrective measures should be carefully weighed regarding the risk of occurrence of volume overload).
Transient or persistent heart failure after myocardial infarction
Patients in whom there is a risk of occurrence of cardiac or cerebral ischaemia in the case of acute arterial hypotension. In the initial phase of treatment, special medical supervision is required.
Elderly patients. See section "Method of administration and dosage".
Surgical intervention. If possible, treatment with ACE inhibitors, such as ramipril, should be discontinued 1 day before surgical intervention.
Monitoring of renal function. Renal function must be assessed before and during treatment and the dose adjusted, especially in the first weeks of treatment. Particularly careful monitoring is required for the condition of patients with renal impairment (see section "Method of administration and dosage"). There is a risk of deterioration of renal function, especially in patients with congestive heart failure or after kidney transplantation, as well as in the case of damage to renal vessels, including in patients with haemodynamically significant unilateral renal artery stenosis.
Angioedema. In patients who received ACE inhibitors, including ramipril, angioedema was observed (see section "Adverse reactions"). The risk of angioedema is increased in patients who simultaneously receive such medicinal products that can cause angioedema, such as inhibitors of the mammalian target of rapamycin (mTOR) (for example, temsirolimus, everolimus, sirolimus) or vildagliptin, or neprilysin (NEP) inhibitors, such as racecadotril.
The combination of ramipril with sacubitril/valsartan is contraindicated due to the increased risk of developing angioedema (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").
In case of development of angioedema, the intake of the medicinal product Cardipril should be discontinued. Emergency therapy must be started immediately. The patient must be under medical supervision for at least 12−24 hours and may be discharged after the complete disappearance of symptoms.
In patients who received ACE inhibitors, including Cardipril, cases of intestinal angioedema were observed (see section "Adverse reactions"). These patients complained of abdominal pain (with or without nausea/vomiting).
Anaphylactic reactions during desensitisation. With the use of ACE inhibitors, the probability of occurrence and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens increases. Before conducting desensitisation, the intake of the medicinal product Cardipril should be temporarily discontinued.
Monitoring of electrolyte balance. Hyperkalaemia. In some patients who received ACE inhibitors, including the medicinal product Cardipril, the occurrence of hyperkalaemia was observed. The risk group for the occurrence of hyperkalaemia includes patients with renal failure, patients aged over 70 years, patients with uncontrolled diabetes mellitus, patients who take potassium salts, potassium-sparing diuretics, as well as other active substances that increase the potassium content in blood plasma, or patients with such conditions as dehydration, acute cardiac decompensation, metabolic acidosis. If the concomitant use of the above-mentioned medicinal products is considered appropriate, then regular monitoring of the level of potassium in blood plasma is recommended (see section "Interaction with other medicinal products and other forms of interaction").
Monitoring of electrolyte balance. Hyponatraemia. In some patients who received ramipril, syndrome of inappropriate secretion of antidiuretic hormone with subsequent development of hyponatraemia was observed. Regular monitoring of serum sodium levels is recommended in elderly persons and in other patients who have a risk of developing hyponatraemia.
Neutropenia/agranulocytosis. Cases of neutropenia/agranulocytosis, as well as thrombocytopenia and anaemia were observed rarely. Bone marrow function suppression has also been reported. With the aim of detecting possible leukopenia, it is recommended to monitor the number of leukocytes in the blood. More frequent monitoring is desirable at the beginning of treatment and for patients with impaired renal function, concomitant collagenosis (for example systemic lupus erythematosus or scleroderma) or those who take other medicinal products that can cause changes in the blood picture (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").
Ethnic differences. ACE inhibitors more often cause angioedema in patients of the Negroid race than in representatives of other races. As with other ACE inhibitors, the hypotensive effect of ramipril may be less pronounced in patients of the Negroid race compared with representatives of other races. This may be due to the fact that in patients of the Negroid race with arterial hypertension, arterial hypertension with low renin activity is more often observed.
Cough. With the use of ACE inhibitors, the occurrence of cough has been reported. It is characteristic that the cough is non-productive, prolonged and disappears after discontinuation of therapy. In the differential diagnosis of cough, one should remember about the possibility of occurrence of cough as a result of the use of ACE inhibitors.

Pregnancy and lactation.
Pregnancy.
The medicinal product is contraindicated for use in pregnant women or women who plan to become pregnant. If pregnancy is established during therapy, the intake of the medicinal product should be immediately discontinued and, if necessary, replaced with another medicinal product permitted for use in pregnant women (see section "Contraindications").
Breastfeeding.
Due to the lack of information regarding the use of ramipril during breastfeeding (see section "Pharmacological properties"), it is not recommended to prescribe this medicinal product to women who breastfeed, and it is desirable to give preference to other medicinal products whose use during lactation is safer, especially during breastfeeding of newborns or premature infants.

Effects on ability to drive and use machines.
Some adverse effects (for example, symptoms of lowering blood pressure, such as dizziness) may impair the patient's ability to concentrate attention and reduce the speed of his reaction, which is risky in situations where these qualities are of particularly great importance (for example, when driving vehicles or working with other mechanisms).
As a rule, this is possible at the beginning of treatment or when switching from therapy with other medicinal products to treatment with the medicinal product Cardipril. After taking the first dose or a subsequent increase in dose, it is undesirable to drive a vehicle or work with other mechanisms for several hours.

Method of administration and dosage.
The medicinal product for oral use.
The medicinal product Cardipril is recommended to be taken daily at the same time. The medicinal product Cardipril can be taken before, during and after meals, since food intake does not affect the bioavailability of the medicinal product. Cardipril capsules should be swallowed whole, washed down with water. They must not be chewed or crushed.
If it is impossible to use the prescribed dose, use ramipril in the appropriate dosage.
Adults.
Patients who use diuretics. At the beginning of treatment with the medicinal product Cardipril, arterial hypotension may occur, the development of which is more likely in patients who simultaneously receive diuretics. In such cases, it is recommended to exercise caution, since in these patients a decrease in circulating blood volume and/or the amount of electrolytes is possible.
It is desirable to discontinue the use of the diuretic 2-3 days before starting treatment with ramipril, if possible (see section "Precautions for use").
In patients with arterial hypertension who cannot have the diuretic discontinued, treatment with the medicinal product Cardipril should be started with a dose of 1.25 mg (use ramipril in the appropriate dosage). Renal function and the level of potassium in the blood should be carefully monitored. Further dosing of the medicinal product Cardipril should be adjusted depending on the target level of blood pressure.
Arterial hypertension.
The dose should be selected individually, depending on the characteristics of the patient's condition (see section "Precautions for use") and the results of control measurements of blood pressure. Ramipril can be used in the form of monotherapy or in combination with other classes of antihypertensive medicinal products (see sections "Pharmacodynamics", "Contraindications", "Interaction with other medicinal products and other forms of interaction" and "Precautions for use").
Initial dose. Treatment with the medicinal product Cardipril should be started gradually, starting with the recommended initial dose of 2.5 mg (use ramipril in the appropriate dosage) per day.
In patients with significant activation of the RAAS, after taking the initial dose, a significant decrease in blood pressure may occur. For such patients, the recommended initial dose is 1.25 mg (use ramipril in the appropriate dosage), and their treatment must be started under medical supervision (see section "Precautions for use").
Dose titration and maintenance dose. The dose can be doubled every 2-4 weeks until the target level of blood pressure is reached; the maximum dose of ramipril is 10 mg per day. As a rule, the medicinal product should be taken 1 time per day.
Prevention of cardiovascular diseases.
Initial dose. The recommended initial dose of ramipril is 2.5 mg (use ramipril in the appropriate dosage) 1 time per day.
Dose titration and maintenance dose. Depending on the individual tolerability of the medicinal product Cardipril, the dose should be gradually increased. It is recommended to double the dose after 1-2 weeks of treatment, and then – after another 2-3 weeks – increase it to the target maintenance dose of 10 mg 1 time per day.
Treatment of kidney disease
Patients with diabetes mellitus and microalbuminuria.
Initial dose. The recommended initial dose of the medicinal product is 1.25 mg 1 time per day (use ramipril in the appropriate dosage).
Dose titration and maintenance dose. Depending on the individual tolerability of the medicinal product Cardipril, during further treatment the dose should be increased. After 2 weeks of treatment, the single daily dose is recommended to be doubled to 2.5 mg (use ramipril in the appropriate dosage), and then to 5 mg after another 2 weeks of treatment.
Patients with diabetes mellitus and at least one cardiovascular risk factor.
Initial dose. The recommended initial dose of ramipril is 2.5 mg (use ramipril in the appropriate dosage) 1 time per day.
Dose titration and maintenance dose. Depending on the individual tolerability of the medicinal product Cardipril, during further treatment the dose should be increased. After 1-2 weeks of treatment, the daily dose of the medicinal product Cardipril is recommended to be doubled to 5 mg, and then to 10 mg after another 2-3 weeks of treatment. The target daily dose is 10 mg.
Patients with non-diabetic nephropathy, as evidenced by the presence of macroproteinuria ≥ 3 g per day.
Initial dose. The recommended initial dose of ramipril is 1.25 mg 1 time per day (use ramipril in the appropriate dosage).
Dose titration and maintenance dose. Depending on the individual tolerability of the medicinal product by the patient, during further treatment the dose should be increased. After 2 weeks of treatment, the single daily dose is recommended to be doubled to 2.5 mg (use ramipril in the appropriate dosage), and then to 5 mg after another 2 weeks of treatment.
Heart failure with clinical manifestations.
Initial dose. For patients whose condition has stabilised after treatment with diuretics, the recommended initial dose of the medicinal product is 1.25 mg per day (use ramipril in the appropriate dosage).
Dose titration and maintenance dose. The dose of ramipril should be titrated by doubling it every 1-2 weeks until the maximum daily dose of 10 mg is reached. It is desirable to distribute the dose into 2 intakes.
Secondary prevention after suffering acute myocardial infarction in the presence of heart failure.
Initial dose. 48 hours after the occurrence of myocardial infarction, patients whose condition is clinically and haemodynamically stable should be prescribed an initial dose of 2.5 mg (use ramipril in the appropriate dosage) 2 times per day for 3 days. If the initial dose of 2.5 mg (use ramipril in the appropriate dosage) is poorly tolerated, then a dose of 1.25 mg (use ramipril in the appropriate dosage) should be used 2 times per day for 2 days with subsequent increase to 2.5 mg (use ramipril in the appropriate dosage) and 5 mg 2 times per day. If the dose cannot be increased to 2.5 mg (use ramipril in the appropriate dosage) 2 times per day, treatment should be discontinued.
Dose titration and maintenance dose. Subsequently, the daily dose should be increased by doubling it with an interval of 1-3 days until the target maintenance dose of 5 mg 2 times per day is reached.
When possible, the maintenance daily dose should be distributed into 2 intakes.
If the dose cannot be increased to 2.5 mg (use ramipril in the appropriate dosage) 2 times per day, treatment should be discontinued. Experience of treating patients with severe (NYHA functional class IV) heart failure immediately after myocardial infarction is still insufficient. If, nevertheless, a decision has been made to treat such patients with this medicinal product, it is recommended to start therapy with a dose of 1.25 mg (use ramipril in the appropriate dosage) 1 time per day and to carry out any increase of it with extreme caution.
Special categories of patients.
Patients with renal impairment. The daily dose for patients with renal impairment depends on the creatinine clearance indicator (see section "Pharmacological properties"):

• - if creatinine clearance is ≥ 60 mL/min, there is no need for correction of the initial dose (2.5 mg per day (use ramipril in the appropriate dosage)), and the maximum daily dose is 10 mg;
• - if creatinine clearance is 30-60 mL/min, there is no need for correction of the initial dose (2.5 mg per day (use ramipril in the appropriate dosage)), and the maximum daily dose is 5 mg;
• - if creatinine clearance is 10-30 mL/min, the initial daily dose is 1.25 mg per day (use ramipril in the appropriate dosage), and the maximum daily dose − 5 mg;
• - patients with arterial hypertension who are on haemodialysis: during haemodialysis, ramipril is eliminated to an insignificant extent; the initial dose is 1.25 mg (use ramipril in the appropriate dosage), and the maximum daily dose – 5 mg; the medicinal product should be taken several hours after the haemodialysis session.

Patients with hepatic impairment (see section "Pharmacological properties"). Treatment with ramipril of patients with hepatic impairment should be started under careful medical supervision, and the maximum daily dose in such cases should be 2.5 mg (use ramipril in the appropriate dosage).

Elderly patients. The initial dose should be lower, and further titration of the dose should be carried out more gradually, given the higher probability of occurrence of undesirable effects, especially in very old and frail patients. In such cases, a lower initial dose should be prescribed – 1.25 mg of ramipril (use ramipril in the appropriate dosage). Also see the information given above regarding the dosing of the medicinal product for patients who receive diuretics.

Children.
The medicinal product Cardipril is not recommended for use in children (under 18 years of age), since data on the efficacy and safety of this medicinal product for such patients are insufficient.

Overdose.
Symptoms. Overdose of ACE inhibitors can cause excessive dilation of peripheral vessels (with pronounced arterial hypotension, shock), bradycardia, electrolyte imbalance and renal failure.
Treatment. The patient's condition should be carefully monitored and symptomatic and supportive therapy should be carried out. The proposed treatment measures include primary detoxification (gastric lavage, administration of adsorbents), as well as measures aimed at restoring stable haemodynamics, including the administration of alpha-1-adrenoceptor agonists or angiotensin II (angiotensinamide). Ramiprilat, the active metabolite of ramipril, is poorly eliminated from the systemic circulation by haemodialysis.

Adverse reactions.
The safety profile of the medicinal product Cardipril contains data on persistent cough and reactions caused by arterial hypotension. Serious adverse reactions include angioedema, hyperkalaemia, impairment of hepatic or renal function, pancreatitis, severe skin reactions and neutropenia/agranulocytosis.
The frequency of occurrence of adverse reactions is classified as follows: very common (≥ 1/10); common (from ≥ 1/100 to < 1/10); uncommon (from ≥ 1/1 000 to < 1/100); rare (from ≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); unknown (cannot be calculated from the available data). In each group, adverse reactions are presented in order of decreasing degree of their seriousness.
Cardiac disorders
Uncommon − myocardial ischaemia (including angina or myocardial infarction), tachycardia, arrhythmia, sensation of increased heartbeat, peripheral oedema.
Blood and lymphatic system disorders
Uncommon – eosinophilia.
Rare – decrease in the number of leukocytes (including neutropenia or agranulocytosis), decrease in the number of erythrocytes, decrease in the level of haemoglobin, decrease in the number of platelets.
Unknown – bone marrow failure, pancytopenia, haemolytic anaemia.
Nervous system disorders
Common – headache, dizziness.
Uncommon – vertigo, paraesthesia, ageusia, dysgeusia.
Rare – tremor, balance disorder.
Unknown – cerebral ischaemia (including ischaemic stroke and transient ischaemic attack), impairment of psychomotor functions, burning sensation, parosmia.
Eye disorders
Uncommon – visual disturbances, including blurred vision.
Rare – conjunctivitis.
Ear and labyrinth disorders
Rare – hearing impairment, noise/tinnitus in the ears.
Respiratory, thoracic and mediastinal disorders
Common – non-productive irritating cough, bronchitis, sinusitis, dyspnoea.
Uncommon – bronchospasm (including exacerbation of asthma), nasal congestion.
Gastrointestinal disorders
Common – inflammatory phenomena in the gastrointestinal tract, digestive disorders, abdominal discomfort, dyspepsia, diarrhoea, nausea, vomiting.
Uncommon – pancreatitis (in isolated cases fatal outcomes were reported exclusively with the use of ACE inhibitors), increase in the level of pancreatic enzymes, angioedema of the small intestine, pain in the upper part of the abdomen, including associated with gastritis, constipation, dry mouth.
Rare – glossitis.
Unknown – aphthous stomatitis.
Renal and urinary disorders
Uncommon – impairment of renal function, including acute renal failure; increase in urine formation, worsening of the course of background proteinuria, increase in the level of urea in the blood; increase in the level of creatinine in the blood.
Skin and subcutaneous tissue disorders
Common – rash, in particular maculopapular.
Uncommon – angioedema, in very exceptional cases – obstruction of the respiratory tract as a result of angioedema, which may have a fatal outcome; pruritus, hyperhidrosis.
Rare – exfoliative dermatitis, urticaria, onycholysis.
Very rare – photosensitivity reaction.
Unknown – toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, exacerbation of the course of psoriasis, psoriatic dermatitis, pemphigoid or lichenoid exanthema or enanthema, alopecia.
Musculoskeletal and connective tissue disorders
Common – muscle spasms, myalgia.
Uncommon – arthralgia.
Endocrine disorders
Unknown – syndrome of inappropriate secretion of antidiuretic hormone (SIADH).
Metabolic and nutritional disorders
Common – increase in the level of potassium in the blood.
Uncommon – anorexia, decreased appetite.
Unknown – decrease in the level of sodium in the blood.
Vascular disorders
Common – arterial hypotension, orthostatic decrease in blood pressure, syncope.
Uncommon – sensation of hot flushes.
Rare – vascular stenosis, hypoperfusion, vasculitis.
Unknown – Raynaud's phenomenon.
General disorders
Common – chest pain, fatigue.
Uncommon – pyrexia.
Rare – asthenia.
Immune system disorders
Unknown – anaphylactic and anaphylactoid reactions, increase in the level of antinuclear antibodies.
Hepatobiliary disorders
Uncommon – increase in the level of hepatic enzymes and/or conjugated bilirubin.
Rare – cholestatic jaundice, damage to hepatic cells.
Unknown – acute hepatic failure, cholestatic or cytolytic hepatitis (in very exceptional cases – with a fatal outcome).
Reproductive system and breast disorders
Uncommon – transient erectile impotence, decreased libido.
Unknown – gynaecomastia.
Psychiatric disorders
Uncommon – decreased mood, anxiety, nervousness, restlessness, sleep disturbance, including somnolence.
Rare – state of confused consciousness.
Unknown – attention disturbance.
Paediatric population. The safety of ramipril was studied with the participation of 325 children and adolescents aged 2−16 years during 2 clinical studies. According to the results, the nature and degree of severity of undesirable reactions in children were similar to those observed in adults, but the frequency of occurrence of some reactions in children was higher than in adults, namely:
Tachycardia, nasal congestion and rhinitis: common (≥ 1/100 to ˂1/10) in the paediatric population and uncommon (≥ 1/1000 to ˂1/100) in the population of adult patients.
Conjunctivitis: common (≥ 1/100 to ˂1/10) in the paediatric population and rare (≥ 1/10 000 to ˂1/1000) in the population of adult patients.
Tremor and urticaria: uncommon (≥ 1/1000 to ˂1/100) in the paediatric population and rare (≥ 1/10 000 to ˂1/1000) in the population of adult patients.
The general safety profile of ramipril in children and adults does not differ significantly.

Shelf life. 3 years.

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

Packaging.
Cardipril 2.5: 10 capsules in a blister, 1 or 3 blisters in a carton.
Cardipril 5 or Cardipril 10: 10 capsules in a blister; 3 blisters in a carton.

Terms of dispensing. On prescription

Date of last update.

15.07.2026