Ramipril

Package leaflet (information for patients)

Tradename
Ramipril

Dosage form
Tablets 10 mg.

Pharmacotherapeutic group
Angiotensin - converting enzyme inhibitor

Pharmacological properties
Pharmacodynamics
Mechanism of action
Ramiprilat, the active metabolite of ramipril, is a long-acting inhibitor of angiotensin - converting enzyme (ACE). In blood plasma and tissues, ACE catalyzes the transition of angiotensin I to angiotensin II (an active vasoconstrictor) and the cleavage of the active vasodilator bradykinin. A decrease in the formation of angiotensin II and an increase in the activity of bradykinin leads to vasodilation and contributes to the cardioprotective and endothelioprotective effect of ramipril.
Angiotensin II stimulates the release of aldosterone, in this regard, ramipril causes a decrease in aldosterone secretion. The overall response to monotherapy with ACE inhibitors is lower in hypertensive black patients (low renin population) than in white patients.
Double blockade of the renin- angiotensin - aldosterone system. Two large randomized controlled trials (ONTARGET ( ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial ) and VA NEPHRON-D ( The Veterans Affairs Nephropathy in Diabetes )) studied the use of a combination of an ACE inhibitor and angiotensin II receptor antagonists (ARA). ONTARGET was a study. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy. These studies did not show significant beneficial effects on renal and / or cardiovascular conditions and mortality, while there was an increased risk of hyperkalemia, kidney damage, hypotension compared with monotherapy Given similar pharmacodynamic properties, these results also apply to other ACE inhibitors and ARBs. shows the combined use of ACE inhibitors and ARA in patients with diabetic nephropathy; ALTITUDE ( Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints ) study was designed to test the benefits of adding aliskiren to standard therapy of ACE inhibitors or ARA in patients with type 2 diabetes mellitus and chronic renal insufficient -accuracy, cardiovascular diseases or their combination. The study was suspended due to the increased risk of adverse outcomes. The mortality from cardiovascular events was numerically more frequent in the group Aliskiren than in the placebo group, the side reaction of different severity ( hyperkalemia, kidney damage, hypotension) are more often observed in group Aliskiren than in the placebo group.
Pharmacodynamic action
Hypotensive action
Taking ramipril causes a pronounced decrease in the resistance of the peripheral arteries. Changes in renal blood flow and glomerular filtration rate are usually not observed. Taking ramipril in hypertensive patients causes a decrease in blood pressure in the "lying" and "standing" positions without a compensatory increase in heart rate.
In most patients, a noticeable hypotensive effect occurs 1-2 hours after ingestion of a single dose. The maximum effect of a single dose is achieved 3-6 hours after ingestion. The antihypertensive effect of a single dose usually lasts for 24 hours.
The maximum antihypertensive effect with continuous treatment with ramipril, as a rule, occurs after 3-4 weeks. It has been shown that the hypotensive effect with long-term therapy persists for 2 years.
Abrupt discontinuation of ramipril does not cause a rapid and excessive reverse increase in blood pressure.
Heart failure
As with traditional diuretic therapy and optional cardiac glycosides, ramipril has been shown to be effective in patients with NYHA functional class II-IV heart failure. Ramipril has beneficial effects on hemodynamics (decreases filling pressure of the left and right ventricles, decreases total peripheral vascular resistance, increases cardiac index), and also reduces neuroendocrine activation.
Pharmacokinetics
Suction
After oral administration, it is rapidly absorbed in the gastrointestinal tract: the maximum content of ramipril in blood plasma is reached within an hour and is at least 56% of the dose taken, practically does not depend on the simultaneous intake of food. The bioavailability of the active metabolite of ramiprilat after oral administration of 2.5 mg and 5 mg of ramipril is 45%. After oral administration, the maximum plasma concentration of ramiprilat reaches in 2-4 hours. The constant plasma concentration of ramiprilat after daily administration of usual doses of ramiprilat is reached approximately on the fourth day of treatment.
Distribution
Protein binding is about 73% for ramipril and about 56% for ramiprilat.
Metabolism
Ramipril is almost completely converted to ramiprilat, diketopiperazine ester, diketopiperazinic acid and the glucuronides of ramipril and ramiprilat.
Withdrawal
Excretion of metabolites is carried out mainly by the kidneys.
Excretion of ramiprilat is carried out in several phases due to the activity of ramiprilat, saturable binding to ACE and weak dissociation with this enzyme. The final phase of elimination of ramiprilat is prolonged at very low plasma concentrations. With repeated administration of ramipril once a day, the "effective" half-life, important from the point of view of dosing, was 13-17 hours for a dosage of 5-10 mg / ml, and a longer one for lower dosages of 1.25-2.5 mg / ml. This difference is due to the strong binding of ramiprilat with ACE.
In breast milk after a single dose of ramipril and its metabolites are not detected quantitatively. However, with repeated use, the effect is unknown.
Patients with impaired renal function
In case of impaired renal function, the excretion of ramiprilat by the kidneys is reduced, the renal clearance of ramiprilat decreases in proportion to the creatinine clearance. This leads to an increase in the plasma concentration of ramiprilat, which decreases more slowly than in patients with intact kidneys.
Patients with impaired liver function
A decrease in hepatic function leads to a slowed down metabolism of ramipril to ramiprilat and a slowed down elimination of ramiprilat ; the plasma content of ramipril in such patients is increased. However, the maximum level of ramiprilat in patients with reduced liver function does not differ from the maximum level observed in patients with normal liver function.

Indications for use
Treatment of arterial hypertension: to lower blood pressure both in monotherapy and in combination with other antihypertensive drugs.
Prevention of cardiovascular accidents: reducing the number of cardiovascular complications (myocardial infarction, stroke and death) in patients with:
- severe atherothrombotic cardiovascular diseases (a history of ischemic heart disease or stroke, obliterating diseases of the arteries of the lower extremities);
- diabetes mellitus and with at least one cardiovascular risk factor

Method of administration and dosage
Inside.
It is recommended that you take Ramipril every day at the same time of the day.
Drug Ramipril take with copious amounts of fluid, and regardless of the meal. Food intake does not significantly affect the absorption of the active component of ramipril (see section Pharmacokinetics ). The tablets must be swallowed whole ( unchewed ).
Adults
Diuretic-treated patients
The start of taking Ramipril may be accompanied by hypotension; this is more common in patients treated with diuretics. The lack of salts and fluid in the body is subject to preliminary correction before starting treatment with Ramipril, diuretics should be previously limited or canceled, no later than 2-3 days (see section Precautions). Treatment of patients who have not stopped taking diuretics should start with the lowest single dose of 1.25 mg of ramipril. It is necessary to monitor renal function and serum potassium. The subsequent dosage of Ramipril should be adjusted in accordance with the target blood pressure level.
Hypertension treatment
The dosage is calculated depending on the expected therapeutic effect and the tolerance of the active substance by the patient in each specific case (see the Precautions section).
Drug Ramipril can be used both as monotherapy and in combination with other classes of drugs for the treatment of hypertension.
Treatment with Ramipril should be started with an initial dose of 2.5 mg daily.
In patients with a highly activated renin- angiotensin - aldesterone system, a significant decrease in blood pressure may follow after taking the initial dose. For these patients, the recommended starting dose is 1.25 mg, and the initiation of treatment should be carried out under medical supervision (see section PRECAUTIONS).
The dose can be doubled at intervals of 2-4 weeks to achieve the target blood pressure level. The maximum daily dose is 10 mg.
The daily dose is taken once a day.
Prevention of cardiovascular accidents
The recommended starting dose is 2.5 mg of Ramipril drug once a day.
The dose is gradually increased depending on the patient's tolerance to the active substance. It is recommended to double the dose after 1-2 weeks of treatment, and after the next 2-3 weeks - to increase the maintenance dose to 10 mg of Ramipril daily.
See also prescribing dosages in patients previously treated with diuretics.
Secondary prevention in patients with acute myocardial infarction with clinical signs of heart failure
After 48 hours following myocardial infarction in clinically and hemodynamically stable patients, the recommended starting dose is 2.5 mg twice daily for three days. If the initial dose of 2.5 mg is not tolerated by the patient, 1.25 mg twice daily should be given for 2 days before increasing the dose to 2.5 mg and 5 mg twice daily. If the dose cannot be increased to 2.5 mg twice daily, treatment should be discontinued.
See also prescribing dosages in patients previously treated with diuretics.
The daily dose is sequentially increased, doubling it with an interval of 1-3 days until a maintenance dose of 5 mg is reached twice a day.
It is recommended to divide the maintenance daily dose into 2 doses. The maximum daily dose is 10 mg.
If it is decided to administer Ramipril therapy in patients with severe (NYHA grade IV) chronic heart failure after myocardial infarction, it is recommended to start with a dose of 1.25 mg once a day. Increase the dose with extreme caution.
Treatment of kidney disease
In patients with diabetes and microalbuminuria
The recommended starting dose is 1.25 mg of Ramipril once a day.
The dose is sequentially increased depending on the patient's tolerance to the active substance. It is recommended to double the daily dose to 2.5 mg after 2 weeks of treatment, and then to 5 mg after the next 2 weeks.
In patients with diabetes and at least one risk factor for cardiovascular disease
The recommended starting dose is 2.5 mg of Ramipril drug once a day.
The dose is sequentially increased depending on the patient's tolerance to the active substance. Recommended daily dose is doubled to 5 mg after 2 weeks of treatment, and then 10 mg after 2-3 following non- del. The maximum daily dose is 10 mg.
In patients with nondiabetic nephropathy with macroproteinuria ≥ 3 g / day
The recommended starting dose is 1.25 mg of Ramipril once a day.
The dose is sequentially increased depending on the patient's tolerance to the active substance. It is recommended to double the daily dose to 2.5 mg after 2 weeks of treatment, and then to 5 mg after the next 2 weeks.
Chronic heart failure treatment
For patients receiving diuretic therapy, the recommended starting dose is 1.25 mg of Ramipril once a day.
It is recommended that the dose of Ramipril be doubled every two weeks to a maximum daily dose of 10 mg. It is preferable to divide the daily dose into 2 doses.
Special categories of patients
Treatment of patients with impaired renal function
The daily dose for patients with impaired renal function is prescribed taking into account creatinine clearance :
- if creatinine clearance is ≥ 60 ml / min, there is no need to adjust the initial dose (2.5 mg daily), the maximum daily dose is 10 mg;
- if creatinine clearance is in the range of 30-60 ml / min, there is no need to adjust the initial dose (2.5 mg daily), the maximum daily dose is 5 mg;
- if the creatinine clearance is within 10-30 ml / min, the initial dose is 1.25 mg daily, and the maximum daily dose is 5 mg;
- in patients with hypertension undergoing hemodialysis: ramipril is poorly dialyzed; the starting dose is 1.25 mg daily and the maximum daily dose is 5 mg; the drug must be taken several hours after hemodialysis.
Patients with impaired liver function
Such patients should be treated with extreme caution and only under medical supervision. The maximum permissible daily dose in such cases is 2.5 mg of Ramipril.
Elderly patients
Initial doses should be lower and their administration should be more gradual due to the increased risk of adverse reactions, especially in elderly and debilitated patients. The recommended starting daily dose is 1.25 mg of Ramipril.
Children
Drug Ramipril is not recommended for use in children and adolescents under the age of 18 years due to lack of appropriate data on its bezo- pasnosti and efficiency.

Side effects
From the cardiovascular system: arterial hypotension; D DKO - chest pain, tachycardia.
From the side of the central nervous system: dizziness, weakness, headache; rarely - sleep and mood disorders.
From the digestive system: diarrhea, constipation, loss of appetite; rarely - stomatitis, abdominal pain, pancreatitis, cholestatic jaundice.
From the respiratory system: dry cough, bronchitis, sinusitis.
From the urinary system: rarely - proteinuria, increased concentration of creatinine and urea in the blood (mainly in patients with impaired renal function).
From the hematopoietic system: rarely - neutropenia, agranulo cell count, thrombocytopenia, anemia.
From laboratory indicators: hypokalemia, giponatrie mia.
Allergic reactions: skin rash, angioedema and other hypersensitivity reactions.
Others: rarely - muscle spasms, impotence, alopecia.

Contraindication
- Hypersensitivity to the active ingredient ramipril and other components of the drug or other ACE inhibitors;
- patients who, according to anamnestic data, previously had angioedema (hereditary, idiopathic, or due to the use of ACE inhibitors);
- extracorporeal treatment methods, during which there is contact of blood with negatively charged surfaces (see the section Interaction with other medicinal products and other forms of interaction);
- established renal artery stenosis (bilateral, in the case of one kidney - unilateral);
- pregnancy and lactation (see sections PRECAUTIONS, Pregnancy and lactation);
- in combination with medicines containing Aliskiren in patients with diabetes mellitus or with moderate / severe renal impairment (GFR <60 ml / min / 1.73 m2).
- age up to 18 years (efficacy and safety have not been established).
Drug Ramipril should not be administered to patients with low blood pressure or hemodynamically unstable conditions.

Overdose
Intoxication symptoms
Symptoms associated with an overdose of ACE inhibitors may include: increased peripheral vasodilation (accompanied by hypotension, shock), bradycardia, electrolyte imbalance, and renal failure. Patients should be under constant supervision, treatment should be determined by the nature and timing of the drug administration, as well as the type and severity of symptoms. In addition to general measures aimed at removing ramipril from the body (eg, gastric lavage, prescribing adsorbents) and measures to restore a hemodynamically stable state, the use of alpha1 adrenergic agonists or angiotensin II may be required. Ramiprilat, the active metabolite of ramipril, is hardly dialyzed.

Precautions
Special categories of patients
Pregnancy
ACE inhibitors such as ramipril or angiotensin II receptor antagonists (ARA) should not be used during pregnancy. If the patient is planning a pregnancy, then before continuing therapy with ACE / ARB inhibitors, it is necessary to choose another treatment for hypertension with a more reliable safety profile for pregnancy. If pregnancy is detected during treatment with ACE / ARB inhibitors, you should immediately stop taking the medication and begin therapy with drugs from other classes (see sections Contraindications and Adverse Reactions).
Patients at risk of hypotension:
- patients with increased activity of the renin- angiotensin - aldosterone system
Patients with increased activity of the renin- angiotensin - aldosterone system are at risk of a sharp drop in blood pressure and deterioration of renal function during ACE inhibition, especially at the beginning of treatment or at the first dose increase of ACE inhibitors or concomitant diuretics.
Possible manifestations of increased activity of the renin- angiotensin - aldosterone system must be taken into account when carrying out continuous medical supervision, including monitoring of blood pressure, in cases, for example:
- patients with severe hypertension;
- patients with decompensated congestive heart failure;
- patients with clinically significant hemodynamic disorders (inflow or outflow) in the left ventricle (for example, aortic stenosis, mitral stenosis);
- patients with unilateral renal artery stenosis with a second functional kidney;
- patients with electrolyte and (or) fluid deficiency (including patients who have previously received diuretic treatment);
- patients with liver cirrhosis and / or ascites;
- patients undergoing major surgery or during anesthesia with hypotensive agents.
It is recommended that dehydration, hypovolemia, or electrolyte deficiency be corrected before starting treatment (in patients with heart failure, such corrective actions should be weighed against the risk of over-volume).
- Transient or persistent heart failure after myocardial infarction;
- patients at risk of cardiac or cerebral ischemia due to acute hypotension.
The initial stages of treatment require special medical supervision.
Double blockade of the renin- angiotensin - aldosterone system is associated with an increased risk of hypotension, hyperkalemia, and renal impairment (including acute renal failure) compared with monotherapy. Double blockade of RAAS with the use of an ACE inhibitor, ARB or Aliskiren cannot be recommended for any patient, especially patients with diabetic nephropathy. In some cases, when the combined use of ACE inhibitors and ARBs is absolutely indicated, careful observation by a specialist and mandatory monitoring of renal function, water-electrolyte balance, and blood pressure is necessary. This applies to the appointment of candesartan or valsartan as adjunctive therapy to ACE inhibitors in patients with chronic heart failure. A double blockade of the RAAS under the close supervision of a specialist and mandatory monitoring of renal function, water and electrolyte balance and blood pressure is possible in patients with chronic heart failure with intolerance to aldosterone antagonists ( spironolactone ), who have persistent symptoms of chronic heart failure, despite other adequate therapy.
Elderly patients
See section Dosage and Administration
Surgery
It is recommended to discontinue treatment with ACE inhibitors (including ramipril ), if possible, the day before surgery.
Renal function monitoring
Renal function should be monitored before prescribing Ramipril. Monitoring of renal function is recommended, in particular, in the first weeks of treatment, especially in patients with renal insufficiency (see section Dosage and Administration). There may be a risk of impaired renal function, especially in patients with congestive heart failure or after kidney transplantation.
Angioedema
Cases of angioedema have been reported in patients treated with ACE inhibitors, including ramipril (see Adverse Reactions).
If angioneurotic edema occurs during treatment, the drug Ramipril should be stopped immediately.
Emergency therapy should be started immediately. The patient should be monitored for at least 12-24 hours and discharged only after all symptoms have disappeared.
A case of angioedema of the intestine has been reported in patients treated with ACE inhibitors, including the drug Ramipril (see section Adverse reactions). The patients had abdominal pain (sometimes accompanied by nausea and vomiting).
Anaphylactic reactions during desensitization
The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom increases with ACE inhibitors. It is assumed that a similar effect may also occur when interacting with other allergens. Before the onset of desensitization, you should consider the possibility of temporary discontinuation of drug Ramipril.
Hyperkalemia
Hyperkalemia has been observed in some patients treated with ACE inhibitors, including Ramipril. Patients at risk of developing hyperkalemia include those with renal impairment; aged> 70 years; uncontrolled diabetes mellitus; consuming potassium salts, potassium-sparing diuretics or other substances that increase plasma potassium; also conditions such as dehydration, acute cardiac decompensation, metabolic acidosis. During concomitant treatment with these drugs, strict monitoring of serum potassium concentration is required (see section Interaction with other drugs and other forms of interaction).
Hyponatremia
In some patients receiving ramipril, the syndrome of inappropriate secretion of antidiuretic hormone (SNS ADH) was observed, leading to the occurrence of hyponatremia. Regular monitoring of serum sodium is recommended in elderly patients and other patients at increased risk of hyponatremia.
Neutropenia / agranulocytosis
Neutropenia / agranulocytosis, as well as thrombocytopenia and anemia, are rare, and bone marrow suppression has also been reported. It is recommended to monitor the leukocyte count to prevent possible leukopenia. More detailed monitoring is recommended at the initial stages of treatment and in patients with impaired renal function with concomitant collagenosis (lupus erythematosus or scleroderma) who have been treated with other drugs that can affect the blood picture (see the section Interaction with other drugs and other forms interactions and adverse reactions).
Ethnic differences
The risk of angioedema with ACE inhibitors is more likely in dark-skinned patients than in whites. The overall response to monotherapy with ACE inhibitors is lower in dark-skinned (Afro- Caribbean ) hypertensive patients (low renin population) than in white patients.
Cough
Cough has been reported with treatment with ACE inhibitors. The cough is unproductive, persistent, and resolves after stopping therapy. When carrying out a differential diagnosis of cough in a patient, the possibility of its connection with the intake of ACE inhibitors should be taken into account.
Tablets with a dosage of 5 mg contain the excipient ponso 4R (E 124), which can cause allergic reactions.

Interaction with other medicinal products
Contraindicated combinations
Extracorporeal treatments that involve blood contact with negatively charged surfaces, such as dialysis or hemofiltration with high-flow membranes (e.g. polyacrylonitrile) and low-density lipoprotein (LDL) apheresis with dextran sulfate, should not be used during drug treatment Ramipril, as it can lead to anaphylactoid reactions (see section Contraindications). If such treatment is necessary, other types of filtration membranes and other (non-ACE inhibitors) classes of antihypertensive agents are used.
Precautions in use
- Potassium salts, heparin, potassium-sparing diuretics and other substances that increase the concentration of potassium in plasma (for example, ARA, trimethoprim, tacrolimus, cyclosporine, spironolactone ): a more pronounced increase in the concentration of potassium in the blood serum ( hyperkalemia ). During concomitant treatment with these drugs, strict monitoring of serum potassium concentration is necessary;
- antihypertensive drugs (diuretics) and other substances that can lower blood pressure (for example, nitrates, tricyclic antidepressants, anesthetics, alcohol consumption, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin ): an increase in the hypotensive effect of drugs Ramipril. The potential risk of hypotension should be excluded (see section Dosage and Administration);
- vasopressive sympathomimetics and other substances (for example, isoproterenol, dobutamine, dopamine, adrenaline): the hypotensive effect of Ramipril may be weakened, careful monitoring of blood pressure is recommended;
- allopurinol, procainamide, cytostatics, immunosuppressants, systemic corticosteroids and other drugs that affect the blood picture: the likelihood of hematological reactions increases (see the Precautions section);
- lithium salts: ACE inhibitors can cause an increase in serum lithium concentration, resulting in increased cardiotoxicity and neurotoxicity of lithium (requires regular monitoring of serum lithium levels);
- antidiabetic agents, including insulin: hypoglycemic reactions may occur. It is recommended to carry out particularly careful monitoring of blood glucose levels;
- non-steroidal anti-inflammatory drugs, pain relievers and acetylsalicylic acid: it is possible to weaken the hypotensive effect of Ramipril drugs ; possible increased risk of renal dysfunction and increased serum potassium concentration;
- « mTOR ( mammalian Target of Rapamycin ) - inhibitors ( estramustine, everolimus, sirolimus ) or vildagliptin : with simultaneous use, an increase in the incidence of angioedema is possible.

Special instructions
In patients with concomitant renal impairment, doses are selected individually in accordance with the CC values. Before starting treatment, all patients need a study of renal function. In the course of treatment with ramipril, renal function, blood electrolyte composition, the level of liver enzymes in the blood, as well as the peripheral blood picture (especially in patients with diffuse connective tissue diseases, in patients receiving immunosuppressants, allopurinol ) are regularly monitored. Patients who have a deficiency of fluid and / or sodium, before starting treatment, it is necessary to correct water-electrolyte disturbances. During treatment with ramipril, hemodialysis using polyacrylonitrile membranes should not be performed (the risk of anaphylactic reactions is increased).

Pregnancy and elbowing
It is not recommended to take Ramipril in the first trimester of pregnancy (see the section on PRECAUTIONS). This drug is contraindicated in the second and third trimesters of pregnancy (see section on Contraindications).
There are no conclusive epidemiological data on the risk of teratogenicity due to the use of ACE inhibitors during the first trimester of pregnancy; however, a small risk cannot be ruled out. If the patient is planning a pregnancy, treatment with ACE inhibitors should be discontinued and replaced with another antihypertensive drug with a safer pregnancy profile. Therapy with ACE / ARB inhibitors in the second and third trimesters of pregnancy can cause fetotoxicity (decreased renal function, oligohydramnios, severe hypoplasia of the skull bones) and neonatal intoxication (renal failure, hypotension, hyperkalemia ). Patients who have had ACE inhibitors since the second trimester of pregnancy are advised to check kidney function and skull using ultrasound. Newborns whose mothers took ACE inhibitors should be screened for hypotension, oliguria, and hypokalemia (see Contraindications and Precautions).
Since it is not known for certain whether ramipril penetrates into human milk and whether it causes undesirable effects in children fed with breast milk, the use of Ramipril during breastfeeding is contraindicated. It is recommended that an alternative treatment be selected with a safety profile that will be preferred during breastfeeding.

Influence on the ability to drive vehicles and work with mechanisms
Does not affect.

Storage conditions
Store in a dry, dark place at a temperature not exceeding 25 ° C, out of the reach of children.

Shelf life
3 years. Do not use after the expiration date printed on the package.

Vacation conditions
On prescription.

Packaging
Ramipril 10 mg Tablets. There are 10 tablets in a blister. 2 blisters are packed in a cardboard box together with an enclosed leaflet.