Composition, form of production and packaging
Tablets are light pink or orange-pink in color, possibly with a marble surface, oval, flat, chamfered, with a risk and engraved "R3" on one side and risks on the side surfaces.
ramipril 5 mg
Auxiliary substances: sodium bicarbonate - 5 mg, lactose monohydrate - 94 mg, pregelatinized starch 1500 - 19.5 mg, croscarmellose sodium - 2.6 mg, sodium stearyl fumarate - 1.3 mg, Pigment Blend PB-22960 (lactose monohydrate - 2.47 mg, iron oxide red - 0.09 mg, iron oxide yellow - 0.04 mg) - 2.6 mg.
7 pcs. - blisters (4) - packs of cardboard.
Tablets are white or almost white, oval, flat, chamfered, with a risk and engraved "R4" on one side and risks on the side surfaces.
ramipril 10 mg
Excipients: sodium bicarbonate - 10 mg, lactose monohydrate - 193.2 mg, pregelatinized starch 1500 - 39 mg, croscarmellose sodium - 5.2 mg, sodium stearyl fumarate - 2.6 mg.
7 pcs. - blisters (4) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2017.
Antihypertensive drug, ACE inhibitor. As a result of inhibition of ACE activity (regardless of plasma renin activity), the hypotensive effect (in the position of the patient lying and standing) develops without a compensatory increase in heart rate.
The suppression of ACE activity reduces the level of angiotensin II, which leads, in turn, to a decrease in the secretion of aldosterone. As a result of a decrease in angiotensin II concentration, by eliminating negative feedback, the plasma renin activity increases.
Ramipril acts on the ACE, circulating in the blood and located in the tissues, incl. vascular wall. Reduces OPSS (afterload), pressure in the pulmonary capillaries (preload); increases cardiac output and increases exercise tolerance.
With prolonged use, ramipril promotes the reverse development of myocardial hypertrophy in patients with arterial hypertension.
Ramipril reduces the incidence of arrhythmia in myocardial reperfusion; improves the blood supply of the ischemic myocardium.
Ramipril inhibits the breakdown of bradykinin and stimulates the formation of nitric oxide (NO) in the endothelium.
The antihypertensive effect begins 1-2 hours after taking the drug inside, the maximum effect develops within 3-6 hours and persists for 24 hours. With daily use, the antihypertensive effect increases for 3-4 weeks and persists with long-term treatment (1-2 of the year). Antihypertensive efficacy does not depend on the sex, age and body weight of the patient.
In patients with acute myocardial infarction, ramipril limits the area of вЂ‹вЂ‹necrosis, improves the prognosis of life; reduces the mortality in the early and distant period of myocardial infarction, the frequency of occurrence of repeated infarctions; reduces the severity of manifestations of heart failure, slows its progression.
With long-term admission (at least 6 months) reduces the degree of pulmonary hypertension in patients with congenital and acquired heart defects.
Ramipril reduces pressure in the portal vein with portal hypertension; inhibits microalbuminuria (in the initial stages) and impairment of renal function in patients with severe diabetic nephropathy. With non-diabetic nephropathy accompanied by proteinuria (more than 3 g / day) and renal insufficiency, it slows down further deterioration in kidney function, reduces proteinuria, reduces the risk of increased creatinine levels or the development of terminal renal failure.
Ramipril has a multiphase pharmacokinetic profile.
After ingestion, ramipril is rapidly absorbed from the digestive tract. The degree of absorption is not less than 50-60% of the administered dose. C max in blood plasma is achieved within 1 h.
Distribution and Metabolism
Almost completely metabolized (mainly in the liver) with the formation of active and inactive metabolites. Its active metabolite, ramiprilate, suppresses ACE activity by about 6 times stronger than ramipril. C max ramiprilate in blood plasma is achieved in 2-4 hours. Among the known inactive metabolites are diketopiperazine ether, diketopiperazic acid, and also glucuronides of ramipril and ramiprilate.
The binding of ramipril and ramiprilata with plasma proteins is approximately 73% and 56%, respectively.
When taken in regular doses 1 time / day C ss ramipril in blood plasma is reached by the 4th day of taking the drug.
T 1/2 ramipril - 5.1 h, T 1/2 ramiprilata 13-17 h.
After oral administration, a 60% dose is excreted in the urine (mainly in the form of metabolites) and about 40% - with feces. About 2% of the administered dose is excreted unchanged in the urine.
Pharmacokinetics in special clinical cases
Elimination of ramipril, ramiprilata and inactive metabolites with urine decreases with renal insufficiency (which leads to an increase in the concentration of ramiprilate).
Decrease in enzymatic activity in the liver with a violation of its function leads to a slowdown in the conversion of ramipril to ramipril, which can cause an increase in the concentration of ramipril in the blood plasma.
- arterial hypertension;
- Chronic heart failure;
- Chronic heart failure after acute myocardial infarction in patients with stable hemodynamics;
- diabetic nephropathy and chronic diffuse kidney disease (nondiabetic nephropathy);
- reduced risk of myocardial infarction, stroke or coronary death in patients with high cardiovascular risk with IHD, including patients who underwent myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting.
Tablets should be taken orally, swallowing them whole, without chewing, washing with a lot of liquid (about 1 cup). Tablets can be taken regardless of the time of ingestion. Tablets can be divided in half, breaking down the risk.
The dose is set individually, taking into account the therapeutic effect and tolerability.
With arterial hypertension, the recommended initial dose is 2.5 mg 1 time / day. Depending on the therapeutic effect, the dose can be increased by doubling the daily dose every 2-3 weeks. The standard maintenance dose is 2.5-5 mg / day. The maximum daily dose is 10 mg.
In chronic heart failure, the recommended initial dose is 1.25 mg 1 time / day. Depending on the therapeutic effect, the dose can be increased by doubling the daily dose every 2-3 weeks. If you need to use the drug in a dose of more than 2.5 mg, this dose can be taken immediately or divided into 2 divided doses. The maximum daily dose is 10 mg.
For treatment after myocardial infarction , it is recommended to start taking the drug 3-10 days after an acute myocardial infarction. The recommended initial dose, depending on the condition of the patient and the time elapsed after an acute myocardial infarction, is 2.5 mg 2 times / day. Depending on the therapeutic effect, the initial dose can be doubled to 5 mg 2 times / day. The maximum daily dose is 10 mg. When intolerance of the drug should reduce the dose.
With nondiabetic or diabetic nephropathy, the recommended initial dose is 1.25 mg 1 time / day daily. Depending on the therapeutic effect, the dose can be increased by doubling the daily dose every 2-3 weeks. If you need more than 2.5 mg of the drug, this dose can be taken immediately or divided into 2 divided doses. The recommended maximum daily dose is 5 mg.
Prevention of myocardial infarction, stroke or death from cardiovascular disorders: the recommended initial dose is 2.5 mg 1 time / day. Depending on the tolerability of the drug, after 1 week of taking the dose should be increased by half compared with the initial dose. This dose should be doubled again after 3 weeks of admission.The recommended maintenance dose is 10 mg 1 time / day.
In elderly patients taking diuretics and / or with heart failure, as well as in case of violations of the liver or kidney function, the dose should be determined by individual selection depending on the patient's response to treatment.
Patients with renal failure require a correction of the dosing regimen. With a moderate impairment of kidney function (QC from 20 to 50 ml / min based on 1.73 m 2 body surface), the initial dose is usually 1.25 mg 1 time / day. The maximum daily dose is 5 mg.
If the SC is not measured, it can be calculated from the serum creatinine level using the Cockcroft formula.
QC (ml / min) = (140 - age)? body weight (kg) / 72? serum creatinine (mg / dL)
For women : the result of the calculation should be multiplied by 0.85.
In cases of liver function disorders , a reduced or increased effect of the Hartil В® preparation may be equally often observed, therefore, in the early stages of treatment of this category of patients, careful medical observation is required. The maximum daily dose in such cases is 2.5 mg.
In patients receiving diuretic therapy, due to the risk of a significant reduction in blood pressure, consideration should be given to the possibility of temporary cancellation or at least a decrease in the dose of diuretics in at least 2-3 days (or longer, depending on the duration of diuretics) prior to taking Hartil. For patients who previously received diuretics, usually the initial dose is 1.25 mg.
From the cardiovascular system: a decrease in blood pressure, orthostatic hypotension, tachycardia; rarely - arrhythmia, increased circulatory disorders of organs caused by narrowing of blood vessels. In case of excessive decrease in blood pressure, mainly in patients with ischemic heart disease and clinically significant narrowing of cerebral vessels, myocardial ischemia (angina or myocardial infarction) and cerebral ischemia (possibly with a dynamic cerebrovascular accident or stroke) may develop.
From the side of the urinary system: the development or strengthening of renal failure, the strengthening of existing proteinuria, a decrease in the volume of urine (at the beginning of the drug).
From the central nervous system and peripheral nervous system: dizziness, headache, weakness, drowsiness, paresthesia, nervous excitability, anxiety, tremor, muscle spasm, mood disorders, convulsions; when used in high doses - insomnia, anxiety, depression, confusion, fainting.
From the sense organs: vestibular disorders, taste disorders (eg, metallic taste), smell, hearing and vision, tinnitus.
On the part of the digestive system: nausea, vomiting, diarrhea or constipation, pain in the epigastric region, dry mouth, thirst, decreased appetite, stomatitis, hypersensitivity or inflammation of the mucous membrane of the cheeks, pancreatitis; rarely - hepatitis, cholestatic jaundice, impaired liver function with the development of acute liver failure.
On the part of the respiratory system: dry cough, bronchospasm (in patients with increased excitability of cough reflex), dyspnea, rhinorrhea, rhinitis, sinusitis, bronchitis.
On the part of the organs of hematopoiesis: anemia, a decrease in the concentration of hemoglobin and hematocrit, thrombocytopenia, leukocytopenia, neutropenia, agranulocytosis, pancytopenia, hemolytic anemia, a decrease in the number of erythrocytes, inhibition of bone marrow hematopoiesis.
Allergic reactions: skin rash, itching, hives, conjunctivitis, photosensitivity; rarely - angioedema, swelling of the face, extremities, lips, tongue, pharynx or larynx, exfoliative dermatitis, multiforme erythema exudative (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), pemphigus (pemphigus), serositis, onycholysis , vasculitis, myositis, myalgia, arthralgia, arthritis, eosinophilia.
On the part of laboratory indicators: hypercreatininaemia, increased urea nitrogen levels, increased activity of hepatic transaminases, hyperbilirubinemia, hyperkalemia, hyponatremia; extremely rare - an increase in the titer of the antinuclear factor.
Other: decreased libido, alopecia, hyperthermia, sweating.
- angioedema in the anamnesis, incl. associated with previous therapy with ACE inhibitors;
- hemodynamically significant bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney;
- arterial hypotension or unstable hemodynamics;
- lactation period (breastfeeding);
- primary hyperaldosteronism;
- renal failure (CC <20 ml / min);
- Hypersensitivity to ramipril and other components of the drug.
With caution apply for hemodynamically significant aortic or mitral stenosis (risk of excessive blood pressure lowering with subsequent renal dysfunction), severe primary malignant hypertension, severe lesions of the coronary and cerebral arteries (risk of blood flow decrease with excessive decrease in blood pressure), unstable angina, severe ventricular disorders rhythm; terminal stage of chronic heart failure; decompensated pulmonary heart; for diseases requiring the appointment of SCS and immunosuppressants (lack of clinical experience) - incl. with systemic connective tissue diseases, severe renal and / or hepatic insufficiency, hyperkalemia, hyponatremia (including against diuretics and a diet with sodium intake restriction); with initial or severe manifestations of fluid deficiency and electrolytes, conditions accompanied by a decrease in BCC (including diarrhea, vomiting); diabetes mellitus; oppression of bone marrow hematopoiesis; after kidney transplant; in elderly patients, in children and adolescents under the age of 18 (efficacy and safety not established).
There is only limited experience with ramipril in patients who are on dialysis.
PREGNANCY AND LACTATION
Contraindicated in pregnancy and lactation.
The drug causes impaired fetal kidney development, decreased fetal and newborn infants, impaired renal function, hyperkalemia, skull hypoplasia, oligohydramnion, limb contracture, skull deformity, and lung hypoplasia.
APPLICATION FOR FUNCTIONS OF THE LIVER
Patients with renal failure require a correction of the dosing regimen. With a moderate impairment of kidney function (KC from 20 to 50 ml / min based on 1.73 m 2 body surface), the initial dose is usually 1.25 mg 1 time / day (1 table 1.25 mg / day). The maximum daily dose should not exceed 5 mg.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
If liver function is impaired, the effect of Hartil may be reduced equally or more frequently, therefore, in the early stages of treatment of this category of patients, careful medical supervision is required. The maximum daily dose in such cases should not exceed 2.5 mg.
APPLICATION FOR CHILDREN
Caution should be used in children and adolescents under the age of 18 years (efficacy and safety not established).
APPLICATION IN ELDERLY PATIENTS
Caution should be used in elderly patients, in children and adolescents under the age of 18 (efficacy and safety not established).
During treatment with Hartil В® , regular medical supervision is necessary.
After taking the first dose, as well as increasing the dose of a diuretic and / or Hartil, patients should stay for 8 hours under the supervision of a doctor to avoid the development of an uncontrolled hypotensive reaction; a multiple measurement of blood pressure is recommended.
If possible, adjust the dehydration, hypovolemia, reduce the number of red blood cells before starting the drug. If these disorders are severe, taking ramipril should not begin or continue until measures are taken to prevent excessive fall in blood pressure and impaired renal function.
Careful observation is required for patients with renal vascular disease (eg, clinically insignificant stenosis of the renal artery or hemodynamically significant stenosis of the artery of a single kidney), impaired renal function, with a marked decrease in blood pressure, mainly in patients with heart failure, and also after kidney transplantation.
Impaired renal function can be identified by elevated levels of urea and serum creatinine, especially if the patient takes diuretics.
Due to a decrease in the synthesis of angiotensin II and the secretion of aldosterone in the serum, a decrease in the sodium level and an increase in the level of potassium are possible. Hyperkalemia is more common in patients with impaired renal function (eg, with diabetic nephropathy) or with simultaneous admission with potassium-sparing diuretics.
In case of excessive decrease in blood pressure, the patient should be laid, raise his legs; it may also be necessary to administer fluid and other measures.
Changes in blood are more likely in patients with impaired renal function and concomitant connective tissue disease (eg, SLE and scleroderma), and in the case of other agents affecting hematopoietic and immune systems.
The serum sodium level should also be monitored regularly in patients taking diuretics concomitantly with Hartil В® . It should also regularly check the number of white blood cells to avoid the development of leukopenia. Control should be more frequent at the beginning of therapy and in patients belonging to any risk group.
There are reports of life-threatening anaphylactoid reactions, sometimes turning into shock, in patients on hemodialysis using membranes with high hydraulic permeability (for example, polyacrylonitrile) while concomitantly administering ACE inhibitors. Anaphylactoid reactions were also observed in patients subjected to LDL apheresis with absorption of dextran sulfate.
If desensitizing therapy undertaken to reduce allergic reactions to insect stings (e.g., bees and wasps), while taking ACE inhibitors may be severe, life-threatening anaphylactoid reaction (drop in blood pressure, respiratory distress, vomiting, cutaneous reactions). Therefore ACE inhibitors should not be given to patients receiving desensitizing therapy.
In lactase deficiency, galactosemia or malabsorption syndrome glucose / lactose should be noted that each tablet formulation Hart В® contains lactose following amounts: tablets of 5 mg - 96.47 mg, tablets of 10 mg - 193.2 mg.
Use in Pediatrics
Experience ramipril in children with severe renal impairment (creatinine clearance <20 mL / min / 1.73 m 2 body surface area) during dialysis and - is limited.
Impact on the ability to drive vehicles and manage mechanisms
At the beginning of the treatment of blood pressure reduction may affect the ability to concentrate. In this case, patients are advised to refrain from driving motor vehicles and activities potentially hazardous activities that require high concentration and psychomotor speed reactions. Subsequently degree limit is determined for each patient individually.
Symptoms: marked reduction of blood pressure, bradycardia, shock, disruption of water and electrolyte balance, acute renal failure.
Treatment: in the case of light overdose - gastric lavage, administration of adsorbents and sodium sulfate (preferably within 30 minutes after administration).
In acute overdose: control and support of vital functions in the ICU; while lowering blood pressure - the introduction of catecholamine and angiotensin II. The patient should be put on the back with legs elevated position, to introduce additional quantities of fluid and sodium.
It is unknown whether ramipril accelerate excretion diuresis, hemofiltration and correction of the pH of urine. This should be taken into account when considering the possibility of hemodialysis and hemofiltration.
When applied simultaneously with allopurinol Hart, corticosteroids, procainamide, cytostatics and other substances that cause changes in the blood, the risk of disturbances on the part of the hemopoietic system.
When applied simultaneously with Hart hypoglycaemic drugs (insulin or sulfonylurea derivatives) may excessive lowering blood glucose. This phenomenon may be related to the fact that ACE inhibitors may increase the sensitivity of tissues to insulin.
When applied simultaneously with other antihypertensive agents (including diuretics) or other agents having hypotensive effect (e.g., nitrates, tricyclic antidepressants, and anesthetics), may enhance the antihypertensive action.
Not recommended simultaneous with ramipril and potassium salts of potassium-sparing diuretics, heparin because of the risk of hyperkalemia.
In an application with lithium therapy experienced higher concentration of lithium in blood serum, which leads to increased risk of cardio- and nephrotoxicity.
NSAID and reduce the effectiveness of sodium salts of ACE inhibitors.
Ramipril can enhance the effects of ethanol.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children at a temperature of no higher than 25 В° C. Shelf life - 2 years.