Expiration date: 08/2025

The composition and form of issue:

Tablets 1 tablet contains:

ramipril 5 or 10 mg

auxiliary substances: sodium hydrogen carbonate lactose monohydrate starch 1500 Pregelatinised sodium croscarmellose sodium stearyl fumarate tablets 2.5 mg also contain iron oxide yellow, and the tablets 5 mg — iron oxide red, iron oxide yellow 

in e blisters 7 PC. in the stack cartons 2, or 4 blisters (for 14 or 28 pieces).

Description pharmaceutical form:

Tablets 5 mg: light pink or orange-pink, perhaps with a marble surface is flat, oval, with facet, scored and engraved "R3" on one side of the pill and the risks on the side surfaces.

Tablets 10 mg: white or almost white, flat, oval, with facet, scored and engraved "R4" — on one side of the pill and the risks on the side surfaces.

Pharmacokinetics:

After intake of rapidly absorbed from the gastrointestinal tract. Cmax in plasma achieved within 1 h. the Extent of absorption is at least 50-60% of the administered dose. Almost completely metabolised (mainly in liver) with the formation of active and inactive metabolites.

Its active metabolite — ramiprilat — inhibits the activity of ACE is approximately 6 times stronger than ramipril. Cmax of ramiprilat in plasma achieved through 2-4 h. Among the known active metabolites — dicketopeperazinovykh ether, diketopiperazine acid and the glucuronide of ramipril and ramiprilat.

The binding of ramipril and ramiprilat from plasma proteins is about 73 and 56%, respectively. When taking usual doses of 1 times a day equilibrium concentration of drug in plasma achieved by the 4th day of taking the drug.

T1/2 ramiprila — 5.1 CH, for ramiprilat is 13 to 17 h. Ramipril has a multi-phase pharmacokinetic profile. Once inside 60% dose excreted in the urine (mostly in the form of metabolites), and approximately 40% in the feces. Approximately 2% of the administered dose is excreted in the urine unchanged.

The excretion of ramipril, ramiprilat and inactive metabolites in the urine is reduced in renal failure (which increases the concentration of ramiprilat).

The loss of enzyme activity in the liver in violation of its function leads to slower conversion of ramipril to ramiprilat, which can cause increased levels of ramipril.

Description pharmacological action:

Ramipril inhibits ACE, resulting in (regardless of the activity of plasma renin) develops hypotensive effect (the position of the patient "lying" and "standing") without a compensatory increase in heart rate.

Inhibition of ACE activity decreases angiotensin II levels, which leads, in turn, to decreased secretion of aldosterone. Due to reduction in concentration of angiotensin II, by removing negative feedback is an increase in the activity of plasma renin. Ramipril acts on the enzyme circulating in the blood and in tissues, including vascular wall. Decreases in systemic vascular resistance or afterload, pulmonary capillary pressure (preload) increases cardiac output and increases tolerance to physical activity.

Long-term use ramipril promotes regression of myocardial hypertrophy in patients with arterial hypertension.

Ramipril reduces the incidence of arrhythmias during myocardial reperfusion injury, improves blood flow to the ischemic myocardium.

Ramipril prevents the breakdown of bradykinin and stimulates the formation of nitric oxide (NO) in the endothelium.

The antihypertensive effect begins in 1-2 h after administration of the drug inside, the maximum effect develops over 3-6 hours and lasts for 24 h. With daily use the antihypertensive effect increases within 3-4 weeks and maintained during long-term therapy (1-2 years).

Antihypertensive efficacy does not depend on gender, age and body weight of the patient. In patients with acute myocardial infarction ramipril limit the spread of necrosis, improves prognosis of life reduces mortality in the early and remote periods of myocardial infarction, the incidence of repeat heart attacks reduces the severity of symptoms of heart failure, slows progression. With prolonged ingestion (not less than 6 months), reduces the degree of pulmonary hypertension in patients with congenital and acquired heart defects.

Ramipril lowers blood pressure in the portal Vienna in portal hypertension slows microalbuminuria (early stage) and worsening renal function in patients with severe diabetic nephropathy. In non-diabetic nephropathy accompanied by proteinuria (over 3 g/day) and renal insufficiency slows down further deterioration of renal function, reduce proteinuria, the risk increase in creatinine or development of ESRD.

Indications:

• hypertension
  
• chronic heart failure
  
• heart failure after acute myocardial infarction in patients with stable hemodynamics
  
• diabetic nephropathy and chronic diffuse renal disease (non-diabetic nephropathy)
  
• reduction in the risk of myocardial infarction, stroke or "coronary death" in patients with CHD, including patients, after myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting.
  

Contraindications:

• hypersensitivity to ramipril or any component of the drug
  
• a history of angioedema, including and associated with previous therapy with ACE inhibitors
  
• hemodynamically significant bilateral renal artery stenosis or stenosis of the artery to a solitary kidney
  
• hypotension or unstable hemodynamics
  
• pregnancy
  
• lactation
  
• primary hyperaldosteronism
  
• renal failure (Cl creatinine <20 ml/min).
  

With caution:

• hemodynamically significant aortic or mitral stenosis (the risk of excessive decline in blood pressure with subsequent impairment of renal function)
  
• heavy primary malignant hypertension
  
• severe lesions of coronary and cerebral arteries (risk of flow reduction in the excessive decline in AD)
  
• unstable angina, severe ventricular arrhythmias, end-stage CHF, asthma "pulmonary" heart
  
• diseases, requiring the appointment of SCS and immunosuppressants (the lack of clinical experience), including systemic diseases obedinitelej fabric
  
• renal and/or hepatic insufficiency
  
• hyperkalemia, hyponatremia (including dioretikov and diet with restriction of consumption of Na+)
  
• primary or pronounced symptoms of deficiency of fluid and electrolytes
  
• state, accompanied by a decrease in BCC (W. diarrhea, vomiting)
  
• diabetes
  
• inhibition of bone marrow hematopoiesis
  
• condition after kidney transplantation
  
• old age
  
• the age of 18 years (efficacy and safety not established).
  

Side effects:

From the circulatory system: reducing AD, ortostatical gipotenzia, tachycardia, rarely — arrhythmia, enhancing circulatory disorders of organs caused by narrowing of the blood vessels. If excessive decline in AD, mainly in patients with coronary artery disease and clinically significant narrowing of the blood vessels of the brain, can develop myocardial ischemia (angina or myocardial infarction) and brain ischemia (perhaps with dynamic cerebrovascular accident or stroke).

From the urogenital system: development or increased renal disease, strengthening the existing proteinuria, decrease in urine (at the beginning of the drug), decreased libido.

CNS: dizziness, headache, weakness, drowsiness, paresthesia, nervous anxiety, anxiety, tremors, muscle spasms, mood disturbances when used in high doses — insomnia, anxiety, depression, confusion, fainting.

From the sensory organs: vestibular disorders, breach of taste (e.g. metallic taste), smell, hearing and vision, tinnitus.

From the digestive system: nausea, vomiting, diarrhoea or constipation, epigastric pain, dry mouth, thirst, decreased appetite, stomatitis, hypersensitivity or inflammation of the buccal mucosa, pancreatitis, rarely — hepatitis, cholestatic jaundice, abnormal liver function with the development of acute liver failure.

The respiratory system: dry cough, bronchospasm (in patients with increased excitability of the cough reflex), dyspnea, rhinorrhea, rhinitis, sinusitis, bronchitis.

Allergic reactions: skin rash, itching, urticaria, conjunctivitis, photosensitivity, rarely — angioedema of face, extremities, lips, tongue, pharynx or larynx, exfoliative dermatitis, erythema multiforme exudative (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), pemphigus (pemphigus), serozit, onycholysis, vasculitis, myositis, myalgia, artralgia, arthritis, eosinophilia.

From the side of blood: anemia, reduction in hemoglobin concentration and hematocrit, thrombocytopenia, leukocytopenia, neutropenia, agranulocytosis, pancytopenia, hemolytic anemia. It is possible to reduce the number of red blood cells, bone marrow depression.

Other: seizures, alopecia, hyperthermia, change in sweating.

Laboratory parameters: gipercreatininemia, increased levels of urea nitrogen, increase in liver transaminases, hyperbilirubinemia, hyperkalemia, hyponatremia, very rarely — increased titer of antinuclear factor.

Effects on the fetus: impaired development of the kidneys of the fetus, reducing AD the fetus and newborn, violation of the kidney, hyperkalemia, hypoplasia of the skull, oligohydramnios, contracture of the limbs, deformation of the skull, hypoplasia of the lungs.

Drug interactions:

Allopurinol, corticosteroids, procainamide, cytostatics and other substances, causing changes in blood increased risk of disorders of the hematopoietic system.

Antidiabetic drugs (insulin or sulfonylurea derivatives): excessive reduction of blood sugar level. This phenomenon may be related to the fact that ACE inhibitors may increase tissue sensitivity to insulin.

Antihypertensive agents (e.g. diuretics) or other agents having antihypertensive action (e.g. nitrates, tricyclic antidepressants and anesthetics): may increase antihypertensive effect.

Potassium salts and potassium-sparing diuretics, heparin: it is not recommended simultaneous reception of with ramipril because of the risk of development of hyperkalemia.

Lithium salts: increased levels of lithium in the blood serum increases the risk of cardio - and nephrotoxicity.

NSAIDs and sodium salt: reduce the effectiveness of ACE inhibitors.

Membranes with high hydraulic permeability and dextran sulfate: there are reports of life-threatening anaphylactoid reactions, sometimes turning into shock, in patients on hemodialysis with the use diaphragms with high hydraulic permeability (for example, from polyacrylonitrile) simultaneous administration of ACE inhibitors. Anaphylactoid reactions also have been observed in patients undergoing LDL apheresis with absorption of dextran sulfate.

When desensitizing therapies to reduce allergic reactions to insect bites (e.g. bees and wasps) while receiving ACE inhibitors can cause severe, life-threatening anaphylactoid reaction (drop in blood pressure, breathing problems, vomiting, skin reactions). Therefore, ACE inhibitors do not give patients receiving desensitizing therapy.

Alcohol: ramipril may enhance the effects of alcohol.

Method of application and dose:

Inside, without chewing, drinking plenty of fluids (about 1 Cup), regardless of mealtime.

Quantity must be determined for each patient individually, taking into account the therapeutic effect and tolerability. Tablets can be split in half, breaking at risk.

Hypertension. The recommended starting dose of 2.5 mg 1 time per day. Depending on the therapeutic effect, the dose can be increased, doubling the daily dose every 2-3 weeks. The usual maintenance dose is 2.5–5 mg a day. The maximum daily dose should not exceed 10 mg.

Chronic heart failure. The recommended initial dose is 1.25 mg 1 times a day. Depending on the therapeutic effect, the dose can be increased, doubling the daily dose every 2-3 weeks. If necessary, taking more than 2.5 mg, the dose can be taken once or divided into 2 doses. The maximum daily dose should not exceed 10 mg.

Treatment after myocardial infarction. The drug is recommended to start on the 3rd-10th day after acute myocardial infarction. The recommended starting dose, depending on patient's condition and the time elapsed after acute myocardial infarction is 2.5 mg 2 times a day. Depending on the therapeutic effect, the initial dose can be doubled to 5 mg 2 times a day. The maximum daily dose should not exceed 10 mg. In case of intolerance of the drug dose should be reduced.

Non-diabetic or diabetic nephropathy. The recommended initial dose is 1.25 mg 1 times per day. Depending on the therapeutic effect, the dose can be increased, doubling the daily dose every 2-3 weeks. If necessary, taking more than 2.5 mg, the dose can be taken once or divided into two doses. The recommended maximum daily dose of 5 mg.

Prevention of myocardial infarction, stroke or death from cardiovascular disorders. The recommended starting dose of 2.5 mg once a day . Depending on tolerability of the drug, after 1 week the dosage should be increased twice in comparison with initial. This dose should be re-doubled after 3 weeks of admission. The recommended maintenance dose — 10 mg 1 time per day.

Special groups of patients

Elderly patients. The use of ramipril in elderly patients receiving diuretics and/or heart failure, and disorders of the liver or kidneys requires special attention. The dosage should be set for the individual selection of doses, depending on the reaction to the drug.

Patients with renal insufficiency. With moderate impairment of renal function (Cl creatinine from 20 to 50 ml/min based on 1.73 m2) initial dose is usually 1.25 mg 1 times per day. The maximum daily dose should not exceed 5 mg.

If creatinine clearance is not measured, it is possible to calculate the level of serum creatinine with the use of equations Cockroft (Cockroft):

For men: creatinine clearance, ml/min = mass of body, kg·(140?age)/72·serum creatinine in mg/DL.

For women: the result of the calculation by the above equation multiplied by 0.85.

Violations liver function. When disorders of liver function may be observed equally often reduced or an increased effect of the drug was Hartil, so in the early stages of treatment, patients with impaired liver function need careful medical supervision. The maximum daily dose in such cases should not exceed 2.5 mg.

Patients receiving diuretic therapy because of the risk of a significant reduction in AD should consider suspending or at least lowering the dose dioretikov, at least 2-3 days (or longer, depending on the duration of action of diuretics) before you start taking drug Hartil. For patients previously treated with diuretics, the usual starting dose is 1.25 mg.

Overdose:

Symptoms: expressed lower AD, aetiology, shock, violation vodno-elektrolitnogo balance, acute renal failure.

Treatment: in the case of mild overdose — gastric lavage, introduction of adsorbents and sodium sulfate (preferably within 30 min after administration).

In acute overdose: monitoring and maintaining vital functions in the conditions of intensive therapy in reducing AD — introduction of catecholamines and angiotensin II. The patient should be laid on his back with the exalted position of the legs shows the introduction of additional quantities of fluid and sodium.

It is unknown whether speed up the excretion ramiprila forced diuresis, hemofiltration and correction of urine pH. This should be considered when considering hemodialysis and hemofiltration (see section "Contraindications").

Special instructions:

While drug treatment has Hartil requires regular medical control.

After the first dose and with increasing dose of diuretic effectively delivered and/or drug Hartil patients should be within 8 h under medical supervision in order to avoid the development of uncontrolled hypertensive reactions, it is recommended that repeated measurement of blood pressure.

If possible, you should correct dehydration, hypovolemia, a decrease in the number of red blood cells before administration of the drug. If these violations are severe, the reception ramiprila should not start or continue until the adoption of measures to prevent excessive drop in blood pressure and impaired renal function.

Careful observation is required in patients with lesions of the renal vessels (for example, clinically insignificant stenosis of the renal artery or hemodynamically significant stenosis of the artery only kidneys), impaired renal function, in severe decline AD, mainly in patients with heart insufficiency and after renal transplantation.

The impairment of renal function can be identified by elevated levels of urea and creatinine of blood serum, especially if the patient is taking diuretics.

Due to the reduced synthesis of angiotensin II and secretion of aldosterone, in the blood serum may decrease sodium levels and increase potassium levels. Hyperkalemia is more common when renal impairment (e.g. diabetic nephropathy) or simultaneous intake with potassium-sparing diuretics.

In the case of excessive loss AD patient should be placed and to lift the lower limbs may also require the introduction of fluids and other measures.

Changes blood more likely in patients with impaired renal function and concomitant connective tissue disease (e.g. systemic lupus erythematosus and scleroderma), and in the case of other agents that affect hematopoietic and immune system. The level of sodium in blood serum should also be checked regularly in patients taking diuretics concurrently with the drug Hartil. You should also regularly check the number of white blood cells to prevent the development of leukopenia. Monitoring should be more frequent at the beginning of therapy and in patients belonging to any risk group.

With lactase deficiency, galactosemia or malabsorption syndrome glucose/lactose should note that each tablet of the drug was Hartil contains the following amounts of lactose: tablets 5 mg — 96,47 mg, tablets 10 mg — 193,2 mg.

Membranes with high hydraulic permeability and dextran sulfate: there are reports of life-threatening anaphylactoid reactions, sometimes turning into shock, in patients on hemodialysis with the use diaphragms with high hydraulic permeability (for example, from polyacrylonitrile) simultaneous administration of ACE inhibitors. Anaphylactoid reactions also have been observed in patients undergoing LDL apheresis with absorption of dextran sulfate.

Experience of applying ramiprila in children, patients with severe renal insufficiency (Cl creatinine less than 20 ml/min/1.73 m2) and in patients during dialysis is limited.

The effect on driving vehicles and activities potentially hazardous activities. At the beginning of treatment decrease in blood pressure can affect the ability of concentration. In this case, patients are advised to refrain from driving vehicles and activities potentially hazardous activities, require high concentration and psychomotor speed reactions. In the future, the degree of restriction is determined for each patient individually.