XARTIL

Active material: Ramipril
When ATH: C09AA05
CCF: ACE inhibitor
ICD-10 codes (testimony): I10, I21, I50.0, I61, I63, N03, N08.3
When CSF: 01.04.01.03
Manufacturer: EGIS PHARMACEUTICALS Plc (Hungary)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Pills yellow or light yellow, possibly with a marble surface, Oval, flat, chamfered, risks and engraving “R2” on one side; with the risk on side surfaces.

Excipients: natriya carbonate, lactose monohydrate, pre-gelatinized starch 1500, Croscarmellose sodium, sodium fumarate, iron oxide yellow.

7 PC. – blisters (2) – packs cardboard.
7 PC. – blisters (4) – packs cardboard.

Pills light pink or salmon-colored, possibly with a marble surface, Oval, flat, chamfered, risks and engraving “R3” on one side; with the risk on side surfaces.

Excipients: natriya carbonate, lactose monohydrate, pre-gelatinized starch 1500, Croscarmellose sodium, sodium fumarate, iron oxide yellow, iron oxide red.

7 PC. – blisters (2) – packs cardboard.
7 PC. – blisters (4) – packs cardboard.

Pills white or nearly white, Oval, flat, chamfered, risks and engraving “R4” on one side; with the risk on side surfaces.

Excipients: natriya carbonate, lactose monohydrate, pre-gelatinized starch 1500, Croscarmellose sodium, sodium fumarate.

7 PC. – blisters (2) – packs cardboard.
7 PC. – blisters (4) – packs cardboard.

Pharmacological action

Antihypertensive drugs, ACE inhibitor. As a result of inhibiting the activity of ACE (independently of plasma renin activity) developing hypotensive effect (with the patient lying down and standing up) without any compensatory increase in heart rate.

Inhibition of ACE activity increases plasma renin activity in blood, reduces levels of angiotensin II and aldosterone. Ramipril effect on ACE, circulating in the blood and in tissues being, incl. in the vascular wall. Decreases round (afterload), the pressure in the pulmonary capillaries (preload); increases cardiac output and increases exercise tolerance.

With prolonged use of ramipril promotes regression of myocardial hypertrophy in patients with hypertension.

Ramipril reduces the incidence of arrhythmias during reperfusion; It improves blood flow to the ischemic myocardium.

Ramipril prevents the breakdown of bradykinin, and stimulates the production of nitric oxide (NO) endothelium.

The antihypertensive effect begins 1-2 hours after oral administration, the maximum effect develops within 3-6 h and maintained for a 24 no. With daily use of anti-hypertensive effect is enhanced for 3-4 weeks and persist long-term treatment (1-2 year). Antihypertensive efficacy does not depend on gender, age and body weight of the patient.

In patients with acute myocardial infarction ramipril zone limits the spread of necrosis, improves the prognosis of life; reduces mortality in the early and late period of myocardial infarction, the incidence of reinfarction; reduces the severity of symptoms of heart failure, slows its progression.

Chronic administration (no less 6 Months) reduces the degree of pulmonary hypertension in patients with congenital and acquired heart defects.

Ramipril reduces the pressure in the portal vein in portal hypertension; retards microalbuminuria (in initial stages) and deterioration of renal function in patients with severe diabetic nephropathy. In nediabeticheskoy nephropathy, accompanied by proteinuria (more 3 g / day) and renal insufficiency, slows down further deterioration of renal function, reduces proteinuria, It reduces the risk of increased serum creatinine or end-stage renal failure development.

Pharmacokinetics

Ramipril has pharmacokinetic profile multiphase.

Absorption

After oral administration ramipril is rapidly absorbed from the gastrointestinal tract. The extent of absorption – no less 50-60% of the administered dose. C_max plasma levels reached within 1 no.

Distribution and metabolism

Almost completely metabolized (primarily – liver) to form active and inactive metabolites. Its active metabolite – ramiprilat inhibits ACE activity around 6 times stronger, Cem ramipril. C_max ramiprilata in plasma achieved through 2-4 no. Among the known active metabolites – diketopiperazine ether, diketopiperazine acid, and takzhe glyukuronidы ramipril and ramiprilata.

Ramipril and ramiprilat binding to plasma proteins is approximately 73% and 56% respectively.

When taken in normal doses 1 time / day C_ss ramipril plasma levels achieved in 4 day dosing.

Deduction

T_1/2 ramiprila – 5.1 no, T_1/2 ramiprilata 13-17 no.

Once inside 60% the dose is excreted in the urine (mainly in the form of metabolites) and about 40% – with feces. About 2% of the administered dose excreted in urine as unchanged.

Pharmacokinetics in special clinical situations

Withdrawal ramipril, ramiprilata and inactive metabolites in the urine is reduced in renal failure (which leads to an increase in their concentration).

Reduction in liver enzyme activity in violation of its function slows down the conversion of ramipril to ramiprilat, which may cause an increased concentration in the blood plasma ramipril.

Testimony

- Arterial hypertension;

- Congestive heart failure;

- Chronic heart failure after acute myocardial infarction in patients with stable hemodynamics;

- Diabetic nephropathy and chronic kidney disease diffuse (nediabeticheskaya nephropathy);

- To reduce the risk of myocardial infarction, stroke or coronary death in patients at high cardiovascular risk with coronary artery disease, including patients, myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting.

Dosage regimen

The tablets should be taken orally, swallowing them whole, without chewing, drinking plenty of fluids (about 1 glass). The tablets can be divided in half, by breaking a risk. Tablets can be taken regardless of mealtime. Dose set individually according to the therapeutic effect and tolerability.

At hypertension The recommended starting dose is 2.5 mg 1 time / day (daily 1 tab. 2.5 mg). Depending on the therapeutic effect of the dose can be increased, doubling the daily dose every 2-3 of the week. Standard maintenance dose is 2.5-5 mg / day (1 tab. 2.5 mg or 1 tab. 5 mg). The maximum daily dose is 10 mg.

At chronic heart failure The recommended starting dose is 1.25 mg 1 time / day (daily 1/2 tab. Xartila^®2.5 mg). Depending on the therapeutic effect of the dose can be increased, doubling the daily dose every 2-3 of the week. If necessary, the drug in a dose of 2.5 mg, this dose can be administered once or divided into 2 admission. The maximum daily dose is 10 mg.

To after treatment of myocardial infarction the drug is recommended to start on 3-10 day after acute myocardial infarction. The recommended starting dose, depending on the patient and the time, elapsed after acute myocardial infarction, amounts to 2.5 mg 2 times / day (1 tab. 2.5 mg 2 times / day). Depending on the therapeutic effect of an initial dose can be doubled to 5 mg (2 tab. by 2.5 mg or 1 tab. 5 mg) 2 times / day. The maximum daily dose – 10 mg. At intolerance of the drug dose should be reduced.

At non-diabetic or diabetic nephropathy The recommended starting dose – 1.25 mg (1/2 tab. 2.5 mg) 1 times / day every day. Depending on the therapeutic effect of the dose can be increased, doubling the daily dose every 2-3 of the week. If you want to receive more 2.5 mg dose that can be administered once or divided into 2 admission. The recommended maximum daily dose – 5 mg.

With the aim of prevention of myocardial infarction, stroke or death from cardiovascular disorders The recommended starting dose – 2.5 mg 1 time / day. Depending on the tolerability, through 1 receiving week dose should be increased to twice its initial. This dose should be re-doubled after 3 weeks of. The recommended maintenance dose – 10 mg 1 time / day.

Elderly patients, receiving diuretics and / or cardiac failure, as well as violations of the liver or the kidneys the dose should be adjusted by individual selection, depending on the patient's response to treatment.

Patients with renal insufficiency requires correction mode. At moderate renal impairment (KK from 20 to 50 ml / min per 1.73 m² body surface) Initial dose is usually 1.25 mg 1 time / day (1/2 tab. 2.5 mg). The maximum daily dose – 5 mg.

If CC is not measured, it can be calculated from serum creatinine using the Cockcroft.

For men:

CC (ml / min) = (140 – age) x body weight (kg)/72 x serum creatinine (mg / dL)

For women: the calculation result should be multiplied by 0.85.

At hepatic dysfunction could equally often observed decrease or increase the effect of the drug Hart^®, so in the early stages of the treatment of these patients requires careful medical supervision. The maximum daily dose in these cases – 2.5 mg.

In patients, receiving diuretic therapy, because of the risk of a significant reduction in blood pressure should be considered a temporary cancellation or at least reduction of the dose of diuretics at least 2-3 day (or longer, depending on the duration of action of diuretics) prior to receiving the Charter^®. For patients, previously treated with diuretics, usual starting dose is 1.25 mg.

Side effect

Cardio-vascular system: decrease in blood pressure, orthostatic hypotension, tachycardia; rarely – arrhythmia, strengthening of circulatory disorders, induced vasoconstriction. If excessive decline in ad, mainly in patients with clinically significant coronary artery disease and narrowing of the blood vessels of the brain, may develop myocardial ischaemia (angina pectoris or myocardial infarction) and brain ischemia (Perhaps with dynamic violation of cerebral circulation or stroke).

From the urinary system: the development or enhancement of renal failure, strengthening existing proteinuria, decrease in urine (at the beginning of the drug).

From the central and peripheral nervous system: dizziness, headache, weakness, drowsiness, paresthesia, nervous anxiety, anxiety, tremor, muscle spasm, mood disorders; when used in high doses – insomnia, anxiety, depression, confusion, swoon.

From the senses: vestibular disorders, taste disturbances (eg, metallic taste), olfactory, hearing and vision, noise in ears.

From the digestive system: nausea, vomiting, diarrhea 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), breathlessness, rhinorrhea, rhinitis, sinusitis, bronchitis.

From the side of hematopoiesis: anemia, reduction of the concentration of hemoglobin and hematocrit, thrombocytopenia, leukopenia, neutropenia, agranulocytosis, pancytopenia, gemoliticheskaya anemia, reduction in the number of red blood cells, suppression of bone marrow hematopoiesis.

From the laboratory parameters: giperkreatininemiя, increased BUN, increase in liver transaminases, giperʙiliruʙinemija, hyperkalemia, giponatriemiya; rarely – increasing titer antinuclear factor.

Allergic reactions: skin rash, itch, hives, conjunctivitis, photosensitivity; rarely – angioneurotic edema of the face, limbs, lips, language, pharynx or larynx, exfoliative dermatitis, erythema multiforme exudative (incl. Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), pemphigus (pemphigus), serositis, onycholysis, vasculitis, myositis, myalgia, arthralgia, arthritis, eozinofilija.

Other: alopecia, hyperthermia, sweating.

Contraindications

- A history of angioedema, incl. associated with previous therapy, ACE inhibitors;

- Hemodynamically significant bilateral renal artery stenosis or stenosis of the artery to a solitary kidney;

- Hypotension or unstable hemodynamics;

- Pregnancy;

- Lactation (breast-feeding);

- Primary hyperaldosteronism;

- Renal failure (CC<20 ml / min);

- Hypersensitivity to ramipril or any other component of the drug.

FROM caution used in hemodynamically significant stenosis of the aortic or mitral (the risk of excessive loss AD with consequent impairment of renal function); severe primary malignant hypertension; severe coronary lesions and cerebral arteries (the danger of reducing blood flow when excessive decline in ad), unstable angina, severe ventricular arrhythmias, end-stage heart failure, декомпенсированном pulmonary heart, for diseases, requiring the appointment of SCS and immunosuppressants (the lack of clinical experience) – incl. in systemic connective tissue diseases, severe renal and / or hepatic insufficiency, hyperkalemia, giponatriemii (incl. in patients receiving diuretics and diet restricted sodium intake), primary or expressed manifestations of deficiency of fluids and electrolytes; states, accompanied by a decrease in the bcc (incl. diarrhea, vomiting), diabetes, suppression of bone marrow hematopoiesis, condition after kidney transplantation, in elderly patients, in children and adolescents under the age of 18 years (efficacy and safety have not been established).

There is only limited experience in patients with ramipril, dialysis.

Pregnancy and lactation

Contraindicated for use in pregnancy and lactation.

The drug causes a disturbance of fetal renal, reduction in blood pressure of the fetus and newborn, impairment of renal function, hyperkalemia, skull hypoplasia, oligogidramnion, contracture limbs, deformation of the skull, pulmonary hypoplasia.

Cautions

During treatment with Hart^® requires regular medical monitoring.

After the first dose, as well as by increasing the dose of the diuretic and / or Charter^® Patients should be within 8 h under medical supervision in order to prevent uncontrolled development of hypotensive reactions; recommended repeated measurement of blood pressure.

If possible, correct the dehydration, gipovolemiю, reduction in the number of red blood cells prior to administration of the drug. If these violations are severe, ramipril should not start or continue to take action, warning excessive drop in blood pressure and renal failure.

Careful supervision is required in patients with lesions of the renal vessels (eg, clinically insignificant renal artery stenosis or hemodynamically significant stenosis of the renal artery only), impaired renal function, In marked decrease in blood pressure, mainly in patients with heart failure, and after kidney transplantation.

Kidney damage can be detected at high levels of urea and serum creatinine, especially if the patient is taking diuretics.

Due to the reduction of synthesis of angiotensin II and aldosterone in the blood serum can reduce sodium and increase potassium levels. Hyperkalemia is more common in kidney function (eg, diabetic nephropathy) or concomitantly with potassium-sparing diuretics.

In case of excessive reduction of blood pressure of the patient should be put, Raise legs; It may also require fluid management and other measures.

Changes in the blood more likely to occur in patients with impaired renal function and concomitant disease of the connective tissue (eg, SLE and scleroderma), and in case of other means, affecting the hematopoietic and immune system.

Sodium levels in serum should also regularly monitor patients, taking diuretics concurrently with the preparation of the Charter^®. It should also regularly check the number of white blood cells to avoid the development of leukopenia. Monitoring should be more frequent at the beginning of therapy and in patients, belonging to any risk.

Experience with ramipril in patients with severe renal insufficiency (CC<20 ml / min / 1.73 m² body surface) and patients during dialysis is limited.

There are reports of life-threatening anaphylactoid reactions, sometimes passing into shock, in patients on hemodialysis using membranes with high hydraulic permeability (eg, from polyacrylonitrile) simultaneous introduction of ACE inhibitors. Anaphylactoid reactions have also been reported in patients, LDL apheresis exposed to dextran sulfate absorption.

When desensitizing therapy, undertaken to reduce allergic reactions to insect stings (eg, bees and wasps), while receiving ACE inhibitors may be severe, life-threatening anaphylactoid reactions (drop in blood pressure, respiratory failure, vomiting, skin reactions). Therefore, ACE inhibitors should not be given to patients, receiving desensitizing therapy.

When lactase deficiency, galactosemia or glucose malabsorption syndrome / lactose should be considered, that each tablet formulation Hart^® It contains the following amounts of lactose: for tablets 1.25 mg contain 79.5 Lactose mg, for tablets 2.5 mg - 158.8 mg, for tablets 5 mg - 96.47 mg, for tablets 10 mg - 193.2 mg.

Use in Pediatrics

Experience ramipril in children with severe renal insufficiency (CC<20 ml / min / 1.73 m² body surface) and during dialysis – limited.

Effects on ability to drive vehicles and management 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 vehicles and Occupation potentially hazardous activities, require high concentration and speed of psychomotor reactions. Subsequently, the degree of restriction is determined for each patient individually.

Overdose

Symptoms: marked reduction in blood pressure, bradycardia, shock, disruption of water and electrolyte balance, acute renal failure.

Treatment: in the case of mild overdose – gastric lavage, administration of adsorbents and sodium sulphate (preferably within 30 minutes after administration).

In acute overdose: monitoring and support of vital functions in the ICU; with a decrease in blood pressure – administration of catecholamines and angiotensin II. The patient should be put on his back with legs elevated position, adding additional fluid and sodium.

Unknown, Whether accelerate the excretion of ramipril forced diuresis, hemofiltration and correction of urinary pH. This should be taken into account when considering the possibility of hemodialysis and hemofiltration.

Drug Interactions

In an application of the Charter^® with allopurinol, kortikosteroidami, prokaynamydom, cytostatics and other substances, cause changes in the blood, increases the risk of violations of the hematopoietic system.

In an application of the Charter^® with hypoglycemic drugs (insulin or sulfonylurea derivatives) possible excessive reduction of blood sugar levels. This phenomenon can be explained by the fact, ACE inhibitors can improve insulin sensitivity.

When applied simultaneously with other antihypertensive agents (incl. with diuretics) or other means, having hypotensive effect (eg, nitrates, tricyclic antidepressants and anesthetics): may increase the antihypertensive effect.

Not recommended simultaneous with ramipril potassium salts and potassium-sparing diuretics, heparin because of the risk of hyperkalemia.

In an application with lithium observed increase in the concentration of lithium in blood serum, which leads to an increased risk of cardio- and nephrotoxicity.

NSAIDs and sodium reduce the effectiveness of ACE inhibitors.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored at temperatures below 25 ° C out of reach of children. Shelf life – 2 year.