Dilasprel® Plus (Dilaprel® Plus)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Dosage form: & nbspTOthe apsules.
Composition:

One capsule contains:

Dosage of 0.625 mg + 2.5 mg

active ingredients: indapamide - 0.625 mg; ramipril - 2,500 mg;

Excipients: lactose monohydrate - 143,875 mg; silicon dioxide colloidal - 1,500 mg; calcium stearate - 1,500 mg;

hard gelatine capsules: body: titanium dioxide - 2.0%, gelatin - up to 100%; lid: titanium dioxide 1.0%, iron dye oxide yellow (iron oxide) 1.7143%, indigo carmine dye 0.3%, gelatin 100%.

Dosage of 1.25 mg + 5 mg

active ingredients: indapamide - 1,250 mg; ramipril - 5.000 mg:

Excipients: lactose monohydrate - 140.750 mg; silicon dioxide colloidal - 1,500 mg; calcium stearate - 1,500 mg;

hard gelatine capsules: titanium dioxide - 2.0%, gelatin - up to 100%.

Description:

Hard gelatin capsules №3 with white body and lid green (dosage 0,625 mg + 2,5 mg) or white (dosage 1,25 mg +5 mg).

The contents of the capsules are a powder or compacted mass of white or almost white color, disintegrating when pressed.

Pharmacotherapeutic group:antihypertensive agent combined (diuretic + ACE inhibitor)
Pharmacodynamics:

Combined antihypertensive drug containing diuretic from the group of sulfonamide derivatives - indapamide and an angiotensin-converting enzyme (ACE) inhibitor - ramipril. The pharmacological action of the combination is due to a combination of the individual properties of each of the components, which in turn enhance each other's action. The drug has antihypertensive, diuretic and vasodilating effects.

DILAPREL® PLUS has a pronounced dose-dependent antihypertensive effect on both systolic and diastolic blood pressure (BP). The antihypertensive effect does not depend on the age and position of the patient's body. Does not affect the metabolism of lipids and carbohydrates, including in patients with diabetes mellitus.

The antihypertensive effect persists for 24 hours.

A stable decrease in blood pressure is achieved within 1 month against the background of using the drug DILAPREL® PLUS without increasing the heart rate (HR). Termination of treatment does not lead to the development of the "withdrawal" syndrome.

Indapamide

Indapamide refers to sulfonamide derivatives with an indole ring and by pharmacological properties is similar to thiazide diuretics that inhibit the reabsorption of sodium ions in the cortical segment of the nephron loop. This increases the release of kidney ions of sodium, chlorine and, to a lesser extent, the ions of potassium and magnesium, which is accompanied by an increase in diuresis and antihypertensive effect. Indapamide reduces the tone of the smooth muscles of the arteries and has a vasodilating effect, reduces the overall peripheral resistance of the vessels (OPSS). These effects are mediated by a decrease in the reactivity of the vascular wall to norepinephrine and angiotensin II; an increase in the synthesis of prostaglandin E2, which has vasodilator activity; suppression of calcium current in smooth muscle cells of blood vessels.

Indapamide reduces the hypertrophy of the left ventricle of the heart.

Indapamide in monotherapy in doses that do not cause a pronounced diuretic effect, has a 24-hour antihypertensive effect. Antihypertensive activity of indapamide is associated with improving the elastic properties of large arteries, reducing arteriolar and general peripheral vascular resistance.

In short, medium duration and long-term studies involving patients with hypertension, it was shown that indapamide:

- does not affect the lipid metabolism, including the concentration of triglycerides, cholesterol, low density lipoprotein (LDL), and high-density lipoprotein (HDL);

- does not affect the metabolism of carbohydrates, including in patients with diabetes mellitus.

Ramipril

The active metabolite of ramipril-ramiprilate, formed under the influence of liver enzymes, is a long-acting inhibitor of ACE (synonyms: kininase II, dipeptidylcarboxydipeptidase I), which is peptidyl dipeptidase. ACE in the blood plasma and tissues catalyzes the conversion of angiotensin I into angiotensin II, which has a vasoconstrictive effect, and the breakdown of bradykinin, which has a vasodilating action. Therefore, when taking ramipril, the formation of angiotensin II decreases and the accumulation of bradykinin occurs, which leads to vasodilation and a decrease in blood pressure. The increased activity of the kallikrein-kinin system in blood and tissues causes cardioprotective and endothelioprotective action of ramipril due to activation of the prostaglandin system and, correspondingly, an increase in the synthesis of prostaglandins stimulating the formation of nitric oxide in endotheliocytes.

Angiotensin II stimulates the production of aldosterone, therefore, taking ramipril leads to a decrease in the secretion of aldosterone and an increase in the content of potassium ions in the blood plasma.

With a decrease in the concentration of angiotensin II in the blood, its inhibiting effect on renin secretion by negative feedback is eliminated, which leads to an increase in renin activity of the blood plasma.

It is assumed that the development of some unwanted reactions (in particular, dry cough) is also associated with an increase in bradykinin activity.

In patients with hypertension taking ramipril leads to a decrease in blood pressure in the "lying" and "standing" positions without a compensatory increase in heart rate. Ramipril significantly reduces OPSS, almost without causing changes in the renal blood flow and the rate of glomerular filtration.

Antihypertensive effect begins to appear 1-2 hours after ingestion of a single dose of ramipril, reaching the highest value in 3-6 hours, and persists for 24 hours. At the course of treatment, the antihypertensive effect can gradually increase, stabilizing usually to 3-4 weeks of regular intake of ramipril, and then persist for a long time. The sudden discontinuation of ramipril does not lead to a rapid and significant increase in blood pressure (the absence of the "withdrawal" syndrome).

In patients with hypertension ramipril slows the development and progression of myocardial hypertrophy and vascular wall.

In patients with a high risk of developing cardiovascular diseases due to vascular lesions (diagnosed coronary heart disease (CHD), obliterating diseases of the peripheral arteries in history, a stroke in the anamnesis) or diabetes with at least one additional risk factor (microalbuminuria, hypertension, increased total cholesterol concentration, lower HDL cholesterol concentration, smoking) the addition of ramipril to standard therapy significantly reduces the incidence of myocardial infarction, stroke, and mortality from cardiovascular causes. Besides, ramipril reduces the overall mortality rate, as well as the need for revascularization procedures, and slows the onset or progression of chronic heart failure.

In the general population of patients, as well as in patients with diabetes mellitus (both with arterial hypertension, and with normal BP indices), ramipril significantly reduces the risk of developing nephropathy and the occurrence of microalbuminuria.

Pharmacokinetics:

The combined use of indapamide and ramipril does not affect their pharmacokinetic indices compared to the use of these drugs in monotherapy.

Indapamide

Suction

The released indapamide quickly and completely absorbed in the gastrointestinal tract. Simultaneous intake of food slightly increases the time of absorption of indapamide, without affecting the completeness of absorption. The maximum concentration in blood plasma is achieved 1-2 hours after ingestion of a single dose of 2.5 mg. With repeated administration of fluctuations in the concentration of indapamide in blood plasma in the interval between doses of the drug are smoothed. There is an individual variability in indapamide absorption indices.

Distribution

About 79% of indapamide binds to blood plasma proteins and, due to the presence of high affinity for elastin, concentrates in the smooth muscles of the vascular walls. It also combines with the erythrocyte carboxyhydrase without inhibiting the activity of this enzyme.

Equilibrium concentration is achieved after 7 days of taking indapamide. When again taking indapamide, there is no cumulation.

Metabolism

Indapamide is metabolized in the liver.

Excretion

The half-life (T1/2) is from 14 to 24 hours (an average of 18 hours). It is excreted as inactive metabolites, mainly by the kidneys (60-80% of the dose) and through the intestine (22%). Not more than 5% Indapamide is excreted from the body by the kidneys in unchanged form.

Pharmacokinetics in specific patient groups

In patients with renal insufficiency, the pharmacokinetic parameters of indapamide do not change significantly.

Ramipril

Suction

After oral administration ramipril quickly absorbed from the gastrointestinal tract (50-60%). Simultaneous food intake slows down its absorption, but does not affect the completeness of absorption.

Distribution

Bioavailability for ramipril after oral administration 2.5-5 mg - 15-28%; for pomegranate - 45%. After taking ramipril inside, the maximum plasma concentrations of ramipril and ramiprilata are reached after 1 and 2-4 hours, respectively. After a daily intake of 5 mg / day, the stable concentration of ramiprilate in blood plasma is reached by day 4. The connection with blood plasma proteins for ramipril - 73%, ramiprilata - 56%.The volume of distribution of ramipril - 90 liters, ramiprilata - 500 liters.

Metabolism

In the liver, it is metabolized to form an active metabolite of ramiprilate (6 times more active inhibits ACE than ramipril) and inactive metabolites - diketopiperazine ether, diketopiperazic acid, as well as ramipril glucuronide and ramiprilate. All metabolites formed, except for ramiprilata. Pharmacological activity does not have.

Excretion

T1/2 for ramipril - 5.1 hours; in the phase of distribution and elimination, a decrease in the concentration of ramipril in the blood plasma occurs with T1/2, equal to 3 hours, followed by a transition phase with T1/2, equal to 15 hours, and a long final phase with very low concentrations of ramipril in plasma and T1/2, equal to 4-5 days.

T1/2 increases with chronic renal failure.

It is excreted by the kidneys - 60%, through the intestines - 40% (mainly in the form of metabolites).

Pharmacokinetics in specific patient groups

In healthy elderly volunteers (65-76 years old), the pharmacokinetics of ramipril and ramiprilate are not significantly different from that of young healthy volunteers.

If the renal function is impaired, excretion of ramipril and itsmetabolites slowed in proportion to a decrease in creatinine clearance (CC); when the liver function is impaired, the conversion into ramiprilat is slowed down; with heart failure, the concentration of ramiprilate increases 1.5-1.8 times.

Indications:

Arterial hypertension of mild to moderate severity.

Contraindications:

- Hypersensitivity to indapamide, ramipril, other ACE inhibitors, sulfonamide derivatives and excipients included in the preparation;

- angioedema in the anamnesis (hereditary or idiopathic, and also associated with previous therapy with ACE inhibitors);

- hemodynamically significant stenosis of the renal arteries (bilateral or unilateral, in the case of a single kidney);

- severe arterial hypotension or conditions with unstable hemodynamics;

- simultaneous use with angiotensin II receptor antagonists in patients with diabetic nephropathy;

- hemodynamically significant stenosis of the aortic or mitral valve, or hypertrophic obstructive cardiomyopathy (GOKMP);

- primary hyperaldosteronism;

- severe renal failure (CC less than 30 ml / min);

- hemodialysis;

- Nephropathy, the treatment of which is carried out by glucocorticosteroids, nonsteroidal anti-inflammatory drugs, immunomodulators and / or other cytotoxic drugs;

- chronic heart failure in the stage of decompensation (clinical experience is not enough);

- hemodialysis or hemofiltration using some membranes with a negatively charged surface, such as high-permeability membranes from polyacrylonitrile (the risk of developing hypersensitivity reactions);

- apheresis of LDL with the use of dextran sulfate (the risk of developing hypersensitivity reactions);

- conducting desensitizing therapy in reactions of hypersensitivity to poisons of Hymenoptera insects such as bees, wasps;

- simultaneous use of drugs containing aliskiren, in patients with diabetes mellitus and in patients with renal insufficiency (CC less than 60 ml / min);

- acute stage of myocardial infarction in patients with such diseases as:

  • severe chronic heart failure (IV functional class by classificationNYHA);
  • unstable angina;
  • life-threatening ventricular arrhythmias;
  • "pulmonary" heart;

- severe hepatic insufficiency (including with encephalopathy);

- hypokalemia;

- simultaneous use with drugs that can cause arrhythmia such as "pirouette";

- simultaneous reception of drugs that extend the interval QT (experience of clinical use is insufficient);

- simultaneous reception with potassium-sparing diuretics, potassium and lithium preparations and in patients with hyperkalemia;

- azotemia, anuria;

- lactose intolerance, lactase deficiency, glucose-galactose malabsorption;

- pregnancy, the period of breastfeeding;

- age to 18 years (efficacy and safety not established).

Carefully:

- Simultaneous use with drugs containing aliskiren, or angiotensin II receptor antagonists (with double blockade of the renin-angiotensin-aldosterone system (RAAS), there is an increased risk of a sharp decline in blood pressure, the development of hyperkalemia and impaired renal function);

- conditions in which excessive reduction in blood pressure is particularly dangerous (with atherosclerotic lesions of the coronary and cerebral arteries);

- severe arterial hypertension, especially malignant hypertension;

- chronic heart failure (III-IV functional class according to the NYHA classification);

- hemodynamically significant one-sided stenosis of the renal artery (in the presence of both kidneys) - in such patients, even a slight increase in the concentration of creatinine in the blood plasma can be a manifestation of unilateral impairment of renal function;

- previous administration of diuretics;

- decrease in the volume of circulating blood (BCC), disturbance of the water-electrolyte balance as a result of insufficient fluid intake, intake of large doses of diuretics, diets with restriction of table salt, diarrhea, vomiting, excessive sweating;

- impaired liver function (clinical experience is inadequate);

- diabetes mellitus (risk of hyperkalemia);

- renal dysfunction (KK 30-60 ml / min) (risk of hyperkalemia and leukopenia);

- condition after kidney transplantation;

- systemic connective tissue diseases (systemic lupus erythematosus, systemic scleroderma);

- oppression of bone marrow hematopoiesis;

- concomitant therapy with myelotoxic drugs, immunosuppressants, capable of causing changes in the picture of peripheral blood(possibly oppression of bone marrow hematopoiesis, development of neutropenia or agranulocytosis);

- Renovascular hypertension;

- hyperuricemia and gout;

- lability of blood pressure;

- hyperparathyroidism;

- interval increase QT on the ECG;

- elderly age over 65 years (risk of strengthening antihypertensive action);

- in patients of the Negroid race.

Pregnancy and lactation:

Application in pregnancy

The use of the drug DILAPREL® PLUS is contraindicated in pregnancy. Before starting treatment, make sure that there is no pregnancy. When planning a pregnancy or when it occurs during the period of treatment, it is necessary to immediately stop taking the drug DILAPREL® PLUS and to prescribe another therapy with established safety profile during pregnancy.

Indapamide

Long-term use of thiazide diuretics in the III trimester of pregnancy can cause hypovolemia in the mother and a decrease in uteroplacental blood flow, which leads to fetoplacental ischemia and delayed fetal development. In rare cases, against the background of diuretics shortly before delivery, neonates develop hypoglycemia and thrombocytopenia.

Ramipril

ACE inhibitors are able to penetrate the placental barrier. With the use of ACE inhibitors during pregnancy, there is a risk of impairment of fetal kidney development, fetal and newborn fetus reduction, renal dysfunction, hyperkalemia, skull bones hypoplasia, oligohydramnion, limb contracture, skull deformation, and lung hypoplasia.

It is recommended to closely monitor newborns who have been exposed to intrauterine exposure to ACE inhibitors for the detection of arterial hypotension, oliguria and hyperkalemia. In oliguria it is necessary to maintain BP and renal perfusion by replenishing BCC and using vasoconstrictors. In newborns, there is a risk of oliguria and neurological disorders, possibly due to a reduction in renal and cerebral blood flow due to a decrease in blood pressure caused by ACE inhibitors (obtained by pregnant and lactating women).

Application in the period of breastfeeding

The use of the drug DILAPREL® PLUS is contraindicated in the period of breastfeeding. If treatment with the drug DILAPREL® PLUS is necessary, then breastfeeding should be discontinued.

Indapamide

Indapamide is excreted in breast milk. Taking thiazide diuretics causes a decrease in the amount of breast milk or suppression of lactation. In a newborn, this may lead to increased sensitivity to sulfonamide derivatives, hypokalemia and "nuclear jaundice".

Ramipril

In animal studies, it was shown that ramipril is excreted with the milk of lactating animals.

Dosing and Administration:

Inside, once a day, preferably in the morning.

Capsules should be swallowed whole and washed down with a sufficient amount of water. The dose is selected depending on the therapeutic effect and the tolerance of the drug to the patient.

Treatment with the drug DILAPREL® PLUS is usually long, and its duration in each case is determined by the doctor.

If not prescribed otherwise, then with normal kidney and liver function, the following dosing regimens are recommended.

Initial dose - 1 capsule with a dosage of 0.625 mg + 2.5 mg, once in the morning. If the dose of DILAPREL® PLUS at this dose is not normalized for 2 weeks or more, the dose may be increased to 1 capsule with a dosage of 1.25 mg + 5 mg of the drug DILAPREL® PLUS per day.

With an insufficient antihypertensive effect of a daily dose of 1.25 mg + 5 mg, a new therapy regimen should be selected.

The maximum daily dose - 2 capsules with a dosage of 1.25 mg + 5 mg once a day.

Application of the drug DILAPREL® PLUS in specific patient groups

Patients with impaired renal function

With QC 60 ml / min and more dose adjustment is not required.

For patients with KK 30-60 ml / min the initial dose is 0.625 mg + 2.5 mg per day, the maximum daily dose is 1.25 mg + 5 mg. Treatment should begin with the selection of doses of indapamide and ramipril in monotherapy.

In severe renal failure (QC less than 30 ml / min), the use of the drug DILAPREL® PLUS is contraindicated.

Patients with hepatic impairment

For patients with impaired liver function, the maximum daily dose is 1 capsule with a dosage of 0.625 mg + 2.5 mg. At the beginning of treatment, careful medical attention is required.

In severe hepatic insufficiency, the use of the drug DILAPREL® PLUS is contraindicated.

Patients of advanced age (over 65 years)

In elderly patients, the function of the kidneys and the content of potassium in the blood plasma should be evaluated before starting the drug DILAPREL® PLUS.The drug DILAPREL® PLUS can be used only with normal kidney function or with minor impairment of kidney function. The dose is selected depending on the degree of decrease in blood pressure, especially with a decrease in bcc and loss of electrolytes, as well as in chronic heart failure (IV functional class by classification NYHA). Such measures allow to avoid a sharp decrease in blood pressure.

The initial dose is 1 capsule with a dosage of 0.625 mg + 2.5 mg per day.

Side effects:

Classification of the incidence of adverse events according to the recommendations of the World Health Organization (WHO):

Often

≥ 1/10;

often

from ≥ 1/100 to <1/10;

infrequently

from ≥ 1/1000 to <1/100;

rarely

from ≥ 1/10000 to <1/1000;

rarely

<1/10000, including individual messages;

frequency unknown

- according to available data to establish the frequency of occurrence is not possible.

Heart Disease:

infrequently - myocardial ischemia, including the development of an attack of angina or myocardial infarction, tachycardia, arrhythmia, palpitations, peripheral edema;

frequency unknown - arrhythmia of the type "pirouette" (possibly fatal), increase in the interval QT on the ECG.

Vascular disorders:

often - excessive reduction of blood pressure, orthostatic hypotension, syncopal conditions; infrequently - "tides" of blood to the skin of the face;

rarely - the occurrence or intensification of circulatory disorders against the background of stenosing vascular lesions, vasculitis;

frequency is unknown - Raynaud's syndrome.

Disturbances from the nervous system:

often - headache, dizziness (feeling of "lightness" in the head);

infrequently - vertigo, paresthesia, agevzia (loss of taste sensitivity), dysgeusia (a violation of taste sensitivity), lethargy;

rarely - tremor, imbalance;

frequency unknown - ischemia of the brain, including ischemic stroke and transient impairment of cerebral circulation, impaired psychomotor reactions (decreased response), burning sensation, parosmia (impaired perception of odors), fainting.

Disturbances on the part of the organ of sight:

infrequent - visual disorders, including blurred image;

rarely - conjunctivitis.

Hearing disorders:

rarely - hearing impairment, tinnitus.

Disorders of the psyche:

infrequent - depressed mood, anxiety, nervousness, motor anxiety, sleep disturbances, including drowsiness;

rarely confusion;

frequency unknown - attention violation.

Disturbances from the respiratory system, chest and mediastinal organs:

often - a "dry" cough (worse at night and in the "lying" position), bronchitis, sinusitis, dyspnea;

infrequently - bronchospasm, including weighting of the course of bronchial asthma, congestion of the nose.

Disorders from the digestive system:

often - inflammatory reactions in the stomach and intestines, digestive disorders, abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting;

infrequently - fatal pancreatitis (cases of pancreatitis with fatal outcome with the intake of ACE inhibitors were observed extremely rarely), increased activity of pancreatic enzymes in the blood plasma, angioedema of the small intestine, pain in the upper abdomen, including those associated with gastritis, constipation, dry mucosa membranes of the oral cavity;

rarely glossitis;

very rarely - pancreatitis;

frequency unknown - aphthous stomatitis (inflammatory reactions of the oral mucosa).

Disturbances from the liver and bile ducts:

often - increased activity of alanine aminotransferase;

infrequently - increased activity of "hepatic" enzymes and concentration of conjugated bilirubin in blood plasma;

rarely - cholestatic jaundice, hepatocellular lesions;

very rarely - a violation of liver function;

frequency unknown - acute hepatic insufficiency, cholestatic or cytolytic hepatitis (extremely rare with fatal outcome), the possibility of developing hepatic encephalopathy in case of hepatic insufficiency.

Disorders from the kidneys and urinary tract:

infrequently - renal dysfunction, including the development of acute renal failure, an increase in the amount of excreted urine, an increase in pre-existing proteinuria, an increase in the concentration of urea and creatinine in the blood plasma;

very rarely - kidney failure; frequency is unknown - hyperuricemia, glucosuria.

Violations of the genitals and mammary gland:

infrequently - erectile dysfunction with transient impotence, decreased libido;

frequency unknown - gynecomastia.

Violations of the blood and lymphatic system:

very often - eosinophilia;

often - thrombocytopenia, decrease in hematocrit;

rarely - leukopenia, including neutropenia and agranulocytosis, erythrocytopenia, decrease in hemoglobin concentration;

very rarely - aplastic anemia, hemolytic anemia; frequency unknown - oppression of bone marrow hematopoiesis, pancytopenia.

Disturbances from the skin and subcutaneous tissues:

often - skin rash, in particular maculopapular;

infrequently, angioedema, including fatal outcome (laryngeal edema can cause airway obstruction leading to death), skin itching, hyperhidrosis (increased sweating), hemorrhagic vasculitis;

rarely - exfoliative dermatitis, urticaria, onycholysis;

very rarely photosensitization reactions;

frequency unknown - toxic epidermal necrolysis. Stevens-Johnson syndrome, erythema multiforme, pemphigus, weight gain of psoriasis, psoriasis-like dermatitis, pemphigoid or lichenoid (lichen) exanthema or enanthema, alopecia, exacerbation of systemic lupus erythematosus.

Disturbances from musculoskeletal and connective tissue:

often - muscle cramps, myalgia;

infrequently - arthralgia.

Disorders from the endocrine system:

frequency is unknown - syndrome of inadequate secretion of antidiuretic hormone.

Disorders from the metabolism and nutrition:

often - hyperkalemia, hypokalemia, hyponatremia;

infrequently - anorexia, decreased appetite;

very rarely - hypercalcemia;

frequency unknown - hyperglycemia, hypochloremia accompanied by hypovolemia, dehydration and orthostatic hypotension (simultaneous loss of chloride ions can lead to compensatory metabolic alkalosis, however, the frequency of development of alkalosis and its severity is negligible).

Immune system disorders:

frequency unknown - anaphylactic or anaphylactoid reactions (with the inhibition of ACE, the severity of anaphylactic or anaphylactoid reactions increases to Poisons of Hymenoptera insects such as bees, wasps), an increase in the titer of antinuclear antibodies.

General disorders:

often - pain in the chest, increased fatigue;

infrequent - increase in body temperature;

rarely - asthenia (weakness).

Overdose:

Symptoms

A marked decrease in blood pressure, bradycardia, nausea, vomiting, convulsions, dizziness, drowsiness, confusion, stupor, water-electrolyte balance disorders (hyponatremia, hypokalemia), oliguria up to anuria (due to hypovolemia), acute renal failure.

Treatment

In light cases of overdose - gastric lavage, intake of adsorbents (activated carbon), sodium sulfate (preferably within 30 minutes) with subsequent recovery of the water-electrolyte balance.It is necessary to monitor the function of vital organs.

In more severe cases, further measures are taken to stabilize blood pressure: intravenous administration 0.9% solution of sodium chloride, plasma substitutes, installation of a temporary artificial pacemaker with a stable bradycardia medication. With a pronounced decrease in blood pressure to therapy for replenishment of bcc and restoration of the water-electrolyte balance, the introduction of alpha-adrenergic agonists (norepinephrine, dopamine). In the case of bradycardia, the appointment of atropine or the installation of a temporary artificial pacemaker is recommended. It is necessary to carefully monitor blood pressure, kidney function and the content of electrolytes in blood plasma.

Experience in the use of forced diuresis, changes in urinary pH, hemofiltration or dialysis are not present.

Hemodialysis is indicated in cases of development of renal failure.

Interaction:

DILAPREL® PLUS

Simultaneous use is contraindicated

With the simultaneous use of lithium drugs and ACE inhibitors, a reversible increase in the concentration of lithium in the blood plasma and an increase in the cardio- and neurotoxic effects of lithium are possible.The additional use of thiazide diuretics can further increase the concentration of lithium due to a decrease in its excretion, and increase the risk of toxic reactions. The simultaneous use of the drug DILAPREL® PLUS with lithium preparations is contraindicated.

Simultaneous use with potassium preparations, potassium-sparing diuretics (amiloride, spironolactone, eplerenone, triamterene), other drugs that can increase the potassium content in the blood plasma (including trimethoprim, tacrolimus, ciclosporin, heparin), increases the risk of hyperkalemia (especially in patients with diabetes mellitus and patients with kidney failure).

With simultaneous application, special care is required

Baclofen potentiates the antihypertensive effect of indapamide and ramipril (requires control of blood pressure, kidney function and, if necessary, dose adjustment of the drug DILAPREL® PLUS).

Simultaneous use with non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 inhibitors and nonselective NSAIDs, for example, acetylsalicylic acid in doses that have anti-inflammatory effect (more than 3 g per day), reduces the antihypertensive effect of indapamide and ramipril; increases the risk of impaired renal function, up to the development of acute renal failure; increases the content of potassium in blood plasma in patients with pre-existing renal dysfunction. This combination is recommended for use with caution, especially in elderly patients. Patients should be compensated for BCC, as well as to monitor kidney function before and after treatment with DILAPREL® PLUS.

With simultaneous application, care is required

Tricyclic antidepressants, antipsychotics (antipsychotics) increase the antihypertensive effect and increase the risk of developing orthostatic hypotension (additive effect).

Glucocorticosteroids, tetracosactide reduce the antihypertensive effect (fluid retention).

With simultaneous use with other antihypertensive agents, the antihypertensive effect of the drug DILAPREL® PLUS is possible.

Indapamide

Simultaneous use is contraindicated

Because of the risk of hypokalemia, it is contraindicated to use indapamide simultaneously with drugs that can cause piruet-type arrhythmias, such as antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide, amiodarone. dofetilide, ibutilide, brethil tosylate, sotalol), some neuroleptics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine, pimozide), benzamides (amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidol, haloperidol), other substances (bepridil, cisapride, difemanyl, erythromycin (intravenously), halofantrine, misolastine, pentamidine, sparfloxacin, moxifloxacin, astemizole, wincamine (intravenously), methadone, terfenadine). Patients with hypokalemia should use drugs that do not cause arrhythmia such as "pirouette".

With simultaneous application, special care is required

With simultaneous use with amphotericin B (intravenously), gluco- and mineralocorticosteroids (for systemic administration), tetracosactide, laxatives, stimulating the motility of the gastrointestinal tract, the risk of hypokalemia (additive effect) increases.A constant control of the potassium content in the blood plasma is necessary, if necessary, its correction. Particular attention should be given to patients who simultaneously receive cardiac glycosides. It is recommended to use laxatives that do not stimulate the motility of the gastrointestinal tract.

Hypokalemia increases the toxic effect of cardiac glycosides. With the simultaneous use of indapamide and cardiac glycosides, it is necessary to monitor the potassium content in the blood plasma, the parameters of the ECG, and, if necessary, adjust the dose of cardiac glycosides.

With simultaneous application, care is required

With the simultaneous use of diuretics with metformin, the development of renal insufficiency is possible, as well as the risk of developing lactic acidosis. Do not use metformin, if the creatinine concentration in the blood plasma exceeds 15 mg / L (135 μmol / L) in men and 12 mg / L (110 μmol / L) in women.

Against the background of taking diuretics, there is a decrease in BCC, the risk of developing acute renal failure increases, especially when using high doses of iodine-containing contrast agents.Before using iodine-containing contrast agents, patients should be compensated for BCC.

With simultaneous application with calcium preparations, the development of hypercalcemia is possible due to a decrease in the excretion of calcium by the kidneys.

With simultaneous use with cyclosporine, tacrolimus, the risk of renal dysfunction (hypercreatinemia) increases.

Ramipril

Simultaneous use is contraindicated

The use of some high-permeability membranes with a negatively charged surface (for example, polyacrylonitrile membranes) during hemodialysis or hemofiltration and the use of dextran sulfate in the apheresis of LDL increases the risk of developing severe anaphylactic reactions. If the patient needs these procedures, then other types of membranes should be used (in the case of plasmapheresis and hemofiltration) or the patient should be taken to receive other types of antihypertensive drugs.

The simultaneous use of ramipril and drugs containing aliskiren, is contraindicated in patients with diabetes mellitus and patients with renal insufficiency (CC less than 60 ml / min).

The simultaneous use of ramipril and receptor antagonists for angiotensin II is contraindicated in patients with diabetic nephropathy.

With simultaneous application, special care is required

With the simultaneous use of ramipril with drugs containing aliskiren, and antagonists of receptors for angiotensin II should be used with caution. Treatment is carried out under the control of kidney function, potassium content and blood pressure level. The combined use of ramipril and telmisartan is not recommended, as it does not provide an enhanced therapeutic effect compared with the use in monotherapy. In addition, a higher incidence of hyperkalemia, renal insufficiency, arterial hypotension and dizziness in combined treatment was recorded.

With simultaneous use with hypoglycemic agents, for example, insulin, hypoglycemic agents for oral administration (sulfonylurea derivatives) due to a decrease in insulin resistance under the influence of ramipril, it is possible to increase the hypoglycemic effect of these drugs until the development of hypoglycemia.It is recommended that blood glucose concentration be carefully monitored at the beginning of the joint use of hypoglycemic agents with ACE inhibitors.

In patients taking both ACE inhibitors and vildagliptin, there was an increase in the incidence of angioedema.

With simultaneous use of ACE inhibitors and inhibitors mTOR (mammalian Target of Rapamycin - a target of rapamycin in mammalian cells, for example, tamsirolimus), an increase in the frequency of angioedema development was observed. When used simultaneously with sympathomimetics (epinephrine, isoproterenol, dobutamine, dopamine), a decrease in the antihypertensive effect of ramipril is observed, regular monitoring of blood pressure is required.

When used simultaneously with other drugs that reduce blood pressure (nitrates, agents for general and local anesthesia, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin), potentiation of the antihypertensive effect is noted. Use with caution of combination of ramipril with preparations blocking RAAS.

With simultaneous application, care is required

When used simultaneously with the drug gold (sodium aurotomy malate) for intravenous administration, rarely hyperemia of the face, nausea, vomiting, arterial hypotension.

When used simultaneously with hypnotics, narcotics and anesthetics, an antihypertensive effect may be enhanced.

With the simultaneous use with allopurinol, procainamide, cytostatics, immunosuppressants, corticosteroids (glucocorticosteroids and mineralocorticosteroids) and other drugs that can affect hematologic indices, the risk of developing hematologic reactions increases.

With the simultaneous use of sodium chloride, it is possible to reduce the antihypertensive effect of ramipril.

With simultaneous use with ethanol, the symptoms of vasodilation become more severe. Ramipril can enhance the adverse effects of ethanol on the body.

With simultaneous use with estrogens, weakened anti-hypertensive effects of ramipril (fluid retention).

Simultaneous use with other ACE inhibitors increases the risk of developing renal failure (including acute renal failure), hyperkalemia.

With simultaneous use of ACE inhibitors with drugs containing trimethoprim, the risk of hyperkalemia increases.

Special instructions:

Patients with prior diuretic therapy

It is necessary, if possible, to cancel diuretics for 2-3 days (depending on the duration of the action of diuretics) before starting treatment with the drug DILAPREL® PLUS, or at least reduce the dose of diuretics taken. Treatment of such patients should start with taking 1 capsule with a dosage of 0.625 mg + 2.5 mg once a day in the morning. After taking the first dose and after increasing the dose of DILAPREL® PLUS, patients should be under medical supervision for at least 8 hours to avoid an uncontrolled hypotensive reaction.

Ischemic heart disease and cerebral circulatory insufficiency The risk of arterial hypotension exists in all patients, but in patients with ischemic heart disease and cerebral circulatory insufficiency, special care should be taken in the treatment with the drug DILAPREL® PLUS. Treatment should begin with a daily dose of 0.625 mg + 2.5 mg (initial dose).

Impaired renal function

Therapy with the drug DILAPREL® PLUS is contraindicated in patients with severe renal insufficiency (KC less than 30 ml / min).In some patients with hypertension without a previous impairment of kidney function, the appearance of symptoms of acute renal failure may occur with DILAPREL® PLUS therapy. In this case, the treatment with the drug DILAPREL® PLUS should be discontinued. In the future, it is possible to resume combination therapy, using low doses of the drug DILAPREL® PLUS, or to use indapamide and ramipril in monotherapy. Such patients need regular monitoring of the potassium content and creatinine concentration in the blood plasma every 2 weeks after the start of therapy and every subsequent 2 months of therapy with the drug DILAPREL® PLUS.

Acute renal failure often develops in patients with severe chronic heart failure or initial renal impairment, including bilateral renal artery stenosis or arterial stenosis of a single functioning kidney. The use of the drug DILAPREL® PLUS is contraindicated in patients with bilateral stenosis of the renal arteries or stenosis of the artery of a single functioning kidney.

Arterial hypotension and disturbance of water-electrolyte balance

Before starting treatment with the drug DILAPREL PLUS, it is necessary to eliminate hyponatremia and hypovolemia. Hyponatremia is associated with a risk of a sudden drop in blood pressure (especially in patients with bilateral stenosis of the renal arteries or stenosis of the artery of a single functioning kidney). Therefore, when observing patients dynamically, attention should be paid to possible symptoms of dehydration and a decrease in the electrolyte content in the blood plasma, for example, after prolonged diarrhea or vomiting. Such patients need regular monitoring of the content of plasma electrolytes. With a marked decrease in blood pressure, an intravenous injection of 0.9% sodium chloride solution may be required.

Transient arterial hypotension is not a contraindication for continuing therapy. After the recovery of bcc and blood pressure, it is possible to resume therapy with the drug DILAPREL® PLUS, using low doses of the drug, or use the drugs indapamide and ramipril in monotherapy.

The content of potassium

The combined use of indapamide and ramipril may lead to the development of hypokalemia, especially in patients with diabetes mellitus or renal insufficiency.Against the background of taking the drug DILAPREL® PLUS, it is necessary to regularly monitor the potassium content in the blood plasma. Patients with hypokalemia use of the drug DILAPREL® PLUS is contraindicated.

Excipients

It should be noted that the composition of excipients of the drug DILAPREL® PLUS includes lactose monohydrate. The use of the drug DILAPREL® PLUS is contraindicated in patients with lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

Indapamide

Dysfunction of the liver

With the use of thiazide and thiazide-like diuretics in patients with impaired hepatic function, it is possible to develop hepatic encephalopathy, especially in the case of disturbance of the water-electrolyte balance. In this case, you should immediately stop taking DILAPREL® PLUS.

Photosensitivity

Against the background of taking thiazide and thiazide-like diuretics, cases of development of photosensitivity reactions were reported. In the case of developing photosensitivity reactions against the background of the drug DILAPREL® PLUS should stop treatment. If it is necessary to continue therapy with the drug DILAPREL® PLUS, it is recommended to protect open skin areasfrom direct exposure to solar and artificial ultraviolet rays.

The content of sodium in the blood plasma

Before the start of treatment it is necessary to determine the sodium content in the blood plasma. Against the background of taking the drug should regularly monitor this figure. All diuretics can cause hyponatremia, which sometimes leads to extremely serious consequences. It is necessary to regularly monitor the sodium content, since initially a decrease in the sodium content in the blood plasma may not be accompanied by the appearance of pathological symptoms. The most careful control of the sodium content is indicated for patients with cirrhosis of the liver and elderly patients.

The content of potassium in blood plasma

Therapy with thiazide and thiazide-like diuretics is associated with a risk of hypokalemia (the level of potassium in the blood plasma is below 3.4 mmol / l) in patients of the following categories: elderly patients who are weakened or are receiving concomitant drug therapy with other antiarrhythmic drugs and drugs that may increase the interval QT, patients with cirrhosis of the liver, peripheral edema or ascites, IHD, heart failure.Hypokalemia in such patients increases the toxic effect of cardiac glycosides and increases the risk of arrhythmias.

In addition, the high-risk group includes patients with an increased interval QT on the ECG, it does not matter whether this increase is due to innate causes or effects of drugs.

Hypokalemia, as well as bradycardia, is a condition conducive to the development of severe arrhythmias and, especially, pirouette-type arrhythmias, which can lead to death. In all the cases described above, it is necessary to regularly monitor the potassium content in the blood plasma. The first measurement of the potassium content in the blood plasma should be performed during the first week after the start of therapy with the drug DILAPREL® PLUS.

If hypokalemia is detected, appropriate treatment should be prescribed.

Calcium in the blood plasma

Thiazide and thiazide-like diuretics reduce the excretion of calcium by the kidneys, leading to a slight and temporary increase in the calcium content in the blood plasma. Expressed hypercalcemia may be a consequence of latent hyperparathyroidism.DILAPREL® PLUS should be withdrawn before the function of parathyroid glands is examined.

The concentration of glucose in the blood plasma

It is necessary to monitor the concentration of glucose in blood plasma in patients with diabetes mellitus, especially in the presence of hypokalemia.

Uric acid

In patients with a high concentration of uric acid in the blood plasma does not increase the risk of gout. Patients with gout may increase the incidence of attacks or exacerbate the course of gout.

Diuretic drugs and kidney function

Thiazide and thiazide-like diuretics are effective only in patients with normal or slightly impaired renal function (plasma creatinine in adults below 25 mg / L or 220 μmol / L). In elderly patients, the normal concentration of creatinine in the blood plasma is calculated taking into account age, body weight and sex.

It should be borne in mind that at the beginning of treatment, patients may experience a decrease in the glomerular filtration rate due to hypovolemia, which in turn is caused by loss of fluid and sodium ions on the background of taking diuretic drugs.As a consequence, the blood plasma can increase the concentration of urea and creatinine. If the function of the kidneys is not impaired, such temporary functional renal failure usually passes without consequences, but with the existing renal failure, the patient's condition may worsen.

Athletes

Indapamide can give a positive result in the conduct of doping control.

Ramipril

Neutropenia / agranulocytosis

In patients taking ACE inhibitors, there may be cases of development of neutropenia / agranulocytosis. The risk of developing neutropenia is dose-dependent and depends on the drug taken and the presence of concomitant diseases. In patients with normal renal function, in the absence of other complications, neutropenia develops rarely and passes on its own after the withdrawal of ACE inhibitors. Particular care should be taken in patients with systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), as well as with immunosuppressant therapy, allopurinol or procainamide, especially with existing renal dysfunction.Such patients may develop a severe infection that does not respond to intensive antibiotic therapy. It is recommended to periodically monitor the number of leukocytes in the blood. The patient should be warned that in case of any signs of an infectious disease (sore throat, fever), you should immediately consult a doctor.

Angioedema (edema of Quincke)

In rare cases, angiotoneurotic edema of the face, extremities, lips, tongue, upper ligament, pharynx and / or larynx can develop on the background of therapy with ACE inhibitors. If these symptoms appear, stop taking DILAPREL® PLUS immediately. It is necessary to monitor the patient's condition until the signs of edema disappear completely. If the swelling affects only the face and lips, then its manifestations usually go without special treatment, but for faster relief of symptoms, you can use antihistamines. Angioedema, accompanied by edema of the pharynx and / or larynx, can lead to airway obstruction and death. In this case, you should immediately enter epinephrine (epinephrine) subcutaneously at a dose of 1: 1000 (0.3 to 0.5 ml) and / or provide airway patency. In the future, such patients should not use ACE inhibitors. Patients with a history of Quincke edema who are not associated with taking ACE inhibitors may be at increased risk for developing Quincke's edema when taking this group's medications.

In rare cases against the background of therapy with ACE inhibitors, intestinal angioedema develops. In this case, patients have abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without a previous angioedema and at a normal level of C-1-esterase. The diagnosis is established using computed tomography of the abdominal cavity, ultrasound, or at the time of surgery. Symptoms disappear after stopping the intake of ACE inhibitors. In patients with abdominal pain receiving ACE inhibitors, the differential diagnosis should take into account the possibility of developing an intestinal angioedema.

Anaphylactoid reactions during desensitization

There are separate reports on the development of long-life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy with the poison of Hymenoptera insects (bees, wasps). ACE inhibitors should be used with caution in patients prone to allergic reactions undergoing desensitization procedures. ACE inhibitors are contraindicated in patients receiving desensitizing therapy with venom of Hymenoptera insects, such as bees, wasps. The development of anaphylactoid reactions can be avoided by the temporary withdrawal of the ACE inhibitor at least 24 hours before the desensitization procedure begins.

Anaphylactoid reactions during apheresis LDL

In rare cases, patients receiving ACE inhibitors may develop life-threatening anaphylactoid reactions in LDL-apheresis with dextran sulfate. To prevent the anaphylactoid reaction, ACE inhibitor therapy should be discontinued before each procedure for LDL apheresis using dextran sulfate.

Anaphylactoid reactions during hemodialysis

In patients receiving ACE inhibitors, during hemodilysis with the use of high-flow membranes, anaphylactoid reactions were noted. Therefore, it is necessary to use a different type of membrane or to use an antihypertensive drug of another pharmacotherapeutic group.

Cough

Against the background of therapy with an ACE inhibitor, it is possible to develop a dry persistent cough, which disappears after the withdrawal of drugs of this group. When a dry cough occurs in a patient, one should keep in mind the possible connection of this symptom with the administration of an ACE inhibitor. If the doctor believes that therapy with an ACE inhibitor is necessary for the patient, the use of the drug DILAPREL® PLUS can be continued.

Risk of arterial hypotension and / or renal failure

In some pathological states, a significant activation of RAAS can occur, especially with severe hypovolemia and a decrease in the content of plasma electrolytes (against a background of a salt-free diet or long-term diuretics), in patients with initially low blood pressure, bilateral stenosis of the renal arteries or with stenosis of the artery of a single kidney, chronic heart failure or cirrhosis of the liver with edema and ascites.The use of an ACE inhibitor causes blockade of RAAS and therefore may be accompanied by a sharp decrease in blood pressure and / or an increase in plasma creatinine concentration, which indicates the development of acute renal failure. These phenomena are more often observed with the first dose of ramipril or during the first two weeks of therapy. Sometimes these conditions develop rapidly in other periods of therapy. In such cases, when the therapy is resumed, it is recommended to use the drug DILAPREL® PLUS in a lower dose and then gradually increase the dose.

Diabetes

When using the drug DILAPREL® PLUS in patients with diabetes mellitus, receiving hypoglycemic agents for oral administration or insulin, during the first month of therapy, it is necessary to regularly monitor the concentration of glucose in the blood.

Renovascular hypertension

The use of ACE inhibitors has a beneficial effect in patients with renovascular hypertension, both awaiting surgery and when surgery is not possible. Treatment with DILAPREL® PLUS should be started with a low dose of the drug in a hospital setting, controlling the kidney function and the potassium content in the blood plasma.Some patients may develop functional kidney failure, which quickly disappears when the drug is withdrawn.

Surgery / General Anesthesia

The use of ACE inhibitors in patients undergoing surgery with general anesthesia can lead to a marked decrease in blood pressure, especially with the use of general anesthetics, which have an antihypertensive effect. It is recommended to stop taking ACE inhibitors 48 hours before surgery, warning the anesthesia doctor about the use of ACE inhibitors.

Anemia

Anemia can develop in patients who have undergone kidney transplantation, or in patients on hemodialysis. At the same time, the decrease in hemoglobin concentration is greater, the higher its initial concentration was. This effect, apparently, is not dose-dependent, but may be related to the mechanism of action of ACE inhibitors. A slight decrease in hemoglobin concentration occurs during the first 6 months of treatment, then the hemoglobin concentration remains stable and completely restored after the drug is discontinued.In such patients, treatment can be continued, but a general blood test should be carried out regularly.

Aortic stenosis / mitral stenosis / Hypertrophic obstructive cardiomyopathy

ACE inhibitors are contraindicated in patients with obstruction of the left ventricular outflow tract and with aortic and / or mitral stenosis and GOKMP.

Liver failure

In rare cases, with the administration of ACE inhibitors, cholestatic jaundice occurs, with the progression of which rapid development of fulminant liver necrosis, sometimes fatal, is possible. When jaundice or a significant increase in the activity of "liver" transaminases on the background of the administration of ACE inhibitors, the patient should stop taking the drug DILAPREL® PLUS.

Hyperkalemia

During treatment with ACE inhibitors, hyperkalemia may develop. Risk factors for hyperkalemia are renal failure, elderly age, diabetes mellitus, some concomitant conditions (decreased BCC, acute heart failure in decompensation, metabolic acidosis), simultaneous intake of potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene, amiloride), as well as preparations of potassium or potassium-containing substitutes for edible salt and the use of other drugs that increase the level of potassium in the blood plasma (for example, heparin). Hyperkalemia can lead to serious heart rhythm disturbances, sometimes with a fatal outcome. Simultaneous use of the above drugs is contraindicated.

Other risk groups

In patients with chronic heart failure (IV functional class by classification NYHA) and patients with type 1 diabetes mellitus (the risk of spontaneous increase in potassium content) treatment should be started with low doses of the drug DILAPREL® PLUS and carried out under the constant supervision of a doctor.

In patients with hypertension and coronary artery disease, beta-blockers should not be discontinued: ACE inhibitors should be used together with beta-blockers.

Elderly patients

In elderly patients, before starting the drug DILAPREL® PLUS, it is necessary to evaluate the function of the kidneys and the content of potassium in the blood plasma. In order to prevent the development of arterial hypotension, a consistent correction of the initial dose of the drug is carried out in accordance with the indices of blood pressure, especially with a decrease in the bcc.

Ethnic differences

ACE inhibitors have a less pronounced antihypertensive effect in patients of the Negroid race compared with representatives of other races.

Effect on the ability to drive transp. cf. and fur:

During the period of treatment with the drug DILAPREL® PLUS, it is necessary to refrain from engaging in potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions, including the management of transport means, as against the background of taking the drug DILAPREL® PLUS, there may be dizziness, decreased speed of psychomotor reactions and attention, especially after taking the first dose.

Form release / dosage:

Capsules, 0.625 mg + 2.5 mg and 1.25 mg + 5 mg.

Packaging:

7, 10, 14 or 20 capsules in a planar cell packaging made of a polyvinylchloride film and aluminum foil.

2 or 4 contour packs of 7 capsules, 1, 2, 3, 5 or 6 contour packs of 10 capsules, 1, 2 or 4 contour packs of 14 capsules, 1 or

3 contour packs of 20 capsules together with instructions for use in a pack of cardboard.

Storage conditions:

Store in a dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription
Registration number:LP-003649
Date of registration:20.05.2016
Expiration Date:20.05.2021
The owner of the registration certificate:VERTEKS, AO VERTEKS, AO Russia
Manufacturer: & nbsp
Representation: & nbspVERTEKS CJSC VERTEKS CJSC Russia
Information update date: & nbsp13.07.2016
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