Noliprel A forte - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate 71.33 mg, magnesium stearate 0.45 mg, maltodextrin 9 mg, silicon dioxide colloidal anhydrous 0.27 mg, sodium carboxymethyl starch (type A) 2.7 mg;

film sheath: macrogol-6000 0.087 mg, premix for a white film sheath SEPIFILM 37781 RBC (glycerol 4.5%, hypromellose 74.8%, macrogol-6000 1.8%, magnesium stearate 4.5%, titanium dioxide (E 171) 14.4%) 2.913 mg.

Description:

Oblong coated tablets coated with a white coating.

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

ATX: & nbsp

C.09.B.A.04 Perindopril in combination with diuretics

Pharmacodynamics:

Noliprel® A forte is a combined preparation containing perindopril arginine and indapamide.

The pharmacological properties of Noliprel® A forte combine individual properties of each of the components.

Mechanism of action

Noliprel® A forte

The combination of perindopril and indapamide increases the antihypertensive effect of each of them.

Perindopril

Perindopril is an inhibitor of the enzyme converting angiotensin I to angiotensin II (an angiotensin-converting enzyme (ACE) inhibitor). ACE, or kinase II, is an exopeptidase,which carries out both the conversion of angiotensin I to the vasoconstrictor compound angiotensin II, and the destruction of bradykinin, which has vasodilatory action, to the inactive heptapeptide.

As a result, perindopril:

- reduces the secretion of aldosterone;

- on the principle of negative feedback increases the activity of renin in the blood plasma;

- long-term use decreases total peripheral vascular resistance (SVR), which is caused mainly by the action on blood vessels in the muscle and kidney. These effects were not accompanied by a delay of sodium ions and a liquid or development of reflex tachycardia. Perindopril It normalizes the myocardium, reducing preload and afterload.

When studying the parameters of hemodynamics in patients with chronic heart failure (CHF), it was revealed:

- decrease of filling pressure in the left and right ventricles of the heart; reduction in OPSS;

- increased cardiac output;

- increased peripheral muscle blood flow.

Indapamide

Indapamide belongs to the group of sulfonamides, for pharmacologically similar to thiazide diuretics. Indapamide inhibits the reabsorption of sodium ions in the cortical segment of the Henle loop, which leads to an increase in kidney excretion of sodium, chlorine and, to a lesser extent, potassium and magnesium ions, thereby increasing diuresis and lowering blood pressure (BP).

Antihypertensive action

Noliprel® A forte

Nolipret® A forte has a dose-dependent antihypertensive effect on both diastolic and systolic blood pressure, both in the standing and lying position.

The antihypertensive effect persists for 24 hours. A stable therapeutic effect develops less than 1 month after the initiation of therapy and is not accompanied by tachycardia. Termination of treatment does not cause withdrawal syndrome.

Noliprel® A forte reduces the degree of left ventricular hypertrophy (GVL), improves the elasticity of the arteries, lowers the OPSS, does not affect lipid metabolism (total cholesterol, high-density lipoprotein cholesterol (HDL), and low-density lipoprotein (LDL), triglycerides).

The effect of the combination of perindopril and indapamide on gastrointestinal peritoneum in comparison with enalapril was proved. In patients with hypertension and GTL,treated with perindopril erbumine 2 mg (equivalent to 2.5 mg perindopril arginine) / indapamide 0.625 mg or enalapril 10 mg once daily, and with an increase in the dose of perindopril erbumin to 8 mg (equivalent to 10 mg perindopril arginine) and indapamide to 2 , 5 mg, or enalapril up to 40 mg once daily, there was a more significant decrease in the left ventricular mass index (LVMI) in the perindopril / indapamide group compared with the enalapril group. The most significant effect on LVMI is observed with the use of perindopril erbumine 8 mg / indapamide 2.5 mg.

Also, a more pronounced antihypertensive effect was observed against combined therapy with perindopril and indapamide compared with enalapril.

In patients with type 2 diabetes mellitus (mean - age 66 years, body mass index 28 kg / m², glycosylated hemoglobin (HbAlc) 7.5%, BP 145/81 mm Hg. The influence of a fixed combination of perindopril / indapamide on the main micro- and macrovascular complications was studied in addition to both the standard therapy of glycemic control and the strategy of intensive glycemic control (IGK) HbAlc < 6,5%).

83% of patients had arterial hypertension, 32% and 10% had macro- and microvascular complications, and 27% had microalbuminuria. Most patients at the time of inclusion in the study received hypoglycemic therapy, 90% of patients - hypoglycemic agents for ingestion (47% of patients in monotherapy, 46% therapy with two drugs, 7% with three drugs). 1% of patients received insulin therapy, 9% - only diet therapy.

Derivatives of sulfonylureas were taken by 72% of patients, metformin - 61%. As concomitant therapy 75% of patients received antihypertensive drugs, 35% of patients - lipid-lowering drugs (mainly inhibitors of HMG-CoA reductase (statins) - 28%), acetylsalicylic acid as antiplatelet agent and other antiplatelet agents (47%).

After 6 weeks of the introductory period, during which patients received perindopril / indapamide therapy, they were allocated to the standard glycemic control group or to the IGK group (Diabeton MB with the possibility of increasing the dose to a maximum of 120 mg / day or the addition of another hypoglycemic agent).

In the IGK group (mean follow-up 4, 8 years, mean HbAlc 6.5%) compared to the standard control group (medium HbAlc 7.3%) shows a significant decrease of 10% relative risk of the combined frequency of macro- and microvascular complications. The advantage was achieved due to a significant reduction in relative risk: major microvascular complications by 14%, the onset and progression of nephropathy by 21%, microalbuminuria by 9%, macroalbuminuria by 30% and the development of complications from the kidneys by 11%.

The advantages of antihypertensive therapy did not depend on the benefits achieved against the background of IGK.

Perindopril

Perindopril is effective in the treatment of arterial hypertension of any severity.

Antihypertensive effect of the drug reaches a maximum in 4-6 hours after a single oral intake and is maintained for 24 hours. 24 hours after taking the drug, a residual (about 80%) residual ACE inhibition is observed. Perindopril has an antihypertensive effect in patients with both low and normal renin activity in blood plasma.

Simultaneous administration of thiazide diuretics increases the severity of antihypertensive action.In addition, the combination of an ACE inhibitor and a thiazide diuretic also leads to a reduction in the risk of hypokalemia with diuretics.

Indapamide

Antihypertensive effect is manifested when the drug is used in doses that have a minimal diuretic effect. Antihypertensive effect of indapamide is associated with an improvement in the elastic properties of large arteries, a decrease in OPSS.

Indapamide reduces LVTH, does not affect the concentration of lipids in the blood plasma: triglycerides, total cholesterol, LLNV, HDL; carbohydrate metabolism (including in patients with concomitant diabetes mellitus).

Pharmacokinetics:

The combination of perindopril and indapamide does not change their pharmacokinetic characteristics in comparison with the separate administration of these drugs.

Perindopril

Ingestion perindopril quickly absorbed. Bioavailability is 65-70%. Approximately 20% of the total amount of absorbed perindopril is converted to perindoprilat, the active metabolite. The intake of the drug during meals is accompanied by a decrease in the metabolism of perindopril in perindoprilat (this effect has no significant clinical significance).

The maximum concentration of perindoprilat in the blood plasma is reached 3-4 hours after ingestion. The association with plasma proteins is less than 30% and depends on the concentration of perindopril in the blood. Dissociation of perindoprilat, associated with ACE, is slowed down. As a consequence, the "effective" half-life (T_1/2) is 25 hours. Repeated administration of perindopril does not lead to its cumulation, and T_1/2perindoprilata at repeated reception corresponds to the period of its activity, thus, the equilibrium state is reached after 4 days.

Perindoprilat is excreted from the body by the kidneys. T_1/2 metabolite is 3-5 hours.

The excretion of perindoprilat is delayed in old age, as well as in patients with cardiac and renal insufficiency.

The dialytic clearance of perindoprilat is 70 ml / min.

The pharmacokinetics of perindopril has been altered in patients with cirrhosis of the liver: its hepatic clearance is reduced by a factor of 2. Nevertheless, the amount of perindoprilata formed does not decrease, so that a dose change is not required.

Perindopril penetrates the placenta.

Indapamide

Indapamide is rapidly and completely absorbed from the gastrointestinal tract.The maximum concentration of the drug in the blood plasma is observed 1 hour after ingestion.

Relationship with blood plasma proteins - 79%.

T_1/2is 14-24 hours (an average of 19 hours). The repeated use of the drug does not lead to its cumulation in the body. It is excreted mainly by the kidneys (70% of the administered dose) and through the intestine (22%) in the form of inactive metabolites. The pharmacokinetics of the drug does not change in patients with renal insufficiency.

Indications:

Essential hypertension.

In patients with arterial hypertension and type 2 diabetes mellitus, to reduce the risk of microvascular complications (from the kidneys) and macrovascular complications from cardiovascular diseases.

Contraindications:

Hypersensitivity to perindopril and other ACE inhibitors, indapamide, other sulfonamides, as well as to other auxiliary components included in the drug, angioedema in the history (including the background of taking other ACE inhibitors); hereditary / idiopathic angioedema, hypokalemia, marked renal failure (creatinine clearance less than 30 ml / min)stenosis of the artery of a single kidney, bilateral stenosis of the renal arteries, severe hepatic insufficiency (including encephalopathy), simultaneous use of drugs that extend the interval QT, simultaneous use with antiarrhythmic drugs that can cause arrhythmia of the pirouette type (see section "Interaction with other drugs"), pregnancy and the period of breastfeeding.

It is not recommended to take the drug together with potassium-sparing diuretics, potassium and lithium preparations, and in patients with elevated potassium levels in the blood plasma.

Because of the lack of sufficient clinical experience, Noliprel® And forte should not be used in patients on hemodialysis, as well as in patients with untreated decompensated heart failure.

Carefully:

Systemic diseases of connective tissue (including systemic lupus erythematosus, scleroderma), immunosuppressant therapy (risk of developing neutropenia, agranulocytosis), oppression of bone marrow hematopoiesis, decreased circulating blood volume (diuretics, salt-free diet, vomiting, diarrhea, hemodialysis), angina pectoris,cerebrovascular diseases, renovascular hypertension, diabetes mellitus, chronic heart failure (IV stages by classification NYHA), hyperuricemia (especially accompanied by gout and urate nephrolithiasis), lability of blood pressure, elderly age; hemodialysis using high-flow membranes or desensitization, before the procedure of apheresis of low-density lipoproteins (LDL); condition after kidney transplantation; stenosis of the aortic valve / hypertrophic cardiomyopathy; Lactose deficiency, galactosemia or glucose-galactose malabsorption syndrome; age to 18 years (effectiveness and safety not established) (see also the sections "Special instructions" and "Interaction with other medicinal products").

Pregnancy and lactation:

The drug is contraindicated in pregnancy.

When planning pregnancy or when it comes on the background of taking Noliprel ® A forte immediately stop taking the drug and prescribe another antihypertensive therapy.

Do not use the drug Noliprel® A forte in the I trimester of pregnancy.

Appropriate controlled studies on the use of ACE inhibitors in pregnant women have not been conducted. The limited data available on the effects of ACE inhibitors in the first trimester of pregnancy suggest that the use of ACE inhibitors did not lead to fetal malformations associated with fetotoxicity, but completely exclude fetotoxic effects of the drug can not be.

Noliprel® A forte is contraindicated in the 2nd and 3rd trimester of pregnancy (see "Contraindications").

It is known that the long-term effect of ACE inhibitors on the fetus in the II and III trimesters of pregnancy can lead to a disruption in its development (decreased kidney function, oligohydramnion, slowing ossification of the skull bones) and development of complications in the newborn (renal failure, arterial hypotension, hyperkalemia).

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.

If the patient received Nolipret A forte during the second or third trimester of pregnancy, it is recommended to perform a newborn ultrasound to evaluate the condition of the skull and the kidney function.

In newborns whose mothers received therapy with ACE inhibitors, there may be arterial hypotension, in connection with which, newborns must be under careful medical supervision.

Lactation period

Nolipret® A forte is contraindicated during lactation.

It is not known whether perindopril with breast milk. Indapamide excreted in breast milk. Taking thiazide diuretics causes a decrease in the amount of breast milk or suppression of lactation. A newborn can develop hypersensitivity to sulfonamide derivatives, hypokalemia and "nuclear" jaundice.

Since the use of perindopril and indapamide during lactation can cause severe complications in the infant, it is necessary to evaluate the importance of therapy for the mother and decide whether to stop breastfeeding or stop taking the drug.

Dosing and Administration:

Inside, preferably in the morning, before eating.

Essential hypertension

1 tablet Nolipret® A forte once a day.

If possible, taking the drug starts with the selection of doses of one-component drugs. In the case of clinical necessity, one can consider the possibility of prescribing a combination therapy with Noliprel A forte immediately after monotherapy.

In patients with arterial hypertension and type 2 diabetes mellitus, to reduce the risk of microvascular complications (from the kidneys) and macrovascular complications from cardiovascular diseases.

It is recommended to begin therapy with a combination of perindopril / indapamide in a dose of 2.5 mg / 0.625 mg (preparation Noliprel® A) 1 time per day. After 3 months of therapy, under condition of good tolerability, it is possible to increase the dose - 1 tablet of Noliprel ® A fort once a day.

Elderly patients

It should be prescribed treatment with the drug after monitoring the function of the kidneys and blood pressure.

Renal insufficiency

The drug is contraindicated in patients with severe renal failure (CC less than 30 ml / min).

For patients with moderate renal insufficiency (CK 30-60 ml / min), it is recommended to start therapy with the necessary doses of drugs (in monotherapy) that are part of Noliprel® A fort.

Patients with QC equal to or greater than 60 mL / min, correction dose is not required. On the background of therapy, regular monitoring of the concentration of creatinine and potassium in the blood plasma is necessary.

Liver failure

(Cm. sections "Contraindications", "Special instructions" and "Pharmacokinetics")

The drug is contraindicated in patients with severe hepatic impairment. With moderate hepatic insufficiency, dose adjustment is not required.

Children and teens

Nolipret® A forte should not be given to children and adolescents under 18 years of age because of lack of data on the efficacy and safety of the drug in patients of this age group.

Side effects:

Perindopril has an inhibitory effect on the "renin-angiotensin-aldosterone" (RAAS) system and reduces the excretion of potassium ions by the kidneys on the background of ingestion of indapamide. In 4% of patients, with the use of Noliprel ® A forte, hypokalemia develops (the level of potassium is less than 3.4 mmol / l).

The frequency of adverse reactions that may occur during therapy is given in the following gradation: very often (> 1/10); often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); rarely (> 1/10000, <1/1000); very rarely (<1/10000); frequency (the frequency can not be calculated from the available data.

From the side of the blood and lymphatic system

Rarely: thrombocytopenia, leukopenia / neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia.

Anemia: in certain clinical situations (patients after kidney transplantation, patients on hemodialysis) ACE inhibitors can cause anemia (see section "Special instructions").

From the central nervous system

Often: paresthesia, headache, dizziness, asthenia, vertigo.

Infrequently; sleep disturbance, lability of mood.

Rarely: confusion of consciousness.

Unspecified frequency: fainting.

From the side of the organ of vision

Often: impaired vision.

From the side of the hearing organ

Often: noise in ears.

From the side of the cardiovascular system

Often: a marked decrease in blood pressure, including orthostatic hypotension.

Rarely: heart rhythm disturbances, including bradycardia, ventricular tachycardia, atrial fibrillation, as well as angina and myocardial infarction, possibly due to excessive reduction in blood pressure in patients at high risk (see section "Special instructions").

Unspecified frequency: arrhythmias type "pirouette" (possibly with a fatal outcome) (see the section "Interaction with other medicinal products").

On the part of the respiratory system, the organs of the thorax and the mediastinum

Often: on the background of the use of ACE inhibitors can occur a dry cough, long which persists during the intake of drugs of this group and disappears after their withdrawal. Dyspnea.

Infrequently: bronchospasm.

Rarely: eosinophilic pneumonia, rhinitis.

From the digestive system

Often: dryness of the oral mucosa, nausea, vomiting, abdominal pain, epigastric pain, impaired taste, decreased appetite, indigestion, constipation, diarrhea.

Rarely: angioedema, intestinal edema, cholestatic jaundice, pancreatitis.

Unspecified frequency: hepatic encephalopathy in patients with hepatic insufficiency (see the sections "Contraindications" and "Special instructions"), hepatitis.

From the skin and subcutaneous fat

Often: skin rash, itching, maculopapular rash.

Infrequently: angioedema, swelling of the face, lips, limbs, tongue mucous membrane, vocal folds and / or larynx; hives (seesection "Special instructions"); reactions of hypersensitivity in patients predisposed to bronchial obstructive and allergic reactions; purpura.

In patients with acute form of systemic lupus erythematosus, the course of the disease may worsen.

Rarely: erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome.

Cases of photosensitivity reaction are noted (see section "Special instructions").

From the musculoskeletal system and connective tissue

Often: muscle spasms.

From the urinary system

Infrequently: renal insufficiency.

Rarely: acute renal insufficiency.

From the side of the reproductive system

Infrequently: impotence.

General disorders and symptoms

Often: asthenia.

Infrequently: increased sweating.

Laboratory indicators

- Hyperkalemia, often transient;

- Mr.eznachitelnoe increase in the concentration of creatinine in urine and plasma, passing after the abolition of therapy, more frequently in patients with renal artery stenosis, the treatment of hypertension with diuretics and in the case of renal failure.

Rarely: hypercalcemia.

Unspecified frequency:

- themagnification QT interval on ECG (compare section "Special instructions");

- Increase in the concentration of uric acid and glucose in the blood;

- increased activity of "liver" enzymes;

- gand apokalemia, especially significant for patients at risk (see section "Special instructions");

- ghypnonemia and hypovolemia leading to dehydration and orthostatic hypotension. Simultaneous hypochloraemia can lead to metabolic alkalosis of compensatory nature (the probability and severity of this effect is low).

Side effects noted during clinical trials

Reported during the study ADVANCE the side effects are consistent with the previously established safety profile of the combination of perindopril and indapamide. Serious adverse events were observed in some patients in the study groups: hyperkalemia (0.1%), acute renal failure (0.1%), hypotension (0.1%) and cough (0.1%).

Three patients in the perindopril / indapamide group had angioneurotic edema (versus 2 in the placebo group).

Overdose:

Symptoms

The most likely symptom of an overdose is a marked decrease in blood pressure,sometimes combined with nausea, vomiting, convulsions, dizziness, drowsiness, confusion and oliguria, which can go to anuria (as a result of hypovolemia). Also, electrolyte disorders (hyponatremia, hypokalemia) may occur.

Treatment

Emergency measures are reduced to excretion from the body: gastric lavage and / or the appointment of activated charcoal, followed by restoration of the water-electrolyte balance.

With a significant decrease in blood pressure, the patient should be transferred to the "lying" position with his legs elevated. If necessary, correct hypovolemia (for example, intravenous infusion 0.9% solution of sodium chloride). Perindoprilat, an active metabolite of perindopril, can be removed from the body by dialysis.

Interaction:

Combinations not recommended for use

Lithium preparations: while simultaneous use of lithium drugs and ACE inhibitors, a reversible increase in the concentration of lithium in the blood plasma and related toxic effects may occur. The additional administration of thiazide diuretics may further increase the concentration of lithium and increase the risk of toxicity.The simultaneous use of a combination of perindopril and indapamide with lithium preparations is not recommended. If necessary, such therapy should be constantly monitored lithium content in blood plasma (see section "Special instructions").

Preparations, combination with which requires special attention and caution

Baclofen: possibly strengthening the hypotensive effect. It is necessary to monitor blood pressure and kidney function, if necessary, correction of the dose of antihypertensive drugs is required.

Non-steroidal anti-inflammatory drugs (NSAIDs), including high doses of acetylsalicylic acid (more than 3 g / day): the appointment of NSAIDs may lead to a decrease in diuretic, natriuretic and antihypertensive effects. With a significant loss of fluid, acute renal failure may develop (due to a decrease in glomerular filtration rate). Before starting treatment, the drug should be filled with fluid loss and regularly monitor kidney function at the beginning of treatment.

Combination of drugs. requiring attention

Tricyclic antidepressants, antipsychotics (antipsychotics): drugs of these classes enhance the antihypertensive effect and increase the risk of orthostatic hypotension (additive effect).

Corticosteroids, tetracosactide: decrease in antihypertensive action (fluid retention and sodium ions due to the action of corticosteroids).

Other antihypertensives: may increase the antihypertensive effect.

Perindopril

Combinations not recommended for use

Potassium-sparing diuretics (amiloride, spironolactone, triamterene) and potassium preparations: ACE inhibitors reduce potassium-induced kidney loss caused by a diuretic. Potassium-sparing diuretics (for example, spironolactone, triamterene, amiloride), potassium preparations and potassium-containing substitutes for edible salt can lead to a significant increase in serum potassium levels up to a lethal outcome. If simultaneous use of an ACE inhibitor and the above drugs is necessary (in the case of confirmed hypokalemia), caution should be exercised and regular monitoring of potassium levels in the blood plasma and ECG parameters should be performed.

Combination of drugs. requiring special attention

Hypoglycemic agents for oral administration (sulfonylurea derivatives) and insulin: the following effects were described for captopril and enalapril. ACE inhibitors can enhance the hypoglycemic effect of insulin and sulfonylureas in patients with diabetes mellitus.

The development of hypoglycemia is very rare (due to an increase in glucose tolerance and a decrease in insulin requirements).

Combination of drugs. requiring attention

Allopurinol, cytostatic and immunosuppressive agents, corticosteroids (for systemic use), and procainamide: simultaneous use with ACE inhibitors may be accompanied by an increased risk of leukopenia.

Means for general anesthesia: simultaneous use of ACE inhibitors and agents for general anesthesia can lead to an increase in antihypertensive effect.

Diuretics (thiazide and "loop"): the use of diuretics in high doses can lead to hypovolemia, and the addition of perindopril to arterial hypotension.

Preparations of gold: when using ACE inhibitors, including, perindopril to patients,(sodium aurothiomalate), a symptomocomplex was described, which includes: flushing of the facial skin, nausea, vomiting, and arterial hypotension.

Indapamide

A combination of drugs that requires special attention

Drugs that can cause arrhythmia of the type "pirouette"": Because of the risk of developing hypokalemia, caution should be exercised while using indapamide with drugs capable of causing piruet-type arrhythmias, for example, with antiarrhythmics (quinidine, hydroquinidine, disopyramide, amiodarone, dofetilide, ibutilide, brethil tosylate, sotalol); some neuroleptics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine); benzamides (amisulpride, sulpiride, sultopride, tiapride); butyrophenones (droperidol, haloperidol); other neuroleptics (pimozide); other drugs, such as bepridil, cisapride, difemanyl methyl sulfate, erythromycin in / in, halofantrine, misolastine, moxifloxacin, pentamidine, sparfloxacin, wincamine in / in, methadone, astemizole, terfenadine. Avoid simultaneous use with the above drugs; risk of hypokalemia, if necessary, to correct it; monitor the QT interval.

Drugs that can cause hypokalemia: amphotericin B (IV), gluco- and mineralocorticosteroids (for systemic administration), tetracosactide, laxatives, stimulating bowel motility: increased risk of hypokalemia (additive effect). It is necessary to control the content of potassium in the blood plasma, if necessary - its correction. Particular attention should be given to patients who simultaneously receive cardiac glycosides. Use laxatives that do not stimulate intestinal motility.

Cardiac glycosides: 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 and the parameters of the ECG and, if necessary, adjust the therapy.

Combination of drugs. requiring attention

Metformin: Functional renal failure, which can occur against the background of taking diuretics, especially "loop", with the simultaneous appointment of metformin increases 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.

Iodine-containing contrast agents: dehydration of the body against the background of taking diuretic drugs increases the risk of acute renal failure, especially when using high doses of iodine-containing contrast agents. Before using iodine-containing contrast agents, patients must compensate for fluid loss.

Salts of calcium: with simultaneous administration, it is possible to develop hypercalcemia due to decreased excretion of calcium ions by the kidneys.

Cyclosporin: it is possible to increase the concentration of creatinine in the blood plasma without changing the concentration of cyclosporine in the blood plasma, even with normal water content and sodium ions.

Special instructions:

Noliprel® A forte

The use of Noliprel A forte 5 mg + 1.25 mg is not accompanied by a significant reduction in the incidence of side effects, with the exception of hypokalemia, compared with perindopril and indapamide in the smallest permitted doses (see section "Side effect"). At the beginning of therapy with two antihypertensive drugs, which the patient did not receive earlier, one can not exclude the increased risk of idiosyncrasy.Careful observation of the patient makes it possible to minimize this risk.

Impaired renal function

Therapy is contraindicated in patients with severe renal failure (CC less than 30 ml / min). In some patients with hypertension without a previous obvious violation of kidney function against the background of therapy, there may be laboratory signs of functional renal failure. In this case, treatment should be discontinued. In the future, you can resume combination therapy, using low doses of drugs, or use drugs in monotherapy.

Such patients need regular monitoring of the level of potassium and creatinine in the blood serum - 2 weeks after the start of therapy and then every 2 months. Renal failure often occurs in patients with severe chronic heart failure or an initial impairment of kidney function, including with renal artery stenosis.

Arterial hypotension and disturbance of water-electrolyte balance

Hyponatremia is associated with a risk of sudden development of arterial hypotension (especially in patients with artery stenosis of a single kidney and bilateral stenosis of the renal arteries).Therefore, when observing patients dynamically, attention should be paid to possible symptoms of dehydration and a decrease in the level of electrolytes in the blood plasma, for example, after diarrhea or vomiting. Such patients need regular monitoring of the level of plasma electrolytes.

With severe arterial hypotension, intravenous administration of 0.9% sodium chloride solution may be required.

Transient arterial hypotension is not a contraindication for the continuation of therapy. After recovering the volume of circulating blood and blood pressure, you can resume therapy using low doses of drugs, or use drugs in monotherapy.

Potassium level

The combined use of perindopril and indapamide does not prevent the development of hypokalemia, especially in patients with diabetes mellitus or renal insufficiency. As in the case of combined use of antihypertensive drugs and diuretic, regular monitoring of the potassium level in the blood plasma is necessary.

Excipients

It should be borne in mind that the composition of excipients of the drug includes lactose monohydrate.Do not prescribe Noliprel® A for fortunately patients with hereditary intolerance to galactose, lactase deficiency and glucose-galactose malabsorption.

Lithium preparations

Simultaneous use of a combination of perindopril and indapamide with lithium preparations is not recommended (see the section "Contraindications", "Interaction with other drugs").

Perindopril

Neutropenia / agranulocytosis

The risk of developing neutropenia against the background of the administration of ACE inhibitors is dose-dependent and depends on the drug taken and the presence of concomitant diseases. Neutropenia rarely occurs in patients without concomitant diseases, but the risk increases in patients with impaired renal function, especially against the background of systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma). After the withdrawal of ACE inhibitors, neutropenia signs pass independently.

To avoid the development of such reactions it is recommended to strictly follow the recommended dose. In the appointment of ACE inhibitors, this group of patients should carefully balance the benefit / risk factor.

Angioedema (edema of Quincke)

When taking ACE inhibitors, including perindopril, in rare cases, development of angioedema of the face, limbs, lips, tongue, glottis and / or larynx can be observed. If symptoms appear, the perindopril should be stopped immediately, and the patient should be observed until the signs of edema disappear completely. If the edema affects only the face and lips, then its manifestations usually pass independently, although antihistamines may be used to treat its symptoms.

Angioedema, accompanied by swelling of the larynx, can lead to death. Swelling of the tongue, glottis or larynx can lead to airway obstruction. When such symptoms occur, immediately enter subcutaneously epinephrine (epinephrine) in a dilution of 1: 1000 (0.3 or 0.5 ml) and / or provide airway patency.

Patients with a history of Quincke edema who are not associated with the administration of ACE inhibitors may be at increased risk of developing it with the use of this group of drugs (see section "Contraindications").

In rare cases, against the background of therapy with ACE inhibitors, angioedema develops in the intestine.

Anaphylactoid reactions during desensitization

There are separate reports on the development of long-term, 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 allergic patients who undergo desensitization procedures. The appointment of an ACE inhibitor should be avoided for patients receiving immunotherapy with venom of Hymenoptera. However, the anaphylactoid reaction can be avoided by temporarily lifting the ACE inhibitor at least 24 hours before the procedure.

Anaphylactoid reactions during apheresis of LDL

In rare cases in patients receiving ACE inhibitors, when performing low-density lipoprotein (LDL) apheresis using dextran sulfate, life-threatening anaphylactoid reactions may develop in hemodialysis patients using high-flow membranes. To prevent the anaphylactoid reaction, therapy with an ACE inhibitor should be temporarily discontinued at least 24 hours before the apheresis procedure.

Cough

Against the background of therapy with an ACE inhibitor, dry cough may occur. Cough persists for a long time against the background of taking this group's drugs and disappears after their withdrawal. When a patient has a dry cough, remember the possible iatrogenic nature of this symptom. If the attending physician believes that therapy with an ACE inhibitor is necessary for the patient, the drug may be continued.

Children and teens

The drug should not be given to children and adolescents under the age of 18 due to lack of data on the efficacy and safety of perindopril in the form of motor therapy or as part of combination therapy in patients of this age group.

The risk of arterial hypotension and / or renal failure (in patients with heart failure, a violation of water-electrolyte balance, etc.)

In some pathological conditions, a significant activation of the renin-angiotensin-aldosterone system can occur, especially in severe hypovolemia and a decrease in the level of plasma electrolytes (against a background of a salt-free diet or long-term diuretics), in patients with initially low blood pressure, with 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 this system and therefore can be accompanied by a sharp decrease in blood pressure and / or an increase in the level of creatinine in the blood plasma, indicating the development of functional renal failure. These phenomena are more often observed with the first dose of the drug 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 in a lower dose and then gradually increase the dose.

Elderly patients

Before you start taking the drug, you need to assess the functional activity of the kidneys and the concentration of potassium in the blood plasma. At the beginning of therapy, the dose of the drug is selected, given the degree of BP reduction, especially in the case of dehydration and loss of electrolytes. Such measures allow to avoid a sharp decrease in blood pressure.

Atherosclerosis

The risk of hypotension exists in all patients but particular care should be taken using the drug in patients with ischemic heart disease and cerebrovascular insufficiency. In such patients, treatment should begin with low doses.

Patients with Renovascular Hypertension

The method of treating reninvascular hypertension is revascularization. Nevertheless, the use of ACE inhibitors has a beneficial effect in this category of patients, both anticipating surgical intervention, and in the case when surgical intervention can not be carried out.

Treatment with Noliprel® A for patients with diagnosed or suspected bilateral stenosis of the renal arteries or stenosis of the single kidney artery should begin with a low dose of the drug in a hospital setting, monitoring the kidney function and the concentration of potassium in the blood plasma. In some patients, functional renal failure may develop, which disappears when the drug is withdrawn.

Other risk groups

In patients with severe heart failure (stage IV) and patients with insulin-dependent diabetes mellitus (the risk of spontaneous increase in potassium concentration) treatment should start with a low dose of the drug and under constant medical supervision.

Patients with arterial hypertension with ischemic heart disease should not stop taking beta-blockers: ACE inhibitors should be used together with beta-blockers.

Anemia

Anemia can develop in patients after kidney transplantation or in people on hemodialysis. At the same time, the decrease in hemoglobin concentration is greater, the higher its initial value 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 within the first 6 months, then it remains stable and completely restored after the drug is discontinued. In such patients, treatment can be continued, however, hematological analyzes should be carried out regularly.

Surgery / General Anesthesia

The use of ACE inhibitors in patients undergoing surgery with the use of general anesthesia can lead to a marked decrease in blood pressure, especially with the use of general anesthetic agents that have an antihypertensive effect.

It is recommended to stop taking long-acting ACE inhibitors, including perindopril, the day before the surgery. It is necessary to warn the anesthesia doctor that the patient is taking ACE inhibitors.

Aortic stenosis / Hypertrophic cardiomyopathy

ACE inhibitors should be administered with caution to patients with left ventricular outflow obstruction.

Liver failure

In rare cases, when taking ACE inhibitors, cholestatic jaundice occurs. With the progression of this syndrome, rapid development of liver necrosis, sometimes fatal, is possible. The mechanism of development of this syndrome is unclear. If jaundice or a significant increase in the activity of "liver" enzymes against the background of taking ACE inhibitors should stop taking the drug and see a doctor (see section "Side effect").

Indapamide

In the presence of violations of the liver, the use of thiazide and thiazide-like diuretics can lead to the development of hepatic encephalopathy. In this case, stop taking the medication immediately.

Water-electrolyte balance

Content of sodium ions in blood plasma

Before the start of treatment it is necessary to determine the content of sodium ions in the blood plasma. Against the background of taking the drug should regularly monitor this figure. All diuretic drugs can cause hyponatremia, which sometimes leads to serious complications.Hyponatremia at the initial stage may not be accompanied by clinical symptoms, so regular laboratory monitoring is necessary. More frequent monitoring of sodium ions is indicated in patients with cirrhosis and. elderly people (see section "Side effect" and "Overdose").

The content of potassium ions in the blood plasma

Therapy with thiazide and thiazide-like diuretics is associated with a risk of hypokalemia. It is necessary to avoid hypokalemia (less than 3.4 mmol / L) in the following categories of patients at high risk: elderly, depleted patients or receiving concomitant medication, patients with cirrhosis, peripheral edema or ascites, coronary heart disease, heart failure. Hypokalemia in these patients increases the toxic effect of cardiac glycosides and increases the risk of arrhythmias.

To the group of the raised risk also patients with the increased interval QT, it does not matter whether this increase is due to innate causes or effects of drugs.

Hypokalemia, like bradycardia, contributes to the development of severe cardiac arrhythmias, especially arrhythmias such as pirouettes, which can be fatal.In all cases described above, more regular monitoring of the potassium ion content in the blood plasma is necessary. The first measurement of the concentration of potassium ions should be carried out within the first week from the start of therapy. If hypokalemia is detected, appropriate treatment should be prescribed.

The content of calcium ions in the blood plasma

Thiazide and thiazide-like diuretics reduce the excretion of calcium ions by the kidneys, leading to a slight and temporary increase in the concentration of calcium in the blood plasma. Expressed hypercalcemia may be a consequence of previously not diagnosed hyperparathyroidism. Before the study of the function of the parathyroid gland, diuretic drugs should be withdrawn.

The content of glucose in the blood plasma

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

Uric acid

In patients with elevated uric acid levels in blood plasma, the frequency of gout attacks may increase with therapy.

Diuretics and kidney function

Thiazide and thiazide-like diuretics are effective only in patients with normal or slightly impaired renal function(the creatinine content in the blood plasma in adults is below 25 mg / l or 220 μmol / l).

At the beginning of treatment with diuretics in patients due to hypovolemia and hyponatremia may be a temporary reduction in glomerular filtration rate and an increase in the concentration of urea and creatinine in the blood plasma. This transient functional renal failure is not dangerous for patients with unchanged renal function, however, in patients with renal insufficiency, its severity may increase.

Photosensitivity

Against the background of taking thiazide and thiazide-like diuretics, cases of development of photosensitivity reactions were reported. In the case of the development of reactions photosensitivity against the background of taking the drug should stop treatment. If it is necessary to continue therapy with diuretics, it is recommended to protect the skin from exposure to sunlight or artificial ultraviolet rays.

Athletes

Indapamide can give a positive reaction during doping control.

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

The action of the substances that make up the drug Noliprel ® A fort, does not lead to a disturbance of psychomotor reactions.However, in some people in response to a decrease in blood pressure, various individual reactions may develop, especially at the beginning of therapy or when adding other antihypertensive drugs to the therapy. In this case, the ability to drive a car or other mechanisms can be reduced.

Form release / dosage:

Tablets, film-coated, 5 mg + 1,25 mg.

Packaging:

For 14 or 30 tablets in a polypropylene bottle, equipped with a dispenser and a stopper containing moisture absorbing gel.

1 bottle (14 and / or 30 tablets) or 3 bottles (30 tablets each) with instructions for medical use in a pack of cardboard with the control of the first autopsy.

When packaging (packaging) / production at the Russian enterprise LLC "Serdiks":

For 14 or 30 tablets in a polypropylene bottle, equipped with a dispenser and a stopper containing moisture absorbing gel.

1 bottle (14 and / or 30 tablets) with instructions for medical use and a cardboard box with the control of the first autopsy.

Packing for hospitals:

To 30 tablets into a polypropylene bottle equipped with a dispenser and a stopper containing a moisture absorbing gel.

For 3 bottles of 30 tablets with instructions for medical use in a pack of cardboard with the control of the first autopsy.

For 30 bottles of 30 tablets in a cardboard pallet for vials with instructions for medical use in a cardboard box with the control of the first autopsy.

Storage conditions:

Special storage conditions are not required.

Shelf life:

3 years.

Not apply at the expiration date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-010489/08

Date of registration:24.12.2008

The owner of the registration certificate:Servier LaboratoriesServier Laboratories France

Manufacturer: & nbsp

SERDIK, LLC Russia

Les Laboratoires Servier Industrie France

Representation: & nbspServier Laboratories Servier Laboratories France

Information update date: & nbsp20.10.2015

Illustrated instructions

Instructions

Noliprel® A forte (Noliprel® A forte)