Expiration date: 04/2026

ATX

C09BA04 Perindopril in combination with diuretics

Pharmacological group

Combined antihypertensive agent (ACE inhibitor + diuretic) [ACE Inhibitors in combinations]

Nosological classification (ICD-10)

E11 non-insulin-dependent diabetes mellitus

I10 Essential (primary) hypertension

Composition

Tablets, film-coated

1 tablet contains active substances:

perindopril arginine 2, 5 mg (corresponding to 1, 6975 mg of perindopril)

indapamide 0, 625 mg

excipients: carboximetilkrahmal sodium (type A) — 2, 7 mg; silicon dioxide colloidal anhydrous — 0, 27 mg, lactose monohydrate — 74, 455 mg, magnesium stearate — 0, 45 mg, maltodextrin — 9 mg

shell film: macrogol 6000 is 0: 087 mg premix for plastic shell white SEPIFILM 37781 RBC (glycerol — 4, 5%, hypromellose — 74, 8%, macrogol 6000 — 1, 8%, magnesium stearate — 4, 5%, titanium dioxide (E171) — 14, 4%) — 2, 913 mg

Description pharmaceutical form

Oblong tablets, film-coated, white, scored on both sides.

Pharmacological action

Pharmacological effect - inhibiting agents, hypotensive, diuretic.

Pharmacodynamics

Noliprel® A — combination drug containing perindopril arginine and indapamide. Pharmacological properties of the drug Noliprel® A combine the individual properties of each component.

1. Mechanism of action

Noliprel® A

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 (ACE inhibitor).

ACE, or kininase II is ectopeptidases, which carries out the conversion of angiotensin I to the vasoconstrictor substance angiotensin II and destruction of bradykinin, has a vasodilator effect, to inactive geptapeptida. The result of perindopril:

• reduces aldosterone secretion,
  
• on the principle of negative feedback increases renin activity in plasma,
  
• long-term use reduces peripheral vascular resistance, mainly due to the operation of vessels in the muscles and the kidneys. These effects are not accompanied by a delay of sodium ions and fluid or the development of reflex tachycardia.
  

Perindopril normalizes myocardium, reducing preload and afterload.

In the study of hemodynamics in patients with chronic heart failure were identified:

• reduction of filling pressure in the left and right ventricles of the heart,
  
• lower SVR
  
• increased cardiac output,
  
• increased muscle peripheral blood flow.
  

Indapamide

Indapamide belongs to the group of sulfonamides, pharmacologically similar to thiazide diuretica. Indapamide inhibits the reabsorption of sodium ions in the cortical segment of the loop of Henle, which leads to the increased secretion by the kidneys of sodium ions, chlorine and, to a lesser extent of potassium ions, and magnesium, thereby increasing urine output and lowering of blood pressure.

2. Antihypertensive effect

Noliprel® A

Noliprel® A has a dose-dependent antihypertensive effect both on DBP and garden standing and lying down. The antihypertensive effect persists for 24 h. a Stable therapeutic effect develops in less than 1 month from the start of therapy and is not accompanied by tachycardia. Discontinuation of treatment does not cause withdrawal syndrome.

Noliprel® A reduces the degree of left ventricular hypertrophy (GTLI), improves elasticity of arteries, reduces PR, no effect on lipid metabolism (total cholesterol, HDL cholesterol and LDL cholesterol, triglycerides).

Proven effect of combination of perindopril and indapamide on HTLJ in comparison with enalapril. In patients with arterial hypertension and GTLI, treated with erbumine of perindopril 2 mg (equivalent to 2, 5 mg of perindopril arginine) /indapamide 0, 625 mg or with enalapril at a dose of 10 mg once a day, and with increasing doses of perindopril erbumine to 8 mg (equivalent to 10 mg perindopril arginine) and indapamide 2 5 mg or enalapril 40 mg once a day, noted a significant decrease in left ventricular mass (IMLI) in the perindopril/indapamide than with enalapril group. The most significant impact on IMLI noted in the application erbumine of perindopril 8 mg/indapamide 2. 5 mg.

Also noted a more pronounced antihypertensive effect on the background of combination therapy with perindopril and indapamide compared with enalapril.

In patients with diabetes mellitus type 2 (average age 66 years, a body mass index of 28 kg/m2, glycated hemoglobin (HbA1c) — 7, 5%, AD — 145/81 mm Hg. calendar) studied the effect of a fixed combination of perindopril/indapamide on major micro - and macrovascular complications in addition to standard therapy glycemic control, and the strategy of intensive glycemic control (GCI) (target HbA1c <, 6, 5%). p="">,

In 83% of patients had arterial hypertension, 32 and 10% of macro - and microvascular complications, 27% — microalbuminuria. The majority of patients at the time of inclusion in the study were receiving hypoglycemic therapy, 90% of patients — hypoglycemic agent for oral administration (47% of patients in monotherapy, and 46% and therapy with two drugs, 7% — therapy with three drugs). 1% of patients received insulin therapy, 9% — only therapy. Sulfonylureas took 72% of patients, Metformin — 61%. As concomitant therapy 75% of patients received antihypertensive drugs, 35% of patients, lipid-lowering products (mainly inhibitors of HMG-COA reductase (statins) is 28%), acetylsalicylic acid as antiplatelet agents and other antiplatelet funds (47%).

After a 6 weeks introductory period, during which patients received therapy with perindopril/ indapamida, they were distributed to the group standard of glycemic control or in the group GCI (gliclazide® MW with the possibility of increasing doses to a maximum of 120 mg/day or addition of other hypoglycaemic agents).

In the group GCI (average duration of follow — 4, 8 years, average HbA1c — 6, 5%) compared with the group of standard control (mean HbA1c — 7, 3%) shows a significant 10% reduction of relative risk of the combined frequency of macro - and microvascular complications.

The advantage was achieved by a significant reduction in the relative risk of major microvascular complications by 14%, the occurrence and progression of nephropathy by 21%, microalbuminuria by 9%, macroalbuminuria 30% and development of complications in the kidney by 11%.

Advantages of antihypertensive therapy did not depend on the benefits achieved against the background of the GCI.

Perindopril

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

Antihypertensive effect of the drug reaching a maximum after 4-6 h after a single oral administration and persists for 24 h after 24 h after ingestion observed expressed (80%) the residual inhibition of the enzyme.

Perindopril has antihypertensive effect in patients with both low and normal renin activity in blood plasma.

Co-administration of thiazide diuretics increases the severity of antigipertenzivnogo actions. In addition, the combination of ACE inhibitor and thiazide diuretic that also reduces the risk of hypokalemia in patients receiving diuretics.

Indapamide

The antihypertensive effect is evident when using the drug in doses that have a minimal diuretic effect.

The antihypertensive action of indapamide is associated with improved elastic properties of large arteries, a decrease in systemic vascular resistance.

Indapamide reduces GTLI, does not affect the concentration of lipids in plasma: triglycerides, total cholesterol, LDL, HDL, carbohydrate metabolism (including patients with diabetes mellitus).

Pharmacokinetics

The combination of perindopril and indapamide does not change their pharmacokinetic characteristics compared to the separate administration of these drugs.

Perindopril

When administered perindopril is rapidly absorbed. The bioavailability is 65-70%.

Approximately 20% of the total quantity of perindopril absorbed is converted into perindoprilat, the active metabolite. Taking the drug during meals accompanied by a decrease of metabolism of perindopril to perindoprilat (this effect has no significant clinical value).

Cmax of perindoprilat in plasma achieved through 3-4 h after ingestion.

Relationship with blood plasma proteins is less than 30% and depends on the concentration of perindopril in blood.

Dissociation of perindoprilat bound with APF, slowed. As a result, the effective T1/2 consists 25 h. reappointment of perindopril does not cumulation and T1/2 Perindoprilat for reproduction corresponds to the period of its activity, thus the equilibrium state is achieved after 4 days.

Perindoprilat is eliminated from the body by the kidneys. T1/2 is 3-5 h. metabolite

Elimination of perindoprilat slowed in the elderly and patients with cardiac and renal failure.

Dialysis clearance of perindoprilat is 70 ml/min.

Pharmacokinetics of perindopril altered in patients with cirrhosis of the liver: the hepatic clearance is decreased in 2 times. However, the number of perindoprilat formed is not reduced, so that changes in dose is not required.

Perindopril crosses the placenta.

Indapamide

Indapamide is rapidly and completely absorbed from the gastrointestinal tract.

Cmax of the drug in the blood plasma observed 1 hour after ingestion.

Relationship with blood plasma proteins is 79%.

T1/2 is 14-24 h (on average 19 h). Re the drug does not lead to its accumulation in the body. Write mainly kidneys (70% of the administered dose) and via the bowel (22%) in the form of inactive metabolites.

The pharmacokinetics of the drug is not altered in patients with renal insufficiency.

The testimony of the drug Noliprel® A

essential hypertension,

patients with arterial hypertension and diabetes mellitus type 2 to reduce the risk of developing microvascular complications (in the kidneys) and macrovascular complications from cardiovascular disease.

Contraindications

• hypersensitivity to perindopril and other ACE inhibitors, indapamide, to other sulfonamides and to other auxiliary components included in the composition of the drug,
  
• a history of angioedema (including in patients receiving other ACE inhibitors),
  
• hereditary/idiopathic angioneurotic edema, hypokalemia, severe renal insufficiency (Cl creatinine less than 30 ml/min),
  
• the stenosis of the artery to a solitary kidney, bilateral renal artery stenosis,
  
• severe liver failure (including encephalopathy),
  
• concomitant use of drugs that lengthen the QT interval,
  
• concurrent use of antiarrhythmic agents that can cause arrhythmia type "pirouette" (see "Interactions"),
  
• pregnancy
  
• the lactation period.
  

Together is not recommended taking the drug with potassium-sparing diuretics, potassium supplements and lithium and the appointment of patients with high content of potassium in the blood plasma.

Due to the lack of sufficient clinical experience Noliprel® A should not be used in patients on hemodialysis, and in patients with untreated decompensated heart failure.

With caution (see also "Special instructions" and "Interaction"): systemic diseases of connective tissue (incl. systemic lupus erythematosus, scleroderma) and therapy with immunosuppressive agents (risk of neutropenia, agranulocytosis), oppression kostnomozgovy blood, smirennyi (reception dioretikov, salt-free diet, vomiting, diarrhea, hemodialysis), angina, cerebrovascular disease, renovascular hypertension, diabetes, congestive heart failure (stage IV NYHA classification), hyperuricemia (especially accompanied by gout and urate nephrolithiasis a), labile blood pressure, older age, hemodialysis using a high-flow membranes or desensitization, before the procedure, LDL apheresis, condition after kidney transplantation, aortic valve stenosis/hypertrophic cardiomyopathy, the presence of lactase deficiency, galactosemia or syndrome of glucose-galactose malabsorption, the age of 18 years (efficacy and safety not established).

Application of pregnancy and breastfeeding

The drug is contraindicated in pregnancy.

When planning pregnancy or during the attack on the background of the drug Noliprel® A you should immediately stop taking the drug and prescribe a different antihypertensive therapy.

You should not use the drug Noliprel® in the first trimester of pregnancy.

Appropriate controlled studies 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 intake of ACE inhibitors does not lead to fetal malformations associated with fetotoksicnosti, but exclude fetotoksicheskoe the effects of the drug impossible.

Noliprel® A is contraindicated in II and III trimester of pregnancy (see "Contraindications").

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

Prolonged use of thiazide diuretics in the third trimester of pregnancy can cause hypovolemia in the mother and reduced uteroplacental blood flow, which leads to placental ischemia and growth retardation. In rare cases in patients receiving diuretics shortly before delivery in newborns develops hypoglycemia and thrombocytopenia.

If the patient received the drug Noliprel® A during the II or III trimester of pregnancy, ultrasound is recommended to the newborn to assess the condition of the skull and renal function.

Newborns of mothers who received therapy with ACE inhibitors, there may be hypotension, in connection with which, newborns should be under close medical supervision.

Lactation

Noliprel® A is contraindicated in lactation.

Unknown, selects whether perindopril in breast milk.

Indapamide is excreted in breast milk. The thiazide diuretics cause a decrease in the amount of breast milk or suppression of lactation. The newborn may develop hypersensitivity to sulfonamide derivatives, hypokalemia and nuclear icterus.

Since the use of perindopril and indapamide in lactation can cause severe complications in infants, it is necessary to evaluate the importance of therapy for the mother and make the decision on the termination of breastfeeding or drug.

Side effects

Perindopril has an inhibitory effect on the RAAS and decreases the excretion of potassium ions by the kidneys in patients receiving indapamide. 4% of patients on the background of the drug Noliprel® A is developing hypokalemia (potassium level less than 3, 4 mmol/l).

Frequency of adverse reactions that can occur during therapy, as shown in the following gradation: very often (>, 1/10), often (>, 1/100, <, 1 10="">, 1/1000, <, 1 100="">, 1/10000, <, 1 1000="" 1="" 10000="" p="">,

From the blood and lymphatic system: very rarely — thrombocytopenia, leucopenia/neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia.

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

CNS: often — paresthesia, headache, dizziness, asthenia, vertigo, rarely — sleep disturbance, mood lability, very rarely confusion unspecified frequency faint.

On the part of the organ of vision: often — blurred vision.

On the part of the organ of hearing: often noise in the ears.

From the CCC: often — expressed lower AD, including orthostatic hypotension, very rarely — violations heart rhythm, including bradycardia, ventricular tachycardia, atrial fibrillation, and angina and myocardial infarction, possibly due to excessive blood pressure lowering in patients at high risk (see "Special indications"), unspecified frequency — arrhythmia type "pirouette" (possibly with a fatal outcome — see "Interactions").

The respiratory system of the chest and mediastinum: often — on a background of ACE inhibitors may occur, dry cough, and long lasting while receiving drugs in this group and disappearing after their withdrawal, shortness of breath, rarely bronchospasm; very rarely eosinophilic pneumonia, rhinitis.

From the digestive system: often — dry mucous membranes of the mouth, nausea, vomiting, abdominal pain, epigastric pain, disorders of taste perception, loss of appetite, dyspepsia, constipation, diarrhea; very rarely angioedema of the intestine, cholestatic jaundice, pancreatitis unspecified frequency — hepatic encephalopathy in patients with hepatic impairment (see "Contraindications", "Special instructions"), hepatitis.

On the part of the skin and subcutaneous fat: often — skin rash, pruritus, maculopapular rash rarely angioedema of the face, lips, extremities, mucous membrane of the tongue, vocal folds and/or larynx, urticaria (see "Special indications"), hypersensitivity reactions in patients predisposed to obstructive and allergic reactions, purpura, in patients with acute systemic lupus erythematosus may worsen the disease, rarely — erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome. Cases of photosensitivity reactions (see "Special instructions").

From the side of musculoskeletal system and connective tissue: often — muscle spasms.

From the urinary system: rarely — renal failure, very rarely — acute renal failure.

From the reproductive system: rarely — impotence.

General disorders and symptoms: often — asthenia, uncommon — increased perspiration.

Laboratory parameters: hyperkalemia, often transient, slight increase in creatinine concentration in urine and in blood plasma, passing after discontinuation of therapy, most patients with renal artery stenosis, in the treatment of hypertension and diuretics in case of renal failure, rarely hypercalcemia, unspecified frequency — increase QT????????? on ECG (see "Special indications"), increasing the concentration of uric acid and glucose in the blood, increased liver enzymes, hypokalemia, particularly significant for patients at risk (see "Special instructions"), hyponatremia and hypovolemia, leading to dehydration and orthostatic hypotension. Simultaneous gipohloremia can lead to metabolic alkalosis compensatory nature (the likelihood and severity of this effect is low).

Side effects noted during clinical trials

Noted during the ADVANCE study side effects are consistent with previously established safety profile of the combination of perindopril and indapamide. Serious adverse events were noted in some patients in the studied groups: hyperkalemia (0, 1%), acute renal failure (0, 1%), hypotension (0, 1%), and cough (0, 1%).

3 patients in group therapy with perindopril/indapamide was observed angioedema (versus 2 in the placebo group).

Interaction

1. Combinations not recommended for use

Lithium drugs: with simultaneous use of drugs lithium and ACE inhibitors may occur reversible increase of lithium concentration in blood plasma and related toxic effects. An additional purpose of thiazide diuretics may further increase the concentration of lithium and increase the risk of toxicity. Simultaneous application of a combination of perindopril and indapamide with lithium preparations is not recommended. When the need for such therapy should continuously monitor the lithium content in the blood plasma (see "Special instructions").

2. The drugs, the combination of which requires special attention and care

Baclofen: may increase hypotensive effect. You should control the AD and kidney function, if necessary, require dose adjustment of antihypertensive drugs.

NSAIDs, including high doses of acetylsalicylic acid (>3 g/day): appointment NSAIDs may reduce diuretic, natriuretic, and antihypertensive effects. When a significant loss of fluid may develop acute renal failure (due to a decrease in glomerular filtration rate). Before treatment it is necessary to compensate for the loss of fluid and to regularly monitor kidney function at the beginning of treatment.

3. The combination of meds that require attention

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

Corticosteroids, tetrakozaktid: decreased antihypertensive effect (water retention and sodium ions as a result of action of corticosteroids).

Other antihypertensives: may increase antihypertensive effect.

Perindopril

1. Combinations not recommended for use

Potassium-sparing diuretics (amiloride, spironolactone, triamterene) and potassium supplements: inhibitors Tapfumaneyi the loss of potassium by the kidneys, caused by the diuretic. Potassium-sparing diuretics (eg, spironolactone, triamterene, amiloride), potassium supplements and potassium-containing salt substitutes may lead to significant increase in the concentration of potassium in the blood serum up to a lethal outcome. If necessary, the simultaneous use of ACE inhibitor and the above-mentioned drugs (in the case of confirmed hypokalemia), caution and conduct regular monitoring of potassium in the blood plasma and ECG parameters.

2. The combination of drugs that require special attention

Hypoglycemic drugs for oral administration (sulfonylureas) and insulin: the following effects were described for captopril and enalapril. ACE inhibitors may increase hypoglycemic effect of insulin and sulfonylurea derivatives in patients with diabetes. Hypoglycemia is very rare (by increasing glucose tolerance and reducing insulin requirements).

3. The combination of meds that require attention

Allopurinol, cytostatic and immunosuppressive means, corticosteroids (when administered systemically) and procainamide: concomitant use with ACE inhibitors may be accompanied by increased risk of leukopenia.

Funds for General anesthesia: concomitant use of ACE inhibitors and funds for General anesthesia may lead to increased antihypertensive effect.

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

Gold drugs: the ACE inhibitors, including perindopril, in patients receiving V/preparat gold (aurothiomalate sodium) was described a complex of symptoms including: flushing of skin, nausea, vomiting, hypotension.

Indapamide

1. The combination of drugs that require special attention

Drugs that can cause arrhythmia type "pirouette": due to the risk of hypokalemia, caution should be exercised with simultaneous use of indapamida with drugs, can cause arrhythmia type "pirouette", for example, antiarrhythmic drugs (quinidine, hydrogenizing, disopyramide, amiodarone, dofetilide, ibutilide, bretilia tosylate, sotalol), certain antipsychotics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, sultoprid, tiapride), butyrophenones (droperidol, haloperidol), other neuroleptics (pimozide), other drugs, such as bepridil, cisapride, diphemanil methylsulfate, erythromycin (in/in), halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, vincamine has (in/in), methadone, astemizole, terfenadine. Should avoid the simultaneous application of the above drugs, the risk of gipokaliemii and, if necessary, to carry out its correction, monitor the QT interval.

Drugs that can cause hypokalaemia: amphotericin b (in/in), the SCS and mineralokortikosteroidy (in the system designation), tetrakozaktid, laxatives, stimulating intestinal motility: increased risk of hypokalemia (additive effect). It is necessary to control the amount of potassium in the blood plasma, if necessary, its correction. Special attention should be given to patients while receiving cardiac glycosides. You should use laxatives, does not stimulate intestinal motility.

Cardiac glycosides: hypokalemia enhances the toxic effect of cardiac glycosides. While the use of indapamide and cardiac glycosides should monitor the content of potassium in the blood plasma and ECG and, if necessary, to adjust therapy.

2. The combination of meds that require attention

Metformin: a functional renal failure that may occur in patients receiving diuretics, especially loop, while the appointment of Metformin increases risk of lactic acidosis. You should not use Metformin if the creatinine concentration in plasma exceeds 15 mg/l (135 µmol/l) in men and 12 mg/l (110 µmol/l) in women.

Iodinated contrast agents: dehydration in patients receiving diuretic drugs increases the risk of developing acute renal failure, especially when using high doses of iodinated contrast agents. Before use of iodinated contrast agents, patients must compensate for loss of fluid.

Calcium salts: while the appointment may develop hypercalcemia due to reduction of excretion of calcium ions by the kidneys.

Cyclosporine: may increase creatinine concentration in blood plasma without changes in the concentration of cyclosporine in the blood plasma, even at normal water content and sodium ions.

Method of application and doses

Inside, preferably morning, before eating.

Essential hypertension

1 table. drug Noliprel® A 1 time per day.

Possible drug begin with the selection of doses of single drugs. In case of clinical necessity, you can consider appointing a combination of drug therapy Noliprel® A immediately after monotherapy.

Patients with arterial hypertension and diabetes mellitus type 2 to reduce the risk of developing microvascular complications (in the kidneys) and macrovascular complications from cardiovascular disease

1 table. Noliprel® A 1 time per day. After 3 months of therapy, with good tolerability, may increase dose to 2 table. Noliprel® A 1 time per day (or 1 table. Noliprel® A Forte 1 per day).

Elderly patients

Should be prescribed drug treatment after control of renal function and blood pressure.

Renal failure

The drug is contraindicated in patients with severe renal insufficiency (Cl creatinine less than 30 ml/min).

For patients with moderate renal insufficiency (Cl creatinine 30-60 ml/min) recommended starting therapy with necessary doses of drugs (as monotherapy) included in Noliprel® A.

Patients with Cl creatinine equal to or greater than 60 ml/min, dose adjustment is not required. During therapy requires regular monitoring of creatinine and potassium in blood plasma.

Hepatic failure (see "Contraindications", "Special instructions", "Pharmacokinetics")

The drug is contraindicated in patients with severe hepatic insufficiency.

When moderate hepatic insufficiency dose adjustment is not required.

Children and adolescents

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

Overdose

Symptoms: the most likely symptom of overdose — expressed lower AD, sometimes in combination with nausea, vomiting, cramps, dizziness, drowsiness, confusion, and oliguria, which can turn into anuria (as a result of hypovolemia). You may also experience electrolyte disorders (hyponatremia, hypokalemia).

Treatment: measures of emergency aid for reduced excretion of the drug from the body: gastric lavage and/or the appointment of activated charcoal, followed by restoration of water and electrolyte balance.

With a significant decrease in blood pressure should transfer the patient in the supine position with raised legs. If necessary, correction of hypovolemia (e.g., in/in infusion of 0 9% sodium chloride solution). Perindoprilat, the active metabolite of perindopril, can be removed from the body by dialysis.

Special instructions

Noliprel® A

The use of the drug Noliprel® 2. 5 mg + 0, 625 mg, containing a low dose of indapamide and perindopril arginine, is not accompanied by a significant reduction in the incidence of side effects, except hypokalemia, compared with perindopril and indapamide least allowed doses (see "Side effects"). At the beginning of therapy with two antihypertensive drugs that the patient has not received previously, it is impossible to exclude an increased risk of developing idiosyncrasies. Careful observation of the patient allows to reduce this risk to a minimum.

Violation of kidney function

Therapy is contraindicated in patients with severe renal insufficiency (Cl creatinine less than 30 ml/min). Some patients with hypertension without previous apparent violations of renal function during therapy may appear laboratory signs of functional renal failure. In this case, the treatment should be discontinued. Further, it is possible to resume the combination therapy, using lower doses of the drugs or use drugs in monotherapy.

Such patients requires regular monitoring of potassium and creatinine in blood serum after 2 weeks after start of treatment and later every 2 months. Renal failure often occurs in patients with severe congestive heart failure or underlying impaired renal function, i.e. renal artery stenosis.

Hypotension and disruption of water and electrolyte balance

Hyponatremia is associated with risk of sudden arterial hypotension (especially in patients with stenosis of the artery to a solitary kidney and bilateral renal artery stenosis). Therefore, the dynamic observation of patients should pay attention to possible symptoms of dehydration and reduction of electrolytes in the blood plasma, for example after diarrhea or vomiting. Such patients requires regular monitoring of electrolytes of blood plasma.

When expressed arterial hypotension may be required in/in the introduction of 0 9% sodium chloride solution.

Transient hypotension is not a contraindication to continue therapy. After the restoration of the BCC and BP can resume therapy using the lowest dose of drugs or use drugs in monotherapy.

The level of potassium

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

Excipients

Note that in the composition of excipients product contains lactose monohydrate. You should not assign Noliprel® A patients with hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption.

Drugs lithium

Simultaneous application of a combination of perindopril and indapamide the drug lithium is not recommended (see "Contraindications", "Interaction").

Perindopril

Neutropenia/agranulocytosis

The risk of neutropenia in patients receiving ACE inhibitors is dose dependent and depends on accept drugs and the presence of comorbidities. Neutropenia rarely occurs in patients without concomitant diseases, but the risk is increased in patients with impaired renal function, especially against the background of systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma). After the abolition of ACE inhibitors signs of neutropenia are themselves.

For the avoidance of such reactions is recommended to strictly follow the recommended dose. In the appointment of ACE inhibitors in this group of patients should be carefully weighed factor in the risk/benefit.

Angioedema (angioedema)

When receiving ACE inhibitors, including the perindopril, in rare cases, there may be development of angioedema face, extremities, lips, tongue, glottis and/or larynx. If you have symptoms of a reception of perindopril should be stopped immediately and the patient should be observed for as long as signs of edema does not disappear completely. If the swelling affects only the face and lips, its manifestations are usually alone, although to treat his symptoms can be used antihistamines.

Angioneurotic edema, accompanied by laryngeal edema, can lead to death. Swelling of the tongue, glottis or larynx may cause airway obstruction. When you see these symptoms should immediately enter n/a epinephrine (adrenaline) at a dilution of 1:1000 (0, 3 or 0, 5 ml) and/or to ensure patency of respiratory tract.

In patients with a history of angioedema was noted, was not associated with intake of ACE inhibitors may be at increased risk of its development when taking drugs in this group (see "Contraindications").

In rare cases during therapy with ACE inhibitors develops angioedema of the intestine.

Anaphylactoid reaction during desensitization

There are separate reports on the development of long-term, life-threatening anaphylactoid reactions patients receiving ACE inhibitors during desensitizing treatment with Hymenoptera venom (bees, wasps). ACE inhibitors should be used with caution in prone to allergic reactions in patients undergoing desensitization. Should avoid prescribing ACE inhibitor patients receiving immunotherapy with Hymenoptera venom. However, anaphylactoid reactions can be avoided by suspending ACE inhibitor at least 24 hours prior to the procedure.

Anaphylactoid reaction during apheresis LDL

In rare cases, patients receiving ACE inhibitors, when performing LDL apheresis using dextran sulfate, during hemodialysis using a high-flow membranes can develop life-threatening anaphylactoid reactions. To prevent anaphylactoid reactions should temporarily discontinue treatment with ACE inhibitor for at least 24 hours before the apheresis procedure.

Cough

The therapy of enzyme inhibitor may experience a dry cough. The long-term remains cough on a background of reception of preparations of this group and disappears after their cancellation. When the patient dry cough should be aware of the possible iatrogenic nature of this symptom. If the attending physician believes that treatment with ACE inhibitor is necessary for the patient, the drug can be continued.

Children and adolescents

The drug should not be administered to children and adolescents under 18 years because of the lack of evidence of efficacy and safety of the use of perindopril as monotherapy or in combination therapy in patients in this age group.

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

In some pathological conditions can be observed a significant activation of the RAAS, especially in severe hypovolemia and decrease in the level of electrolytes in the blood plasma (on the background salt-free diet or prolonged treatment with diuretics), patients with baseline low blood pressure, with bilateral renal artery stenosis or stenosis of the artery only kidneys, chronic heart failure or cirrhosis with edema and ascites.

The use of ACE inhibitors causes a blockade of the system and therefore may be accompanied by sharp decrease in blood pressure and/or increased creatinine in blood plasma, indicating the development of functional renal failure. These phenomena often observed when taking the first dose or during the first two weeks of therapy. Sometimes this condition develops acutely and in other periods of therapy. In such cases, resuming treatment is recommended to use the drug in lower dose and then gradually increase the dose.

Elderly patients

Before taking the drug it is necessary to evaluate the functional activity of the kidneys and the concentration of potassium in the blood plasma. At the beginning of therapy, dose picked, given the degree of blood pressure reduction, especially in the case of dehydration and loss of electrolytes. Such measures allow to avoid a sharp decline in blood pressure.

Atherosclerosis

The risk of hypotension exists in all patients, but special care should be observed in applying the drug in patients with coronary artery disease and cerebrovascular insufficiency. In such patients, treatment should begin with low doses.

Patients with renovascular hypertension

Treatment of renovascular hypertension is revascularization. However, the use of ACE inhibitors has a beneficial effect in this group of patients awaiting surgery, and in the case where surgical intervention is impossible.

Drug treatment Noliprel® A patients with diagnosed or suspected bilateral renal artery stenosis or stenosis of the artery to a solitary kidney should begin with a low dose in the hospital, monitoring renal function and potassium concentration in blood plasma. Some patients may develop a functional renal failure, which disappears when the drug is removed.

Other risk groups

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

Patients with arterial hypertension with coronary artery disease should not stop taking beta-blockers: ACE inhibitors should be used in conjunction with beta-blockers.

Anemia

Anemia can develop in patients after kidney transplantation or in persons on hemodialysis. The decrease in hemoglobin concentration the higher was his initial figure. This effect apparently is not dose-dependent, but may be associated with the mechanism of action of ACE inhibitors.

A slight decrease in hemoglobin concentration occurs within the first 6 months, then it remains stable and fully recovered after drug withdrawal. In such patients, treatment can be continued, but hematological tests should be carried out regularly.

Surgery/General anesthesia

The use of ACE inhibitors in patients undergoing surgery with the use of General anesthesia, may lead to a marked reduction of HELL, especially when you use the funds for General anesthesia, providing gipotenzivne effect.

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

Aortic stenosis/hypertrophic cardiomyopathy

ACE inhibitors must be careful not be given to patients c obstruction of the output tract of the left ventricle.

Liver failure

In rare cases in patients receiving ACE inhibitors occurs cholestatic jaundice. With the progression of this syndrome possible the rapid development of hepatic necrosis, sometimes fatal. The mechanism of development of this syndrome is unclear. When the jaundice or a significant increase in liver enzymes in patients receiving ACE inhibitors should stop taking the drug and contact your doctor (see "Side effects").

Indapamide

In the presence of impaired hepatic function receiving and tiazidopodobnye thiazide diuretics may cause hepatic encephalopathy. In this case, you should immediately stop taking the drug.

Fluid and electrolyte balance

The contents of sodium ions in blood plasma. Before treatment should determine the content of sodium ions in blood plasma. On the background of the drug should regularly monitor this indicator. All diuretic drugs can cause hyponatremia, which sometimes leads to serious complications. Hyponatremia at the initial stage may not be accompanied by clinical symptoms, therefore requires regular laboratory monitoring. More frequent monitoring of the content of sodium ions is indicated for patients with cirrhosis and the elderly (see "Side effects" and "Overdose").

The content of potassium ions in the blood plasma. Therapy thiazide diuretics and tiazidopodobnye associated with the risk of gipokaliemii. It is necessary to avoid hypokalemia (less than 3, 4 mmol/l) in the following categories of patients from high-risk groups: the elderly, or malnourished patients receiving concomitant medication, patients with liver cirrhosis, peripheral edema or ascites, coronary artery disease, heart failure. Hypokalemia enhances toxic effects of cardiac glycosides and increases the risk of arrhythmias.

A high-risk group also includes patients with increased QT interval, it does not matter, caused by this increase in congenital causes or the action of drugs.

Hypokalemia as bradycardia, promotes severe heart rhythm disorders, especially arrhythmia type "pirouette", which can be fatal. In all the cases mentioned above, a need for more regular monitoring of the content of potassium ions in blood plasma. The first measurement of the concentration of potassium ions must be held during the first weeks of therapy.

The detection of hypokalemia must be assigned the appropriate treatment.

The contents of calcium ions in the blood plasma. Tiazidopodobnye and thiazide diuretics reduce the excretion of calcium by the kidneys, resulting in a slight and temporary increase in the calcium concentration in the blood plasma. Marked hypercalcemia may be the result of previously undiagnosed hyperparathyroidism. Before the study, parathyroid function should stop taking diuretics.

The glucose content in the blood plasma. It is necessary to control the level of blood glucose in patients with diabetes, especially in the presence of hypokalemia.

Uric acid. In patients with increased uric acid levels in plasma during therapy may increase the incidence of gout attacks.

Diuretic and renal function. Tiazidopodobnye and thiazide diuretics effective in full measure only in patients with normal or slightly impaired kidney function (the content of creatinine in plasma in adults below 25 mg/l or 220 µmol/l).

At the beginning of treatment in patients with diuretic because of hypovolemia and hyponatremia may be a temporary decrease in glomerular filtration rate and an increase in the concentration of urea and creatinine in blood plasma. This transitory functional renal insufficiency is not dangerous for patients with intact renal function, however, in patients with renal insufficiency and its intensity may increase.

Photosensitivity

In patients receiving thiazide diuretics and tiazidopodobnye reported cases of development of photosensitivity reactions. In the case of reactions of photosensitivity in patients receiving the drug should be discontinued treatment. If necessary, continue diuretic therapy is recommended to protect your skin from exposure to sunlight or artificial UV rays.

Athletes

Indapamide can give a positive reaction at carrying out of doping control.

Effects on ability to drive or mechanical devices. The effect of the substances included in the drug Noliprel® A does not lead to violation of emotional reactions. However, some people in response to decreased blood pressure may develop different individual reactions, especially at the beginning of therapy or when added to therapy with other antihypertensive drugs. In this case, the ability to drive or other mechanisms can be reduced.

Release form

Tablets, film-coated, 2. 5 mg + 0, 625 mg.

At 14 or 30 pills in a bottle made of polypropylene, equipped with a spout and a stopper containing a desiccant gel.

1 bottle (14 and/or 30 tablets) or 3 vials (30 pills) with instructions for medical use in the stack cartons with tamper-evident.

During packaging (packaging)/manufacturing in the Russian company OOO "Serdix":

At 14 or 30 pills in a bottle made of polypropylene, is provided with a spout and a stopper containing a desiccant gel.

1 bottle (14 and/or 30 tablets) instructions for medical use in the stack cartons with tamper-evident.

Packaging for hospitals: 30 pills in a bottle made of polypropylene, is provided with a spout and a stopper containing a desiccant gel.

For 3 bottles of 30 pills with instructions for medical use in the stack cartons with tamper-evident.

30 bottles of 30 tablets in a cardboard tray full of vials with instructions for medical use in cardboard carton with tamper-evident.

Conditions of supply of pharmacies

According to the recipe.

Storage conditions of the drug Noliprel® A

Special storage conditions are required.

Keep out of reach of children.

The shelf life of the drug Noliprel® A

3 years.

Do not use after the expiry date printed on the package.