active ingredients: perindopril arginine, indapamide;
1 tablet contains 5 mg of perindopril arginine, which corresponds to 3,395 mg of perindopril and 1,25 mg of indapamide;
auxiliary substances: lactose, magnesium stearate (E 470 V), maltodextrin, silicon colloidal dioxide (E 551), sodium starch (type a), macrogol 6000, glycerin (E 422), hypromellose ( E 464), titanium dioxide (E 171).
Basic physico-chemical properties:
manufactured by "Laboratories Servier industry", France: white, oblong tablets, coated with a film
production " Servier (Ireland) industries Ltd.", Ireland: white, oblong tablets coated with a film, embossed "" on the one hand.
Perindopril and diuretics. Code ATX C09B A04.
Noliprel arginine Forte is a combination of arginine perindopril ACE inhibitor and sulfonamide diuretics of indapamide. Its pharmacological effect is due to the properties of each component (perindopril and indapamide) and their additive synergism.
mechanism of action
Noliprel arginine Forte has an additive synergistic effect of two antihypertensive components.
The mechanism of action of perindopril
Perindopril - an ACE inhibitor, which converts angiotensin I to angiotensin II (a vasoconstrictor substance), additionally stimulates aldosterone secretion by the adrenal cortex and breakdown of bradykinin (vazodilatiruyuschego substance) to the inactive heptapeptide. Inhibition of ACE leads to: reduced secretion of aldosterone; increased renin activity in the blood plasma, while aldosterone has no negative effects; reducing the overall peripheral resistance of blood vessels due to the predominant influence on the blood vessels of muscles and kidneys while there is no delay of water and salts or reflex tachycardia, even in the case of long-term treatment. In addition, perindopril reduces blood pressure (BP) in patients with normal and low renin in the blood plasma. Perindopril acts through its active metabolite perindoprilat. The other metabolites are inactive. Perindopril reduces the work of heart via vasodilatory effect on veins (possibly due to changes in the metabolism of prostaglandins) - decrease preload, and reducing the total peripheral vascular resistance - decrease postnagruzki on the heart. Studies conducted involving patients with heart failure, proved that the use of perindopril leads to a reduction in filling pressure of the left and right ventricles, reduced total peripheral vascular resistance, increased cardiac output and improved cardiac index, an increase in regional blood flow in the muscles. Improves the performance of tests with physical activity.
The mechanism of action of indapamide
Indapamide is a sulfonamide derivative with an indole ring, pharmacologically related to thiazide diuretics. Indapamide inhibits reabsorption of sodium in the cortical segment of the kidneys. This increases the excretion of sodium and chlorides and to a lesser extent - potassium and magnesium in the urine, thus increasing urination and providing a hypotensive effect.
Noliprel Forte arginine has a dose-dependent hypotensive effect on systolic (SBP) and diastolic (DBP) blood pressure in patients with hypertension of any age who are in the supine position and standing. The antihypertensive effect of the drug lasts 24 hours. Blood pressure reduction is achieved in less than one month without the occurrence of tachyphylaxis; discontinuation of treatment does not cause withdrawal syndrome. In the course of clinical studies, it is proved that the simultaneous administration of perindopril and indapamide leads to a hypotensive effect of synergistic origin, which is the result of individual effects of the components of the drug.
PICXEL is a multicenter randomized double-blind controlled study, during which the results of echocardiography assessed the effect of a combination of perindopril and indapamide on left ventricular hypertrophy compared to enalapril in monotherapy. During the PICXEL STUDY, patients with arterial hypertension and left ventricular hypertrophy (with left ventricular mass index>120 g/m2 in men and>100 g/m2 in women) were randomized into two groups: one group of patients took 2 mg of perindopril tertbutylamine (equivalent to 2.5 mg of perindopril arginine)/0.625 mg of indapamide, the other - 10 mg of enalapril 1 once a day during the year. The doses were adapted according to the parameters of blood PRESSURE: the dose of perindopril tertbutylamine increased to 8 mg (equivalent to 10 mg of perindopril arginine), indapamide - up to 2.5 mg, enalapril-up to 40 mg 1 time per day. Drugs in the starting dose continued to take 34% of patients in the group of perindopril/indapamide (2 mg of perindopril and 0.625 mg of indapamide) and 20% in the group of enalapril (10 mg). Among all randomized patients at the end of treatment, the left ventricular mass index decreased significantly more in patients receiving perindopril/indapamide (-10.1 g/m2) than in the group of enalapril (-1.1 g/m2). The difference between the two groups was -8.3 (95% confidence interval [CI] from -11.5 to -5.0, p<0.0001). The best effect on reducing the left ventricular mass index was achieved by taking the maximum doses of perindopril/indapamide (10 mg/2.5 mg). Blood pressure decreased more effectively in the perindopril/indapamide group: the difference between the mean decrease in blood PRESSURE between the two groups of patients was -5.8 mm Hg. article (95% CI from to -7,9 -3,7, p<0.0001) and GARDEN -2,3 mm Hg. article (95% CI between -3.6 to -0.9, p = 0,0004) for the GAO.
ADVANCE - international multicenter randomized study with bi-factorial (2 ? 2) design, aimed at determining the benefits of lowering blood pressure by a fixed combination of perindopril/indapamide compared with placebo on the background of the current standard therapy (double blind comparison) and the advantages of the strategy of intensive control of glycemia (level HbAlc ? 6.5%) based on glyclazide MR (Diabeton MR) compared with the standard control of glycemia (PROBE design [prospective randomized open method]) on the impact on the main macro- and microvascular events in patients with type II diabetes . The primary end point consisted of the main macrovascular (cardiovascular death, non-lethal myocardial infarction, non-lethal stroke) and microvascular (new cases or worsening of nephropathy, retinopathy) events. The study involved 11140 patients with type II diabetes. The average age of patients was 66 years , BMI 28 kg/m2, duration of diabetes 8 years, HbAlc 7.5% and SAD/dad 145/81 mm Hg. art. Among them, 83% of patients had hypertension, 32% and 10% had a history of micro - and macro-vascular diseases in accordance and 27% had microalbuminuria. Concomitant therapy included drugs to reduce blood PRESSURE (75%), to reduce lipids (35%, mainly statins - 28%), acetylsalicylic acid or other antiplatelet drugs (47%). During the 6 weeks period for the introduction of the study patients received a combination of perindopril/indapamide and continued to take their usual hypoglycemic therapy. Further patients on a randomized basis they were assigned to receive placebo (n = 5571) or combination of perindopril/indapamide (n = 5569). Noliprel arginine Forte, 5 mg/1.25 mg, film-coated tablets, is not acceptable for starting therapy. Treatment was started with perindopril arginine 2.5 mg/indapamide 0,625 mg 1 tablet 1 time per day. After 3 months, provided good tolerance dose increased. That is, prescribed drug Noliprel arginine Forte, 5 mg/1.25 mg, film coated tablets, 1 tablet 1 time per day. Treatment for 4.3 years with a combination of perindopril/indapamide led to a significant decrease of 9% in the relative risk of primary endpoint indicators (95% CI [0.828; 0.996], p = 0.041). The advantages of treatment with perindopril/indapamide compared with placebo were due to: a significant decrease in the relative risk of total mortality by 14% (95% CI [0.75; 0.98], p = 0.025); a significant reduction in the relative risk of cardiovascular mortality by 18% (95% CI [0.68; 0.98], p = 0.027); a significant reduction in the relative risk of all types of renal complications by 21% (95% CI [0.74; To 0.86], p<0.001). In the subgroup of patients with arterial hypertension treated with perindoprilom/indapamide, there was a significant decrease in the relative risk of major macro - and microvascular complications by 9% (95% CI [0.82; 1.0], p = 0.052) compared with the placebo group. In the subgroup of patients taking perindopril/indapamide, compared with placebo group, it was also noted: a significant reduction in the relative risk of total mortality by 16% (95% CI [0.73; 0.97], p = 0.019); a significant reduction in the relative risk of cardiovascular mortality by 20% (95% CI [0.66; 0.97], p = 0.023); a significant reduction in the relative risk of all types of renal complications by 20% (95% CI [0.73; 0.87], p<0.001). The benefits of treatment aimed at lowering blood pressure, independent of the benefits achieved in patients treated in accordance with the strategy of intensive control of glycemia.
Pharmacodynamic effects associated with perindopril
Perindopril effectively reduces blood PRESSURE at all degrees of hypertension mild, moderate and severe. The decrease in SBP and DBP observed in the supine position and standing. The maximum antihypertensive effect occurs about 4-6 h after a single dose and persists for more than days. Perindopril has a high level of final blocking of the enzyme (approximately 80%) after 24 hours after ingestion. In patients who responded to treatment, normalization of blood PRESSURE is achieved in a month and remains without occurrence tachyphylaxises. Discontinuation of therapy is not accompanied by withdrawal syndrome. Perindopril has vasodilator properties and restores elasticity of the large arteries, corrects histomorphometric changes in resistance arteries and reduce left ventricular hypertrophy. The addition of thiazide diuretics, if necessary, leads to additional synergy. The combined use of ACE inhibitor and thiazide diuretic reduces the risk of hypokalemia, which may occur in the appointment of diuretics in monotherapy.
Pharmacodynamic effects associated with indapamide
When used as monotherapy indapamide has a antihypertensive effect, lasts 24 hours. This effect manifests itself in doses, in which the diuretic properties are minimal. Antihypertensive effect of indapamide is proportional to improving the elasticity of the arteries and reducing the resistance of arterioles and General peripheral vascular resistance. Indapamide reduces left ventricular hypertrophy. When the dose is exceeded, the antihypertensive effect of thiazide and thiazide-like diuretics reaches the plateau level, while the number of side effects increases. If the treatment is not effective enough, do not increase the dose. Moreover, as has been shown in studies of various durations (short, medium and long) involving patients with arterial hypertension, indapamide does not affect lipid metabolism (triglycerides, low and high density lipoproteins) and does not affect carbohydrate metabolism, even in patients with arterial hypertension and diabetes.
Pharmacokinetic properties of perindopril and indapamide in combination do not differ from the properties of these components in their individual application.
Pharmacokinetic properties of perindopril
Absorption and bioavailability. After taking perindopril quickly absorbed, the maximum concentration is reached after 1: 00. The half-life of perindopril from blood plasma is 1: 00. Since eating reduces the conversion of perindopril perindopril, and therefore decreases its bioavailability, perindopril arginine should be taken orally in a single dose in the morning before meals.
Distribution. The volume of distribution of unbound perindoprilat is approximately 0.2 l/kg. Binding of perindoprilat to plasma proteins of blood is 20%, mostly from the APF, and depends on the concentration.
Metabolism. Perindopril is a drug. So, 27% of the dose of perindopril to enter the bloodstream in the form of the active metabolite perindoprilat. In addition to active perindoprilat, perindopril forms 5 inactive metabolites. The maximum concentration of perindoprilat in blood plasma is achieved after 3-4 hours.
Conclusion. Perindoprilat is excreted in the urine, the period of the final half-life of the unbound fraction is approximately 17 hours. State of equilibrium being achieved in for 4 days.
Linearity/non-linearity. The linear relationship between the dose of perindopril and its concentration in blood plasma was demonstrated.
A special category of patients
Patients of advanced age . The output of perindoprilat is reduced in elderly patients and in persons with cardiac or renal insufficiency.
The impairment of renal function. For patients with renal insufficiency should be adapted dose depending on the degree of renal impairment (CC).
The need for dialysis. Dialysis clearance of perindoprilat is 70 ml/min.
Cirrhosis. The kinetics of perindopril changes in patients with liver cirrhosis: hepatic clearance of the main molecule is reduced by half. However, the amount of created perindoprilata does not decrease, and, therefore, such patients do not need to pick up the dose (see Sections "Method of application and dose" and "Features of application").
Pharmacokinetic properties of indapamide
Suctions. Indapamide is rapidly and completely absorbed in the digestive tract. The maximum concentration in blood plasma is achieved after 1: 00 after taking the drug.
Distribution. Binding to plasma proteins is 79%.
Metabolism and excretion. The half - life is 14-24 hours (18 hours on average). Re-appointment does not lead to cumulation. Conclusion mainly with urine (70% dose) and feces (22%) in the form of inactive metabolites.
A special category of patients
The impairment of renal function. In patients with renal insufficiency, pharmacokinetic parameters do not change.
Treatment of essential hypertension in adult patients.
Noliprel Forte arginine shown, if necessary, additional blood pressure control with the use of perindopril as monotherapy.
Associated with perindopril:
hypersensitivity to the active substance or to any other ACE inhibitor
angioneurotic edema (angioedema) in anamnesis associated with previous therapy with ACE inhibitors
congenital or idiopathic angioedema
pregnancy or pregnancy planning (see section " application during pregnancy or breastfeeding»);
simultaneous use with medicines containing aliskiren, patients with diabetes or impaired renal function (glomerular filtration rate 2 ) (see "Interaction with other medicinal products and other forms of interaction" and "Pharmacological»);
extracorporeal methods of treatment, which lead to the contact of blood with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction»);
significant bilateral stenosis of renal arteries or stenosis of the artery of a single kidney (see section "Peculiarities of application").
Related to indapamide:
hypersensitivity to the active substance or to other sulfonamides;
severe renal failure (creatinine clearance
violation of liver function of severe degree;
as a General rule, this drug should not be prescribed in combination with non-antiarrhythmic drugs that can cause the development of paroxysmal ventricular tachycardia type " pirouette»;
the period of breast-feeding (see section "Use during pregnancy or breastfeeding").
Associated with drug Noliprel arginine Forte:
hypersensitivity to any auxiliary substance.
Due to the lack of sufficient clinical experience, Noliprel arginine Forte should not be used:
patients on hemodialysis;
patients with untreated decompensated heart failure.
Interaction with other medicinal products and other forms of interaction
Interactions common to perindopril and indapamide
Simultaneous use is not recommended
Lithium. While the use of lithium and ACE inhibitors reported a reversible increase in the concentration of lithium in serum and increase its toxicity. The simultaneous use of perindopril with indapamide and lithium is not recommended, but if it is really necessary, you should carefully monitor the concentration of lithium in the blood serum (see section "application Features").
Simultaneous use, which requires special attention
Baclofen. Increases the antihypertensive effect. It is necessary to monitor blood pressure and, if necessary, adjust the dose of antihypertensive agent.
Nonsteroidal anti-inflammatory drugs (NSAIDs) (including aspirin at a dose of ? 3 g/day). With the simultaneous use of ACE inhibitors and NSAIDs, such as acetylsalicylic acid in anti-inflammatory doses, COX-2 inhibitors and non-selective NSAIDs, it is possible to weaken the antihypertensive effect . The simultaneous use of ACE inhibitors and NSAIDs may lead to increased risk of deterioration of renal function, including the development of acute renal failure, and increase the level of potassium in serum, especially in patients with impaired renal function. This combination should be prescribed with caution, especially in elderly patients. Patients need to restore water balance before treatment and control kidney function at the beginning and during combination therapy.
The concurrent application that requires attention
Imipraminovogo (tricyclic) antidepressants, antipsychotics funds. Increase the antihypertensive effect and increase the risk of orthostatic hypotension (additive effect).
Interactions related to perindopril
These clinical studies suggest that dual blockade of the renin-angiotensin(RAAS) as a result of simultaneous use of ACE inhibitors, blockers of receptors of angiotensin II or aliskiren associated with an increase in the incidence of adverse reactions, such as hypotension, hyperkalemia and worsening of renal function (including acute renal failure) compared with use of one drug affecting the RAAS (see sections "Contraindications", "precautions" and "Pharmacological").
Drugs that cause hyperkalemia. Some drugs or therapeutic drug classes, such as aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, heparin, immunosuppressive agents (such as cyclosporine or tacrolimus, trimethoprim), may cause hyperkalemia. The combination of these drugs increases the risk of hyperkalemia.
Simultaneous use is contraindicated (see section " Contraindications»)
Aliskiren. In patients with diabetes or impaired renal function increases the risk of hyperkalemia, deterioration of kidney function and cardiovascular disease and mortality.
Extracorporeal methods of treatment. The simultaneous use of extracorporal methods of treatment, resulting in contact of blood with negatively charged surfaces such as dialysis or hemofiltration with certain membranes with high hydraulic permeability (for example polyacrylonitrile) and apheresis of low-density lipoproteins with the use of dextran sulfate may increase the risk of severe anaphylactoid reactions (see section "Contraindications"). In case of the need for such treatment, you should consider using a dialysis membrane of a different type or application of another class of antihypertensive drugs.
Simultaneous use is not recommended
Aliskiren. In all other groups of patients, as in patients with diabetes mellitus or with impaired renal function, the risk of hyperkalemia, deterioration of renal function and cardiovascular disease and mortality increases (see section "Features of application").
Concomitant therapy with ACE inhibitor and angiotensin receptor blockers. The publications reported that in patients with established atherosclerosis, heart failure or in patients with diabetes mellitus with the defeat of target organs, concomitant therapy with ACE inhibitor and angiotensin receptor blockers was accompanied by an increase in the frequency of arterial hypotension, fainting, hyperkalemia and deterioration of renal function (including acute renal failure) compared to the use of one drug, affects the renin-angiotensin-aldosterone system. The use of a double blockade (that is, a combination of ACE inhibitor and angiotensin II receptor antagonist) is possible only in some cases, provided careful monitoring of kidney function, blood potassium levels and blood pressure (see section "application Features").
Estramustin. There is a risk of increasing the frequency of adverse reactions, such as angioedema (angioedema).
Potassium-sparing diuretics (e.g. triamterene, amiloride), potassium (salt). There is a risk of hyperkalemia (potentially lethal), especially in patients with impaired renal function (gipercalziemicescoy additive effect). The combination of perindopril with the above-mentioned drugs is not recommended (see section "peculiarities of application"). If the simultaneous use of these drugs is still shown, they should be used with caution and with frequent monitoring of potassium levels in the blood serum. Information about the use of spironolactone in patients with heart failure is given in the paragraph "Simultaneous use, which requires special attention."
Racecadotril. It is known that the treatment of ACE inhibitors (eg perindopril) can lead to the development of angioneurotic edema. This risk may increase with the concomitant use of racecadotril (a drug used to treat acute diarrhea).
MTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus). Patients simultaneously receiving mTOR inhibitors, are at increased risk for development of angioedema (see Section "Peculiarities of use").
Simultaneous use, which requires special attention
Antidiabetic agents (insulin, hypoglycemic drugs for oral administration). The results of epidemiological studies indicate that concomitant use of ACE inhibitors and antidiabetic medicines (insulins, hypoglycemic agent for oral administration) may enhance the hypoglycaemic effect with the risk of hypoglycemia. It is more likely that this phenomenon may occur during the first weeks of combination treatment and in patients with impaired renal function.
Diuretics. In patients taking diuretics, especially with the presence of water and sodium deficiency, after starting therapy with ACE inhibitor may excessively decrease blood pressure. The likelihood of hypotensive effects can be reduced by the cancellation of the admission of a diuretic, increasing blood volume or salt intake prior to initiation of therapy with perindopril you should start at a low dose with gradual increases. Patients with hypertension, when previous therapy dioretikami could cause a shortage of water/sodium, you should stop taking diuretics before the beginning of the application of ACE inhibitor (in this case receiving a diuretic may eventually be restored) or to start treatment with ACE inhibitor with a low dose with gradual increases. Patients with congestive heart failure, diuretic is used, treatment with ACE inhibitor should begin with a minimum dose, possibly after reducing the dose of diuretic. In all cases, it is necessary to monitor kidney function (creatinine level) for the first few weeks of therapy with ACE inhibitor.
Potassium-sparing diuretics (eplerenone, spironolactone). With the simultaneous use of eplerenone or spironolactone at doses ranging from 12.5 mg to 50 mg per day with low doses of ACE inhibitors in patients with heart failure II-IV functional classes on the scale of the new York cardiology Association (NYHA ) and the emission fraction<40%, which previously took ACE inhibitors and loop diuretics, there is a risk of hyperkalemia, potentially lethal, especially in case of non-compliance with the recommendations for the purpose of such a combination. Before using this combination, make sure that there is no hyperkalemia and impaired renal function. It is recommended to conduct a thorough monitoring of potassium and creatininemia weekly during the first month of treatment and monthly thereafter.
The concurrent application that requires attention
Antihypertensive agents and vasodilators. The simultaneous use of these drugs can enhance the antihypertensive effects of perindopril. Concurrent use with nitroglycerin and other nitrates or other vasodilators may contribute to a further decrease in blood pressure.
Allopurinol, cytostatics, immunosuppressive agents, systemic corticosteroids or procainamide. Concurrent use with ACE inhibitors may lead to increased risk of leukopenia (see Section "Peculiarities of use").
Anesthetic. ACE inhibitors may increase the hypotensive effects of certain anaesthetic drugs (see Section "Peculiarities of use").
Gliptone (linagliptin, saxagliptin, sitagliptin, vildagliptin). While the use of an ACE inhibitor increases the risk of angioedema due to inhibition of the activity of dipeptidyl peptidase-IV (DPP-IV) gliptins.
The sympathomimetics. Sympathomimetics can weaken the antihypertensive effect of ACE inhibitors.
Preparations of gold. In the treatment of patients with injectable gold preparations (sodium aurothiomalate) and the simultaneous use of ACE inhibitors, including perindopril, in rare cases, the reported occurrence nitritoid reactions (facial flushing, nausea, vomiting and hypotension).
Interaction associated with indapamidum
Simultaneous use, which requires special attention
Drugs that can cause the development of paroxysmal ventricular tachycardia type "pirouette". Due to the risk of hypokalemia, indapamide should be administered with caution in combination with drugs that can cause the development of paroxysmal ventricular tachycardia type "pirouette", such as antiarrhythmic drugs class IA (quinidine, hydrogenizing, disopyramide), anti-arrhythmic drugs class III (amiodarone, dofetilide, ibutilide, bretylium, sotalol); some neuroleptics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamide (amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidol, haloperidol), other neuroleptics (pimozide); other substances, such as bepridil, cisapride, diphemanil, erythromycin for intravenous use, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, vincamine has for intravenous use, methadone, astemizole, terfenadine. You should avoid reducing potassium in the blood plasma and, if necessary, correct it, as well as control the QT-interval.
Drugs that reduce potassium in the blood. Amphotericin B for use, glucocorticoids and mineralocorticoids (systemic action), tetracosactide, laxatives that stimulate peristalsis, increase the risk of lowering the level of potassium in the blood serum (additive effect). It is necessary to monitor the content of potassium in the blood plasma and correct it if necessary, in particular while treating digitalis. Laxatives should be used that do not stimulate peristalsis.
The drug digitalis. Lowering the level of potassium in the blood increases the toxic effects of digitalis preparations. It is necessary to monitor the level of potassium in the blood and ECG, and if necessary, revise the therapy.
The concurrent application that requires attention
Potassium-sparing diuretics (amiloride, spironolactone, triamterene). Despite the rational use of this combination in some patients, there may be hypokalemia or hyperkalemia (especially in patients with renal insufficiency or diabetes). It is necessary to monitor the level of potassium in the blood plasma, carry out ECG monitoring and, if necessary, revise the therapy.
Metformin. May cause lactic acidosis due to the development of functional renal insufficiency associated with taking diuretics, especially loop. Metformin should not be used if the blood plasma creatinine level exceeds 15 mg/l (135 mmol/l) in men and 12 mg/l (110 mmol/l) in women.
Iodine-contrast agents. In the case of dehydration caused by the use of diuretics, the risk of acute renal failure, especially when using large doses of iodine-contrast agents. Before using iodine-contrast preparations, it is necessary to restore the water balance.
Calcium (salt). There is a risk of increasing the calcium content in the blood due to a decrease in its excretion in the urine.
Cyclosporine, tacrolimus. There is a risk of increasing the content of creatinine in the blood without changing the concentration of circulating cyclosporine, even in the absence of water and sodium deficiency.
Corticosteroids, tetracosactide (systemic action). Reduce the antihypertensive effect (water retention and sodium ions under the influence of corticosteroids).
Special warnings common to perindopril and indapamide.
Lithium. The simultaneous use of lithium and a combination of perindopril/indapamide is usually not recommended (see section "Interaction with other drugs and other types of interactions").
Special warnings related to perindopril
Dual blockade of the renin-angiotensin(RAAS). There is evidence that the simultaneous use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of arterial hypotension, hyperkalemia and decreased renal function (including acute renal failure). Therefore, the use of dual RAAS blockade due to the simultaneous reception of ACE inhibitors, blockers of receptors of angiotensin II or aliskiren is not recommended (see "Interaction with other medicinal products and other forms of interaction" and "Pharmacological"). If the therapy with double blockade of RAAS is considered absolutely necessary, it should be carried out only under the supervision of a specialist and with frequent careful monitoring of kidney function, electrolyte levels and blood pressure. Patients with diabetic nephropathy should not be used simultaneously, ACE inhibitors and blockers of angiotensin II receptors.
Potassium-preserving agents, additives or salt substitutes containing potassium. The combination of perindopril and potassium-sparing agents, additives or salt substitutes containing potassium is usually not recommended (see section "Interactions with other drugs and other interactions").
Neutropenia/agranulocytosis/thrombocytopenia/anemia. Patients taking ACE inhibitors were reported to have neutropenia/agranulocytosis, thrombocytopenia and anemia. In patients with normal renal function in the absence of other risk factors for neutropenia is rare. Perindopril should be used very cautiously in patients with collagenoses, during therapy with immunosuppressants, allopurinol or procainamide or a combination of these risk factors, especially in the presence of impaired renal function. Some of these patients noted the development of serious infectious diseases, sometimes resistant to intensive antibiotic therapy. If used in such patients perindopril is recommended to periodically monitor the number of leukocytes in the blood. In addition, patients should be informed about the need to inform the doctor about any of infectious disease (e.g. sore throat, fever) (see "Interaction with other medicinal products and other forms of interactions" and "Adverse reactions").