Instructions for Co-Prenelia tablets 4 mg + 1.25 mg blister No. 30
Composition
active ingredients: perindopril, indapamide.
1 tablet contains: perindopril tertbutylamine – 4 mg (corresponding to 3.338 mg of perindopril) and indapamide – 1.25 mg;
Excipients: microcrystalline cellulose; lactose, monohydrate; colloidal anhydrous silicon dioxide; magnesium stearate.
Dosage form
Pills.
Main physicochemical properties:
4 mg/1.25 mg tablets: white, oval tablets with a score on both sides and an embossed “+” image on each side of the score on one side of the tablet;
Pharmacotherapeutic group
Combinations of angiotensin-converting enzyme (ACE) inhibitors. Perindopril and diuretics.
ATX code C09B A04.
Pharmacological properties
Pharmacodynamics
Co-prenelia is a combination of the ACE inhibitor perindopril tert-butylamine and the sulfonamide diuretic indapamide. Its pharmacological action is due to the properties of each component (perindopril and indapamide) and their additive synergism.
Mechanism of action
Mechanism of action of perindopril
Perindopril is an ACE inhibitor that converts angiotensin I to angiotensin II (a vasoconstrictor substance), additionally stimulating the secretion of aldosterone by the adrenal cortex and the breakdown of bradykinin (a vasodilating substance) to inactive heptapeptides. ACE inhibition leads to: a decrease in aldosterone secretion; an increase in plasma renin activity, while aldosterone has no negative effect; a decrease in total peripheral vascular resistance due to the predominant effect on muscle and renal vessels; no water and salt retention or reflex tachycardia is observed, even with long-term treatment. In addition, perindopril reduces blood pressure (BP) in patients with normal and low plasma renin levels. Perindopril acts through its active metabolite perindoprilat. Other metabolites are inactive. Perindopril reduces cardiac work due to a vasodilatory effect on the veins (possibly due to changes in prostaglandin metabolism) - reducing preload, and due to a decrease in total peripheral vascular resistance - reducing afterload on the heart. Studies conducted with the participation of patients with heart failure have shown that the use of perindopril leads to a decrease in the filling pressure of the left and right ventricles, a decrease in total peripheral vascular resistance, an increase in cardiac output and an improvement in the cardiac index, an increase in regional blood flow in the muscles. The indicators of physical exercise tests are improved.
Mechanism of action of indapamide
Indapamide is a sulfonamide derivative with an indole ring, pharmacologically related to thiazide diuretics. Indapamide inhibits sodium reabsorption 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, thereby increasing urine output and providing an antihypertensive effect.
Pharmacodynamic effects
Co-prenelia has a dose-dependent antihypertensive effect on systolic (SAT) and diastolic (DBP) blood pressure in hypertensive patients of all ages in both supine and standing positions.
This antihypertensive effect lasts for 24 hours. The reduction in blood pressure is achieved in less than 1 month without tachyphylaxis; discontinuation of treatment does not lead to an increase in blood pressure. During clinical trials, the concomitant administration of perindopril and indapamide produced antihypertensive effects of a synergistic nature compared to the use of each component alone.
Pharmacodynamic effects associated with perindopril
Perindopril effectively lowers blood pressure in all degrees of arterial hypertension: mild, moderate and severe. A decrease in systolic and diastolic blood pressure is observed both in the supine and standing positions. The maximum antihypertensive effect develops 4–6 hours after taking a single dose and persists for more than a day. Perindopril has a high level of final blockade of the ACE inhibitor (approximately 80%) 24 hours after taking it. In patients who have responded to treatment, normalization of blood pressure is achieved after a month and is maintained without the occurrence of tachyphylaxis. Discontinuation of therapy is not accompanied by a withdrawal effect. Perindopril has vasodilator properties, restores the elasticity of large arteries, corrects histomorphometric changes in arterial resistance and reduces left ventricular hypertrophy. The addition of a thiazide diuretic, if necessary, leads to additional synergy. The combined use of an ACE inhibitor and a thiazide diuretic reduces the risk of hypokalemia, which can occur when a diuretic is prescribed as monotherapy.
When used as monotherapy, indapamide has an antihypertensive effect that lasts 24 hours. This effect is manifested in doses in which the diuretic properties are minimal. The antihypertensive effect of indapamide is proportional to the improvement of arterial elasticity and the reduction of arteriolar resistance and total peripheral vascular resistance. Indapamide reduces left ventricular hypertrophy. When the dose is exceeded, the antihypertensive effect of thiazide and thiazide-like diuretics reaches a plateau, while the number of undesirable effects increases. If the treatment is not effective enough, the dose of the drug should not be increased. Moreover, as shown in studies of different durations (short, medium and long) in 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 mellitus.
Pharmacokinetics
The pharmacokinetic properties of perindopril and indapamide when used in combination do not differ from the properties of these components when used separately.
Pharmacokinetic properties of perindopril
Absorption and bioavailability. After oral administration, perindopril is rapidly absorbed, with peak plasma concentrations occurring within 1 hour. The plasma half-life of perindopril is 1 hour. Since food intake reduces the conversion of perindopril to perindoprilat and, consequently, its bioavailability, perindopril tert-butylamine should be taken orally in a single daily dose in the morning before meals.
Distribution: The volume of distribution of unbound perindoprilat is approximately 0.2 l/kg. The binding of perindoprilat to plasma proteins is 20%, mainly to ACE, and is concentration-dependent.
Biotransformation. Perindopril is a prodrug. Thus, 27% of the taken dose of perindopril enters the bloodstream in the form of the active metabolite perindoprilat. In addition to the active perindoprilat, perindopril forms 5 more inactive metabolites. The maximum concentration of perindoprilat in the blood plasma is reached after 3–4 hours.
Excretion: Perindoprilat is excreted in the urine, with a terminal half-life of the unbound fraction of approximately 17 hours. Steady state is reached after 4 days.
Linearity/non-linearity: There is a linear relationship between the dose of perindopril and its plasma concentration.
Special categories of patients
Elderly patients: The elimination of perindoprilat is reduced in elderly patients and in those with cardiac or renal insufficiency.
Renal impairment: For patients with renal insufficiency, the dose should be adapted depending on the degree of renal impairment (creatinine clearance).
Need for dialysis. The dialysis clearance of perindoprilat is 70 ml/min.
Cirrhosis of the liver. The kinetics of perindopril are altered in patients with cirrhosis of the liver: the hepatic clearance of the parent molecule is halved. However, the amount of perindoprilat formed is not reduced and, therefore, no dose adjustment is required in such patients (see sections “Method of administration and dosage” and “Special warnings and precautions for use”).
Pharmacokinetic properties of indapamide
Absorption: Indapamide is rapidly and completely absorbed from the gastrointestinal tract. Peak plasma concentrations are reached approximately 1 hour after oral administration.
Distribution: Plasma protein binding is 79%.
Biotransformation and elimination. The elimination half-life is 14–24 hours (average 18 hours). Repeated administration does not lead to accumulation. Excretion occurs mainly in the urine (70% of the dose) and feces (22%) in the form of inactive metabolites.
Special categories of patients
Renal impairment: Pharmacokinetic parameters are not altered in patients with renal insufficiency.
Indication
Treatment of essential hypertension.
Contraindication
Related to perindopril:
Hypersensitivity to perindopril or to any other ACE inhibitor; history of angioedema (Quincke's edema) associated with previous treatment with ACE inhibitors; congenital or idiopathic angioedema; pregnancy or planning pregnancy (see section "Use during pregnancy and lactation");
simultaneous use with drugs containing aliskiren in patients with diabetes mellitus or renal impairment (glomerular filtration rate < 60 ml/min/1.73 m2) (see sections “Interaction with other medicinal products and other types of interactions” and “Pharmacodynamics”);
concomitant use with sacubitril/valsartan (see section "Interaction with other medicinal products and other forms of interaction"); extracorporeal treatments that result in contact of blood with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction");
significant bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney (see section "Special warnings and precautions for use").
Hypersensitivity to indapamide or to any other sulfonamides; severe and moderate renal impairment (creatinine clearance < 60 ml/min); hepatic encephalopathy; severe hepatic impairment; hypokalemia; this medicinal product should not be administered in combination with non-antiarrhythmic drugs that may cause the development of paroxysmal ventricular tachycardia of the "pirouette" type; breastfeeding period (see section "Use during pregnancy or breastfeeding").
Related to the drug Co-prenelia:
hypersensitivity to any excipient.
Due to the lack of sufficient clinical experience, Co-prenyl should not be used:
patients on hemodialysis; patients with untreated decompensated heart failure.
Interaction with other medicinal products and other types of interactions
Interactions that are the same for perindopril and indapamide
Concomitant use is not recommended.
Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant use of lithium and ACE inhibitors. Concomitant use of perindopril with indapamide and lithium is not recommended, but if necessary, serum lithium concentrations should be carefully monitored (see section 4.4).
Concomitant use requiring special attention
Baclofen. The antihypertensive effect is increased. It is necessary to monitor blood pressure and, if necessary, adjust the dose of the antihypertensive agent.
Systemic non-steroidal anti-inflammatory drugs (NSAIDs) (including acetylsalicylic acid at a dose of ≥ 3 g/day). With the simultaneous use of ACE inhibitors and NSAIDs, for example, acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors and non-selective NSAIDs, a weakening of the antihypertensive effect is possible. The simultaneous use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function, including the development of acute renal failure, and an increase in serum potassium, especially in patients with impaired renal function. Such a combination should be prescribed with caution, especially in elderly patients. Patients should be rehydrated before starting treatment and renal function should be monitored at the beginning and during combination therapy.
Concomitant use requiring attention
Imipramine-like (tricyclic) antidepressants, neuroleptics. Enhance the antihypertensive effect and increase the risk of developing orthostatic hypotension (additive effect).
Interactions related to perindopril
Clinical trial data suggest that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with an increased incidence of adverse reactions such as hypotension, hyperkalaemia and worsening renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).
Drugs that cause hyperkalemia. Some drugs or therapeutic classes of drugs, such as aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, heparins, immunosuppressive agents (such as cyclosporine or tacrolimus, trimethoprim), may cause hyperkalemia. The combination of these drugs increases the risk of hyperkalemia.
Concomitant use is contraindicated (see Contraindications section).
Aliskiren: The concomitant use of perindopril and aliskiren in patients with diabetes mellitus or renal impairment is contraindicated due to an increased risk of hyperkalemia, worsening of renal function and cardiovascular morbidity and mortality (see section 4.3).
Extracorporeal therapies. Extracorporeal therapies using certain high-density membranes with negatively charged surfaces, such as hemodialysis or hemofiltration (e.g., polyacrylonitrile membranes), and low-density lipoprotein apheresis using dextran sulfate are contraindicated due to the increased risk of hypersensitivity reactions. If the patient requires these procedures, other types of membranes should be used or the patient should be switched to other antihypertensive drugs.
Sacubitril/valsartan. Concomitant use of perindopril with sacubitril/valsartan is contraindicated because neprilysin inhibition with concomitant use of an ACE inhibitor may increase the risk of angioedema. Sacubitril/valsartan should be administered no earlier than 36 hours after the last dose of perindopril therapy. Perindopril therapy should be initiated no earlier than 36 hours after the last dose of sacubitril/valsartan (see section 4.3).
Aliskiren: The concomitant use of perindopril and aliskiren is not recommended in all patient groups other than diabetic patients or patients with impaired renal function due to an increased risk of hyperkalemia, worsening of renal function, cardiovascular morbidity and mortality (see section 4.4).
Concomitant therapy with an ACE inhibitor and an angiotensin receptor blocker. In patients with established atherosclerosis, heart failure or diabetic patients with target organ damage, concomitant therapy with an ACE inhibitor and an angiotensin receptor blocker has been reported to be associated with an increased incidence of hypotension, syncope, hyperkalaemia and deterioration of renal function (including acute renal failure) compared with the use of a single medicinal product that affects the renin-angiotensin-aldosterone system. The use of dual blockade (i.e. the combination of an ACE inhibitor and an angiotensin II receptor antagonist) is only possible in exceptional cases, subject to careful monitoring of renal function, blood potassium levels and blood pressure (see section 4.4).
Estramustine: There is a risk of increased incidence of adverse reactions such as angioedema.
Co-trimoxazole (trimethoprim/sulfamethoxazole): Patients taking concomitant co-trimoxazole (trimethoprim/sulfamethoxazole) may be at increased risk of developing hyperkalemia (see section 4.4).
Potassium-sparing diuretics (e.g. triamterene, amiloride), potassium salts. There is a risk of hyperkalemia (potentially fatal), especially in patients with impaired renal function (additive hyperkalemic effect). The combination of perindopril with the above-mentioned drugs is not recommended (see section "Special warnings and precautions for use"). If concomitant use of these drugs is nevertheless indicated, they should be used with caution and with frequent monitoring of serum potassium. Information on the use of spironolactone in patients with heart failure is given in the section "Concomitant use requiring special attention".
Concomitant use requiring special attention
Antidiabetic agents (insulin, oral hypoglycemic agents). Epidemiological studies have shown that concomitant use of ACE inhibitors and antidiabetic agents (insulins, oral hypoglycemic agents) may lead to an increased blood sugar-lowering effect with a risk of hypoglycemia. This phenomenon is most likely to occur during the first weeks of combined treatment and in patients with impaired renal function.
Potassium-sparing diuretics (eplerenone, spironolactone): use of eplerenone or spironolactone in doses of 12.5 mg to 50 mg per day and low doses of ACE inhibitors.
When treating heart failure class II-IV (NYHA) with an ejection fraction < 40% and prior administration of ACE inhibitors and loop diuretics, the risk of hyperkalemia is potentially dangerous, especially if the recommendations for the use of this combination are not followed.
Before prescribing the combination, it is necessary to ensure the absence of hyperkalemia and impaired renal function.
Close monitoring of potassium and creatinine levels is recommended weekly during the first month of treatment and monthly thereafter.
Other diuretics: In patients receiving diuretics, and especially in patients with hypovolemia and/or hyponatremia, an excessive decrease in blood pressure may occur after initiation of treatment with ACE inhibitors. The possibility of hypotensive effects can be reduced by discontinuing the diuretic, by replacing fluid or salt losses before initiating treatment with perindopril, and by starting perindopril at a low dose and gradually increasing the dose.
In the case of arterial hypertension, when previous treatment with diuretics may have led to hypovolemia/hyponatremia, either the diuretic should be discontinued before starting treatment with an ACE inhibitor, in which case a diuretic (non-potassium-sparing) can then be reintroduced; or treatment with an ACE inhibitor should be started at low doses and gradually increased.
When taking diuretics in the treatment of chronic heart failure, the ACE inhibitor should be started at very low doses, possibly after reducing the dose of the concomitant non-potassium-sparing diuretic.
In all cases, renal function (creatinine level) should be monitored during the first weeks of treatment with an ACE inhibitor.
Racecadotril: ACE inhibitors (including perindopril) are known to cause angioedema. This risk may be increased when used with racecadotril (a medicine used for acute diarrhoea).
mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus): Patients receiving concomitant mTOR inhibitors may be at increased risk of developing angioedema (see section 4.4).
Concomitant use requiring attention
Allopurinol, cytostatics, immunosuppressive agents, systemic corticosteroids or procainamide. Concomitant use with ACE inhibitors may lead to an increased risk of leukopenia (see section "Special warnings and precautions for use").
Anaesthetics: ACE inhibitors may enhance the hypotensive effect of some anaesthetics (see section 4.4).
Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin). When used simultaneously with an ACE inhibitor, the risk of angioedema increases due to inhibition of dipeptidyl peptidase-IV (DPP-IV) activity by the gliptin.
Sympathomimetics: Sympathomimetics may attenuate the antihypertensive effect of ACE inhibitors.
Gold preparations: In patients treated with injectable gold preparations (sodium aurothiomalate) and concomitant use of an ACE inhibitor, including perindopril, nitritoid reactions (facial flushing, nausea, vomiting and hypotension) have been reported rarely.
Interactions related to indapamide
Concomitant use requiring special attention
Drugs that may induce paroxysmal ventricular tachycardia of the "pirouette" type. Due to the risk of hypokalemia, indapamide should be prescribed with caution in combination with drugs that may induce paroxysmal ventricular tachycardia of the "pirouette" type, such as class IA antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide); class III antiarrhythmic drugs (amiodarone, dofetilide, ibutilide, bretylium, 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, diphemanil, erythromycin for intravenous use, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, vincamine for intravenous use, methadone, astemizole, terfenadine. It is necessary to prevent a decrease in potassium in the blood plasma and, if necessary, correct it, as well as monitor the QT interval.
Drugs that lower blood potassium. Amphotericin B for intravenous use, glucocorticoids and mineralocorticoids (systemic), tetracosactide, laxatives that stimulate peristalsis increase the risk of a decrease in serum potassium (additive effect). It is necessary to monitor the potassium content in the blood plasma and correct it if necessary, especially during concomitant treatment with digitalis preparations. Laxatives that do not stimulate peristalsis should be used.
Digitalis preparations. Decreased blood potassium levels increase the toxic effects of digitalis preparations. Blood potassium levels and ECG should be monitored and therapy reviewed if necessary.
Concomitant use requiring attention
Potassium-sparing diuretics (amiloride, spironolactone, triamterene). Although this combination may be appropriate in some patients, hypokalemia or hyperkalemia may occur (especially in patients with renal insufficiency or diabetes mellitus). Plasma potassium levels should be monitored, ECG monitoring should be performed, and therapy should be reviewed if necessary.
Metformin: May cause lactic acidosis due to functional renal failure associated with diuretics, especially loop diuretics. Metformin should not be used if plasma creatinine levels exceed 15 mg/L (135 μmol/L) in men and 12 mg/L (110 μmol/L) in women.
Iodine contrast media. In case of dehydration caused by the use of diuretics, the risk of developing acute renal failure increases, especially when using large doses of iodocontrast media. Before using iodocontrast media, it is necessary to restore water balance.
Calcium salts. There is a risk of increased blood calcium levels due to decreased urinary excretion.
Cyclosporine, tacrolimus: There is a risk of an increase in blood creatinine without a change in circulating cyclosporine concentrations, even in the absence of water and sodium depletion.
Corticosteroids, tetracosactide (systemic action). Reduce the antihypertensive effect (water and sodium retention under the influence of corticosteroids).
Application features
Special precautions
Special precautions, common to perindopril and indapamide
Lithium: The concomitant use of lithium and the combination of perindopril/indapamide is generally not recommended (see section 4.5).
Dual blockade of the renin-angiotensin-aldosterone system (RAAS). There is evidence that the concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Therefore, the use of dual blockade of the RAAS due to the concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended (see sections “Interaction with other medicinal products and other forms of interaction” and “Pharmacodynamics”). If dual RAAS blockade is considered absolutely necessary, it should be carried out only under specialist supervision and with frequent and careful monitoring of renal function, electrolytes and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Potassium-sparing medicinal products, potassium-containing salt supplements or salt substitutes: The combination of perindopril and potassium-sparing medicinal products, potassium-containing salt supplements or salt substitutes is generally not recommended (see section 4.5).
Neutropenia/agranulocytosis/thrombocytopenia/anaemia. Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function in the absence of other risk factors. Perindopril should be used with caution in patients with collagen vascular diseases, immunosuppressants, allopurinol or procainamide or a combination of these risk factors, especially in the presence of impaired renal function. Some of these patients have developed serious infections, sometimes resistant to intensive antibiotic therapy. Periodic monitoring of white blood cell counts is recommended when perindopril is used in such patients. In addition, patients should be advised to report any signs of infection (e.g. sore throat, fever) to their physician (see sections 4.5 and 4.8).
Renovascular hypertension. There is an increased risk of hypotension and renal failure in patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney when treated with ACE inhibitors (see section 4.3). Diuretic therapy may be an additional risk factor. Deterioration of renal function may occur with only minor changes in serum creatinine, even in patients with unilateral renal artery stenosis.
Anaphylactoid reactions during desensitization. Isolated cases of prolonged, life-threatening anaphylactoid reactions have been reported in patients receiving ACE inhibitors during desensitization therapy with bee venom. ACE inhibitors should be used with caution in allergic patients after desensitization and should be avoided during immunotherapy with bee venom. However, in patients requiring both ACE inhibitors and desensitization, such reactions can be avoided by temporarily discontinuing the ACE inhibitor at least 24 hours before desensitization therapy.
Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis. Life-threatening anaphylactoid reactions have been reported rarely in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. These reactions can be avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.
Primary aldosteronism: Patients with primary hyperaldosteronism generally do not respond to antihypertensive drugs that act through inhibition of the renin-angiotensin system. Therefore, the use of this product is not recommended.
Patients after kidney transplantation: There are no data on the use of perindopril tert-butylamine in patients after a recent kidney transplantation.
Hypotension. Symptomatic hypotension has been reported in patients with symptomatic heart failure with or without concomitant renal insufficiency. Symptomatic hypotension is more likely to occur in patients with more severe heart failure, those receiving high doses of loop diuretics, those with hyponatraemia or those with functional renal insufficiency. To reduce the risk of symptomatic hypotension, patients should be closely monitored during initiation of therapy and during dose titration (see sections 4.2 and 4.8). The same precautions apply to patients with ischaemic heart disease or cerebrovascular disease, in whom an excessive fall in blood pressure could result in myocardial infarction or stroke.
Coronary heart disease: If an episode of unstable angina (of any severity) occurs during the first month of treatment with perindopril, the risk-benefit ratio should be carefully weighed before deciding whether to continue therapy.
Pregnancy: ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, ACE inhibitor treatment should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.8).
Special precautions related to indapamide
Hepatic encephalopathy: In patients with impaired liver function, the use of thiazide and thiazide-like diuretics may cause hepatic encephalopathy. In such cases, the diuretic should be discontinued immediately.
Photosensitivity: Photosensitivity reactions have been reported with thiazide and thiazide-like diuretics (see section 4.8). If photosensitivity reactions occur during treatment, discontinuation of the drug is recommended. If re-administration is necessary, it is recommended to protect exposed areas from the sun or artificial ultraviolet light sources.
Precautions
Precautions that are the same for perindopril and indapamide
Impaired renal function. In the presence of severe and moderate renal insufficiency (creatinine clearance < 60 ml/min), treatment with Co-prenelia is contraindicated. If in some patients with arterial hypertension without existing signs of renal dysfunction, the results of laboratory blood tests show signs of functional renal insufficiency, treatment with the drug should be discontinued with the possibility of its resumption at a lower dose or only one of its components. Such patients should be monitored frequently for potassium and creatinine in the blood: 2 weeks after the start of treatment and then every 2 months during the period of therapeutic stabilization. Cases of renal insufficiency were observed mainly in patients with severe heart failure or impaired renal function, including renal artery stenosis. This drug should not be used in patients with significant bilateral
