Instructions Noliprel Arginine film-coated tablets container No. 30
Composition
active ingredients: perindopril arginine, indapamide;
1 tablet contains 2.5 mg of perindopril arginine, corresponding to 1.6975 mg of perindopril, and 0.625 mg of indapamide;
Excipients: lactose monohydrate, magnesium stearate (E 470 B), maltodextrin, colloidal anhydrous silicon dioxide (E 551), sodium starch glycolate (type A), macrogol 6000, glycerol (E 422), hypromellose (E 464), titanium dioxide (E 171).
Dosage form
Film-coated tablets.
Main physicochemical properties:
manufactured by Servier Industries Laboratories, France: white, oblong tablets, film-coated, embossed with a line on both sides;
manufactured by Servier (Ireland) Industries Ltd, Ireland: white, oblong tablets, film-coated, embossed with "" on one side and embossed in the form of a line on both sides.
Pharmacotherapeutic group
Perindopril and diuretics. ATX code C09B A04.
Pharmacological properties
Pharmacodynamics.
Noliprel® arginine is a combination of the ACE inhibitor perindopril arginine 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
Noliprel® arginine has an additive synergistic effect of the two antihypertensive components.
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; there is no water and salt retention or reflex tachycardia, even with long-term treatment. In addition, perindopril reduces blood pressure (BP) in patients with normal and low levels of renin in the blood plasma. 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
PICXEL is a multicenter, randomized, double-blind, controlled study that evaluated the effect of the combination of perindopril and indapamide on left ventricular hypertrophy compared with enalapril monotherapy, as assessed by echocardiography. In PICXEL, patients with hypertension and left ventricular hypertrophy (left ventricular mass index > 120 g/m2 in men and > 100 g/m2 in women) were randomized into two groups: one group of patients received 2 mg perindopril tert-butylamine (equivalent to 2.5 mg perindopril arginine)/0.625 mg indapamide, and the other group received 10 mg enalapril once daily for one year. The doses were adjusted according to blood pressure: the dose of perindopril tert-butylamine was increased to 8 mg (equivalent to 10 mg perindopril arginine), indapamide to 2.5 mg, and enalapril to 40 mg once daily. The starting dose was continued by 34% of patients in the perindopril/indapamide group (2 mg perindopril and 0.625 mg indapamide) and 20% in the enalapril group (10 mg). Among all randomized patients, the left ventricular mass index at the end of treatment decreased significantly more in patients receiving perindopril/indapamide (-10.1 g/m²) than in the enalapril group (-1.1 g/m²). The difference between the two groups was -8.3 (95% confidence interval [CI] -11.5 to -5.0, p < 0.0001). The best effect on reducing left ventricular mass index was achieved with perindopril/indapamide at doses higher than those approved for Noliprel® arginine and Noliprel® arginine forte. Blood pressure was reduced more effectively in the perindopril/indapamide group: the difference in mean BP reduction between the two groups of patients was -5.8 mmHg (95% CI -7.9 to -3.7, p < 0.0001) for systolic blood pressure and -2.3 mmHg (95% CI -3.6 to -0.9, p = 0.0004) for diastolic blood pressure.
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 ACE blockade (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 syndrome. 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 that can occur when the diuretic is prescribed as monotherapy.
Pharmacodynamic effects associated with indapamide
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 arginine 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 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 within 4 days.
Linearity/non-linearity: A linear relationship between the dose of perindopril and its plasma concentration has been demonstrated.
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
Noliprel® arginine is indicated for the treatment of essential hypertension in adult patients.
Contraindication
Related to perindopril:
hypersensitivity to the active substance or to any other ACE inhibitor;
a history of angioedema (Quincke's edema) associated with previous treatment with ACE inhibitors (see section "Special warnings and precautions for use");
congenital or idiopathic angioedema;
pregnancy or planning a pregnancy (see section "Use during pregnancy or breastfeeding");
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”);
simultaneous use with sacubitril/valsartan. Noliprel® arginine should not be used earlier than 36 hours after taking the last dose of sacubitril/valsartan (see sections “Special instructions for use” and “Interaction with other medicinal products and other types of interactions”);
extracorporeal treatments that result in blood coming into contact with negatively charged surfaces (see section “Interaction with other medicinal products and other types of interactions”);
significant bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney (see section "Special warnings and precautions for use").
Related to indapamide:
hypersensitivity to the active substance or to any other sulfonamides;
severe renal failure (creatinine clearance < 30 ml/min);
hepatic encephalopathy;
severe liver dysfunction;
hypokalemia.
Related to the drug Noliprel® arginine:
hypersensitivity to any excipient.
Due to the lack of sufficient clinical experience, Noliprel® arginine should not be used:
patients on hemodialysis;
patients with untreated decompensated heart failure.
Interaction with other medicinal products and other types of interactions
Interactions common to perindopril and indapamide
Concomitant use is not recommended.
Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported with concomitant use of ACE inhibitors (ACEIs). Concomitant use of perindopril with indapamide and lithium is not recommended, but if necessary, serum lithium concentrations should be carefully monitored.
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.
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, such as 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).
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 and 4.4).
Drugs that increase the risk of angioedema. Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as it increases the risk of angioedema. Sacubitril/valsartan should not be started earlier than 36 hours after the last dose of perindopril. Perindopril therapy should not be started earlier than 36 hours after the last dose of sacubitril/valsartan (see sections “Contraindications” and “Special warnings and precautions for use”).
Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin) may lead to an increased risk of angioedema (see section 4.4).
Drugs causing hyperkalemia. Blood potassium levels usually remain within normal limits, but hyperkalemia may occur in some patients taking Noliprel® arginine. Some drugs or therapeutic classes of drugs, such as aliskiren, potassium salts, potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, heparins, immunosuppressive drugs such as cyclosporine or tacrolimus, trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim acts as a potassium-sparing diuretic similar to amiloride, may cause hyperkalemia. The combination of these drugs increases the risk of hyperkalemia. Therefore, the simultaneous use of Noliprel® arginine with the above drugs is not recommended. If concomitant use of these substances is necessary, they should be used with caution and blood potassium levels should be monitored frequently.
Concomitant use is contraindicated.
Aliskiren: Patients with diabetes mellitus or renal impairment are at increased risk of hyperkalemia, worsening of renal function, and cardiovascular morbidity and mortality.
Extracorporeal treatments that result in contact of blood with negatively charged surfaces, such as dialysis or haemofiltration using certain membranes with high hydraulic permeability (e.g. polyacrylonitrile) and low-density lipoprotein apheresis using dextran sulphate, due to an increased risk of severe anaphylactoid reactions (see section 4.3). If necessary, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.
Concomitant use is not recommended.
Aliskiren: In all other patient groups, as well as in patients with diabetes mellitus or impaired renal function, the risk of hyperkalemia, worsening of renal function and cardiovascular morbidity and mortality is increased (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 drug that affects the RAAS. The use of dual blockade (i.e. the combination of an ACE inhibitor and an angiotensin II receptor antagonist) is possible only in exceptional cases, subject to careful monitoring of renal function, blood potassium levels and blood pressure (see section "Special instructions").
Estramustine: There is a risk of increased incidence of adverse reactions such as angioedema.
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".
Antidiabetic agents (insulin, oral hypoglycemic agents). Concomitant use of ACE inhibitors and antidiabetic agents (insulins, oral hypoglycemic agents) may increase the blood sugar-lowering effect with the risk of hypoglycemia. This phenomenon is more likely to occur during the first weeks of combined treatment and in patients with impaired renal function.
Diuretics. In patients taking diuretics, especially in the presence of water and sodium depletion, excessive blood pressure may occur after the initiation of ACE-inhibitor therapy. The likelihood of developing hypotensive effects can be reduced by discontinuing the diuretic, increasing the circulating blood volume or salt intake before starting perindopril therapy, which should be started at a low dose and gradually increased. In patients with hypertension in whom previous diuretic therapy may have caused water/sodium depletion, the diuretic should be discontinued before starting ACE-inhibitor therapy (in which case the diuretic may be resumed over time) or the ACE-inhibitor should be started at a low dose and gradually increased. In patients with congestive heart failure who are taking a diuretic, ACE-inhibitor therapy should be started at the lowest dose, possibly after a reduction in the diuretic dose. In all cases, renal function (creatinine levels) should be monitored during the first few weeks of ACE inhibitor therapy.
Potassium-sparing diuretics (eplerenone, spironolactone). When eplerenone or spironolactone at doses of 12.5 mg to 50 mg per day are used concomitantly with low-dose ACE inhibitors in patients with heart failure of New York Heart Association (NYHA) functional classes II-IV and an ejection fraction < 40%, who have previously received ACE inhibitors and loop diuretics, there is a risk of hyperkalemia, potentially fatal, especially if the recommendations for the appointment of such a combination are not followed. Before starting the use of such a combination, it is necessary to ensure the absence of hyperkalemia and impaired renal function. It is recommended to carefully monitor potassium and creatinine weekly during the first month of treatment and monthly thereafter.
Concomitant use requiring attention
Antihypertensives and vasodilators. Concomitant use of these drugs may enhance the hypotensive effects of perindopril. Concomitant use with nitroglycerin and other nitrates or with other vasodilators may contribute to an additional decrease in blood pressure.
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").
Anesthetics: ACE inhibitors may enhance the hypotensive effect of some anesthetics (see section 4.4).
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 ACE inhibitors, 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 (the list is not exhaustive) class IA antiarrhythmic drugs (e.g. quinidine, hydroquinidine, disopyramide); class III antiarrhythmic drugs (e.g. amiodarone, dofetilide, ibutilide, bretylium, sotalol); certain antipsychotics: phenothiazines (e.g. chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (e.g. amisulpride, sulpiride, sultopride, tiapride), butyrophenones (e.g. droperidol, haloperidol), other antipsychotics (e.g. pimozide); other substances (e.g. bepridil, cisapride, diphemanil, intravenous erythromycin, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, intravenous vincamine, methadone, astemizole, terfenadine). A decrease in plasma potassium levels should be prevented and corrected if necessary, and the QT interval should be monitored.
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 drugs. Laxatives that do not stimulate peristalsis should be used.
Digitalis preparations. Hypokalemia and/or hypomagnesemia contribute to the toxic effects of digitalis. It is recommended to monitor the level of potassium, magnesium in the blood plasma and ECG, and adjust the treatment if necessary.
Concomitant use requiring attention
Potassium-sparing diuretics (amiloride, spironolactone, triamterene). 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, if necessary, therapy should be reviewed.
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 calcium levels in the blood due to reduced 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.
Noliprel® arginine combination has not been shown to significantly reduce adverse reactions compared to the use of the corresponding doses of its components as monodrugs, with the exception of hypokalemia (see section "Adverse reactions"). If a patient starts taking two new antihypertensive active substances at once, an increase in the frequency of idiosyncratic reactions cannot be ruled out. To minimize this risk, the patient's condition should be carefully monitored.
Lithium: Concomitant use with the combination of perindopril/indapamide is generally not recommended (see section 4.5).
Special precautions related to perindopril
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).
Hypersensitivity/angioedema (angioedema). Rare cases of angioedema of the face, extremities, lips, tongue, glottis and/or larynx have been reported in patients taking ACE inhibitors, including perindopril (see section 4.8). This may occur at any time during treatment. In such cases, the drug should be discontinued immediately and the patient should be monitored until symptoms resolve. If the swelling is limited to the face and lips, the patient usually improves without treatment, although antihistamines have been useful in reducing symptoms. Angioedema associated with laryngeal oedema can be fatal. If swelling spreads to the tongue, glottis, or larynx, potentially leading to airway obstruction, urgent emergency treatment is required, which may include subcutaneous administration of epinephrine 1:1000 (0.3-0.5 ml) and/or airway management. Angioedema has been reported more frequently in black patients receiving ACE inhibitors than in non-black patients. Patients with a history of angioedema unrelated to ACE inhibitors are at increased risk of developing angioedema while receiving ACE inhibitors. Rare cases of intestinal angioedema have been reported in patients receiving ACE inhibitors. These patients have experienced abdominal pain (with or without nausea and vomiting); sometimes intestinal angioedema was not accompanied by previous facial angioedema and C1-esterase inhibitor levels were normal. The diagnosis of angioedema was made by procedures such as abdominal computed tomography or ultrasound, or during surgery; after discontinuation of the ACE inhibitor, the symptoms of angioedema disappeared. In patients who present with abdominal pain while taking an ACE inhibitor, a differential diagnosis should be made to exclude intestinal angioedema. Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to an increased risk of angioedema. Sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of perindopril. If sacubitril/valsartan treatment is discontinued, perindopril therapy should be initiated no earlier than 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.5). Concomitant use of ACE inhibitors with neutral endopeptidase (NEP) inhibitors (e.g. racecadotril), mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin) may lead to an increased risk of angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see sections 4.5 and 4.5). Caution should be exercised when initiating treatment with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin) in patients already taking ACE inhibitors.
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 starting 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.
Patients on hemodialysis: Anaphylactoid reactions have been reported in patients receiving ACE inhibitors while on hemodialysis using high-flux polyacrylic membranes (e.g. AN 69®). Such patients should be switched to a different type of dialysis membrane or to a different class of antihypertensive agent.
Primary aldosteronism: Patients with primary hyperaldosteronism usually do not respond to antihypertensive medicinal products that act by inhibiting the renin-angiotensin system. Therefore, the use of this medicinal product is not recommended in such patients.
Patients after kidney transplantation. Experience with perindopril administration
