Instructions for Co-Prenesa tablets 2 mg + 0.625 mg blister No. 30
Composition
active ingredients: perindopril, indapamide;
1 tablet contains 2 mg perindopril tert-butylamine and 0.625 mg indapamide;
Excipients: calcium chloride, hexahydrate; lactose, monohydrate; crospovidone; microcrystalline cellulose; sodium bicarbonate; colloidal silicon dioxide; magnesium stearate.
Dosage form
Pills.
Main physicochemical properties:
2 mg/0.625 mg tablets: round, slightly biconvex tablets from white to almost white in color with beveled edges and engraved with a short line on one side.
Pharmacotherapeutic group
Combinations of angiotensin-converting enzyme inhibitors. Perindopril and diuretics. ATC code C09B A04.
Pharmacological properties
Pharmacodynamics
Co-Prenesa® is a combination of perindopril tert-butylamine salt, an angiotensin-converting enzyme (ACE) inhibitor, and indapamide, a sulfonamide diuretic. The pharmacological action of the drug is due to the properties of each component (perindopril and indapamide) and their additive synergism.
Mechanism of action
Associated with the drug Co-Prenesa®
Co-Prenesa® is characterized by additional enhancement of the antihypertensive effect of both components.
Associated with perindopril
Perindopril is an ACE inhibitor that converts angiotensin I to angiotensin II, a vasoconstrictor; in addition, the enzyme stimulates the secretion of aldosterone by the adrenal cortex and also stimulates the breakdown of the vasodilator substance bradykinin to form an inactive heptapeptide.
Inhibition of ACE leads to a decrease in plasma angiotensin II concentration, which increases plasma renin activity (by inhibiting negative feedback on renin release) and reduces aldosterone secretion. Perindopril also has an antihypertensive effect in patients with low and normal plasma renin levels.
With continuous treatment, this leads to a decrease in peripheral vascular resistance due to the effect on muscle and renal vessels without salt and water retention or reflex tachycardia.
Perindopril acts through its active metabolite, perindoprilat. Other metabolites are inactive.
Perindopril reduces the workload on the heart by a vasodilatory effect on the veins, which is probably caused by changes in prostaglandin metabolism (reduction of preload); by reducing total peripheral resistance (reduction of afterload).
In studies conducted with patients with heart failure, a decrease in left and right ventricular filling pressure was observed; a decrease in total peripheral vascular resistance; an increase in cardiac output and normalization of the cardiac index; and an increase in regional blood flow in the muscles.
Exercise test scores are improving significantly.
Related to indapamide
Indapamide is a sulfonamide derivative with an indole ring, pharmacologically related to thiazide diuretics. Indapamide reduces sodium reabsorption in the cortical segment. It increases the excretion of sodium and chlorine in the urine, and to a lesser extent, the excretion of potassium and magnesium, thus leading to increased diuresis and antihypertensive action.
Characteristics of antihypertensive action
Associated with the drug Co-Prenesa®
In patients with hypertension, regardless of age, the drug exhibits a dose-dependent antihypertensive effect on diastolic and systolic blood pressure in the supine or standing position.
This antihypertensive effect lasts for 24 hours.
Normalization of blood pressure occurs within a month and is maintained without the occurrence of tachyphylaxis.
If the drug is discontinued, there is no withdrawal effect.
During clinical trials, concomitant administration of perindopril and indapamide produced antihypertensive effects of a synergistic nature compared to each component alone.
The effect of the low-dose combination of Co-Prenes®, 2 mg/0.625 mg, on cardiovascular morbidity and mortality has not been studied.
Associated with perindopril
Perindopril is active in mild, moderate and severe arterial hypertension. It reduces systolic and diastolic blood pressure both in the supine and standing positions. The maximum hypotensive effect is achieved 4-6 hours after a single dose of the drug and lasts for at least 24 hours. Perindopril has a high level of final ACE inhibitor blockade (approximately 80%) 24 hours after administration.
In patients with a reversible reaction, blood pressure stabilization occurs on average within 1 month of treatment and is maintained without the appearance of tachyphylaxis.
Discontinuation of treatment is not accompanied by a withdrawal syndrome.
Perindopril has vasodilating properties and improves the elasticity of large arteries, corrects structural changes in the arteries and causes a decrease in left ventricular hypertrophy. Additional therapy with a thiazide diuretic leads to additional synergy.
The combination of an ACE inhibitor and a thiazide reduces the risk of diuretic-induced hypokalemia compared with either component alone.
The concomitant use of ACE inhibitors and angiotensin II receptor blockers has been investigated in two large-scale randomized controlled trials [ONTARGET (ONgoing Telmisartan Alone and Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)].
ONTARGET is a study in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes mellitus with evidence of target organ damage. VA NEPHRON-D is a study in patients with type 2 diabetes mellitus and diabetic nephropathy.
The studies did not show a significant beneficial effect for patients with renal and/or cardiovascular diseases and on mortality from them, while compared with monotherapy there was an increased risk of hyperkalemia, acute kidney injury and/or hypotension. Given the similarity of pharmacodynamic properties, these results are also applicable to other ACE inhibitors and angiotensin II receptor blockers.
Concomitant use of ACE inhibitors and angiotensin II receptor blockers is contraindicated in patients with diabetic nephropathy.
ALTITUDE (Aliskiren in Type 2 Diabetes with Cardiovascular and Renal Endpoints) is a study of the treatment benefits of adding aliskiren to standard therapy with an ACE inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes and/or chronic kidney disease, cardiovascular disease. The study was stopped early due to an increased risk of adverse events. Cardiovascular mortality, stroke, and reports of adverse events and serious complications (hyperkalemia, hypotension, or renal dysfunction) were more frequent in the aliskiren group compared with the placebo group.
Use in children
There are no data on the use of Co-Prenesa® in children.
Related to indapamide
Indapamide as monotherapy exhibits an antihypertensive effect lasting 24 hours. This occurs at doses at which the diuretic effect is weak.
Its antihypertensive effect is proportional to the improvement of arterial condition and the reduction of total and arteriolar peripheral vascular resistance. Indapamide reduces left ventricular hypertrophy.
When the dose of thiazide diuretics and thiazide-related diuretics is increased, the antihypertensive effect reaches its limit, and side effects continue to increase. If treatment is ineffective, the dose should not be increased.
Moreover, it has been proven that in short-term, medium-term and long-term treatment of patients with arterial hypertension, indapamide does not affect lipid metabolism (triglycerides, low- and high-density lipoproteins), does not affect carbohydrate metabolism, even in patients with arterial hypertension and diabetes mellitus.
Pharmacokinetics
Associated with the drug Co-Prenesa®
Concomitant administration of perindopril and indapamide does not change their pharmacokinetic properties compared to the administration of the individual components.
Associated with perindopril
Absorption and bioavailability
After oral administration, perindopril is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 1 hour. The plasma half-life of perindopril is 1 hour.
Metabolism
Perindopril is a prodrug. 27% of the total amount of perindopril absorbed is converted to the active metabolite perindoprilat. In addition, five more inactive metabolites are formed. The maximum concentration of perindoprilat in the blood plasma is reached within 3-4 hours.
Since the presence of food in the stomach leads to a decrease in the conversion of perindopril to perindoprilat and therefore to a decrease in bioavailability, perindopril should be administered orally as a single daily dose in the morning before meals.
A linear relationship between perindopril dose and plasma exposure has been demonstrated.
Distribution
The volume of distribution of unbound perindoprilat is approximately 0.2 l/kg. Protein binding is negligible (less than 20% of perindoprilat is bound to ACE), but is concentration-dependent.
Breeding
Perindoprilat is excreted in the urine, and the half-life of the unbound fraction is approximately 17 hours, leading to a steady state within 4 days.
Linearity/nonlinearity
A linear relationship between the dose of perindopril and its plasma concentration has been demonstrated.
Special groups
Elderly patients
In the elderly and patients with heart or kidney failure, the excretion of perindoprilat is reduced.
Kidney dysfunction
In case of impaired renal function, it is recommended to change the dose depending on the degree of impairment (creatinine clearance).
In case of dialysis
Perindoprilat is removed from the circulation by dialysis, its clearance is 70 ml/min.
Cirrhosis
In liver cirrhosis, the kinetics of perindopril change, with the hepatic clearance of the original molecule being halved, but the amount of perindoprilat formed does not change, so the dose of the drug may not be changed in this disease.
Related to indapamide
Absorption
Indapamide is released rapidly and almost completely absorbed from the gastrointestinal tract.
The maximum concentration of indapamide in the blood serum is reached approximately 1 hour after taking the drug. The binding of indapamide to plasma proteins is 79%.
Biotransformation and excretion
The plasma half-life is 14 to 24 hours (average 18 hours). Regular administration of the drug does not lead to accumulation of indapamide. 70% of indapamide is excreted mainly by the kidneys and 22% is excreted with feces in the form of inactive metabolites.
Kidney dysfunction
The pharmacokinetic parameters of the drug are unchanged in patients with renal impairment.
Indication
Essential hypertension.
Contraindication
Related to perindopril
Hypersensitivity to the active substance or to any other component of the drug, as well as to other ACE inhibitors;
history of angioedema (Quincke's edema) associated with previous treatment with ACE inhibitors (see section "Special precautions for use");
hereditary or idiopathic angioedema;
simultaneous administration with drugs containing the active substance aliskiren to patients with diabetes mellitus or renal insufficiency (glomerular filtration rate < 60 ml/min/1.73 m2) (see sections “Interaction with other medicinal products and other types of interactions” and “Special instructions for use”);
pregnant women or women planning a pregnancy;
concomitant use with sacubitril/valsartan (see sections “Interaction with other medicinal products and other types of interactions” and “Special precautions for use”);
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 indapamide, other sulfonamides; severe renal failure (creatinine clearance < 30 ml/min); hepatic encephalopathy or severe liver dysfunction; hypokalemia;
As a general rule, the drug is not recommended to be prescribed in combination with non-antiarrhythmic drugs, which may cause the development of paroxysmal ventricular tachycardia of the "pirouette" type (see section "Interaction with other medicinal products and other types of interactions");
breastfeeding period (see section "Use during pregnancy or breastfeeding").
Related to the drug Co-Prenesa®
Co-Prenes®, 2 mg/0.625 mg, 4 mg/1.25 mg and 8 mg/2.5 mg
Hypersensitivity to any component of the drug.
Due to the lack of sufficient therapeutic experience, Co-Prenesa® should not be used:
patients on hemodialysis; patients with untreated decompensated heart failure.
Co-Prenes®, 2 mg/0.625 mg, 4 mg/1.25 mg
Severe renal impairment (creatinine clearance < 30 ml/min).
Co-Prenes®, 8 mg/2.5 mg
Severe and moderate renal impairment (creatinine clearance < 60 ml/min).
Interaction with other medicinal products and other types of interactions
Common to perindopril and indapamide
Concomitant use is not recommended.
When lithium was administered concomitantly with ACE inhibitors, reversible increases in serum lithium concentrations and signs of toxicity were observed. Concomitant use of thiazide diuretics may further increase the risk of lithium toxicity when taking ACE inhibitors. The use of perindopril with lithium is not recommended, but if combination therapy is necessary, careful monitoring of serum lithium levels should be performed.
Concomitant use requiring special monitoring
Baclofen: increased antihypertensive effect. Blood pressure and renal function should be monitored and the dosage adjusted if necessary.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
NSAIDs, in particular acetylsalicylic acid at anti-inflammatory dosage regimens, cyclooxygenase-2 inhibitors and non-selective NSAIDs, may reduce the antihypertensive effect of ACE inhibitors. In addition, NSAIDs and ACE inhibitors additionally increase serum potassium levels, which may lead to deterioration of renal function, including the possibility of acute renal failure, especially in patients with impaired renal function. The combination should be used with caution, especially in elderly patients. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy and periodically thereafter.
Concomitant use requiring monitoring
Imipramine-like antidepressants (tricyclics), neuroleptics: increased hypotensive effect and increased risk of orthostatic hypotension (additive effect).
Clinical trial data suggest that dual blockade of the RAAS through the concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher incidence of adverse reactions, such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure), compared with the use of a single drug affecting the RAAS (see sections "Pharmacodynamics", "Contraindications" and "Special Instructions").
Drugs that can cause hyperkalemia
Some drugs or therapeutic classes of drugs may cause hyperkalemia, such as aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs, heparins, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim. The combination of these drugs increases the risk of hyperkalemia.
Contraindicated combinations
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 "Contraindications").
Extracorporeal treatments that result in contact of blood with negatively charged surfaces, such as high-flux membranes for dialysis or hemofiltration (e.g. polyacrylic membranes) and for low-density lipoprotein apheresis with dextran sulfate, increase the risk of severe anaphylactoid reactions (see section 4.3). If such treatment is necessary, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive drug.
Sacubitril/Valsartan
Concomitant use of perindopril with sacubitril/valsartan is contraindicated, as concomitant use of ACE inhibitors and sacubitril/valsartan increases the risk of angioedema. Sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of perindopril. Perindopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.4).
Concomitant use is not recommended.
Aliskiren
The concomitant use of perindopril and aliskiren in all other patient groups, except patients with diabetes mellitus or patients with impaired renal function, is not recommended due to an increased risk of hyperkalemia, worsening of renal function and cardiovascular morbidity and mortality (see section "Special warnings and precautions for use").
Concomitant therapy with ACE inhibitors and angiotensin receptor blockers
It has been reported in the literature that in patients with established atherosclerosis, heart failure, or diabetic patients with receptor damage, the simultaneous use of ACE inhibitors and angiotensin receptor blockers was accompanied by an increased incidence of arterial hypotension, syncope, hyperkalemia and deterioration of renal function (including acute renal failure) compared with monotherapy with drugs that affect the RAAS. The use of dual blockade (i.e. the combination of an ACE inhibitor with angiotensin II receptor antagonists) is possible only in individual cases with careful monitoring of renal function, potassium levels and blood pressure.
Estramustine
There is a risk of an increased incidence of adverse reactions such as angioedema.
Potassium-sparing diuretics (e.g. triamterene, amiloride…), potassium (salts)
Hyperkalemia (potentially fatal), especially in combination 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"). However, if the simultaneous administration of the above-mentioned substances is necessary, they should be used with caution and the level of potassium in the blood plasma should be carefully monitored. For the use of spironolactone in heart failure, see section "Concomitant use requiring special monitoring".
Co-trimoxazole (trimethoprim/sulfamethoxazole)
Patients receiving concomitant co-trimoxazole (trimethoprim/sulfamethoxazole) are at increased risk of hyperkalemia (see section 4.4).
Concomitant use requiring special monitoring
Antidiabetic drugs (insulin, hypoglycemic sulfonamides - with captopril and enalapril)
Epidemiological studies have shown that the concomitant use of ACE inhibitors and antidiabetic agents (insulins, oral hypoglycaemic agents) may lead to an increased blood glucose-lowering effect with a risk of hypoglycaemia. This phenomenon appears to be more likely during the first weeks of combined treatment and in patients with impaired renal function.
In patients taking diuretics, and especially in those with impaired water and electrolyte metabolism, an excessive decrease in blood pressure is possible after starting treatment with an ACE inhibitor. The likelihood of developing a hypotensive effect is reduced by discontinuing the diuretic, increasing the circulating blood volume or salt intake before starting therapy with perindopril. Treatment should be started with low doses and gradually increased.
In hypertension, when a previously prescribed diuretic may have caused water/electrolyte depletion, it should be discontinued before starting treatment with an ACE inhibitor (in such cases, the diuretic may be resumed over time) or an ACE inhibitor should be prescribed at a low dose with gradual titration.
In congestive heart failure on diuretic therapy, ACE inhibitor therapy should be initiated at the lowest dose, possibly after reducing the diuretic dose.
In any case, it is necessary to monitor kidney function (creatinine level) during the first weeks of treatment with an ACE inhibitor.
Potassium-sparing diuretics (eplerenone or spironolactone)
Concomitant use of eplerenone or spironolactone at doses of 12.5-50 mg per day with low-dose ACE inhibitors is necessary:
When treating patients with heart failure II-IV functional classes according to the New York Heart Association (NYHA) classification of chronic heart failure and an ejection fraction < 40%, who previously used ACE inhibitors and loop diuretics, there is a risk of hyperkalemia, potentially fatal, especially if recommendations for prescribing such a combination are not followed.
Before prescribing this combination, it is necessary to ensure the absence of hyperkalemia and renal failure.
It is recommended to carefully monitor potassium and creatinine levels weekly during the first month of treatment and monthly thereafter.
Racecadotril
ACE inhibitors (e.g. perindopril) are known to cause angioedema. This risk is increased when used concomitantly with racecadotril (a medicine used to treat acute diarrhoea).
mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus)
Patients taking mTOR inhibitors concomitantly are at increased risk of developing angioedema (see section 4.4).
Concomitant use requiring monitoring
Antihypertensives and vasodilators
Concomitant use of antihypertensive agents may enhance the hypotensive effect of perindopril. Concomitant use with nitroglycerin and other nitrates or with other vasodilators may contribute to an additional decrease in blood pressure.
Allopurinol, cytostatics or immunosuppressants, systemic corticosteroids (systemic use) or procainamide: Concomitant administration of these drugs and ACE inhibitors may lead to an increased risk of leukopenia (see section "Special precautions for use"). Anaesthetics: ACE inhibitors may potentiate the hypotensive effects of certain anaesthetics (see section "Special precautions for use").
Gold preparations: with the simultaneous use of ACE inhibitors, including perindopril, and injectable gold preparations (sodium aurothiomalate), reactions similar to those occurring with the use of nitrates (facial flushing, nausea, vomiting and arterial hypotension) may rarely occur.
Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin)
When used simultaneously with an ACE inhibitor, the risk of angioedema increases due to a decrease in dipeptidyl peptidase-IV (DPP-IV) activity by gliptin.
Sympathomimetics may weaken the antihypertensive effect of ACE inhibitors.
Related to indapamide
Concomitant use requiring special monitoring
Drugs that induce torsades de pointes: Due to the risk of hypokalemia, indapamide should be used with caution in concomitant use with drugs that induce torsades de pointes: class Ia antiarrhythmics (quinidine, hydroquinine, disopyramide); class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide, bretylium); some neuroleptics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoroperazine), benzamides (amisulpride, sulpride, sultopride, tiapride), butyrophenones (droperidol, haloperidol), other neuroleptics (pimozide); other substances such as bepridil, cisapride, diphemanil, erythromycin IV, halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, vincamine IV, methadone, astemizole, terfenadine. Low potassium levels should be prevented and corrected if necessary: monitor QT interval.
Potassium-depleting drugs, amphotericin B (intravenous administration), systemic glucocorticoids and mineralocorticoids (systemic administration), tetracosactide, stimulant laxatives: increased risk of hypokalemia (additive effect). Plasma potassium levels should be monitored and corrected if necessary; special care should be taken when using digitalis glycosides. Laxatives that stimulate peristalsis should not be used.
Cardiac glycosides: There is a risk of increased toxicity of cardiac glycosides. Plasma potassium and ECG monitoring should be performed and, if necessary, therapy should be reviewed.
Concomitant use with indapamide may lead to an increased incidence of hypersensitivity reactions to allopurinol.
Concomitant use requiring monitoring
Potassium-sparing diuretics (amiloride, spironolactone, triamterene)
Despite the rationality of prescribing this combination 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: In functional renal failure associated with the use of diuretics, especially loop diuretics, the risk of lactic acidosis due to metformin is increased. Metformin should not be used if the plasma creatinine level is above 15 mg/L (135 μmol/L) in men and 12 mg/L (110 μmol/L) in women.
Iodine contrast media: In case of dehydration associated with the use of diuretics during the use of iodocontrast media, especially in high doses, the risk of developing acute renal failure increases. It is necessary to restore the water balance before the administration of iodocontrast media.
Calcium salts: risk of hypercalcemia due to decreased renal calcium excretion.
Cyclosporine, tacrolimus: risk of increased plasma creatinine concentration without any change in circulating cyclosporine levels, even in the absence of volume/salt depletion.
Corticosteroids, tetracosactide (systemic administration)
Decreased antihypertensive effect (salt and water retention due to corticosteroids).
Application features
Uses requiring special precautions
Common to perindopril and indapamide
Lithium
The concomitant use of lithium and perindopril/indapamide combinations is generally not recommended (see section “Interaction with other medicinal products and other types of interactions”).
Related to perindopril
Dual blockade of RAAS
Concomitant use of ACE inhibitors and angiotensin II receptor blockers or aliskiren has been associated with an increased incidence of hypotension, syncope, hyperkalaemia and worsening of renal function (including acute renal failure). Dual blockade (i.e. the combination of an ACE inhibitor with angiotensin II receptor antagonists) or aliskiren is not recommended.
But if necessary, it can be used in individual cases and under careful monitoring of kidney function, potassium levels, and blood pressure.
The simultaneous use of ACE inhibitors and angiotensin II receptor blockers is not possible for patients with diabetic nephropathy.
In patients with diabetes mellitus or renal insufficiency (glomerular filtration rate < 60 ml/min/1.73 m2), concomitant administration with aliskiren is contraindicated (see sections “Contraindications” and “Interaction with other medicinal products and other types of interactions”).
Neutropenia/agranulocytosis/thrombocytopenia/anemia
Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and in the absence of other risk factors. Perindopril should be used with caution in patients with collagen vascular disease or in patients receiving immunosuppressants, allopurinol or procainamide, or in combination with any of these risk factors, especially in the presence of impaired renal function. Some patients have developed serious infections, which in some cases have not been adequately treated with antibiotics. If perindopril is used in such patients, periodic monitoring of white blood cell counts should be performed and patients should be instructed to report any signs of infection, such as sore throat or fever (see sections 4.5 and 4.8).
Renovascular hypertension
Patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are at increased risk of hypotension and renal failure when treated with ACE inhibitors (see section 4.3). Diuretics may be a beneficial factor. The decline in renal function may be accompanied by only minor changes in serum creatinine levels, even in patients with unilateral renal artery stenosis.
Hypersensitivity/angioedema
Laryngeal angioedema can be fatal. With swelling of the tongue, glottis, or larynx, airway obstruction is likely. In these cases, emergency treatment is necessary. This may include subcutaneous administration of epinephrine 1:1000 (0.3-0.5 ml) and/or maintenance of a patent airway.
ACE inhibitors cause angioedema more often in patients of the Negroid race than in representatives of other races.
Patients with a history of angioedema unrelated to ACE inhibitors are at increased risk of developing angioedema when treated with ACE inhibitors.
Rare cases of intestinal angioedema have been reported in patients taking ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); intestinal angioedema has sometimes been without previous facial angioedema and C1-esterase inhibitor levels have been normal. The diagnosis of angioedema has been made by procedures such as abdominal computed tomography or ultrasound, or at the time of surgery; symptoms of angioedema have resolved after discontinuation of the ACE inhibitor. In patients presenting with abdominal pain while taking ACE inhibitors, a differential diagnosis should be made to exclude intestinal angioedema.
Concomitant use of mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus)
Patients receiving concomitant mTOR inhibitors may be at increased risk of angioedema (including airway or tongue oedema, with or without respiratory compromise) (see section 4.5). Concomitant use of perindopril with sacubitril/valsartan is contraindicated due to the increased risk of angioedema (see section 4.3). Sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of perindopril. If treatment with sacubitril/valsartan is discontinued, perindopril should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.5). Concomitant use of other neutral endopeptidase (NEP) inhibitors, such as racecadotril, and ACE inhibitors may also lead to an increased risk of angioedema (see section 4.5). Therefore, a careful benefit-risk assessment should be performed before initiating treatment with NEP inhibitors, such as racecadotril, in patients taking perindopril.
Anaphylactoid reactions during desensitization
In patients receiving ACE inhibitors during desensitization procedures (e.g., to wasp or bee venom), isolated cases of prolonged anaphylactoid reactions, which were life-threatening, have been reported. ACE inhibitors should be used with caution in patients with allergies during desensitization procedures and avoided in those undergoing venom immunotherapy. However, these reactions can be avoided by temporarily stopping ACE inhibitors for at least 24 hours before treatment in patients requiring both ACE inhibitors and desensitization.
Anaphylactoid reactions during low-density lipoprotein (LDL) plasmapheresis
Rarely, life-threatening anaphylactoid reactions have occurred in patients receiving ACE inhibitors during LDL apheresis with dextran sulfate. These reactions have been managed by temporarily discontinuing ACE inhibitors prior to each apheresis.
Patients on hemodialysis
Anaphylactoid reactions have been observed in patients undergoing hemodialysis with high-flux membranes (e.g. AN 69®) and receiving concomitant treatment with ACE inhibitors. In such patients, consideration should be given to
