Perindopril Plus Indapamide, tablets coated. captivity. about. 1.25 mg+4 mg, 30 pcs.
Classification of the frequency of side effects (WHO): very common (>1/10). often (from >1/100 to <1/10), infrequently (from >1/1000 to <1/100), rarely (from >1/10,000 to <1/1000). very rare (<1/10,000), frequency unknown (frequency cannot be calculated from available data).
From the hematopoietic system: infrequently - eosinophilia, hyponatremia, very rarely - thrombocytopenia, leukopeia/neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia. In certain clinical situations (kidney transplant patients, hemodialysis patients), ACE inhibitors may cause anemia.
From the side of the central nervous system: often - paresthesia, headache, dizziness, vertigo; infrequently - sleep disturbance, mood lability; very rarely - confusion; frequency unknown - fainting.
From the side of the organ of vision: often - visual impairment.
On the part of the hearing organ: often - tinnitus.
From the cardiovascular system: infrequently - marked decrease in blood pressure (including orthostatic hypotension), palpitations; very rarely - cardiac arrhythmias (including bradycardia, ventricular tachycardia, atrial fibrillation), angina pectoris and myocardial infarction, possibly due to an excessive decrease in blood pressure in high-risk patients; frequency unknown - ari (possibly fatal), increased QT interval on the ECG.
From the respiratory system: often - during the use of ACE inhibitors, a dry cough may occur, which persists for a long time while taking drugs of this group and disappears after their withdrawal, shortness of breath; uncommon - bronchospasm; very rarely - eosiophilic pneumonia, rhinitis.
From the digestive system: often - dryness of the oral mucosa, nausea, vomiting, abdominal pain, epigastric pain, impaired taste perception, decreased appetite, dyspepsia, constipation, diarrhea: very rarely - pancreatitis, angioedema of the intestine, cholestatic jaundice; frequency unknown - hepatic encephalopathy in patients with liver failure, increased activity of liver transaminases.
From the skin: often - skin rash, itching, maculopapular rash; uncommon - angioedema of the face, lips, extremities, mucous membrane of the tongue, vocal folds and/or larynx, urticaria, hypersensitivity reactions in patients predisposed to broncho-obstructive and allergic reactions, hemorrhagic vasculitis. In patients with acute form of systemic lupus erythematosus, the course of the disease may worsen; very rarely - erythema multiforme, toxic epidermal necrolysis. Stevens-Johnson syndrome. Cases of photosensitivity reactions have been reported.
From the musculoskeletal system: often - muscle spasms.
From the urinary system: infrequently - renal failure; very rarely - acute renal failure, frequency unknown - hepatitis.
From the reproductive system: infrequently - erectile dysfunction.
Laboratory indicators: rarely - hypercalcemia; frequency unknown - hypokatemia, especially significant for patients at risk; hyponatremia and gyvolemia, leading to dehydration and orthostatic hypotension; increase in the concentration of uric acid and glucose in the blood while taking the drug: a slight increase in the concentration of creatinine in the urine and in the blood plasma, which occurs after discontinuation of therapy, more often in patients with renal artery stenosis, when treating hypertension with diuretics and in the case of renal failure; hyperkalemia, often transient.
Other: often - asthenia; infrequently - increased sweating.
When using ACE inhibitors, a syndrome of impaired secretion of antidiuretic hormone was rarely observed.
Indapamide/Perindopril-Teva
Common to perindopril and indapamide
The use of the drug Indapamide/Perindopril-Teva is not accompanied by a significant reduction in the frequency of side effects, with the exception of hypokalemia, compared to taking individual components of the drug in the lowest doses approved for use (see section “Side Effects”). At the beginning of therapy with two antihypertensive drugs that the patient has not previously received, an increase in the incidence of idiosyncrasy cannot be excluded. Careful monitoring of the patient can minimize this risk.
Lithium preparations
The combined use of a combination of perindopril and indapamide with lithium preparations is not recommended (see section “Interaction with other drugs”).
Renal dysfunction
Therapy is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 ml/min). In some patients with arterial hypertension without previous obvious renal impairment, laboratory signs of functional renal failure may appear during therapy. In this case, treatment should be stopped. In the future, you can resume combination therapy using low doses of drugs, or use only one of the drugs. Such patients require regular monitoring of the concentration of potassium and creatinine in the blood - 2 weeks after the start of therapy and subsequently every 2 months during the period when the dose of the drug is selected. Renal failure occurs more often in patients with severe heart failure or underlying renal failure, including renal artery stenosis.
The drug Indapamide/Perindopril-Teva is not recommended for use in cases of bilateral renal artery stenosis or in the case of a single functioning kidney.
Hypotension and water-electrolyte imbalance
In the case of initial hyponatremia, there is a risk of sudden development of arterial hypotension, in particular in patients with renal artery stenosis. Therefore, systematic assessment of symptoms of dehydration and decreased plasma electrolyte levels, such as after diarrhea or vomiting, is necessary. Such patients require regular monitoring of blood plasma electrolyte levels.
In case of severe arterial hypotension, intravenous administration of isotonic saline solution may be required.
Transient hypotension is not a contraindication for continued therapy. After restoration of circulating blood volume and blood pressure, therapy can be resumed using low doses, or only one of the drugs can be used.
Potassium content
The combined use of perindopril and indapamide does not prevent the development of hypokalemia, especially in patients with diabetes mellitus or renal failure. As with the use of any antihypertensive drug in combination with a diuretic, regular monitoring of the concentration of potassium in the blood plasma is necessary.
Excipients
The drug Indapamide/Perindopril-Teva contains an excipient - lactose monohydrate and is contraindicated in patients with hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption.
Sodium content
The drug Indapamide/Perindopril-Teva contains less than 1 mmol of sodium (less than 23 mg) per tablet, that is, practically “sodium-free”.
Childhood
The drug Indapamide/Perindopril-Teva is contraindicated in children and adolescents under the age of 18 years due to the lack of data on the effectiveness and safety of the use of perindopril and indapamide, both separately and together in patients of this age group.
Indapamide
Hepatic encephalopathy
In the presence of liver dysfunction, taking thiazide and thiazide-like diuretics can lead to the development of hepatic encephalopathy. In such a situation, you should immediately stop taking the diuretic.
Photosensitivity
While taking thiazide and thiazide-like diuretics, cases of photosensitivity reactions have been reported (see section "Side effects"). If photosensitive reactions develop while taking the drug, treatment should be discontinued. If it is necessary to continue diuretic therapy, it is recommended to protect the skin from exposure to sunlight or artificial ultraviolet rays.
Water and electrolyte balance
Concentration of sodium ions in blood plasma
The concentration of sodium ions in the blood plasma must be determined before starting treatment, and then regularly monitored while taking the drug. A decrease in the concentration of sodium ions at the initial stage may not be accompanied by clinical symptoms, so regular laboratory monitoring is necessary. More frequent monitoring of sodium ion levels is indicated for patients with liver cirrhosis and elderly patients (see sections “Side effects” and “Overdose”). Treatment with any diuretics can cause hyponatremia, sometimes with very serious consequences. Hyponatremia accompanied by hypovolemia can lead to dehydration and orthostatic hypotension. A concomitant decrease in the content of chlorine ions can lead to the development of secondary compensatory metabolic alkalosis: the frequency of its occurrence and severity are insignificant.
Concentration of potassium ions in blood plasma
Decreased potassium concentrations with hypokalemia are the main risk associated with therapy with thiazide and thiazide-like diuretics.
It is necessary to prevent the risk of a decrease in the concentration of potassium ions (less than 3.4 mmol/l) in the following categories of high-risk patients: elderly and/or malnourished patients, both receiving and not receiving concomitant drug therapy, patients with cirrhosis of the liver with edema and ascites, coronary heart disease, heart failure. Hypokalemia in these patients increases the toxic effect of cardiac glycosides and increases the risk of arrhythmia.
Patients with a prolonged QT interval, either congenital or drug-induced, are also at increased risk.
Hypokalemia, like bradycardia, contributes to the development of severe heart rhythm disturbances, especially polymorphic ventricular tachycardia of the “pirouette” type, which can be fatal. In all the cases described above, more frequent monitoring of the content of potassium ions in the blood plasma is necessary. The first measurement of potassium ion content should be carried out within the first week from the start of therapy.
If hypokalemia is detected, appropriate correction should be made.
Concentration of calcium ions in blood plasma
Thiazide and thiazide-like diuretics may reduce the excretion of calcium ions by the kidneys, leading to a slight and temporary increase in plasma calcium concentrations. A marked increase in the concentration of calcium ions may be associated with undiagnosed hyperparathyroidism. Before studying the function of the parathyroid glands, you should stop taking diuretics.
Blood glucose concentration
It is necessary to monitor the concentration of glucose in the blood in patients with diabetes, especially when the concentration of potassium ions is low.
Uric acid
Patients with elevated plasma uric acid concentrations tend to have an increased incidence of gout attacks.
Diuretics and kidney function
Thiazide and thiazide-like diuretics are fully effective only in patients with normal or slightly impaired renal function (creatinine concentration in adult patients below 25 mg/l or 220 µmol/l).
In elderly patients, plasma creatinine levels should be assessed taking into account age, weight and sex, according to the Cockroft formula:
Creatinine clearance (CC) = (140 - age) x weight / [0.814 x plasma creatinine concentration],
where: age in years, weight in kg, plasma creatinine concentration in µmol/l.
The formula is suitable for older men; for older women, the result should be multiplied by a factor of 0.85.
At the beginning of diuretic treatment in patients, due to hypovolemia (due to the excretion of water and sodium ions), a temporary decrease in glomerular filtration rate and an increase in the concentration of urea and creatinine in the blood plasma may be observed. This transient functional renal failure does not have adverse consequences for patients with initially normal renal function, but may aggravate pre-existing renal impairment before treatment.
Athletes
Athletes should pay attention to the fact that the drug contains an active substance that can give a positive result during a doping test.
Acute myopia and secondary angle-closure glaucoma
Sulfonamides and their derivatives can cause the development of an idiosyncratic reaction, leading to temporary myopia and acute angle-closure glaucoma. Without proper treatment, acute angle-closure glaucoma can lead to vision loss. First of all, you need to stop taking the drug as soon as possible. If intraocular pressure continues to be high, immediate medical or surgical treatment may be required. Risk factors that can lead to the development of acute angle-closure glaucoma include an allergy to sulfonamide or penicillin.
Perindopril
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence of an increased risk of arterial hypotension, hyperkalemia and decreased renal function (including acute renal failure) when ACE inhibitors are used together with ARB II or aliskiren. Therefore, double blockade of the RAAS by combining an ACE inhibitor with ARA II or aliskiren is not recommended (see sections “Pharmacodynamics”, “Interaction with other drugs”). If a double blockade is absolutely necessary, it should be performed under the strict supervision of a specialist with regular monitoring of renal function, plasma electrolytes and blood pressure.
The use of ACE inhibitors in combination with ARA II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see sections “Contraindications” and “Interaction with other drugs”).
Potassium-sparing diuretics, potassium supplements, potassium-containing table salt substitutes and food supplements
The combined use of perindopril and potassium-sparing diuretics, as well as potassium preparations, potassium-containing table salt substitutes and food additives is not recommended (see section “Interaction with other drugs”).
Neutropenia/agranulocytosis/thrombocytopenia/anemia
There are reports of the development of neutropenia/agranulocytosis, thrombocytopenia and anemia while taking ACE inhibitors. In patients with normal renal function and without concomitant risk factors, neutropenia rarely occurs. Perindopril should be used with extreme caution against the background of systemic connective tissue diseases, as well as while taking immunosuppressants, allopurinol or procainamide, or a combination of these factors, especially in patients with initially impaired renal function.
Some patients developed severe infectious diseases, in some cases resistant to intensive antibiotic therapy. When prescribing perindopril to such patients, it is recommended to periodically monitor the number of leukocytes in the blood. Patients should tell their doctor about any signs of infectious diseases (for example, sore throat, fever) (see sections "Side effects" and "Interaction with other drugs").
Anemia may develop in patients after kidney transplantation or in patients undergoing hemodialysis. In this case, the decrease in hemoglobin is greater, the higher its initial value. This effect does not appear to be dose-dependent, but may be related to the mechanism of action of ACE inhibitors.
A slight decrease in hemoglobin occurs during the first 6 months of treatment, then it remains stable and is completely restored after discontinuation of the drug. In such patients, treatment can be continued, but hematological tests should be carried out regularly.
Renovascular hypertension
In patients with bilateral renal artery stenosis or arterial stenosis of a single functioning kidney, the risk of hypotension and renal failure increases while using an ACE inhibitor (see section “Contraindications”). Taking diuretics may be an additional risk factor (see section "Contraindications"). Deterioration of renal function can be observed with even a slight change in serum creatinine concentration, even in patients with unilateral renal artery stenosis.
The treatment method for renovascular hypertension is revascularization. However, the use of ACE inhibitors may have a positive effect in this category of patients, both awaiting surgery and in cases where surgery is not possible.
If therapy with the indapamide/perindopril combination is prescribed to patients with established or suspected renal artery stenosis, it should be initiated with low doses in a hospital setting under monitoring of renal function and potassium levels, since some patients developed functional renal failure, which regressed after discontinuation of therapy .
Hypersensitivity/angioedema
When taking ACE inhibitors, including perindopril, in rare cases, the development of angioedema of the face, extremities, lips, tongue, vocal folds and/or larynx may occur (see section “Side effects”). This can happen at any time during therapy. If symptoms occur, perindopril should be discontinued immediately and the patient should be observed until signs of edema have completely resolved. If the swelling affects only the face and lips, it usually goes away on its own, and antihistamines can be used as symptomatic therapy.
Angioedema, accompanied by swelling of the larynx, can be fatal. Swelling of the tongue, vocal folds, or larynx can lead to airway obstruction. If such symptoms appear, appropriate therapy should be started immediately, for example, epinephrine (adrenaline) administered subcutaneously at a dilution of 1:1000 (0.3-0.5 ml) and/or ensure airway patency.
A higher risk of developing angioedema has been reported in black patients.
Patients with a history of angioedema not associated with taking ACE inhibitors may have an increased risk of developing it when taking drugs of this group (see section "Contraindications").
In rare cases, angioedema of the intestine develops during therapy with ACE inhibitors.
In this case, patients experienced abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without previous angioedema of the face and with normal levels of C1-esterase. Diagnosis was made using abdominal computed tomography, ultrasound, or at the time of surgery. Symptoms resolved after discontinuation of ACE inhibitors. Therefore, in patients with abdominal pain receiving ACE inhibitors, when carrying out differential diagnosis, it is necessary to take into account the possibility of developing angioedema of the intestine.
Combined use with combination drugs containing valsartan + sacubitril
The combined use of perindopril with combination drugs containing valsartan + sacubitril is contraindicated, as the risk of developing angioedema is increased (see section "Contraindications"). The use of a combination drug containing valsartan + sacubitril is possible no earlier than 36 hours after the last dose of perindopril. The use of perindopril is possible no earlier than 36 hours after stopping the combination drug containing valsartan + sacubitril (see sections “Contraindications” and “Interaction with other drugs”). When ACE inhibitors are used together with other neprilysin inhibitors (for example, racecadotril), there may be an increased risk of developing angioedema (see section "Interaction with other drugs"). In patients receiving perindopril therapy, before starting treatment with neprilysin inhibitors (for example, racecadotril ) a careful assessment of the risk/benefit ratio is necessary.
mTOR (mammalian target of rapamycin) inhibitors (eg, snrolimus, everolimus, temsirolimus)
When used together with mTOR inhibitors (for example, sirolimus, everolimus, temsirolimus), the risk of developing angioedema (for example, swelling of the airways or tongue, with or without impairment of respiratory function) increases (see section "Interaction with other drugs").
Anaphylactoid reactions during desensitization
There are isolated reports of the development of long-term, life-threatening anaphylactic reactions in patients receiving ACE inhibitors during desensitizing therapy with the venom of hymenoptera insects (bees, wasps). ACE inhibitors should be used with caution in patients prone to allergic reactions undergoing desensitization procedures. The use of an ACE inhibitor should be avoided in patients receiving immunotherapy with hymenoptera venom. However, in patients who require both the use of an ACE inhibitor and a desensitization procedure, an anaphylactoid reaction can be avoided by temporarily discontinuing the ACE inhibitor at least 24 hours before the procedure.
Anaphylactoid reactions during LDL apheresis
In rare cases, life-threatening anaphylactoid reactions have developed in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. To prevent an anaphylactoid reaction, ACE inhibitor therapy should be temporarily discontinued before each apheresis procedure.
Patients on hemodialysis
Anaphylactoid reactions have been reported in patients receiving ACE inhibitors during hemodialysis using high-flux membranes (eg, AN69®). Therefore, it is advisable to use a different type of membrane or use an antihypertensive agent of a different pharmacotherapeutic group.
Primary hyperaldosteronism
Patients with primary hyprealdosteronism are usually not susceptible to antihypertensive drugs whose action is based on inhibition of the RAAS. Therefore, the use of the drug in such patients is not recommended.
Cough
During therapy with an ACE inhibitor, a dry persistent cough may occur, which disappears after discontinuation of the drug. If a patient develops a dry cough, one should be aware of the possible iatrogenic nature of this symptom. If the attending physician believes that ACE inhibitor therapy is necessary for the patient, it is possible to continue taking the drug.
Children
The effectiveness and tolerability of perindopril in children and adolescents as monotherapy or in combination with other drugs has not been established.
Risk of arterial hypotension and/or renal failure (in patients with heart failure, fluid and electrolyte imbalance, etc.)
In some pathological conditions, significant activation of the renin-angiotensin-aldosterone system may be observed, especially with severe hypovolemia and a decrease in the content of electrolytes in the blood plasma (during a salt-free diet or long-term use of diuretics), in patients with initially low blood pressure, renal artery stenosis, congestive heart failure or cirrhosis of the liver with edema and ascites.
The use of an ACE inhibitor causes blockade of the RAAS and therefore may be accompanied by a sharp decrease in blood pressure and/or an increase in the concentration of creatinine in the blood plasma, indicating the development of functional renal failure. These phenomena are more often observed when taking the first dose of the drug or during the first two weeks of therapy. In rare cases, these conditions develop acutely and during other periods of therapy. In such cases, when resuming therapy, it is recommended to use the drug at a lower dose and then gradually increase the dose.
Elderly age
Before starting perindopril, it is necessary to assess the functional activity of the kidneys and the potassium content in the blood plasma. At the beginning of therapy, the dose of the drug is selected taking into account the degree of reduction in blood pressure, especially in the case of dehydration and loss of electrolytes. Such measures help to avoid a sharp decrease in blood pressure.
Atherosclerosis
The risk of arterial hypotension exists in all patients, however, special care should be taken when using the drug in patients with coronary heart disease and cerebrovascular insufficiency. In such patients, treatment should begin with low doses of the drug.
Heart failure/severe heart failure
In patients with severe heart failure (NYHA functional class IV), treatment should begin with a low dose of the drug and under close medical supervision.
Hypertensive patients with coronary artery disease should not stop taking beta-blockers: ACE inhibitors should be used together with beta-blockers.
Patients with diabetes mellitus
In patients with insulin-dependent diabetes mellitus (risk of spontaneous increase in potassium levels), treatment should begin with minimal doses and be under constant medical supervision.
Glycemic levels should be carefully monitored in patients with diabetes mellitus who have previously received oral hypoglycemic agents or insulin, particularly during the first month of ACE inhibitor therapy (see section "Interactions with other drugs").
Ethnic differences
Perindopril, like other ACE inhibitors, has a less pronounced antihypertensive effect in patients of the Negroid race compared to representatives of other races. This difference may be due to the fact that black patients with arterial hypertension are more likely to have low renin activity.
Surgery/anesthesia
The use of ACE inhibitors may lead to hypotension, especially when used concomitantly with anesthetic agents that have antihypertensive effects. Therefore, it is recommended to stop taking long-acting ACE inhibitors such as perindopril the day before surgery if possible.
Aortic or mitral valve stenosis/hypertrophic obstructive cardiomyopathy
ACE inhibitors should be prescribed with caution to patients with left ventricular outflow tract obstruction.
Liver failure
In rare cases, cholestatic jaundice occurs while taking ACE inhibitors. As this syndrome progresses, fulminant liver necrosis may develop, sometimes with death. The mechanism of development of this syndrome is unclear. If jaundice appears or if there is a significant increase in the activity of liver enzymes while taking ACE inhibitors, the patient should stop taking the ACE inhibitor and be under appropriate medical supervision (see section “Side Effects”).
Hyperkalemia
Hyperkalemia may develop during treatment with ACE inhibitors, including perindopril. Risk factors for hyperkalemia include renal failure, deterioration of renal function, age over 70 years, diabetes mellitus, certain concomitant conditions, in particular dehydration, acute cardiac decompensation, metabolic acidosis, concomitant use of potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene, amiloride ), as well as potassium preparations or potassium-containing table salt substitutes, as well as the use of other drugs that increase the level of potassium in the blood plasma (for example, heparin, co-trimoxazole, also known as the combination of sulfomethoxazole + trimethoprim, other ACE inhibitors, angiotensin II receptor antagonists , acetylsalicylic acid (3 g/day or more), cyclooxygenase-2 (COX-2) inhibitors and non-selective NSAIDs, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim).
The use of potassium supplements, potassium-sparing diuretics, and potassium-containing table salt substitutes can lead to a significant increase in potassium levels in the blood, especially in patients with reduced renal function. Hyperkalemia can cause serious, sometimes fatal, abnormal heart rhythms. If the combined use of the above drugs is necessary, treatment should be carried out with caution against the background of regular monitoring of potassium concentrations in the blood serum (see section “Interaction with other drugs”).
Indapril
Perindopril, indapamide
The use of the drug Indapril is not accompanied by a significant reduction in the frequency of side effects (see section “Side Effects”). When initiating therapy with two antihypertensive drugs that the patient has not previously received, an increased risk of idiosyncrasy cannot be excluded. Careful monitoring of the patient can minimize this risk.
Lithium preparations
The simultaneous use of a combination of perindopril and indapamide with lithium preparations is not recommended (see section “Interaction with other drugs”).
Renal dysfunction
Therapy is contraindicated in patients with severe renal failure (creatinine clearance less than 30 ml/min). In some patients with hypertension without previous obvious renal impairment, laboratory signs of functional renal failure may appear during therapy. In this case, treatment should be stopped. In the future, you can resume combination therapy using low doses of drugs, or use drugs in monotherapy.
Such patients require regular monitoring of serum potassium and creatinine levels - 2 weeks after the start of therapy and every 2 months thereafter. Renal failure most often occurs in patients with severe chronic heart failure or underlying renal impairment, including stenosis of one or two renal arteries.
As a rule, the use of perindopril and indapamide is not recommended for patients with bilateral renal artery stenosis or stenosis of a single functioning kidney.
Arterial hypotension and water-electrolyte imbalance
Hyponatremia is associated with a risk of sudden development of arterial hypotension (especially in patients with stenosis of one or two renal arteries). Therefore, during dynamic monitoring of patients, attention should be paid to possible symptoms of dehydration and decreased levels of electrolytes in the blood plasma, for example, after diarrhea or vomiting. Such patients require regular monitoring of plasma electrolyte levels.
In case of severe arterial hypotension, intravenous administration of 0.9% sodium chloride solution may be required.
Transient arterial hypotension is not a contraindication for continued therapy. After restoration of circulating blood volume and blood pressure, therapy can be resumed using drugs in monotherapy.
Potassium level
The combined use of perindopril and indapamide does not prevent the development of hypokalemia, especially in patients with diabetes mellitus or renal failure. As in the case of the combined use of antihypertensive drugs and a diuretic, regular monitoring of the level of potassium in the blood plasma is necessary.
Excipients
It should be taken into account that the excipients of the drug include lactose monohydrate. The drug should not be prescribed to patients with hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption.
Perindopril
Neutropenia/agranulocytosis
The risk of developing neutropenia while taking ACE inhibitors is dose-dependent and depends on the drug taken and the presence of concomitant diseases. Neutropenia rarely occurs in patients without concomitant diseases, however, the risk increases in patients with impaired renal function, especially against the background of systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma).
After discontinuation of ACE inhibitors, clinical signs of neutropenia disappear on their own.
Perindopril should be used with extreme caution in patients with diffuse connective tissue diseases, while taking immunosuppressive drugs, allopurinol or procainamide, and when used together, especially in patients with underlying renal impairment. Some patients developed severe infections, in some cases resistant to intensive antibiotic therapy. When prescribing perindopril to such patients, it is recommended to periodically monitor the number of leukocytes in the blood. Patients should report any signs of infectious diseases (eg, sore throat, fever) to their doctor.
Hypersensitivity/angioedema (Quincke's edema)
When taking ACE inhibitors, including perindopril, in rare cases, the development of angioedema of the face, extremities, lips, tongue, glottis and/or larynx may occur. If symptoms appear, perindopril should be discontinued immediately and the patient should be observed until signs of edema completely disappear. If the swelling affects only the face and lips, it usually resolves on its own, although antihistamines may be used to treat symptoms.
Angioedema, accompanied by swelling of the larynx, can be fatal. Swelling of the tongue, glottis, or larynx can lead to airway obstruction. If such symptoms appear, you should immediately administer epinephrine (adrenaline) subcutaneously at a dilution of 1:1000 (0.3 or 0.5 ml) and/or ensure airway patency.
Patients with a history of angioedema not associated with taking ACE inhibitors may have an increased risk of developing it when taking drugs of this group (see section “Contraindications”).
In rare cases, angioedema of the intestine develops during therapy with ACE inhibitors. In this case, patients experience abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without previous angioedema of the face and with normal levels of C-1 esterase. The diagnosis is made using computed tomography of the abdominal region, ultrasound, or at the time of surgery. Symptoms disappear after stopping ACE inhibitors. In patients with abdominal pain receiving ACE inhibitors, the possibility of developing angioedema of the intestine must be taken into account when making a differential diagnosis.
Anaphylactoid reactions during desensitization
There are isolated reports of the development of long-term, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy with the venom of hymenoptera insects (bees, wasps).
ACE inhibitors should be used with caution in patients prone to allergic reactions undergoing desensitization procedures. Prescription of an ACE inhibitor should be avoided in patients receiving immunotherapy with hymenoptera venom. However, anaphylactoid reaction can be avoided by temporarily discontinuing ACE inhibitors at least 24 hours before the procedure.
Anaphylactoid reactions during LDL apheresis
In rare cases, life-threatening anaphylactoid reactions may occur in patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis using dextran sulfate. To prevent an anaphylactoid reaction, ACE inhibitor therapy should be temporarily discontinued before each apheresis procedure.
Hemodialysis
Anaphylactoid reactions have been reported in patients receiving ACE inhibitors during hemodialysis using high-flux membranes (eg, AN69®). Therefore, it is advisable to use a different type of membrane or use an antihypertensive drug of a different pharmacotherapeutic group.
Potassium-sparing diuretics and potassium supplements
As a rule, the combined use of perindopril and potassium-sparing diuretics, as well as potassium preparations and potassium-containing salt substitutes is not recommended (see section “Interaction with other drugs”).
Cough
During therapy with an ACE inhibitor, a dry cough may occur. The cough persists for a long time while taking drugs of this group and disappears after their discontinuation. If a patient develops a dry cough, one should be aware of the possible connection of this symptom with taking an ACE inhibitor. If the attending physician believes that ACE inhibitor therapy is necessary for the patient, the drug may be continued.
Children and teenagers
Indapril should not be prescribed to children and adolescents under the age of 18 years due to the lack of data on the effectiveness and safety of the use of perindopril as monotherapy or as part of combination therapy in patients in this age group.
Risk of arterial hypotension and/or renal failure (in patients with chronic heart failure, fluid and electrolyte imbalance, etc.)
In some pathological conditions, significant activation of the renin-angiotensin-aldosterone system may be observed, especially with severe hypovolemia and a decrease in the level of plasma electrolytes (against the background of a salt-free diet or long-term use of diuretics), in patients with initially low blood pressure, stenosis of one or two kidneys arteries, chronic heart failure or cirrhosis of the liver with the presence of edema and ascites.
The use of an ACE inhibitor causes a blockade of this system and therefore may be accompanied by a sharp decrease in blood pressure and/or an increase in the level of creatinine in the blood plasma, indicating the development of functional renal failure. These phenomena are more often observed when taking the first dose of the drug or during the first two weeks of therapy. Sometimes these conditions develop acutely and during other periods of therapy. In such cases, when resuming therapy, it is recommended to use the drug at a lower dose and gradually increase the dose.
Elderly patients
Before starting to take the drug, it is necessary to assess the functional activity of the kidneys and the concentration of potassium in the blood plasma. At the beginning of therapy, the dose of the drug is selected taking into account the degree of reduction in blood pressure, especially in the case of dehydration and loss of electrolytes. Such measures help to avoid a sharp decrease in blood pressure.
Atherosclerosis
The risk of arterial hypotension exists in all patients, however, special care should be taken when using the drug in patients with coronary heart disease and cerebrovascular insufficiency. In such patients, treatment should be started with low doses.
Patients with renovascular hypertension
The treatment method for renovascular hypertension is revascularization. However, the use of ACE inhibitors has a beneficial effect in patients both awaiting surgery and in cases where such surgery cannot be performed.
In patients with diagnosed or suspected renal artery stenosis, treatment should begin with lower doses of perindopril and indapamide. Some patients may develop functional renal failure, which disappears when the drug is discontinued.
Other risk groups
In persons with chronic heart failure (functional class IV according to the NYHA classification) and patients with insulin-dependent diabetes mellitus (risk of spontaneous increase in potassium concentration), treatment should begin with lower doses of perindopril and indapamide and under constant medical supervision. Patients with arterial hypertension and coronary heart disease should not stop taking beta-blockers: ACE inhibitors should be used together with beta-blockers.
Patients with diabetes mellitus
When prescribing the drug to patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, blood glucose levels should be carefully monitored during the first month of therapy.
Ethnic differences
Perindopril, like other ACE inhibitors, apparently has a less pronounced hypotensive effect in patients of the Negroid race compared to representatives of other races. Perhaps this difference is due to the fact that patients with arterial hypertension of the Negroid race more often have low renin activity.
Surgery / General anesthesia
The use of ACE inhibitors in patients undergoing surgery using general anesthesia can lead to a significant decrease in blood pressure, especially when using general anesthesia agents that have a hypotensive effect. It is recommended to stop taking long-acting ACE inhibitors, including perindopril, 12 hours before surgery.
Aortic stenosis / Mitral stenosis / Hypertrophic cardiomyopathy
ACE inhibitors should be prescribed with caution to patients with left ventricular outflow obstruction.
Liver failure
In rare cases, cholestatic jaundice occurs while taking ACE inhibitors. As this syndrome progresses, fulminant liver necrosis develops, sometimes with death. The mechanism of development of this syndrome is unclear. If jaundice occurs while taking ACE inhibitors, the patient should consult a doctor. If there is a significant increase in the activity of liver enzymes while taking ACE inhibitors, you should stop taking the drug (see section “Side Effects”).
Anemia
Anemia can develop in patients after kidney transplantation or in patients on hemodialysis. In this case, the decrease in hemoglobin concentration is greater, the higher its initial value: This effect is apparently not dose-dependent, but may be associated with the mechanism of action of ACE inhibitors.
Hyperkalemia
Hyperkalemia may develop during treatment with ACE inhibitors, including perindopril. Risk factors for hyperkalemia are renal failure, impaired renal function, old age, diabetes mellitus, some concomitant conditions (dehydration, acute decompensation of heart failure, metabolic acidosis), concomitant use of potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene, amiloride), as well as drugs potassium or potassium-containing substitutes for table salt, as well as the use of other drugs that increase the level of potassium in the blood plasma (for example, heparin). The use of potassium supplements, potassium-sparing diuretics, potassium-sparing table salt substitutes can lead to a significant increase in potassium levels in the blood, especially in patients with reduced renal function. Hyperkalemia can cause serious, sometimes fatal, abnormal heart rhythms. If combined use of the above drugs is necessary, treatment should be carried out with caution, against the background of regular monitoring of potassium levels in the blood serum (see section “Interaction with other drugs”).
Indapamide
When thiazide and thiazide-like diuretics are prescribed to patients with impaired liver function, hepatic encephalopathy may develop. In this case, diuretics should be stopped immediately.
Photosensitivity
While taking thiazide and thiazide-like diuretics, cases of photosensitivity reactions have been reported (see section "Side effects"). If photosensitivity reactions develop while taking the drug, treatment should be discontinued. If it is necessary to continue diuretic therapy, it is recommended to protect the skin from exposure to sunlight and artificial UV rays.
Water and electrolyte balance
Content of sodium ions in blood plasma
Before starting treatment, it is necessary to determine the content of sodium ions in the blood plasma. While taking the drug, this indicator should be regularly monitored. All diuretics can cause hyponatremia, which sometimes leads to serious complications. Hyponatremia at the initial stage may not be accompanied by clinical symptoms, so regular laboratory monitoring is necessary. More frequent monitoring of sodium ion levels is indicated for patients with liver cirrhosis and the elderly (see sections “Side effects” and “Overdose”).
Content of potassium ions in blood plasma
Therapy with thiazide and thiazide-like diuretics is associated with a risk of hypokalemia. Hypokalemia (less than 3.4 mmol/l) should be avoided in the following high-risk patients: elderly patients, debilitated patients or those receiving concomitant drug therapy, patients with liver cirrhosis, peripheral edema or ascites, coronary artery disease, heart failure. Hypokalemia in these patients enhances the toxic effect of cardiac glycosides and increases the risk of developing arrhythmias.
The high-risk group also includes patients with an increased QT interval, and it does not matter whether this increase is caused by congenital causes or the effect of drugs.
Hypokalemia, like bradycardia, contributes to the development of severe cardiac arrhythmias, especially arrhythmias, which can be fatal. In all the cases described above, more regular monitoring of the content of potassium ions in the blood plasma is necessary. The first measurement of potassium ion concentration should be carried out within the first week from the start of therapy.
If hypokalemia is detected, appropriate treatment should be prescribed.
Content of calcium ions in blood plasma
Thiazide and thiazide-like diuretics reduce the excretion of calcium ions by the kidneys, leading to a slight and temporary increase in the concentration of calcium in the blood plasma. Severe hypercalcemia may be a consequence of previously undiagnosed hyperparathyroidism. Before studying the function of the parathyroid glands, you should stop taking diuretic drugs.
Plasma glucose levels
It is necessary to monitor blood glucose levels in patients with diabetes mellitus, especially in the presence of hypokalemia.
Uric acid
In patients with elevated levels of uric acid in the blood plasma during therapy, the frequency of gout attacks may increase.
Diuretics and kidney function
Thiazide and thiazide-like diuretics are fully effective only in patients with normal or slightly impaired renal function (plasma creatinine in adults below 25 mg/mol or 220 µmol/l). In elderly patients, creatinine clearance is calculated taking into account age, body weight and gender. At the beginning of treatment with diuretics, patients due to hypovolemia and hyponatremia may experience a temporary decrease in glomerular filtration rate and an increase in the concentration of urea and creatinine in the blood plasma. This transient functional renal failure is not dangerous for patients with unchanged renal function, but its severity may increase in patients with renal failure.
Athletes
Indapamide may give a positive reaction during doping control.
Dual blockade of the renin-angiotensin-aldosterone system
Dual blockade of the renin-angiotensin-aldosterone system is associated with an increased risk of hypotension, hyperkalemia and renal dysfunction (including acute renal failure) compared with monotherapy. Dual blockade of the RAAS using ACE inhibitors, ARB II or Aliskiren cannot be recommended for any patient, especially patients with diabetic nephropathy.
In some cases, when the combined use of ACE inhibitors or ARB II is absolutely indicated, careful supervision by a specialist and mandatory monitoring of renal function, water and electrolyte balance, and blood pressure are necessary. This applies to the use of candesartan or valsartan as adjunctive therapy to ACE inhibitors in patients with chronic heart failure. Carrying out double blockade of the RAAS under the careful supervision of a specialist and mandatory monitoring of renal function, water-electrolyte balance and blood pressure is possible in patients with chronic heart failure with intolerance to aldosterone antagonists (spironolactone), who have persistence of symptoms of chronic heart failure, despite other adequate therapy.
