Instructions for use NOLIPREL® FORTE A (NOLIPREL FORTE A)
Perindopril
Neutropenia, agranulocytosis
Neutropenia/agranulocytosis, thrombocytopenia and anemia were observed while taking ACE inhibitors. In patients with normal liver function and in the absence of other complicating factors, neutropenia rarely develops. Perindopril should be used with extreme caution in patients with diffuse connective tissue diseases, while taking immunosuppressants, allopurinol or procainamide, especially in patients with pre-existing liver dysfunction. Some of these 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
When taking ACE inhibitors, incl. and perindopril, in rare cases, the development of angioedema of the face, extremities, lips, mucous membranes, tongue, vocal cords and/or larynx may occur. These reactions may occur at any time during therapy. In such cases, the drug should be stopped immediately and the necessary monitoring should be carried out until the symptoms disappear completely. If the swelling affects only the face and lips, it usually goes away on its own, although antihistamines can be used to treat symptoms.
Angioedema, accompanied by swelling of the larynx, can be fatal. Swelling of the tongue, vocal cords, or larynx can lead to airway obstruction. If these symptoms appear, you should immediately administer epinephrine solution 1:
- 1000 (0.3-0.5 ml) subcutaneously and/or ensure airway patency.
There are reports that black patients are more likely to experience angioedema when taking ACE inhibitors than white patients.
Patients who have had angioedema not associated with taking ACE inhibitors may have an increased risk of developing it when taking drugs of this group.
In rare cases, angioedema of the intestine develops during therapy with ACE inhibitors. In this case, patients experience abdominal pain (with or without nausea and vomiting), in some cases, without previous angioedema of the face and with normal C1-esterase levels. The diagnosis is made using computed tomography of the abdominal region, ultrasound, or at the time of surgery. Symptoms disappear after stopping 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.
Anaphylactoid reactions during desensitization
There are isolated reports of the development of persistent, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy with hymenopteric venom (including bee and aspen). ACE inhibitors should be prescribed with extreme caution to patients prone to allergic reactions and undergoing desensitization; their use should be avoided in patients undergoing immunotherapy with insect venom allergens. However, if the patient requires both treatment with ACE inhibitors and desensitization, then the onset of such reactions can be prevented by temporarily stopping the use of ACE inhibitors at least 24 hours before starting the course of desensitization therapy.
Anaphylactoid reactions during LDL apheresis
In rare cases, life-threatening anaphylactoid reactions may occur 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 some patients undergoing hemodialysis using high-flux membranes (eg, AN69®) and concomitantly receiving one of the ACE inhibitors. For such patients, the use of a different type of membrane or a different class of antihypertensive drug should be considered.
Cough
Taking an ACE inhibitor may cause a dry cough. The cough persists for a long time while taking the drug, but disappears when the drug is discontinued. This symptom may have an iatrogenic etiology. If the need to take an ACE inhibitor remains, then continued treatment should be considered.
Risk of arterial hypotension and/or renal failure (in case of heart failure, water and electrolyte deficiency)
With significant loss of water and electrolytes (strict salt-free diet or long-term treatment with diuretics), especially in patients with initially low blood pressure, with renal artery stenosis, congestive heart failure or cirrhosis of the liver, accompanied by edema and ascites, pronounced stimulation of the RAAS occurs. Therefore, inhibition of RAAS activity when taking an ACE inhibitor may lead to a sudden decrease in blood pressure and/or an increase in serum creatinine, indicating functional renal failure. This is most likely when you first take the drug and during the first 2 weeks of treatment. In some, albeit very rare cases, such a disorder develops acutely, and the onset of the process is difficult to predict. In such cases, treatment should be resumed with a lower dose, gradually increasing it.
Elderly patients
Before starting treatment, kidney function and potassium levels should be monitored. To avoid sudden arterial hypotension, the initial dose of the drug is adjusted depending on the degree of decrease in blood pressure, especially in the case of dehydration and loss of electrolytes.
Patients with established atherosclerosis
The risk of arterial hypotension exists in all patients, but the drug should be used with extreme caution in patients with coronary artery disease or cerebrovascular insufficiency. In such cases, treatment should be started with a low dose.
Renovascular hypertension
Renovascular hypertension is treated by revascularization. However, the use of ACE inhibitors may be beneficial in patients with renovascular hypertension awaiting surgery or when surgery is not available.
In patients with an established diagnosis of renal artery stenosis or if it is suspected, treatment with Noliprel® forte A should begin in the hospital with a small dose under monitoring of renal function and potassium levels, because Some patients developed renal failure, which was reversible when treatment was discontinued.
Other risk groups
In patients with severe acute heart failure (grade IV) and in patients with insulin-dependent diabetes mellitus (a tendency to spontaneously increase potassium levels), treatment with Noliprel® forte A should be started with low doses and carried out under constant medical supervision.
Patients with arterial hypertension and coronary insufficiency should not stop taking beta-blockers:
- An ACE inhibitor should be used in addition to a beta blocker.
Diabetes
In diabetic patients already taking oral hypoglycemic agents or insulin, glycemic levels should be carefully monitored, especially during the first month of taking an ACE inhibitor.
Ethnic differences
Perindopril, like other ACE inhibitors, may have a less pronounced hypotensive effect in patients of black race compared to representatives of other races. Perhaps this difference is due to the fact that arterial hypertension in black patients very often occurs against the background of low renin activity.
Surgery/anesthesia
ACE inhibitors can cause a drop in blood pressure during anesthesia, especially if the anesthetic used has a hypotensive effect. Therefore, long-acting ACE inhibitors such as perindopril should, if possible, be discontinued 24 hours before surgery.
Aortic or mitral valve stenosis/hypertrophic cardiomyopathy
Use ACE inhibitors with caution in patients with left ventricular outflow tract obstruction.
Liver dysfunction
In rare cases, ACE inhibitors have been associated with a syndrome that begins with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not yet clear. In patients receiving ACE inhibitors, if jaundice or a marked increase in liver enzyme activity develops, the ACE inhibitor should be discontinued and a thorough medical examination should be performed.
Hyperkalemia
Elevated serum potassium levels have been reported in some patients treated with ACE inhibitors, including perindopril. Risk factors for the development of hyperkalemia include renal failure, deterioration of renal function, age (> 70 years), diabetes mellitus, intercurrent events such as dehydration, acute heart failure, metabolic acidosis, concomitant use of potassium-sparing diuretics (eg, spironolactone, eplerenone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes, or taking other drugs that cause increases in serum potassium (eg, heparin). Taking potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, especially in patients with impaired renal function, may result in significant increases in serum potassium levels. Hyperkalemia can cause serious arrhythmias, sometimes fatal. If concomitant administration of perindopril or the above drugs is considered necessary, they should be taken with caution and with regular monitoring of serum potassium levels.
Indapamide
In patients with impaired liver function, taking thiazide and thiazide-like diuretics can cause hepatic encephalopathy. In this case, the diuretic should be stopped immediately.
Photosensitivity
Cases of photosensitivity have been reported with the use of thiazide and thiazide-like diuretics. If photosensitivity is noted during treatment, it is recommended to stop taking the drug. If re-administration of a diuretic is considered necessary, it is recommended to protect the skin from the sun and artificial UV radiation.
Water and electrolyte balance
Sodium level.
Before starting treatment, it is necessary to evaluate the sodium content, and further such studies should be carried out regularly. Taking any diuretic medication can cause a decrease in sodium levels, which sometimes leads to a number of serious complications. Initially, a decrease in sodium levels may be asymptomatic, which is why it is necessary to regularly monitor its content. In elderly patients and patients with liver cirrhosis, monitoring should be carried out even more often.
Potassium level.
The main danger when taking thiazide and thiazide-like diuretics is potassium deficiency and, accordingly, hypokalemia. Consideration of the risk of potassium levels falling below acceptable levels (< 3.4 mmol/L) is necessary in persons at increased risk, such as elderly patients and/or patients with impaired or malnutrition, regardless of whether they are taking one or more medications drugs, in patients with liver cirrhosis, which is accompanied by edema and ascites, in patients with coronary artery disease and in patients with heart failure. In such cases, hypokalemia increases the toxicity of cardiac glycosides and increases the risk of developing arrhythmias. Patients with congenital or iatrogenic prolongation of the QT interval are also at risk. Hypokalemia, like bradycardia, is a risk factor for the development of serious cardiac arrhythmias, especially torsade de pointes (TdP), which can be fatal. In any case, potassium levels should be monitored as often as possible. The first determination of plasma potassium should be carried out within the first week after the start of treatment. If potassium levels decrease, dose adjustment is necessary.
Calcium level.
Thiazide and thiazide-like diuretics can reduce the excretion of calcium in the urine, which leads to a temporary and slight increase in the concentration of calcium in the blood. A marked increase in calcium levels may be associated with undiagnosed hyperparathyroidism. In this case, treatment should be stopped until the function of the parathyroid gland is examined.
Blood glucose level
In patients with diabetes mellitus, it is necessary to constantly monitor blood glucose levels, especially if potassium levels are simultaneously low.
Uric acid
Patients with high levels of uric acid in the blood may be predisposed to developing gout.
Effect on kidney function
Thiazide and thiazide-like diuretics are most effective when renal function is normal or only slightly impaired (serum creatinine is below approximately 2.5 mg/dL, i.e. 220 µmol/L for an adult patient). In elderly patients, plasma creatinine levels should be adjusted for age, weight and gender using the Cockcroft formula:
- For men: CC (ml/min) = (140 – age) x body weight (kg)/0.814 x serum creatinine (µmol/l)
- the calculation result should be multiplied by 0.85.
For women:
At the beginning of treatment, taking diuretics can lead to loss of water and sodium, which in turn leads to hypovolemia. Hypovolemia causes a decrease in glomerular filtration rate. It may be accompanied by an increase in creatinine and urea in the blood. This renal failure is temporary and does not cause undesirable consequences in patients with normal renal function, but in cases of existing impairment, renal failure may worsen.
Athletes
Please note that indapamide may cause a positive reaction during doping control.
Noliprel® forte A
The combination of lithium and the combination of perindopril with indapamide is generally not recommended.
Kidney failure.
In patients with severe renal failure (creatinine clearance <30 ml/min), this combination is contraindicated. Treatment should be discontinued if a patient suffers from arterial hypertension without visible kidney damage, but in whom renal failure is detected during a blood test (renal complex). Treatment can be resumed either with this combination at lower doses or with only one component. Such patients should usually undergo frequent monitoring of serum creatinine and potassium levels for the first time - after 2 weeks of treatment, then once every 2 months during the period of therapeutic stability.
Renal failure was mainly observed in patients with acute heart failure and was also observed in renal artery stenosis. This drug is generally not recommended for patients with bilateral renal artery stenosis or for patients with only one kidney.
Arterial hypotension, deficiency of water and electrolytes.
The risk of a sudden drop in blood pressure increases with low sodium levels (especially in patients with renal artery stenosis). Therefore, during treatment, the state of water and electrolyte balance should be periodically monitored, which may be disturbed due to diarrhea or vomiting. In case of severe arterial hypotension, intravenous infusion of an isotonic solution may be necessary.
Transient arterial hypotension is not a contraindication for continued treatment. After restoration of adequate blood volume and blood pressure, treatment can be resumed either with this combination at lower doses, or with only one component.
Potassium content.
The combination of perindopril and indapamide does not prevent the onset of hypokalemia, especially in patients with diabetes mellitus and in patients with renal failure. As with any antihypertensive drug taken in combination with a diuretic, plasma potassium levels should be regularly monitored during treatment with this combination.
Excipients.
Noliprel® forte A should not be prescribed to patients with lactose intolerance, lapp lactase deficiency or impaired absorption of glucose-galactose.
Use in pediatrics
The effectiveness and tolerability of perindopril in children and adolescents as mono- or as part of combination therapy has not been sufficiently studied.
Impact on the ability to drive vehicles and operate machinery
Perindopril and indapamide in the form of monotherapy or in combination as part of the drug Noliprel® forte A do not affect the ability to concentrate and the speed of psychomotor reactions. However, in some patients, especially at the beginning of treatment or when combined with another antihypertensive drug, individual reactions may develop with a decrease in blood pressure. This leads to impaired ability to drive vehicles or other mechanisms.
Results of preclinical safety studies
The toxicity of the perindopril/indapamide combination is slightly higher than the toxicity of each component. No renal toxicity was detected in rats. However, this combination causes gastrointestinal toxicity in dogs; in rats, the toxic effect on the maternal body increases (compared to perindopril). These undesirable effects occurred at doses with a very high safety margin compared to the therapeutic doses used.
Preclinical studies conducted separately with perindopril and indapamide revealed neither genotoxic nor teratogenic potential.
Noliprel A forte, 30 pcs., 1.25 mg+5 mg, film-coated tablets
Common to perindopril and indapamide
The use of the drug Noliprel® A forte 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”). 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.
Nocturnal dysfunction
Therapy is contraindicated in patients with severe renal failure (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 potassium levels and creatinine concentrations in the blood serum - 2 weeks after the start of therapy and every 2 months thereafter. Renal failure occurs more often in patients with severe chronic heart failure or underlying renal impairment, including renal artery stenosis. The drug Noliprel® A forte is not recommended in cases of bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney.
Arterial hypotension and water-electrolyte imbalance
In the case of initial hyponatremia, there is a risk of sudden development of arterial hypotension, especially in patients with renal artery stenosis. Therefore, during dynamic monitoring of patients, attention should be paid to possible symptoms of dehydration and decreased electrolyte levels in the blood plasma, for example, after diarrhea or vomiting. Such patients require regular monitoring of blood 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 low doses of drugs, 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 combination of any antihypertensive drug and a diuretic, regular monitoring of plasma potassium levels is necessary.
Excipients
It should be taken into account that the excipients of the drug include lactose monohydrate. Noliprel® A should not be prescribed to patients with hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption.
Lithium preparations
The simultaneous use of a combination of perindopril and indapamide with lithium preparations is not recommended (see section “Interaction with other drugs”).
Childhood
The drug 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 and indapamide, both separately and together, in patients in this age group.
Perindopril
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence of an increased risk of arterial hypotension, hyperkalemia and renal dysfunction (including acute renal failure) when ACE inhibitors are used simultaneously 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 “Interaction with other drugs” and “Pharmacodynamics”). If a double blockade is absolutely necessary, then this 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 angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see section "Contraindications").
Potassium-sparing diuretics, potassium supplements, potassium-containing table salt substitutes and food supplements
The simultaneous administration 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
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 (including systemic lupus erythematosus, scleroderma), as well as while taking immunosuppressants, allopurinol or procainamide, or a combination of these factors, especially in patients with initially impaired renal function .
Some of these 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 tell their doctor about any signs of infectious diseases (for example, sore throat, fever) (see sections "Interaction with other drugs" and "Side effects").
Anemia
Anemia may develop in patients after kidney transplantation or in those on 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, 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.
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 appear, the drug should be stopped immediately and the patient should be observed until signs of edema completely disappear. If the swelling affects only the face and lips, it usually goes away on its own, although 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 patency of the airway.
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.
mTOR (mammalian target of rapamycin) inhibitors (eg, sirolimus, everolimus, temsirolimus)
In patients receiving concomitant therapy with mTOR inhibitors, the risk of developing angioedema (including swelling of the airways or tongue with or without respiratory impairment) may be increased (see section "Interaction with other drugs").
Anaphylactoid reactions during desensitization
There are isolated reports of the development of prolonged, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy with hymenoptera venom (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, 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.
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.
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.
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, chronic heart failure or cirrhosis of the liver with 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 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.
Renovascular hypertension
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.
Treatment with Noliprel® A forte is not indicated in patients with diagnosed or suspected renal artery stenosis, since therapy should be started in a hospital setting with lower doses of the combination of perindopril and indapamide.
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.
Diabetes
In patients with type 1 diabetes mellitus (risk of spontaneous increase in potassium levels), treatment should begin with a low dose of the drug and under close medical supervision.
During the first month of therapy with ACE inhibitors, plasma glucose concentrations should be carefully monitored in patients with diabetes mellitus receiving oral hypoglycemic agents or insulin (see section "Interaction with other drugs").
Ethnic differences
Perindopril, like other ACE inhibitors, has a clearly 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/General anesthesia
The behavior of general anesthesia against the background of ACE inhibitors can lead to a pronounced decrease in blood pressure, especially when using general anesthesia agents that have an antihypertensive effect.
It is recommended, if possible, to stop taking long-acting ACE inhibitors, including perindopril, the day before surgery. It is necessary to warn the anesthesiologist that the patient is taking ACE inhibitors.
Aortic or mitral 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 consult a doctor (see section “Side Effects”).
Hyperkalemia
Hyperkalemia may develop during treatment with ACE inhibitors, including perindopril. Risk factors for hyperkalemia are renal failure, impaired renal function, age over 70 years, diabetes mellitus, some concomitant conditions (dehydration, acute cardiac decompensation, metabolic acidosis), concomitant use of potassium-sparing diuretics (such as spironolactone and its derivative eplerenone, triamterene, amiloride ), as well as potassium preparations or potassium-containing substitutes for table salt, as well as the use of other drugs that help increase the content of potassium in the blood plasma (for example, heparins, ACE inhibitors, angiotensin II receptor antagonists, acetylsalicylic acid at a dose of 3 g/day or more, inhibitors cyclooxygenase-2 (COX-2) 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 simultaneous 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
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.
Water and electrolyte balance
Content of sodium ions in blood plasma
The content of sodium ions in the blood plasma must be determined before starting treatment, and then regularly monitored while taking the drug. 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 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 simultaneous decrease in the content of chlorine ions can lead to the development of secondary compensatory metabolic alkalosis: the frequency of its occurrence and the severity of its manifestations are insignificant.
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, malnourished patients (both those receiving and not receiving concomitant drug therapy), patients with cirrhosis (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 developing arrhythmias.
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 arrhythmias, 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.
Content of calcium ions in blood plasma
Thiazide and thiazide-like diuretics can reduce the excretion of calcium ions by the kidneys, leading to a slight and temporary increase in calcium levels 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 diuretics.
Plasma glucose concentration
It is necessary to monitor blood glucose concentrations in patients with diabetes mellitus, especially in the presence of hypokalemia.
Uric acid
When the concentration of uric acid in the blood plasma increases 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 concentration in adults 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 × weight / 0.814 × 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 is not dangerous for patients with initially normal renal function, but its severity may increase in patients with renal failure.
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 or artificial ultraviolet rays.
Athletes
Indapamide may give a positive reaction during doping control.
Acute myopia and secondary angle-closure glaucoma
Sulfonamides and their derivatives can cause the development of idiosyncratic reactions leading to temporary (transient) 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.
Effect on the ability to drive a car or use mechanical devices
The effect of the substances included in the drug Noliprel® A forte does not lead to disturbances in psychomotor reactions. However, in some people, in response to a decrease in blood pressure, various individual reactions may develop, especially at the beginning of therapy or when other antihypertensive drugs are added to the therapy. In this case, the ability to drive a car or operate other machinery may be reduced.
