Instructions for use NOLIPREL® BI-FORTE (NOLIPREL BI-FORTE)

Instructions for use NOLIPREL® BI-FORTE (NOLIPREL BI-FORTE)

The combination of lithium and the combination of perindopril with indapamide is generally not recommended.

Perindopril

Neutropenia, agranulocytosis, thrombocytopenia, anemia

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 non-black 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, abdominal pain is noted (with or without nausea and vomiting), in some cases, without previous angioedema of the face and with a normal level of C1-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. 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.

Potassium-sparing diuretics, potassium salts

Usually, the combined use of perindopril with potassium-sparing diuretics or potassium salts is not recommended.

Double blockade of the RAAS

There is evidence that the combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren increases the risk of hypotension, hyperkalemia and renal dysfunction (including acute renal failure). In this regard, double blockade of the RAAS by combined use of an ACE inhibitor and an angiotensin II receptor antagonist or aliskiren is not recommended.

If dual blockade of the RAAS is considered absolutely necessary, it should be carried out under specialist supervision and with careful frequent monitoring of renal function, blood pressure and electrolytes.

Patients with diabetic nephropathy should not take ACE inhibitors and angiotensin II receptor antagonists concomitantly.

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.

Patients with an established diagnosis of renal artery stenosis or if it is suspected are not recommended to prescribe Noliprel® Bi-Forte, because in such cases, treatment with the perindopril/indapamide combination should be started in a hospital and lower doses should be used than a single dose of Noliprel® Bi-Forte.

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 the Negroid race compared to representatives of other races. Perhaps this difference is due to the fact that arterial hypertension in patients of the Negroid race 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

ACE inhibitors should be used 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

In some patients treated with ACE inhibitors, including perindopril, cases of increased serum potassium levels were observed. 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) × body weight (kg)/0.814 × serum creatinine (µmol/l)

For women:

the calculation result should be multiplied by 0.85.

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® Bi-forte

Kidney failure

For patients with moderate to severe renal failure (creatinine clearance <60 ml/min), Noliprel® Bi-forte is contraindicated.

Treatment should be discontinued if a blood test reveals renal failure in a patient suffering from arterial hypertension and without clinical symptoms of kidney damage. Treatment can be resumed with the drug at a lower dose, or with only one of the components.

Routine medical monitoring of these patients should include frequent monitoring of serum potassium and creatinine levels, initially 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 or underlying renal impairment, including renal artery stenosis.

It is not recommended to use Noliprel® Bi-forte in patients with bilateral renal artery stenosis or in patients with a solitary kidney.

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® Bi-forte 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 is taken in addition to a beta blocker.

Arterial hypotension, deficiency of water and electrolytes in the body

With low sodium levels, especially in patients with renal artery stenosis, there is a risk of a sudden drop in blood pressure. Therefore, tests should be systematically carried out to identify clinical signs of deficiency in the body of water and electrolytes, which may occur against the background of attacks of diarrhea or vomiting. Plasma electrolyte levels should be regularly monitored.

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 satisfactory blood volume and blood pressure, treatment can be resumed either with the drug at a lower dose, or with only one of its components.

Potassium level

The combination of perindopril and indapamide does not prevent the onset of hypokalemia, especially in patients with diabetes mellitus or in patients with renal failure. As with any antihypertensive drug containing a diuretic, regular monitoring of plasma potassium levels should be carried out.

Excipients

Noliprel® Bi-forte should not be prescribed to patients with hereditary lactose intolerance, lapp lactase deficiency or glucose-galactose malabsorption syndrome.

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® Bi-forte do not affect the ability to concentrate. 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.

Preclinical safety data

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.

Perindopril

In chronic oral toxicity studies (in rats and monkeys), the receptor organ is the kidney, and the damage is reversible.

No mutagenicity was observed in in vitro or in vivo studies.

Reproductive toxicity studies (in rats, mice, rabbits and monkeys) showed no evidence of embryotoxicity or teratogenicity. However, ACE inhibitors as a class have been shown to have adverse effects on late fetal development, leading to fetal death and congenital defects in rodents and rabbits:

• kidney damage and an increase in perinatal and postnatal mortality were observed.

No carcinogenicity was observed in studies with long-term administration in rats and mice.

Indapamide

When indapamide was administered orally in the highest doses to different types of animals (doses 40-8000 times higher than the therapeutic dose), an increase in the diuretic effect was observed. In acute toxicity studies of indapamide administered intravenously or intraperitoneally, the main symptoms of poisoning were related to the pharmacological effects of indapamide, such as bradypnea and peripheral vasodilation.

When indapamide was tested for mutagenicity and carcinogenicity, negative results were obtained.

Compound

Overdose

Symptoms: the most likely symptom of overdose is a marked decrease in blood pressure, sometimes in combination with nausea, vomiting, convulsions, dizziness, drowsiness, confusion and oliguria, which can develop into anuria (as a result of hypovolemia). Electrolyte disturbances (hyponatremia, hypokalemia) may also occur.

Treatment: emergency measures are limited to removing the drug from the body: gastric lavage and/or taking activated charcoal, followed by restoration of water and electrolyte balance.

If there is a significant decrease in blood pressure, the patient should be placed in a supine position with legs elevated, and, if necessary, correct hypovolemia (for example, intravenous infusion of 0.9% sodium chloride solution). Perindoprilat, the active metabolite of perindopril, can be removed from the body by dialysis.

Side effects

The use of perindopril inhibits the renin-angiotensin-aldosterone system and helps reduce the loss of potassium in the blood plasma caused by indapamide. Hypokalemia (potassium level <3.4 mmol/l) occurs in 6% of patients treated with Noliprel® Bi-forte. The most frequently reported adverse reactions were: when using perindopril - dizziness, headache, paresthesia, dysgeusia, visual disturbances, vertigo, tinnitus, hypotension, cough, shortness of breath, abdominal pain, constipation, dyspepsia, diarrhea, nausea , vomiting, itching, rash, muscle cramps and asthenia when using indapamide - hypersensitivity reactions, mainly dermatological, in patients prone to developing allergic and asthmatic reactions, and maculopapular rashes.

Pharmacodynamics

Noliprel® A Bi-forte is a combination drug containing perindopril arginine and indapamide. The pharmacological properties of the drug Noliprel® A Bi-forte combine the individual properties of each of its active components.

1. Mechanism of action

Noliprel® A Bi-forte

The combination of perindopril arginine and indapamide enhances the antihypertensive effect of each of them.

Perindopril

Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II (ACE inhibitor). ACE, or kininase II, is an exopeptidase that carries out both the conversion of angiotensin I into the vasoconstrictor substance angiotensin II, and the destruction of bradykinin, which has a vasodilatory effect, into an inactive heptapeptide. As a result, perindopril:

- reduces the secretion of aldosterone;

- according to the principle of negative feedback, it increases the activity of renin in the blood plasma;

- with long-term use, it reduces the peripheral vascular resistance, which is mainly due to the effect on the vessels in the muscles and kidneys. These effects are not accompanied by sodium or fluid retention or the development of reflex tachycardia.

Perindopril normalizes myocardial function, reducing preload and afterload.

When studying hemodynamic parameters in patients with chronic heart failure (CHF), it was revealed:

- decrease in filling pressure in the left and right ventricles of the heart;

— decrease in OPSS;

- increased cardiac output and increased cardiac index;

- increased muscle peripheral blood flow.

Indapamide

Indapamide belongs to the group of sulfonamides; its pharmacological properties are similar to thiazide diuretics. Indapamide inhibits the reabsorption of sodium ions in the cortical segment of the loop of Henle, which leads to an increase in the excretion of sodium, chlorine and, to a lesser extent, potassium and magnesium ions by the kidneys, thereby increasing diuresis and reducing blood pressure.

2. Antihypertensive effect

Noliprel® A Bi-forte

Noliprel® A Bi-forte has a dose-dependent antihypertensive effect on both DBP and SBP in the standing and lying position. The antihypertensive effect of the drug lasts for 24 hours. A stable therapeutic effect develops less than 1 month from the start of therapy and is not accompanied by tachycardia. Stopping treatment does not cause withdrawal syndrome.

Noliprel® A Bi-forte reduces the degree of left ventricular hypertrophy (LVH), improves arterial elasticity, reduces peripheral vascular resistance, and does not affect lipid metabolism (total cholesterol, HDL and LDL cholesterol, triglycerides).

The effect of using a combination of perindopril and indapamide on LVG in comparison with enalapril has been proven. In patients with arterial hypertension and LVH who received therapy with perindopril erbumine 2 mg (equivalent to 2.5 mg of perindopril arginine)/indapamide 0.625 mg or enalapril at a dose of 10 mg once daily, and with an increase in the dose of perindopril erbumine to 8 mg (equivalent to 10 mg perindopril arginine) and indapamide up to 2.5 mg, or enalapril up to 40 mg once daily, a more significant decrease in left ventricular mass index (LVMI) was noted in the perindopril/indapamide group compared with the enalapril group. In this case, the most significant effect on LVMI was observed with the use of perindopril erbumine 8 mg/indapamide 2.5 mg.

A more pronounced antihypertensive effect was also noted during combination therapy with perindopril and indapamide compared to enalapril.

Perindopril

Perindopril is effective in the treatment of arterial hypertension of any severity.

The antihypertensive effect of the drug reaches its maximum 4–6 hours after a single oral dose and persists for 24 hours. 24 hours after taking the drug, a pronounced (about 80%) residual ACE inhibition is observed.

Perindopril has an antihypertensive effect in patients with both low and normal plasma renin activity.

The simultaneous administration of thiazide diuretics increases the severity of the antihypertensive effect. In addition, the combination of an ACE inhibitor and a thiazide diuretic also reduces the risk of hypokalemia while taking diuretics.

Indapamide

The antihypertensive effect occurs when the drug is used in doses that have a minimal diuretic effect.

The antihypertensive effect of indapamide is associated with an improvement in the elastic properties of large arteries and a decrease in peripheral vascular resistance.

Indapamide reduces LVG, does not affect the concentration of lipids in the blood plasma: triglycerides, total cholesterol, LDL cholesterol, HDL cholesterol; carbohydrate metabolism (including in patients with concomitant diabetes mellitus).

Note!

Description of the drug Noliprel Bi-Forte table. p/o No. 90 on this page is a simplified author’s version of the apteka911 website, created on the basis of the instructions for use.
Before purchasing or using the drug, you should consult your doctor and read the manufacturer's original instructions (attached to each package of the drug). Information about the drug is provided for informational purposes only and should not be used as a guide to self-medication. Only a doctor can decide to prescribe the drug, as well as determine the dose and methods of its use.

Use during pregnancy and breastfeeding

Pregnancy

Noliprel® A Bi-forte is contraindicated during pregnancy (see “Contraindications”).

If you are planning pregnancy or if it occurs while taking the drug, you should immediately stop taking the drug and prescribe other antihypertensive therapy. There have been no adequate controlled studies of ACE inhibitors in pregnant women. The limited available data on the effects of the drug in the first trimester of pregnancy indicate that the drug did not lead to malformations associated with fetotoxicity.

Noliprel® A Bi-forte should not be used in the first trimester of pregnancy. Noliprel® A Bi-forte is contraindicated in the second and third trimesters of pregnancy.

It is known that long-term exposure of the fetus to ACE inhibitors in the second and third trimesters of pregnancy can lead to disruption of its development (decreased renal function, oligohydramnios, delayed ossification of the skull bones) and the development of complications in the newborn (renal failure, arterial hypotension, hyperkalemia).

Long-term use of thiazide diuretics in the third trimester of pregnancy can cause hypovolemia in the mother and a decrease in uteroplacental blood flow, which leads to fetoplacental ischemia and fetal growth retardation. In rare cases, while taking diuretics shortly before birth, newborns develop hypoglycemia and thrombocytopenia.

If the patient received Noliprel® A Bi-forte during the second or third trimesters of pregnancy, it is recommended to perform an ultrasound of the newborn to assess the condition of the skull bones and kidney function.

In newborns whose mothers received therapy with ACE inhibitors, arterial hypotension may be observed, and therefore newborns should be under close medical supervision.

Breastfeeding period

Noliprel® A Bi-forte is contraindicated during breastfeeding.

It is not known whether perindopril is excreted in breast milk.

Indapamide is excreted in breast milk. Taking thiazide diuretics causes a decrease in the amount of breast milk or suppression of lactation. The newborn may develop hypersensitivity to sulfonamide derivatives, hypokalemia and kernicterus.

It is necessary to assess the significance of therapy for the mother and make a decision to stop breastfeeding or stop taking the drug.

Directions for use and doses

Inside, 1 tablet. 1 time per day, preferably in the morning, before meals.

Elderly patients (see "Special instructions")

In elderly patients, creatinine Cl is calculated taking into account age, body weight and gender. Elderly patients with normal renal function are prescribed Noliprel® A Bi-forte, 1 tablet. Once a day, the degree of blood pressure reduction should be monitored.

Renal failure (see "Special Instructions")

The drug is contraindicated in patients with moderate and severe renal failure (Cl creatinine <60 ml/min).

Patients with creatinine Cl equal to or exceeding 60 ml/min during therapy require regular monitoring of the concentration of creatinine and potassium in the blood plasma.

Liver failure (see “Contraindications”, “Pharmacokinetics”)

The drug is contraindicated in patients with severe liver failure.

For moderately severe liver failure, no dose adjustment is required.

Children and teenagers

Noliprel® A Bi-forte should not be prescribed to children and adolescents under 18 years of age due to the lack of data on the effectiveness and safety of the drug in patients in this age group.

Pharmacokinetics

Noliprel® A Bi-forte

The combined use of perindopril and indapamide does not change their pharmacokinetic characteristics compared to the separate administration of these drugs.

Perindopril

When taken orally, perindopril is rapidly absorbed. Cmax in blood plasma is achieved 1 hour after oral administration. T1/2 is 1 hour. Perindopril has no pharmacological activity. Approximately 27% of the total amount of perindopril taken orally enters the bloodstream in the form of an active metabolite, perindoprilate.

In addition to perindoprilate, 5 more metabolites are formed that do not have pharmacological activity. Cmax of perindoprilate in blood plasma is achieved 3–4 hours after oral administration. Eating slows down the conversion of perindopril to perindoprilat, thereby affecting bioavailability. Therefore, the drug should be taken once a day, in the morning, before meals.

There is a linear relationship between the concentration of perindopril in the blood plasma and its dose. The Vd of unbound perindoprilate is approximately 0.2 l/kg. The association of perindoprilate with plasma proteins, mainly with ACE, depends on the concentration of perindopril and is about 20%.

Perindoprilat is excreted from the body by the kidneys. The effective T1/2 of the unbound fraction is about 17 hours, the equilibrium state is reached within 4 days.

The elimination of perindoprilate is slowed down in old age, as well as in patients with heart and renal failure.

The dialysis clearance of perindoprilate is 70 ml/min.

The pharmacokinetics of perindopril is changed in patients with liver cirrhosis: its hepatic clearance is reduced by 2 times. However, the amount of perindoprilate formed does not decrease, which does not require dose adjustment (see “Dosage and Administration” and “Special Instructions”).

Indapamide

Indapamide is quickly and completely absorbed from the gastrointestinal tract.

Cmax of indapamide in blood plasma is observed 1 hour after oral administration.

Connection with blood plasma proteins - 79%.

T1/2 is 14–24 hours (average 18 hours). Repeated administration of the drug does not lead to its accumulation in the body. It is excreted mainly by the kidneys (70% of the administered dose) and through the intestines (22%) in the form of inactive metabolites.

The pharmacokinetics of the drug does not change in patients with renal failure.