Noliprel^® (Tablets) Instructions for Use

Marketing Authorization Holder

Les Laboratoires Servier (France)

Manufactured By

Les Laboratoires Servier Industrie (France)

ATC Code

C09BA04 (Perindopril and diuretics)

Active Substances

Indapamide (Rec.INN registered by WHO)

Perindopril (Rec.INN registered by WHO)

Dosage Form

Noliprel®

Tablets 2 mg+625 mcg: 14 or 30 pcs.

Dosage Form, Packaging, and Composition

Tablets are white, oblong, with a score on both sides.

Excipients: anhydrous colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose.

14 pcs. – blisters (1) – sachets (1) with a water-absorbing tablet – cardboard packs.
30 pcs. – blisters (1) – sachets (1) with a water-absorbing tablet – cardboard packs.

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive combination agent (ACE inhibitor + diuretic)

Pharmacological Action

Noliprel^® is a combined preparation containing Perindopril (an ACE inhibitor) and Indapamide (a diuretic from the sulfonamide group). The pharmacological properties of Noliprel^® combine the individual properties of each of the components.

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

Mechanism of action

Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II (ACE inhibitor). Angiotensin-converting enzyme, or kinase, is an exopeptidase that both converts angiotensin I into the vasoconstrictor substance angiotensin II and degrades bradykinin, which has a vasodilating effect, into an inactive heptapeptide. As a result, Perindopril reduces the secretion of aldosterone; by the principle of negative feedback, it increases plasma renin activity; with prolonged use, it reduces total peripheral resistance, which is mainly due to its effect on blood vessels in muscles and kidneys. These effects are not accompanied by salt and fluid retention or the development of reflex tachycardia.

Perindopril normalizes myocardial function by reducing preload and afterload. When studying hemodynamic parameters in patients with chronic heart failure, the following were revealed: a decrease in filling pressure in the left and right ventricles of the heart; decrease in total peripheral resistance; increased cardiac output and increased cardiac index; increased muscle peripheral blood flow.

Indapamide belongs to the sulfonamide group and is close in pharmacological properties 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 renal excretion of sodium and chloride ions and, to a lesser extent, potassium and magnesium ions, thereby enhancing diuresis and reducing blood pressure.

Antihypertensive action

Noliprel^® has a dose-dependent antihypertensive effect on both diastolic and systolic blood pressure in the standing and lying positions. The antihypertensive effect of the drug lasts for 24 hours. The therapeutic effect occurs in less than 1 month from the start of therapy and is not accompanied by tachycardia. Discontinuation of treatment does not cause withdrawal syndrome. A synergistic antihypertensive effect of perindopril and indapamide compared with monotherapy with these drugs has been noted.

Noliprel^® reduces the degree of left ventricular hypertrophy, improves arterial elasticity, reduces total peripheral resistance, and does not affect lipid metabolism (total cholesterol, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, triglycerides).

The effect of Noliprel^® on cardiovascular morbidity and mortality rates has not been studied.

The PICXEL study examined the effect of the combination of perindopril and indapamide on left ventricular hypertrophy (LVH) compared with enalapril. The severity of LVH was assessed using echocardiography.

After randomization, patients with arterial hypertension and LVH (LVMI value – left ventricular mass index – more than 120 g/m² in men and more than 100 g/m² in women) received therapy with perindopril 2 mg + indapamide 0.625 mg or enalapril 10 mg once a day for one year. To achieve blood pressure control, the doses of the drugs were increased: perindopril – up to a maximum of 8 mg and indapamide – up to 2.5 mg, and enalapril – up to 40 mg once a day. Only 34% of patients continued to receive Perindopril 2 mg + Indapamide 0.625 mg (in the enalapril group, 20% of patients continued to take the drug at a dose of 10 mg).

At the end of therapy, a more significant reduction in LVMI was noted in the Perindopril/Indapamide group (-10.1 g/m²) compared with the indapamide group (-1.1 g/m²). The difference in the degree of reduction of this indicator between the groups was -8.3 g/m²(95% CI (-11.5, -5.0), p< 0.0001).

In the group of patients receiving combination therapy with perindopril and indapamide, a more pronounced antihypertensive effect was noted compared with the enalapril group. The difference in the degree of blood pressure reduction between the groups in the general patient population was -5.8 mm Hg (95% CI (-7.9, -3.7), p< 0.0001) for systolic blood pressure, and -2.3 mm Hg (95% CI (-3.6, -0.9), p= 0.0004) for diastolic blood pressure.

Perindopril is effective in the treatment of arterial hypertension of any severity. The antihypertensive effect of the drug reaches a maximum 4-6 hours after a single dose and lasts for 24 hours. 24 hours after taking the drug, a pronounced (about 80%) residual inhibition of ACE is observed. Perindopril has an antihypertensive effect in patients with both low and normal plasma renin activity.

Perindopril has a vasodilating effect, promotes the restoration of elasticity of large arteries and the structure of the vascular wall of small arteries, and also reduces left ventricular hypertrophy.

Concomitant administration of thiazide diuretics enhances the severity of the antihypertensive effect. In addition, the combination of an ACE inhibitor and a thiazide diuretic also leads to a reduction in the risk of hypokalemia while taking diuretics.

Indapamide as monotherapy has an antihypertensive effect that lasts for 24 hours. The antihypertensive effect manifests itself 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 total peripheral vascular resistance. Indapamide reduces left ventricular hypertrophy.

Thiazide and thiazide-like diuretics reach a plateau of therapeutic effect at a certain dose, while the frequency of side effects continues to increase with a further increase in the drug dose. Therefore, the dose of the drug should not be increased if the therapeutic effect is not achieved when taking the recommended dose.

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

Pharmacokinetics

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

Perindopril

When taken orally, Perindopril is rapidly absorbed. C_max in blood plasma is reached 1 hour after oral administration. T_1/2 of the drug from blood plasma is 1 hour. Perindopril does not have pharmacological activity. Approximately 27% of the total amount of perindopril taken orally enters the bloodstream in the form of the active metabolite perindoprilat. In addition to perindoprilat, 5 more metabolites are formed that do not have pharmacological activity. C_max of perindoprilat in blood plasma is reached 3-4 hours after oral administration. Food intake slows down the conversion of perindopril to perindoprilat, thus affecting bioavailability. Therefore, the drug should be taken once a day, in the morning, before meals.

There is a linear relationship between the plasma concentration of perindopril and its dose. V_d of free perindoprilat is approximately 0.2 l/kg. The binding of perindoprilat to plasma proteins, mainly to ACE, depends on the concentration of perindopril and is about 20%.

Perindoprilat is excreted from the body by the kidneys. The effective T_1/2 of the free fraction is about 17 hours, so the equilibrium state is reached within 4 days.

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

The dialysis clearance of perindoprilat is 70 ml/min.

The pharmacokinetics of perindopril are altered in patients with liver cirrhosis: its hepatic clearance is reduced by 2 times. However, the amount of perindoprilat formed does not decrease, which does not require dose adjustment.

Indapamide

Indapamide is rapidly and completely absorbed from the gastrointestinal tract. C_max of the drug in blood plasma is observed 1 hour after oral administration.

Binding to plasma proteins is 79%. T_1/2 is 14-24 hours (average 18 hours). Repeated use 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 do not change in patients with renal failure.

Indications

• Essential arterial hypertension.

ICD codes

Dosage Regimen

Orally, preferably in the morning, before meals, 1 tablet of Noliprel^® once a day. If after one month from the start of therapy the desired antihypertensive effect has not been achieved, the dose of the drug can be doubled to a dosage of 4 mg + 1.25 mg (marketed under the trade name Noliprel^® forte).

For elderly patients, before starting the drug, it is necessary to assess renal function and plasma potassium concentration. At the beginning of therapy, the dose of the drug is selected taking into account the degree of blood pressure reduction, especially in case of dehydration and loss of electrolytes. Therapy should be started with 1 tablet of Noliprel^® once a day.

The drug is contraindicated in patients with severe renal failure (creatinine clearance less than 30 ml/min). For patients with moderate renal failure (creatinine clearance 30-60 ml/min), the maximum dose of Noliprel^® is 1 tablet/day. In some patients with hypertension without prior obvious renal impairment, laboratory signs of functional renal failure may appear during therapy. In this case, treatment should be discontinued. Subsequently, combination therapy can be resumed using low doses of the drugs, or the drugs can be used in monotherapy mode. Renal failure occurs more often in patients with severe heart failure or pre-existing renal impairment, including renal artery stenosis.

For patients with creatinine clearance equal to or greater than 60 ml/min, no dose adjustment is required. During therapy, monitoring of plasma creatinine and potassium levels is necessary.

The drug is contraindicated in patients with severe hepatic impairment. For moderate hepatic impairment, no dose adjustment is required.

Noliprel^® should not be prescribed to children and adolescents under 18 years of age due to the lack of data on efficacy and safety in patients of this age group.

Adverse Reactions

Perindopril has an inhibitory effect on the renin-angiotensin-aldosterone system and reduces potassium loss by the kidneys while taking indapamide. In 2% of patients, hypokalemia (potassium level less than 3.4 mmol/l) develops while using Noliprel^®.

The frequency of adverse reactions that may occur during therapy is presented in the following gradation: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10000, <1/1000); very rare (<1/10000); frequency not known (frequency cannot be estimated from the available data), including individual reports.

From the blood and lymphatic system very rare – thrombocytopenia, leukopenia/neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia; in certain clinical situations (patients after kidney transplantation, patients on hemodialysis), ACE inhibitors can cause anemia.

From the central nervous system common – paresthesia, headache, dizziness, asthenia; uncommon – sleep disturbance, mood lability; very rare – confusion.

From the organ of vision common – visual disturbance.

From the organ of hearing common – tinnitus.

From the cardiovascular system: uncommon – marked decrease in blood pressure (including orthostatic hypotension) very rare – cardiac arrhythmias (including bradycardia, ventricular tachycardia, atrial fibrillation), angina pectoris and myocardial infarction, possibly due to excessive blood pressure reduction in high-risk patients.

From the respiratory system common – while taking ACE inhibitors, a dry cough may occur (persisting for a long time while taking drugs of this group and disappearing after their discontinuation), shortness of breath; uncommon – bronchospasm; very rare – eosinophilic pneumonia, rhinitis.

From the digestive system common – constipation, dry mouth, nausea, vomiting, abdominal pain, epigastric pain, taste disturbance, decreased appetite, dyspepsia, diarrhea; rare – intestinal angioedema, cholestatic jaundice; very rare – pancreatitis. In patients with hepatic insufficiency, hepatic encephalopathy may develop.

From the skin and subcutaneous tissue common – rash, skin rash, itching, maculopapular rash; uncommon – angioedema of the face, lips, extremities, mucous membranes of the tongue, glottis and/or larynx; urticaria; hypersensitivity reactions, mainly skin, in patients predisposed to asthmatic and allergic reactions; hemorrhagic vasculitis; very rare – erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome. In patients with acute disseminated lupus erythematosus, an exacerbation of the disease may occur. Cases of photosensitivity reactions have been reported.

From the musculoskeletal system and connective tissue common – muscle cramps.

From the urinary system uncommon – renal failure. Very rare – acute renal failure.

From the reproductive system: uncommon – impotence.

General disorders and symptoms common – asthenia; uncommon – sweating.

Laboratory parameters: hypokalemia (especially significant for patients at risk), hyponatremia and hypovolemia (leading to dehydration and orthostatic hypotension), increased levels of uric acid and glucose in the blood while taking the drug, a slight increase in plasma urea and creatinine levels (transient after discontinuation of therapy, more often in patients with renal artery stenosis, when treating arterial hypertension with diuretics and in case of renal failure), hyperkalemia (more often transient); rare – hypercalcemia.

Contraindications

Perindopril

• Hypersensitivity to perindopril and other ACE inhibitors;
• History of angioedema (including while taking other ACE inhibitors);
• Hereditary / idiopathic angioedema;
• Pregnancy;
• Breastfeeding period.

Indapamide

• Hypersensitivity to indapamide and other sulfonamides;
• Severe renal failure (creatinine clearance less than 30 ml/min);
• Severe hepatic failure (including with encephalopathy);
• Hypokalemia;
• Simultaneous use with antiarrhythmic agents capable of causing torsades de pointes type arrhythmia;
• Breastfeeding period.

Noliprel^®

• Hypersensitivity to the excipients included in the drug;
• Concomitant use of the drug with potassium-sparing diuretics, potassium and lithium preparations, and in patients with elevated plasma potassium levels;

Presence of lactase deficiency, galactosemia or glucose-galactose malabsorption syndrome;

• Simultaneous use of drugs that prolong the QT interval;
• Patients with untreated chronic heart failure in the stage of decompensation;
• Age under 18 years (efficacy and safety have not been established).

Due to the lack of sufficient clinical experience, Noliprel^® should not be used in patients on hemodialysis.

With caution: systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), therapy with immunosuppressants (risk of developing neutropenia, agranulocytosis), bone marrow hematopoiesis depression, reduced circulating blood volume (taking diuretics, salt-free diet, vomiting, diarrhea), angina pectoris, cerebrovascular diseases, renovascular hypertension, diabetes mellitus, chronic heart failure (NYHA functional class IV), hyperuricemia (especially accompanied by gout and urate nephrolithiasis), labile blood pressure, old age; hemodialysis using high-flux membranes (e.g., AN69) or desensitization, before low-density lipoprotein (LDL) apheresis procedure; status after kidney transplantation; aortic valve stenosis/hypertrophic cardiomyopathy.

Use in Pregnancy and Lactation

Noliprel^® is contraindicated during pregnancy. The drug should not be used in the first trimester of pregnancy. If pregnancy is planned or occurs while taking the drug, the drug should be discontinued immediately and another antihypertensive therapy should be prescribed. Appropriate controlled studies of ACE inhibitors in pregnant women have not been conducted. The available limited data on the effect of the drug in the first trimester of pregnancy indicate that the drug did not lead to malformations associated with fetotoxicity.

It is known that prolonged exposure of the fetus to ACE inhibitors during the second and third trimesters of pregnancy can lead to impaired development (decreased renal function, oligohydramnios, delayed ossification of the skull bones) and the development of complications in the newborn (such as 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, leading to fetoplacental ischemia and fetal growth retardation. In rare cases, when diuretics are taken shortly before delivery, newborns may develop hypoglycemia and thrombocytopenia.

If the patient received Noliprel^® during the second or third trimester of pregnancy, an ultrasound examination of the fetus is recommended to assess the condition of the skull bones and renal function.

Noliprel^® is contraindicated during breastfeeding. It is not known whether Perindopril passes into breast milk.

Indapamide passes into breast milk. Taking thiazide diuretics causes a decrease in the amount of breast milk or suppression of lactation. The child may develop hypersensitivity to sulfonamide derivatives, hypokalemia, and “nuclear” jaundice.

Since the use of perindopril and indapamide during lactation can cause severe complications in the breastfed infant, the significance of therapy for the mother should be assessed and a decision should be made to either discontinue breastfeeding or discontinue the use of these drugs.

Use in Hepatic Impairment

The drug is contraindicated in patients with severe hepatic impairment. In moderate hepatic impairment, no dose adjustment is required.

Use in Renal Impairment

The drug is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 ml/min). For patients with moderate renal impairment (creatinine clearance 30-60 ml/min), the maximum dose of Noliprel^® is 1 tablet/day. In some patients with hypertension without prior apparent renal impairment, laboratory signs of functional renal failure may appear during therapy. In this case, treatment should be discontinued. Subsequently, combination therapy can be resumed using low doses of the drugs, or the drugs can be used in monotherapy. Renal failure occurs more frequently in patients with severe heart failure or pre-existing renal impairment, including renal artery stenosis.

In patients with creatinine clearance equal to or greater than 60 ml/min, no dose adjustment is required. During therapy, plasma creatinine and potassium levels should be monitored.

Pediatric Use

Noliprel^® should not be prescribed to children and adolescents under 18 years of age due to the lack of data on efficacy and safety in patients of this age group.

Special Precautions

The use of Noliprel^® is not accompanied by a significant reduction in the frequency of side effects, with the exception of hypokalemia, compared with perindopril and indapamide at the lowest approved doses. At the start of 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 minimizes this risk.

The simultaneous use of the combination of perindopril and indapamide with lithium preparations is not recommended.

Renal impairment

Therapy is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 ml/min). In some patients with hypertension without prior apparent renal impairment, laboratory signs of functional renal failure may appear during therapy. In this case, treatment should be discontinued. Subsequently, combination therapy can be resumed using low doses of the drugs, or the drugs can be used in monotherapy. Such patients require regular monitoring of serum potassium and creatinine levels – 2 weeks after the start of therapy and then every 2 months. Renal failure occurs more frequently in patients with severe heart failure or pre-existing renal impairment, including stenosis of one or both 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 solitary functioning kidney.

Arterial hypotension and water-electrolyte imbalance

Hyponatremia is associated with the risk of sudden onset of arterial hypotension (especially in patients with stenosis of one or both renal arteries). Therefore, when monitoring patients, attention should be paid to possible symptoms of dehydration and decreased plasma electrolyte levels, 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 continuing therapy. After restoration of circulating blood volume and blood pressure, therapy can be resumed using low doses of the drugs, or the drugs can be used 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 with the combined use of antihypertensive drugs 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^® should not be prescribed to patients with hereditary galactose intolerance, lactase deficiency, or 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, but 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, signs of neutropenia resolve on their own. Perindopril should be used with particular caution in patients with diffuse connective tissue diseases, while taking immunosuppressive drugs, allopurinol or procainamide, and with simultaneous exposure to these factors, especially in patients with pre-existing renal impairment. Some patients have developed severe infections, in some cases resistant to intensive antibiotic therapy. When prescribing perindopril to such patients, it is recommended to periodically monitor the white blood cell count. Patients should report any signs of infectious diseases (e.g., sore throat, fever) to their doctor.

Hypersensitivity/angioedema (Quincke’s edema)

When taking ACE inhibitors (including perindopril), in rare cases, 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 the signs of edema have completely resolved. If the edema involves only the face and lips, its manifestations usually resolve on their own, although antihistamines may be used to treat its symptoms.

Angioedema involving laryngeal edema can be fatal. Swelling of the tongue, glottis, or larynx can lead to airway obstruction. If such symptoms occur, epinephrine (adrenaline) 1:1000 dilution (0.3 or 0.5 ml) should be administered subcutaneously immediately and/or airway patency should be ensured.

Patients with a history of angioedema not associated with ACE inhibitor use may have an increased risk of its development when taking drugs of this group.

In rare cases, intestinal angioedema 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 preceding facial angioedema and with normal C-1 esterase levels. The diagnosis is made using computed tomography of the abdominal area, ultrasound, or at the time of surgery. Symptoms disappear after discontinuation of ACE inhibitors. In patients with abdominal pain receiving ACE inhibitors, the possibility of intestinal angioedema should be considered in the differential diagnosis.

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. The 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 may develop in patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis using dextran sulfate. To prevent an anaphylactoid reaction, therapy with an ACE inhibitor should be temporarily discontinued before each apheresis procedure.

Hemodialysis

In patients receiving ACE inhibitors, anaphylactoid reactions have been observed during hemodialysis using high-flux membranes (e.g., 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 preparations

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.

Cough

A dry cough may occur during therapy with an ACE inhibitor. 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, a possible connection of this symptom with taking an ACE inhibitor should be considered. If the attending physician believes that therapy with an ACE inhibitor is necessary for the patient, the drug may be continued.

Use in pediatrics

Noliprel^® should not be prescribed to children and adolescents under 18 years of age due to the lack of data on the efficacy and safety of perindopril use as monotherapy or in combination therapy in patients of this age group.

Risk of arterial hypotension and/or renal failure (in patients with heart failure, water-electrolyte imbalance, etc.)

In some pathological conditions, significant activation of the renin-angiotensin-aldosterone system may be observed, especially in cases of severe hypovolemia and decreased plasma electrolyte levels (against the background of a salt-free diet or long-term diuretic use), in patients with initially low blood pressure, stenosis of one or both renal arteries, chronic heart failure, or liver cirrhosis with edema and ascites.

The use of an ACE inhibitor causes blockade of this system and therefore may be accompanied by a sharp decrease in blood pressure and/or an increase in plasma creatinine levels, 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 at other times during 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 patients

Before starting the drug, renal function and plasma potassium concentration should be assessed. At the beginning of therapy, the dose of the drug is selected taking into account the degree of blood pressure reduction, especially in case of dehydration and electrolyte loss. Such measures help to avoid a sharp decrease in blood pressure.

Atherosclerosis

The risk of arterial hypotension exists in all patients, but special caution should be exercised when using the drug in patients with coronary artery disease and cerebrovascular insufficiency. In such patients, treatment should be started with low doses.

Patients with renovascular hypertension

The method of treatment for renovascular hypertension is revascularization. Nevertheless, the use of ACE inhibitors has a beneficial effect in patients both awaiting surgery and when such an operation is not possible.

Treatment of patients with diagnosed or suspected renal artery stenosis with Noliprel^® should be started with a low dose of the drug in a hospital setting, monitoring renal function and plasma potassium concentration. In some patients, functional renal failure may develop, which disappears after discontinuation of the drug.

Other risk groups

In individuals with chronic heart failure (stage IV) and patients with insulin-dependent diabetes mellitus (risk of spontaneous increase in potassium concentration), treatment should be started with a low dose of the drug (half a tablet) and under constant medical supervision.

Patients with arterial hypertension and coronary artery 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 Black patients compared to representatives of other races. This difference may be due to the fact that Black patients with arterial hypertension more often have low renin activity.

Surgical intervention / General anesthesia

The use of ACE inhibitors in patients undergoing surgery with general anesthesia can lead to a pronounced decrease in blood pressure, especially when using general anesthetic agents that have a hypotensive effect.

It is recommended to discontinue 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 tract obstruction.

Hepatic impairment

In rare cases, cholestatic jaundice occurs while taking ACE inhibitors. With the progression of this syndrome, fulminant liver necrosis develops, sometimes with a fatal outcome. The mechanism of development of this syndrome is unclear. If jaundice or a significant increase in the activity of “liver” enzymes occurs while taking ACE inhibitors, the drug should be discontinued and a doctor should be consulted.

Anemia

Anemia may develop in patients after kidney transplantation or in persons on hemodialysis. In this case, the decrease in hemoglobin concentration is greater the higher its initial level was. This effect does not appear to be dose-dependent but may be related to 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, decreased renal function, old age, diabetes mellitus, some concomitant conditions (dehydration, acute decompensation of heart failure, metabolic acidosis), simultaneous use of potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene, amiloride), as well as potassium preparations or potassium-containing salt substitutes, and the use of other drugs that contribute to an increase in plasma potassium levels (e.g., heparin). The use of potassium preparations, potassium-sparing diuretics, and potassium-containing salt substitutes can lead to a significant increase in blood potassium levels, especially in patients with reduced renal function. Hyperkalemia can lead to serious, sometimes fatal, cardiac arrhythmias. If combined use of the above drugs is necessary, treatment should be carried out with caution, with regular monitoring of serum potassium levels.

Indapamide

When prescribing thiazide and thiazide-like diuretics to patients with impaired liver function, hepatic encephalopathy may develop. In this case, diuretics should be discontinued immediately.

Photosensitivity

Cases of photosensitivity reactions have been reported while taking thiazide and thiazide-like diuretics. 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 UV rays.

Plasma sodium ion content

Before starting treatment, the plasma sodium ion content should be determined. During drug administration, this indicator should be regularly monitored. All diuretic drugs 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 content is indicated for patients with liver cirrhosis and elderly persons.

Plasma potassium ion content

Therapy with thiazide and thiazide-like diuretics is associated with the risk of developing hypokalemia. Hypokalemia (less than 3.4 mmol/L) should be avoided in the following categories of high-risk patients: elderly patients, debilitated patients or those receiving combined 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 arrhythmias.

Patients with an increased QT interval are also at increased risk, regardless of whether this increase is caused by congenital causes or the action of drugs.

Hypokalemia, like bradycardia, contributes to the development of severe cardiac arrhythmias (especially torsades de pointes arrhythmia), which can be fatal. In all the cases described above, more regular monitoring of plasma potassium ion content is necessary. The first measurement of potassium ion concentration should be performed within the first week of starting therapy.

If hypokalemia is detected, appropriate treatment should be prescribed.

Plasma Calcium Ion Levels

Thiazide and thiazide-like diuretics reduce the renal excretion of calcium ions, leading to a slight and temporary increase in plasma calcium concentration. Severe hypercalcemia may be a consequence of previously undiagnosed hyperparathyroidism. Diuretic drugs should be discontinued before testing parathyroid function.

Plasma Glucose Levels

Blood glucose levels should be monitored in patients with diabetes mellitus, especially in the presence of hypokalemia.

Uric Acid

In patients with elevated plasma uric acid levels, the frequency of gout attacks may increase during therapy.

Diuretic Agents and Renal Function

Thiazide and thiazide-like diuretics are fully effective only in patients with normal or mildly impaired renal function (plasma creatinine concentration in adults below 25 mg/L or 220 µmol/L). In elderly patients, creatinine clearance should be calculated taking into account age, body weight, and sex.

At the beginning of diuretic treatment, patients may experience a temporary decrease in glomerular filtration rate and an increase in plasma urea and creatinine concentrations due to hypovolemia and hyponatremia. This transient functional renal failure is not dangerous for patients with unchanged renal function, but its severity may increase in patients with renal insufficiency.

Athletes

Indapamide may give a positive reaction during doping control.

Effect on the Ability to Drive and Operate Machinery

The substances contained in the drug Noliprel^® do not lead to impaired psychomotor reactions. However, some patients may develop various individual reactions in response to a decrease in blood pressure, especially at the beginning of therapy or when other antihypertensive agents are added to the ongoing therapy. In this case, the ability to drive a car or operate other machinery may be reduced.

Overdose

Symptoms most likely include a pronounced decrease in blood pressure, sometimes in combination with nausea, vomiting, convulsions, dizziness, drowsiness, confusion, and oliguria, which may progress to anuria (as a result of hypovolemia). Electrolyte disturbances (hyponatremia, hypokalemia) may also occur.

Treatment emergency measures consist of removing the drug from the body (gastric lavage and/or administration of activated charcoal) followed by restoration of water and electrolyte balance. In case of a significant decrease in blood pressure, the patient should be placed in a supine position with legs elevated; if necessary, correct hypovolemia (e.g., intravenous infusion of 0.9% sodium chloride solution). Perindoprilat, the active metabolite of perindopril, can be removed from the body by dialysis.

Drug Interactions

Perindopril, Indapamide

Undesirable Drug Combinations

Lithium preparations: concurrent use of lithium preparations and ACE inhibitors may cause a reversible increase in plasma lithium concentration and associated toxic effects. Additional prescription of thiazide diuretics may contribute to a further increase in lithium concentration and increase the risk of toxicity manifestations. Concurrent use of the perindopril and indapamide combination with lithium preparations is not recommended. If such therapy is conducted, regular monitoring of plasma lithium levels is necessary.

Combinations Requiring Special Attention

Baclofen: increased antihypertensive effect may occur. Blood pressure and renal function should be monitored; if necessary, adjustment of the dose of antihypertensive drugs is required.

NSAIDs (including high doses of acetylsalicylic acid (more than 3 g/day)): administration of NSAIDs may lead to a reduction in the diuretic, natriuretic, and antihypertensive effects. In case of significant fluid loss, as well as in elderly patients, acute renal failure may develop (due to a decrease in glomerular filtration rate). Patients need to compensate for fluid loss and carefully monitor renal function at the beginning of treatment.

Combinations Requiring Attention

Tricyclic antidepressants, antipsychotic agents (neuroleptics): drugs of these classes enhance the antihypertensive effect and increase the risk of orthostatic hypotension (additive effect).

Corticosteroids, tetracosactide: reduction of the antihypertensive effect (fluid and sodium ion retention as a result of corticosteroid action).

Other antihypertensive agents: enhancement of the antihypertensive effect is possible.

Perindopril

Undesirable Drug Combinations

Potassium-sparing diuretics (amiloride, spironolactone, triamterene, both as monotherapy and in combination) and potassium preparations: ACE inhibitors reduce the potassium loss caused by the diuretic. Potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium preparations, and potassium-containing salt substitutes can lead to a significant increase in serum potassium concentration, even to a fatal outcome. If concurrent use of an ACE inhibitor and the aforementioned drugs is necessary (in case of confirmed hypokalemia), caution should be exercised and regular monitoring of plasma potassium concentration and ECG parameters should be conducted.

Combinations Requiring Special Attention

Hypoglycemic agents (insulin, sulfonylurea derivatives): the effects described below have been reported for captopril and enalapril. ACE inhibitors may enhance the hypoglycemic effect of insulin and sulfonylurea derivatives in patients with diabetes mellitus. The development of hypoglycemia is observed very rarely (due to increased glucose tolerance and reduced insulin requirement).

Combinations Requiring Attention

Allopurinol, cytotoxic and immunosuppressive agents, corticosteroids (for systemic use) and procainamide: concurrent use with ACE inhibitors may be associated with an increased risk of leukopenia.

General anesthetics: concurrent use of ACE inhibitors and general anesthetics may lead to an enhanced hypotensive effect.

Diuretics (thiazide and loop): use of diuretics in high doses may lead to hypovolemia, and the addition of perindopril to therapy may lead to hypotension.

Gold preparations: when prescribing ACE inhibitors (including perindopril) to patients receiving injectable gold preparations (sodium aurothiomalate), nitratoid reactions (facial flushing, nausea, vomiting, hypotension) have been observed.

Indapamide

Combinations Requiring Special Attention

Drugs capable of causing torsades de pointes type arrhythmia: due to the risk of hypokalemia, caution should be exercised when using indapamide concurrently with drugs capable of causing torsades de pointes type arrhythmia, for example, antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide, amiodarone, dofetilide, ibutilide, bretylium, sotalol); some antipsychotics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine); benzamides (amisulpride, sulpiride, sultopride, tiapride); butyrophenones (droperidol, haloperidol); other antipsychotics (pimozide); other drugs such as bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, intravenous vincamine, methadone, astemizole, terfenadine. The development of hypokalemia should be avoided and, if necessary, corrected; monitor the QT interval.

Drugs capable of causing hypokalemia: amphotericin B (intravenous), gluco- and mineralocorticoids (for systemic use), tetracosactide, stimulant laxatives: increased risk of hypokalemia (additive effect). Monitoring of plasma potassium levels is necessary, with correction if needed. Particular attention should be paid to patients simultaneously receiving cardiac glycosides. Non-stimulant laxatives should be used.

Cardiac glycosides: hypokalemia enhances the toxic effect of cardiac glycosides. When using indapamide and cardiac glycosides concurrently, plasma potassium levels and ECG parameters should be monitored and therapy adjusted if necessary.

Combinations Requiring Attention

Metformin: functional renal failure, which can occur during diuretic therapy, especially with ‘loop’ diuretics, increases the risk of lactic acidosis when metformin is prescribed concurrently. Metformin should not be used if plasma creatinine levels exceed 15 mg/L (135 µmol/L) in men and 12 mg/L (110 µmol/L) in women.

Iodinated contrast media: dehydration during diuretic therapy increases the risk of acute renal failure, especially when using high doses of iodinated contrast media. Before using iodinated contrast media, patients must compensate for fluid loss.

Calcium salts: concurrent administration may lead to hypercalcemia due to reduced renal excretion of calcium ions.

Cyclosporine: an increase in plasma creatinine levels may occur without changes in circulating cyclosporine concentration, even with normal fluid and sodium levels.

Storage Conditions

The drug should be stored out of the reach of children. List B.

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the packaging. The drug in the blister must be used within 2 months after opening the sachet.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.