Noliprel A forte, 5 mg+1, 25 mg 30 pcs.

Noliprel A forte is an ACE inhibitor, hypotensive, diuretic.

Pharmacodynamics

Noliprel® A forte is a combined drug containing perindopril arginine and indapamide. The pharmacological properties of Noliprel® A forte combine the individual properties of each of the components.

1. Mechanism of action

Noliprel® A forte

The combination of perindopril and indapamide enhances the antihypertensive effects of each.

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 both converts angiotensin I into the vasoconstrictor angiotensin II and degrades bradykinin, which has a vasodilatory effect, into an inactive heptapeptide. As a result, perindopril:

– reduces aldosterone secretion;

– by the principle of negative feedback it increases plasma renin activity;

– with long-term use, it decreases RPS, which is mainly due to the effect on the vessels in the muscles and kidneys. These effects are not accompanied by retention of sodium ions and fluids or development of reflex tachycardia.

Perindopril normalizes myocardial function by reducing preload and postload.

In a study of hemodynamic parameters in patients with chronic heart failure (CHF), it was found:

– decreased filling pressures in the left and right ventricles of the heart;

– decreased ROSS;

– increased cardiac output;

– increased muscular peripheral blood flow.

Indapamide

Indapamide belongs to the group of sulfonamides; its pharmacological properties are similar to thiazide diuretics. Indapamide inhibits reabsorption of sodium ions in the cortical segment of the loop of Genle, which leads to increased renal excretion of sodium ions, chlorine and to a lesser extent potassium and magnesium ions, thereby increasing diuresis and reducing BP.

2. Antihypertensive effects

Noliprel® A forte

Noliprel® A forte has dose-dependent antihypertensive effects on both BP and BP in both standing and lying position. The antihypertensive effect is maintained for 24 hours. Stable therapeutic effect develops in less than 1 month from the start of therapy and is not accompanied by tachycardia. Discontinuation of therapy does not cause withdrawal syndrome.

Noliprel® A forte reduces degree of left ventricular hypertrophy (LVH), improves arterial elasticity, decreases PPS, does not influence lipid metabolism (total cholesterol, HDL and LDL cholesterol, triglycerides).

The effect of perindopril and indapamide combination on HTLV compared with enalapril has been proven. In patients with arterial hypertension and HTLD treated with perindopril erbumin 2 mg (equivalent to 2.5 mg perindopril arginine)/indapamide 0.625 mg or enalapril at a dose of 10 mg once daily, and when the perindopril erbumin dose was increased to 8 mg (equivalent to 10 mg of perindopril arginine) and indapamide to 2.5 mg, or enalapril to 40 mg once daily, a more significant reduction in left ventricular mass index (LVMI) was noted in the perindopril/indapamide group compared to the enalapril group. The most significant effect on BMI was noted with perindopril erbumin 8 mg/indapamide 2.5 mg.

There was also a more pronounced antihypertensive effect on combined therapy with perindopril and indapamide compared to enalapril.

In patients with type 2 diabetes mellitus (mean age 66 years, body mass index 28 kg/m2, glycosylated hemoglobin (HbA1c) 7.5%, BP 145/81 mm Hg).) We studied the effect of a fixed perindopril/indapamide combination on major micro- and macrovascular complications in addition to both standard glycemic control therapy and an intensive glycemic control (IGC) strategy (target HbA1c –

In 83% of patients had arterial hypertension, 32 and 10% had macro- and microvascular complications, and 27% had microalbuminuria. Most patients were receiving hypoglycemic therapy at the time of study inclusion, with 90% of patients receiving oral hypoglycemic agents (47% of patients on monotherapy, 46% on two-drug therapy, and 7% on three-drug therapy). 1% of patients received insulin therapy and 9% received diet therapy alone. Sulfonylurea derivatives were taken by 72% of patients, metformin by 61%. As concomitant therapy, 75% of patients received hypotensive agents, 35% of patients received hypolipidemic agents (mainly HMG-CoA reductase inhibitors (statins) – 28%), acetylsalicylic acid as an antiplatelet agent and other antiplatelet agents (47%).

After a 6-week introductory period during which patients received perindopril/indapamide therapy, they were allocated to the standard glycemic control group or to the IGC group (Diabeton® MV with an option to increase the dose to a maximum of 120 mg/day or the addition of another hypoglycemic agent).

The IGC group (mean duration of follow-up 4.8 years, mean HbA1c 6.5%) compared with the standard control group (mean HbA1c 7.3%) showed a significant 10% relative risk reduction in the combined incidence of macro- and microvascular complications.

The benefit was achieved by significantly reducing the relative risks of: major microvascular complications by 14%, nephropathy onset and progression by 21%, microalbuminuria by 9%, macroalbuminuria by 30%, and renal complications by 11%.

The benefits of hypotensive therapy were independent of the benefits achieved on IGC.

Perindopril

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

The antihypertensive effect of the drug reaches its maximum 4-6 hours after a single oral dose and lasts for 24 hours. 24 hours after the drug administration there is a significant (about 80%) residual inhibition of ACE.

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

The concomitant administration of thiazide diuretics increases the severity of antihypertensive effect. In addition, combination of ACE inhibitor and thiazide diuretic also leads to decrease of risk of hypokalemia during diuretic therapy.

Indapamide

The antihypertensive effect is seen when the drug is used in doses with minimal diuretic action.

The antihypertensive effect of indapamide is associated with improvement of elastic properties of large arteries and reduction of PPS.

Indapamide decreases HDL, does not influence plasma concentration of lipids: triglycerides, total cholesterol, LDL, HDL; carbohydrate metabolism (including in patients with concomitant diabetes mellitus).

Pharmacokinetics

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

Perindopril

Perindopril is rapidly absorbed when taken orally. Bioavailability is 65-70%.

About 20% of the total amount of perindopril absorbed is converted to perindoprilate, which is the active metabolite. Administration of the drug with meals is accompanied by a decrease in metabolism of perindopril to perindoprilat (this effect is not of significant clinical significance).

The Cmax of perindoprilat in plasma is reached 3-4 hours after oral administration.

The binding to plasma proteins is less than 30% and depends on the blood concentration of perindoprilat.

The dissociation of ACE-bound perindoprilat is delayed. As a consequence, the effective T1/2 is 25 h. Repeated administration of perindopril does not cause cumulation, and the T1/2 of perindoprilat when repeatedly administered corresponds to its period of activity, so that an equilibrium state is reached after 4 days.

Perindoprilat is excreted by the kidneys. T1/2 of the metabolite is 3-5 hours.

The excretion of perindoprilat is delayed in elderly patients and in patients with cardiac and renal insufficiency.

The dialysis clearance of perindoprilat is 70 ml/min.

The pharmacokinetics of perindopril is altered in patients with cirrhosis: its hepatic clearance is reduced by half. However, the amount of perindoprilat produced is not decreased, so no change in the dose of the drug is required.

Perindopril penetrates the placenta.

Indapamide

Indapamide is rapidly and completely absorbed from the gastrointestinal tract.

Cmax of the drug in plasma is observed 1 hour after oral administration.

The binding to plasma proteins is 79%.

The T1/2 is 14-24 h (on average 19 h). Reuse of the drug does not lead to cumulation in the body. It is eliminated mainly by the kidneys (70% of the administered dose) and through the intestine (22%) in the form of inactive metabolites.

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

Indications

Essential arterial hypertension; patients with arterial hypertension and type 2 diabetes mellitus to reduce the risk of developing microvascular complications (from the kidneys) and macrovascular complications from cardiovascular diseases.

Pharmacological effect

Noliprel A forte – ACE inhibitory, hypotensive, diuretic.

Pharmacodynamics

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

1. Mechanism of action

Noliprel® A forte

The combination of perindopril 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 and 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;

– 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 forte

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

Noliprel® A 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 were treated with perindopril erbumine 2 mg (equivalent to 2.5 mg perindopril arginine)/indapamide 0.625 mg or enalapril 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 a day, 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.

In patients with type 2 diabetes (mean age 66 years, body mass index 28 kg/m2, glycosylated hemoglobin (HbA1c) 7.5%, blood pressure 145/81 mmHg), the effect of a fixed combination of perindopril/indapamide on major micro- and macrovascular complications was studied in addition to both standard glycemic control therapy and an intensive strategy. glycemic control (GCC) (target HbA1c –

83% of patients had arterial hypertension, 32% and 10% had macro- and microvascular complications, and 27% had microalbuminuria. The majority of patients were receiving hypoglycemic therapy at the time of inclusion in the study, 90% of patients were receiving oral hypoglycemic agents (47% of patients in monotherapy, 46% in two-drug therapy, 7% in three-drug therapy). 1% of patients received insulin therapy, 9% received only diet therapy. Sulfonylurea derivatives were taken by 72% of patients, metformin by 61%. As concomitant therapy, 75% of patients received antihypertensive drugs, 35% of patients received lipid-lowering drugs (mainly HMG-CoA reductase inhibitors (statins) – 28%), acetylsalicylic acid as an antiplatelet agent and other antiplatelet drugs (47%).

After a 6-week run-in period, during which patients received perindopril/indapamide therapy, they were allocated to the standard glycemic control group or the IGC group (Diabeton® MB with the possibility of increasing the dose to a maximum of 120 mg/day or adding another hypoglycemic agent).

The IHC group (average follow-up duration – 4.8 years, average HbA1c – 6.5%) compared with the standard control group (average HbA1c – 7.3%) showed a significant 10% reduction in the relative risk of the combined incidence of macro- and microvascular complications.

The benefit was achieved due to a significant reduction in the relative risk of: major microvascular complications by 14%, the occurrence and progression of nephropathy by 21%, microalbuminuria by 9%, macroalbuminuria by 30% and the development of renal complications by 11%.

The benefits of antihypertensive therapy were independent of the benefits achieved with IGCs.

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, HDL; carbohydrate metabolism (including in patients with concomitant diabetes mellitus).

Pharmacokinetics

The combination of perindopril and indapamide does not change their pharmacokinetic characteristics compared to taking these drugs separately.

Perindopril

When taken orally, perindopril is rapidly absorbed. Bioavailability is 65–70%.

Approximately 20% of the total amount of absorbed perindopril is converted to perindoprilat, the active metabolite. Taking the drug with food is accompanied by a decrease in the metabolism of perindopril to perindoprilat (this effect does not have significant clinical significance).

Cmax of perindoprilate in blood plasma is achieved 3–4 hours after oral administration.

The binding to plasma proteins is less than 30% and depends on the concentration of perindopril in the blood.

The dissociation of perindoprilate associated with ACE is slowed down. As a result, the effective T1/2 is 25 hours. Repeated administration of perindopril does not lead to its cumulation, and T1/2 of perindoprilat upon repeated administration corresponds to the period of its activity, thus an equilibrium state is achieved after 4 days.

Perindoprilat is excreted from the body by the kidneys. T1/2 of the metabolite is 3–5 hours.

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, so no change in the dose of the drug is required.

Perindopril crosses the placenta.

Indapamide

Indapamide is quickly and completely absorbed from the gastrointestinal tract.

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

Connection with blood plasma proteins – 79%.

T1/2 is 14–24 hours (average 19 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.

Special instructions

The use of Noliprel® A forte 5 mg + 1.25 mg 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 (see “Side effects”). When starting therapy with two antihypertensive drugs that the patient has not previously received, an increased risk of developing idiosyncrasies cannot be excluded. Careful monitoring of the patient can minimize this risk.

Renal dysfunction

Therapy is contraindicated in patients with severe renal failure (creatinine Cl 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 drugs in monotherapy.

Such patients require regular monitoring of potassium and creatinine levels 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, incl. with renal artery stenosis.

Arterial hypotension and water-electrolyte imbalance

Hyponatremia is associated with a risk of sudden development of arterial hypotension (especially in patients with arterial stenosis of a solitary kidney and bilateral renal artery stenosis). Therefore, during dynamic monitoring of patients, attention should be paid to possible symptoms of dehydration and decreased levels of electrolytes in the blood plasma, for example, after diarrhea or vomiting. Such patients require regular monitoring of plasma electrolyte levels.

In case of severe arterial hypotension, intravenous administration of 0.9% sodium chloride solution may be required.

Transient arterial hypotension is not a contraindication for continued therapy. After restoration of blood volume and blood pressure, therapy can be resumed using low doses of drugs, or drugs can be used as monotherapy.

Potassium level

The combined use of perindopril and indapamide does not prevent the development of hypokalemia, especially in patients with diabetes mellitus or renal failure. As in the case of the combined use of an antihypertensive drug and a diuretic, regular monitoring of the level of potassium in the blood plasma is necessary.

Excipients

It should be taken into account that the excipients of the drug include lactose monohydrate. Noliprel® A forte 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 “Contraindications”, “Interaction”).

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 disappear on their own.

To prevent the development of such reactions, it is recommended to strictly follow the recommended dose. When prescribing ACE inhibitors to this group of patients, the benefit/risk factor should be carefully assessed.

Angioedema (Quincke’s edema)

When taking ACE inhibitors, incl. and perindopril, in rare cases, the development of angioedema of the face, extremities, lips, tongue, glottis and/or larynx may occur. If symptoms appear, perindopril should be discontinued immediately and the patient should be observed until signs of edema completely disappear. If the swelling affects only the face and lips, it usually resolves on its own, although antihistamines may be used to treat symptoms.

Angioedema, accompanied by swelling of the larynx, can be fatal. Swelling of the tongue, glottis, or larynx can lead to airway obstruction. If such symptoms appear, you should immediately administer subcutaneous epinephrine (adrenaline) at a dilution of 1:1000 (0.3 or 0.5 ml) and/or ensure airway patency.

Patients with a history of angioedema not associated with taking ACE inhibitors may have an increased risk of developing it when taking drugs of this group (see “Contraindications”).

In rare cases, angioedema of the intestine develops during therapy with ACE inhibitors.

Anaphylactoid reactions during desensitization

There are isolated reports of the development of long-term life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy with the venom of hymenoptera insects (bees, wasps). ACE inhibitors should be used with caution in patients prone to allergic reactions undergoing desensitization procedures. Prescription of an ACE inhibitor should be avoided in patients receiving immunotherapy with hymenoptera venom. However, 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 occur in patients receiving ACE inhibitors, during LDL apheresis using dextran sulfate, or in patients receiving hemodialysis using high-flow membranes. To prevent an anaphylactoid reaction, ACE inhibitor therapy should be temporarily discontinued at least 24 hours before the apheresis procedure.

Cough

During therapy with an ACE inhibitor, a dry cough may occur. The cough persists for a long time while taking drugs of this group and disappears after their discontinuation. If a patient develops a dry cough, one should be aware of the possible iatrogenic nature of this symptom. If the attending physician believes that ACE inhibitor therapy is necessary for the patient, the drug may be continued.

Children and teenagers

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 as monotherapy or as part of combination therapy in patients in this age group.

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

In some pathological conditions, significant activation of the RAAS system may be observed, especially with severe hypovolemia and a decrease in the level of plasma electrolytes (due to a salt-free diet or long-term use of diuretics), in patients with initially low blood pressure, with bilateral renal artery stenosis or with stenosis of the artery of a single kidney, 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 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 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 patients

Before starting to take the drug, it is necessary to assess the functional activity of the kidneys and the concentration of potassium in the blood plasma. At the beginning of therapy, the dose of the drug is selected taking into account the degree of reduction in blood pressure, especially in the case of dehydration and loss of electrolytes. Such measures help to avoid a sharp decrease in blood pressure.

Atherosclerosis

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

Patients with renovascular hypertension

The treatment method for renovascular hypertension is revascularization. However, the use of ACE inhibitors has a beneficial effect in this category of patients, both awaiting surgery and in cases where surgery is not possible.

Treatment with Noliprel® A forte in patients with diagnosed or suspected bilateral renal artery stenosis or stenosis of the artery of a single kidney should be started with a low dose of the drug in a hospital setting, monitoring renal function and potassium concentration in the blood plasma. Some patients may develop functional renal failure, which disappears when the drug is discontinued.

Other risk groups

In persons with severe heart failure (stage IV) and patients with insulin-dependent diabetes mellitus (risk of a spontaneous increase in potassium concentration), treatment should begin with a low dose of the drug 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.

Anemia

Anemia can develop in patients after kidney transplantation or in people on hemodialysis. In this case, the decrease in hemoglobin concentration 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 concentration 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 performed regularly.

Surgery/general anesthesia

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

It is recommended to stop taking long-acting ACE inhibitors, incl. perindopril, the day before surgery. It is necessary to warn the anesthesiologist that the patient is taking ACE inhibitors.

Aortic stenosis/hypertrophic 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, liver necrosis may rapidly develop, sometimes with death. The mechanism of development of this syndrome is unclear. If jaundice appears or a significant increase in the activity of liver enzymes while taking ACE inhibitors, you should stop taking the drug and consult a doctor (see “Side effects”).

Indapamide

In the presence of liver dysfunction, taking thiazide and thiazide-like diuretics can lead to the development of hepatic encephalopathy. In this case, you should immediately stop taking the drug.

Water and electrolyte balance

Content of sodium ions in blood plasma. Before starting treatment, it is necessary to determine the content of sodium ions in the blood plasma. While taking the drug, this indicator should be regularly monitored. All diuretics can cause hyponatremia, which sometimes leads to serious complications. Hyponatremia at the initial stage may not be accompanied by clinical symptoms, so regular laboratory monitoring is necessary. More frequent monitoring of sodium ion levels is indicated for patients with liver cirrhosis and the elderly (see “Side effects” and “Overdose”).

Content of potassium ions in blood plasma. Therapy with thiazide and thiazide-like diuretics is associated with a risk of hypokalemia. Hypokalemia (less than 3.4 mmol/l) should be avoided in the following categories of high-risk patients: elderly people, debilitated patients or those receiving concomitant drug therapy, patients with liver cirrhosis, peripheral edema or ascites, coronary artery disease, heart failure. Hypokalemia in these patients enhances the toxic effect of cardiac glycosides and increases the risk of developing arrhythmias.

The high-risk group also includes patients with an increased QT interval, and it does not matter whether this increase is caused by congenital causes or the effect of drugs.

Hypokalemia, like bradycardia, contributes to the development of severe cardiac arrhythmias, especially torsade de pointes, which can be fatal. In all the cases described above, more regular monitoring of the content of potassium ions in the blood plasma is necessary. The first measurement of potassium ion concentration should be carried out within the first week from the start of therapy.

If hypokalemia is detected, appropriate treatment should be prescribed.

Content of calcium ions in blood plasma. Thiazide and thiazide-like diuretics reduce the excretion of calcium ions by the kidneys, leading to a slight and temporary increase in the concentration of calcium in the blood plasma. Severe hypercalcemia may be a consequence of previously undiagnosed hyperparathyroidism. Before studying the function of the parathyroid gland, you should stop taking diuretics.

Glucose content in blood plasma. It is necessary to monitor blood glucose levels in patients with diabetes mellitus, especially in the presence of hypokalemia.

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

Diuretics and kidney function. Thiazide and thiazide-like diuretics are fully effective only in patients with normal or slightly impaired renal function (plasma creatinine in adults below 25 mg/l or 220 µmol/l).

At the beginning of diuretic treatment in patients, due to hypovolemia and hyponatremia, 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 unchanged renal function, but its severity may increase in patients with renal failure.

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.

Athletes

Indapamide may give a positive reaction during doping control.

Impact on the ability to drive a car or perform work that requires increased speed of physical and mental reactions. The effect of the substances included in the drug Noliprel® A forte does not lead to disturbances in psychomotor reactions. However, some people may develop different individual reactions in response to lowering blood pressure, especially at the beginning of therapy or when other antihypertensive drugs are added to therapy. In this case, the ability to drive a car or operate other machinery may be reduced.

Active ingredient

Indapamide, Perindopril

Composition

Active ingredients:

perindopril arginine 5 mg;

indapamide 1.25 mg;

Excipients:

sodium carboxymethyl starch (type A) – 2.7 mg;

colloidal silicon dioxide anhydrous – 0.27 mg;

lactose monohydrate – 71.33 mg;

magnesium stearate – 0.45 mg;

maltodextrin – 9 mg;

Film casing:

macrogol 6000 – 0.087 mg;

premix for white film shell SEPIFILM 37781 RBC (glycerol – 4.5%; hypromellose – 74.8%; macrogol 6000 – 1.8%; magnesium stearate – 4.5%; titanium dioxide (E171) – 14.4%) – 2.913 mg.

Pregnancy

The drug is contraindicated during pregnancy.

If you are planning pregnancy or if it occurs while taking Noliprel® A forte, you should immediately stop taking the drug and prescribe other antihypertensive therapy.

Noliprel® A forte should not be used in the first trimester of pregnancy.

There have been no adequate controlled studies on the use of ACE inhibitors in pregnant women. The limited available data on the effects of ACE inhibitors in the first trimester of pregnancy indicate that taking ACE inhibitors did not lead to fetotoxicity-related fetal malformations, but fetotoxic effects of the drug cannot be completely excluded.

Noliprel® A 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 forte during the second or third trimester of pregnancy, it is recommended to conduct an ultrasound examination of the newborn to assess the condition of the skull and kidney function.

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

Noliprel® A forte is contraindicated during lactation. 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.

Since the use of perindopril and indapamide during lactation can cause serious complications in an infant, it is necessary to evaluate the significance of therapy for the mother and decide whether to stop breastfeeding or stop taking the drug.

Contraindications

hypersensitivity to perindopril and other ACE inhibitors, indapamide, other sulfonamides, as well as to other auxiliary components included in the drug;
history of angioedema (including while taking other ACE inhibitors);
hereditary/idiopathic angioedema;
hypokalemia;
severe renal failure (creatinine Cl less than 30 ml/min);
stenosis of the artery of a single kidney;
bilateral renal artery stenosis;
severe liver failure (including with encephalopathy);
simultaneous use of drugs that prolong the QT interval;
simultaneous use with antiarrhythmic drugs that can cause pirouette-type arrhythmia (see “Interaction”);
pregnancy;
breastfeeding period.

Side Effects

From the circulatory and lymphatic system: very rarely – thrombocytopenia, leukopenia/neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia.

Anemia: in certain clinical situations (patients after kidney transplantation, patients on hemodialysis), ACE inhibitors can cause anemia (see “Special Instructions”).

From the side of the central nervous system: often – paresthesia, headache, dizziness, asthenia, vertigo; infrequently – sleep disturbance, mood lability; very rarely – confusion; unspecified frequency – fainting.

From the side of the organ of vision: often – visual impairment.

On the part of the hearing organ: often – tinnitus.

From the cardiovascular system: often – a pronounced decrease in blood pressure, incl. orthostatic hypotension; very rarely – heart rhythm disturbances, incl. bradycardia, ventricular tachycardia, atrial fibrillation, as well as angina pectoris and myocardial infarction, possibly due to an excessive decrease in blood pressure in high-risk patients (see “Special Instructions”); unspecified frequency – pirouette-type arrhythmias (possibly fatal – see “Interaction”).

From the respiratory system, chest organs and mediastinum: often – during the use of ACE inhibitors, a dry cough may occur, which persists for a long time while taking drugs of this group and disappears after their withdrawal, shortness of breath; infrequently – bronchospasm; very rarely – eosinophilic pneumonia, rhinitis.

From the digestive system: often – dryness of the oral mucosa, nausea, vomiting, abdominal pain, epigastric pain, impaired taste perception, decreased appetite, dyspepsia, constipation, diarrhea; very rarely – angioedema of the intestine, cholestatic jaundice, pancreatitis; unspecified frequency – hepatic encephalopathy in patients with liver failure (see “Contraindications” and “Special Instructions”), hepatitis.

From the skin and subcutaneous fat: often – skin rash, itching, maculopapular rash; uncommon – angioedema of the face, lips, extremities, mucous membrane of the tongue, vocal folds and/or larynx; urticaria (see “Special Instructions”); hypersensitivity reactions in patients predisposed to broncho-obstructive and allergic reactions; purpura, in patients with an acute form of systemic lupus erythematosus, the course of the disease may worsen; very rarely – erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome. Cases of photosensitivity reactions have been reported (see “Special Instructions”).

From the musculoskeletal system and connective tissue: often – muscle spasms.

From the urinary system: infrequently – renal failure; very rarely – acute renal failure.

From the reproductive system: infrequently – impotence.

General disorders and symptoms: often – asthenia; infrequently – increased sweating.

Laboratory indicators: hyperkalemia, more often transient; a slight increase in the concentration of creatinine in the urine and in the blood plasma, which occurs after discontinuation of therapy, more often in patients with renal artery stenosis, when treating hypertension with diuretics and in cases of renal failure; rarely – hypercalcemia; unspecified frequency – increased QT interval on the ECG (see “Special Instructions”), increased concentrations of uric acid and glucose in the blood, increased activity of liver enzymes, hypokalemia, especially significant for patients at risk (see “Special Instructions”), hyponatremia and hypovolemia, leading to dehydration and orthostatic hypotension. Simultaneous hypochloremia can lead to compensatory metabolic alkalosis (the likelihood and severity of this effect is low).

Interaction

1. Combinations not recommended for use

Lithium preparations: with simultaneous use of lithium preparations and ACE inhibitors, a reversible increase in the concentration of lithium in the blood plasma and associated toxic effects may occur. Additional administration of thiazide diuretics may further increase lithium concentrations and increase the risk of toxicity. The simultaneous use of a combination of perindopril and indapamide with lithium preparations is not recommended. If such therapy is necessary, the lithium content in the blood plasma should be constantly monitored (see “Special Instructions”).

2. Drugs, combination with which requires special attention and caution

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

NSAIDs, including high doses of acetylsalicylic acid (more than 3 g/day): the administration of NSAIDs may lead to a decrease in diuretic, natriuretic and hypotensive effects. With significant fluid loss, acute renal failure may develop (due to a decrease in glomerular filtration rate). Before starting treatment with the drug, it is necessary to replace fluid loss and regularly monitor kidney function at the beginning of treatment.

3. Combination of drugs requiring attention

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

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

Other antihypertensive drugs: the antihypertensive effect may be enhanced.

Perindopril

1. Combinations not recommended for use

Potassium-sparing diuretics (amiloride, spironolactone, triamterene) and potassium supplements: ACE inhibitors reduce diuretic-induced renal potassium loss. Potassium-sparing diuretics (for example, spironolactone, triamterene, amiloride), potassium supplements and potassium-containing table salt substitutes can lead to a significant increase in serum potassium levels, including death. If simultaneous use of an ACE inhibitor and the above drugs is necessary (in case of confirmed hypokalemia), caution should be exercised and regular monitoring of potassium levels in the blood plasma and ECG parameters should be carried out.

2. Combination of drugs requiring special attention

Oral hypoglycemic agents (sulfonylureas) and insulin: the following effects have been described for captopril and enalapril. ACE inhibitors may enhance the hypoglycemic effect of insulin and sulfonylureas in patients with diabetes mellitus. The development of hypoglycemia is very rare (due to an increase in glucose tolerance and a decrease in the need for insulin).

3. Combination of drugs requiring attention

Allopurinol, cytostatic and immunosuppressive agents, corticosteroids (when used systemically) and procainamide: simultaneous use with ACE inhibitors may be accompanied by an increased risk of leukopenia.

Agents for general anesthesia: simultaneous use of ACE inhibitors and agents for general anesthesia may lead to an enhanced antihypertensive effect.

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

Gold preparations: when using ACE inhibitors, including perindopril, in patients receiving intravenous gold preparation (sodium aurothiomalate), a symptom complex was described, including: facial skin flushing, nausea, vomiting, arterial hypotension.

Indapamide

1. Combinations that require special attention

Drugs that can cause torsades de pointes: due to the risk of hypokalemia, caution should be exercised when indapamide is used concomitantly with drugs that can cause torsades de pointes, such as antiarrhythmics (quinidine, hydroquinidine, disopyramide, amiodarone, dofetilide, ibutilide, bretylium tosylate, sotalol); some neuroleptics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine); benzamides (amisulpride, sulpiride, sultopride, tiapride); butyrophenones (droperidol, haloperidol); other antipsychotics (pimozide); other drugs such as bepridil, cisapride, difemanil methyl sulfate, erythromycin (iv), halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, vincamine (iv), methadone, astemizole, terfenadine. Simultaneous use with the above drugs should be avoided; there is a risk of developing hypokalemia; if necessary, correct it; monitor the QT interval.

Drugs that can cause hypokalemia: amphotericin B (iv), corticosteroids and mineralocorticosteroids (when administered systemically), tetracosactide, laxatives that stimulate intestinal motility: increased risk of hypokalemia (additive effect). It is necessary to monitor the potassium content in the blood plasma and, if necessary, correct it. Particular attention should be paid to patients concomitantly receiving cardiac glycosides. Laxatives that do not stimulate intestinal motility should be used.

Cardiac glycosides: hypokalemia enhances the toxic effect of cardiac glycosides. With the simultaneous use of indapamide and cardiac glycosides, the potassium content in the blood plasma and ECG readings should be monitored and therapy should be adjusted if necessary.

2. Combination of drugs requiring attention

Metformin: functional renal failure, which can occur while taking diuretics, especially loop diuretics, with simultaneous administration of metformin increases the risk of developing lactic acidosis. Metformin should not be used if the plasma creatinine concentration exceeds 15 mg/l (135 µmol/l) in men and 12 mg/l (110 µmol/l) in women.

Iodinated contrast agents: Dehydration while taking diuretics increases the risk of acute renal failure, especially when using high doses of iodinated contrast agents. Before using iodinated contrast agents, patients need to compensate for fluid loss.

Calcium salts: with simultaneous administration, hypercalcemia may develop due to decreased excretion of calcium ions by the kidneys.

Cyclosporine: it is possible to increase the concentration of creatinine in the blood plasma without changing the concentration of cyclosporine in the blood plasma, even with normal levels of water and sodium ions.

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 administration of activated charcoal, followed by restoration of water and electrolyte balance.

If blood pressure decreases significantly, the patient should be placed in a lying position with legs elevated. 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.

Storage conditions

No special storage conditions required

Shelf life

3 years

Manufacturer

Servier Rus LLC, Russia