Catad_pgroup Combined antihypertensives

Noliprel - instructions for use

INSTRUCTIONS
on medical use of the drug

Registration number:
Trade name of the drug: Noliprel ®
INN or group name: perindopril + indapamide
Dosage form: pills

Compound:

1 tablet contains:
Active substances: perindopril erbumine (perindopril tertbutylamine) 2 mg, which corresponds to 1.669 mg of perindopril base, indapamide - 0.625 mg.
Excipients: colloidal anhydrous silicon dioxide, microcrystalline cellulose, lactose monohydrate, magnesium stearate.

DESCRIPTION
White oblong tablets with a score line on both sides.

Pharmacotherapeutic group:

antihypertensive combination drug (ACE inhibitor and diuretic).

ATX code: S09BA04

PHARMACOLOGICAL PROPERTIES
Pharmacodynamics
Noliprel ® is a combination drug containing perindopril (angiotensin-converting enzyme inhibitor) and indapamide (a diuretic from the group of sulfonamide derivatives). The pharmacological properties of the drug 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
Perindopril is an inhibitor of the enzyme that converts angiotensin I into angiotensin II (ACE inhibitor). Angiotensin-converting enzyme, or kinase, is an exopeptidase that both converts angiotensin I into the vasoconstrictor angiotensin II and breaks down the vasodilator bradykinin 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 total peripheral vascular resistance, which is mainly due to the effect on the vessels in the muscles and kidneys. These effects are not accompanied by salt 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, the following was revealed:

• decreased filling pressure in the left and right ventricles of the heart;
• decrease in total peripheral vascular resistance;
• increased cardiac output and increased cardiac index;
• increased muscle peripheral blood flow.

Indapamide
Indapamide belongs to the group of sulfonamides; its pharmacological properties are close 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, chloride and, to a lesser extent, potassium and magnesium ions by the kidneys, thereby increasing diuresis and reducing blood pressure (BP).

Hypotensive effect
Noliprel ®
Noliprel ® has a dose-dependent hypotensive effect on both diastolic and systolic blood pressure (BP) in the standing and lying position. 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. Stopping treatment does not cause withdrawal syndrome.

A synergistic hypotensive effect of perindopril and indapamide was noted compared to monotherapy with these drugs.

Noliprel ® reduces the degree of left ventricular hypertrophy, improves arterial elasticity, reduces total peripheral vascular resistance, 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 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 - 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 daily during a year. To achieve blood pressure control, drug doses were increased: perindopril - up to a maximum of 8 mg, 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 in this indicator between groups was -8.3 g/m² (95% CI (-11.5, -5.0), p In the group of patients receiving combination therapy with perindopril and indapamide, compared with the enalapril group there was a more pronounced hypotensive effect was noted. The difference in the degree of blood pressure reduction between groups in the general patient population was –5.8 mmHg (95% CI (–7.9, –3.7), p 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 dose and lasts 24 hours. 24 hours after taking the drug, pronounced (about 80%) residual ACE inhibition is observed.
Perindopril has an antihypertensive effect in patients with both low and normal plasma renin activity.
Perindopril has a vasodilating effect, helps restore the 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 reduces the risk of hypokalemia while taking diuretics.

Indapamide
Indapamide as monotherapy has an antihypertensive effect that lasts 24 hours. 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 total peripheral vascular resistance.
Indapamide reduces left ventricular hypertrophy.
Thiazide and thiazide-like diuretics at a certain dose reach a plateau of therapeutic effect, while the frequency of side effects continues to increase with further increases in the dose of the drug. Therefore, you should not increase the dose of the drug if a 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
Noliprel ®
The combined use of perindopril and indapamide does not change their pharmacokinetic characteristics compared to the separate administration of these drugs.

Perindopril
When taken orally, perindopril is rapidly absorbed. The maximum concentration in blood plasma is achieved 1 hour after oral administration. The half-life (T&sub1/2;) of the drug from blood plasma is 1 hour. Perindopril has no pharmacological activity. Approximately 27% of the total amount of perindopril ingested enters the bloodstream in the form of the active metabolite perindoprilate. In addition to perindoprilate, 5 more metabolites are formed that do not have pharmacological activity. The maximum concentration of perindoprilate in the blood plasma is achieved 3-4 hours after oral administration.
Eating slows down the conversion of perindopril to perindoprilat, thereby affecting bioavailability. Therefore, the drug should be taken once a day, in the morning, before meals.
There is a linear relationship between the concentration of perindopril in the blood plasma and its dose. The volume of distribution of free perindoprilate is approximately 0.2 l/kg. The association of perindoprilate with plasma proteins, mainly with ACE, depends on the concentration of perindopril and is about 20%,
Perindoprilat is excreted from the body by the kidneys. “Effective” T&sub1/2; free fraction is about 17 hours, so the equilibrium state is achieved within 4 days.
The elimination of perindoprilate is slowed down in old age, as well as in patients with heart and renal failure.
The dialysis clearance of perindoprilate is 70 ml/min.
The pharmacokinetics of perindopril is changed in patients with liver cirrhosis: its hepatic clearance is reduced by 2 times. However, the amount of perindoprilate formed does not decrease, which does not require dose adjustment (see sections “Dosage and Administration” and “Special Instructions”).

Indapamide
Indapamide is quickly and completely absorbed from the gastrointestinal tract.
The maximum concentration of the drug in the blood plasma is observed 1 hour after oral administration.
Connection with blood plasma proteins – 79%.
T&sub1/2; is 14-24 hours (on average 18 hours). Repeated administration of the drug does not lead to its accumulation in the body. It is excreted mainly by the kidneys (70% of the administered dose) and through the intestines (22%) in the form of inactive metabolites.
The pharmacokinetics of the drug does not change in patients with renal failure.

INDICATIONS FOR USE
Essential arterial hypertension.

CONTRAINDICATIONS

Perindopril

• Hypersensitivity to perindopril and other ACE inhibitors.
• History of angioedema (Quincke's edema) (including while taking other ACE inhibitors).
• Hereditary/idiopathic angioedema.
• Pregnancy (see section “Pregnancy and breastfeeding”).

Indapamide

• Hypersensitivity to indapamide and other sulfonamides.
• Severe renal failure (creatinine clearance (CC) less than 30 ml/min).
• Severe liver failure (including encephalopathy).
• Hypokalemia.
• Simultaneous use with antiarrhythmic drugs that can cause pirouette-type arrhythmia (see section “Interaction with other drugs”).
• Breastfeeding period (see section “Pregnancy and breastfeeding period”).

Noliprel ®
Hypersensitivity to the excipients included in the drug.
Co-administration of the drug with potassium-sparing diuretics, potassium and lithium preparations, and in patients with elevated potassium levels in the blood plasma.
The presence of lactase deficiency, galactosemia or glucose-galactose malabsorption syndrome.
Concomitant use of drugs that prolong the QT interval.
Due to the lack of sufficient clinical experience, Noliprel ® should not be used in patients on hemodialysis.
Patients with untreated chronic heart failure in the stage of decompensation.
Age up to 18 years (efficacy and safety have not been established).

WITH CAUTION (see also sections “Special instructions” and “Interaction with other drugs”)
Systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), immunosuppressant therapy (risk of developing neutropenia, agranulocytosis), inhibition of bone marrow hematopoiesis, reduced circulating blood volume (taking diuretics, salt-free diet, vomiting, diarrhea), angina pectoris, cerebrovascular diseases , renovascular hypertension, diabetes mellitus, chronic heart failure (functional class IV according to the NYHA classification), hyperuricemia (especially accompanied by gout and urate nephrolithiasis), blood pressure lability, old age; hemodialysis using high-flux membranes (for example, AN69 ®) or desensitization, before the procedure of low-density lipoprotein (LDL) apheresis; condition after kidney transplantation; Aortic valve stenosis/hypertrophic cardiomyopathy.

Pregnancy and breastfeeding period
Pregnancy
Noliprel ® is contraindicated during pregnancy (see section “Contraindications”). Noliprel ® should not be used in the first trimester of pregnancy. If you are planning pregnancy or if it occurs while taking the drug, you should immediately stop taking it and prescribe other antihypertensive therapy.
There have been no adequate controlled studies of ACE inhibitors in pregnant women. The limited data available on exposure to the drug in the first trimester of pregnancy indicate that the drug did not cause malformations associated with fetotoxicity.
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 (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, 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 ® during the second or third trimester of pregnancy, it is recommended to conduct an ultrasound examination of the fetus to assess the condition of the skull bones and kidney function.
Breastfeeding period
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 serious complications in the infant, it is necessary to evaluate the significance of therapy for the mother and decide whether to stop breastfeeding or stop taking these drugs.

METHOD OF APPLICATION AND DOSES
Orally, preferably in the morning, before meals, 1 tablet of Noliprel ® 1 time per day. If, one month after the start of therapy, the desired hypotensive effect has not been achieved, the dose of the drug can be doubled to a dosage of 4 mg + 1.25 mg (manufactured by the company under the trade name Noliprel ® forte).

Elderly patients (see section "Special instructions")
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.
Therapy should begin with 1 tablet of Noliprel ® once a day.

Renal failure (see section "Special instructions")
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 per day.
In some patients with hypertension without previous obvious renal impairment, laboratory signs of functional renal failure may appear during therapy. In this case, treatment should be stopped. In the future, you can resume combination therapy using low doses of drugs, or use drugs in monotherapy.
Renal failure occurs more often in patients with severe heart failure or underlying renal impairment, including renal artery stenosis.
Patients with CC equal to or exceeding 60 ml/min do not require dose adjustment. During therapy, it is necessary to control the level of creatinine and potassium in the blood plasma.

Liver failure (see sections “Contraindications”, “Special instructions”, “Pharmacokinetics”)
The drug is contraindicated in patients with severe liver failure.
For moderately severe liver failure, no dose adjustment is required.

Children and teenagers
Noliprel ® 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 in this age group.

SIDE EFFECT
Perindopril has an inhibitory effect on the renin-angiotensin-aldosterone system and reduces potassium loss by the kidneys when taking indapamide. In 2% of patients, while using the drug Noliprel ®, hypokalemia develops (potassium level less than 3.4 mmol/l).
The frequency of adverse reactions that may occur during therapy is given in the following gradation: very often (>1/10); often (>1/100, 1/1000, 1/10000, From the circulatory and lymphatic system
Very rarely:

• thrombocytopenia, leukopenia/neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia.
• in certain clinical situations (patients after kidney transplantation, patients on hemodialysis), ACE inhibitors can cause anemia (see section "Special instructions").

From the central nervous system
Often: paresthesia, headache, dizziness, asthenia.
Infrequently: sleep disturbance, mood lability.
Very rarely: confusion.
From the side of the organ of vision
Often: visual disturbance.
From the side of the hearing organ
Often: noise in ears.
From the cardiovascular system
Infrequently: pronounced decrease in blood pressure, including orthostatic hypotension.
Very rarely: heart rhythm disturbances, including 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 section "Special Instructions").
From the respiratory system
Often: During the use of ACE inhibitors, a dry cough may occur, which persists for a long time while taking drugs of this group and disappears after their discontinuation. Dyspnea.
Infrequently: bronchospasm.
Very rarely: eosinophilic pneumonia, rhinitis.
From the digestive system
Often: constipation, dry mouth, nausea, vomiting, abdominal pain, epigastric pain, impaired taste perception, decreased appetite, dyspepsia, diarrhea.
Rarely: angioedema of the intestine, cholestatic jaundice.
Very rarely: pancreatitis
In patients with liver failure, hepatic encephalopathy may develop.
From the skin and subcutaneous fat
Often: rash, skin rash, pruritus, maculopapular rash.
Infrequently:

• angioedema of the face, lips, extremities, mucous membranes of the tongue, glottis and/or larynx; urticaria (see section “Special instructions”).
• hypersensitivity reactions, mainly skin, in patients predisposed to asthmatic and allergic reactions.
• hemorrhagic vasculitis.

In patients with an acute form of disseminated lupus erythematosus, an exacerbation of the disease may occur.
Very rarely: erythema multiforme, toxic epidermal necrolysis, Stephen-Jones syndrome.
Cases of photosensitivity reactions have been reported (see section "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.
Common disorders and symptoms
Often: asthenia.
Infrequently: sweating

Laboratory indicators:

• Hypokalemia, especially significant for patients at risk (see section "Special Instructions").
• 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 the level of urea and creatinine in the blood plasma that occurs after discontinuation of therapy, more often in patients with renal artery stenosis, when treating hypertension with diuretics and in cases of renal failure.
• Hyperkalemia, often transient.

Rarely: hypercalcemia.

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

INTERACTION WITH OTHER MEDICINES
Perindopril, indapamide
Undesirable combination of drugs

• 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. In the case of such therapy, regular monitoring of the lithium content in the blood plasma is necessary (see section “Special instructions”).

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

• Tricyclic antidepressants, antipsychotics (neuroleptics):
drugs of these classes enhance the antihypertensive effect and increase the risk of orthostatic hypotension (additive effect).
• Glucocorticosteroids, tetracosactide: decreased hypotensive effect (retention of fluid and sodium ions as a result of the action of glucocorticosteroids).
• Other antihypertensive drugs: the hypotensive effect may be enhanced.

Perindopril
Undesirable combination of drugs
Potassium-sparing diuretics (amiloride, spironolactone, triamterene, both as monotherapy and in combination) and potassium supplements: ACE inhibitors reduce diuretic-induced renal potassium loss. Potassium-sparing diuretics (eg, spironolactone, triamterene, amiloride), potassium supplements, and potassium-containing table salt substitutes can lead to significant increases in serum potassium concentrations, including death. If combined use of an ACE inhibitor and the above drugs is necessary (in case of confirmed hypokalemia), caution should be exercised and regular monitoring of plasma potassium concentrations and ECG parameters should be carried out.

A combination of products that requires special attention

• Hypoglycemic agents (insulin, sulfonylurea derivatives): 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).

A combination that requires 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: the combined use of ACE inhibitors and general anesthesia may lead to an increased hypotensive 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 hypotension.
• Gold preparations: When prescribing ACE inhibitors, including perindopril, to patients receiving injectable gold preparations (sodium aurothiomalate), nitrate-like reactions (facial flushing, nausea, vomiting, hypotension) were noted.

Indapamide
A combination of products that requires special attention

• Medicines that can cause pirouette arrhythmia: due to the risk of developing hypokalemia, caution should be exercised when using indapamide together with drugs that can cause pirouette-type arrhythmia, for example, antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide, amiodarone, dofetilide, ibutilide, bretylium, sotalol); some antipsychotics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoroperazine); benzamides (amisulpride, sulpiride, sultopride, tiapride); butyrophenones (droperidol, haloperidol); other antipsychotics (pimozide); other drugs such as bepridil, cisapride, difemanil, erythromycin IV, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, vincamine IV, methadone, astemizole, terfenadine. The development of hypokalemia should be avoided and, if necessary, corrected; monitor the QT interval.
• Medicines that can cause hypokalemia: amphotericin B (iv), gluco- and mineralocorticosteroids (when administered systemically), tetracosactide, laxatives that stimulate intestinal motility: increased risk of hypokalemia (additive effect). It is necessary to monitor the level of potassium in the blood plasma and, if necessary, correct it. Particular attention should be paid to patients simultaneously 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 level of potassium in the blood plasma and ECG readings should be monitored and, if necessary, therapy should be adjusted.

A combination that requires 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 plasma creatinine levels exceed 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 developing acute renal failure, especially when using high doses of iodine-containing contrast agents. Before using iodine-containing contrast agents, patients must 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 level of creatinine in the blood plasma without changing the concentration of circulating cyclosporine, even with normal fluid and sodium ion levels.

SPECIAL INSTRUCTIONS
Perindopril, indapamide
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 in the lowest approved doses (see section “Side Effects”). When initiating therapy with two antihypertensive drugs that the patient has not previously received, an increased risk of idiosyncrasy cannot be excluded. Careful monitoring of the patient can minimize this risk.

Lithium preparations
The simultaneous use of a combination of perindopril and indapamide with lithium preparations is not recommended (see section “Interaction with other drugs”).

Renal dysfunction
Therapy is contraindicated in patients with severe renal failure (creatinine clearance less than 30 ml/min). In some patients with hypertension without previous obvious renal impairment, laboratory signs of functional renal failure may appear during therapy. In this case, treatment should be stopped. In the future, you can resume combination therapy using low doses of drugs, or use drugs in monotherapy.
Such patients require regular monitoring of serum potassium and creatinine levels - 2 weeks after the start of therapy and every 2 months thereafter.
Renal failure occurs more often in patients with severe heart failure or underlying renal impairment, including stenosis of one or two renal arteries.
As a rule, the use of perindopril and indapamide is not recommended for patients with bilateral renal artery stenosis or stenosis of a single functioning kidney.

Arterial hypotension and water-electrolyte imbalance
Hyponatremia is associated with a risk of sudden development of arterial hypotension (especially in patients with stenosis of one or two renal arteries). Therefore, during dynamic monitoring of patients, attention should be paid to possible symptoms of dehydration and decreased levels of electrolytes in the blood plasma, for example, after diarrhea or vomiting. Such patients require regular monitoring of plasma electrolyte levels.
In case of severe arterial hypotension, intravenous administration of 0.9% sodium chloride solution may be required.
Transient arterial hypotension is not a contraindication for continued therapy. After restoration of circulating blood volume and blood pressure, therapy can be resumed using 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 antihypertensive drugs and a diuretic, regular monitoring of the level of potassium in the blood plasma is necessary.

Excipients
It should be taken into account that the excipients of the drug include lactose monohydrate. Noliprel ® should not be prescribed to patients with hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption.

Perindopril
Neutropenia/agranulocytosis
The risk of developing neutropenia while taking ACE inhibitors is dose-dependent and depends on the drug taken and the presence of concomitant diseases. Neutropenia rarely occurs in patients without concomitant diseases, 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.
Perindopril should be used with extreme 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 underlying renal impairment. Some patients developed severe infections, in some cases resistant to intensive antibiotic therapy. When prescribing perindopril to such patients, it is recommended to periodically monitor the number of leukocytes in the blood.
Patients should report any signs of infectious diseases (eg, sore throat, fever) to their doctor.

Hypersensitivity/angioedema (Quincke's edema)
When taking ACE inhibitors, including perindopril, in rare cases, the development of angioedema of the face, extremities, lips, tongue, glottis and/or larynx may occur. If symptoms appear, perindopril should be discontinued immediately and the patient should be observed until signs of edema completely disappear. If the swelling affects only the face and lips, it usually resolves on its own, although antihistamines may be used to treat symptoms.
Angioedema, accompanied by swelling of the larynx, can be fatal. Swelling of the tongue, glottis, or larynx can lead to airway obstruction. If such symptoms appear, you should immediately administer epinephrine (adrenaline) subcutaneously at a dilution of 1:1000 (0.3 or 0.5 ml) and/or ensure airway patency.
Patients with a history of angioedema not associated with taking ACE inhibitors may have an increased risk of developing it when taking drugs of this group (see section “Contraindications”).
In rare cases, angioedema of the intestine develops during therapy with ACE inhibitors. In this case, patients experience abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without previous angioedema of the face and with normal levels of C-1 esterase. The diagnosis is made using computed tomography of the abdominal region, ultrasound, or at the time of surgery. Symptoms disappear after stopping ACE inhibitors. In patients with abdominal pain receiving ACE inhibitors, the possibility of developing angioedema of the intestine must be taken into account when making a differential diagnosis.

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

Hemodialysis
Anaphylactoid reactions have been reported in patients receiving ACE inhibitors during hemodialysis using high-flux membranes (eg, AN69®). Therefore, it is advisable to use a different type of membrane or use an antihypertensive drug of a different pharmacotherapeutic group.

Potassium-sparing diuretics and potassium supplements
As a rule, the combined use of perindopril and potassium-sparing diuretics, as well as potassium preparations and potassium-containing table salt substitutes is not recommended (see section “Interaction with other drugs”).

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

Children and teenagers
Noliprel ® 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 renin-angiotensin-aldosterone system may be observed, especially with severe hypovolemia and a decrease in the level of plasma electrolytes (against the background of a salt-free diet or long-term use of diuretics), in patients with initially low blood pressure, stenosis of one or two kidneys arteries, chronic heart failure or cirrhosis of the liver with the presence of edema and ascites.
The use of an ACE inhibitor causes a blockade of this system and therefore may be accompanied by a sharp decrease in blood pressure and/or an increase in 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 heart disease and cerebrovascular insufficiency. In such patients, treatment should be started with low doses.

Patients with renovascular hypertension
The treatment method for renovascular hypertension is revascularization. However, the use of ACE inhibitors has a beneficial effect in patients both awaiting surgery and in cases where such surgery cannot be performed.
Treatment with Noliprel ® in patients with diagnosed or suspected renal artery stenosis should begin 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 chronic heart failure (stage IV) and patients with insulin-dependent diabetes mellitus (risk of spontaneous increase in potassium concentration), treatment should begin with a low dose of the drug (half a tablet) and under constant medical supervision.
Patients with arterial hypertension and coronary heart disease should not stop taking beta-blockers: ACE inhibitors should be used together with beta-blockers.

Patients with diabetes mellitus
When prescribing the drug to patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, blood glucose levels must be carefully monitored during the first month of therapy.

Ethnic differences
Perindopril, like other ACE inhibitors, apparently has a less pronounced hypotensive effect in patients of the Negroid race compared to representatives of other races. Perhaps this difference is due to the fact that patients with arterial hypertension of the Negroid race more often have low renin activity.

Surgery/General anesthesia
The use of ACE inhibitors in patients undergoing surgery 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, 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.

Liver failure
In rare cases, cholestatic jaundice occurs while taking ACE inhibitors. As this syndrome progresses, fulminant liver necrosis develops, sometimes with death. The mechanism of development of this syndrome is unclear. If jaundice or a significant increase in the activity of liver enzymes occurs while taking ACE inhibitors, you should stop taking the drug and consult a doctor (see section “Side Effects”).

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.

Hyperkalemia
Hyperkalemia may develop during treatment with ACE inhibitors, including perindopril. Risk factors for hyperkalemia include renal failure, decreased renal function, advanced age, diabetes mellitus, certain concomitant conditions (dehydration, acute decompensated heart failure, metabolic acidosis), concomitant use of potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene, amiloride), and potassium preparations or potassium-containing substitutes for table salt, as well as the use of other drugs that increase the level of potassium in the blood plasma (for example, heparin). The use of potassium supplements, potassium-sparing diuretics, and potassium-containing table salt substitutes can lead to a significant increase in potassium levels in the blood, especially in patients with reduced renal function. Hyperkalemia can cause serious, sometimes fatal, abnormal heart rhythms. If combined use of the above drugs is necessary, treatment should be carried out with caution, against the background of regular monitoring of potassium levels in the blood serum (see section “Interaction with other drugs”).

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

Photosensitivity
While taking thiazide and thiazide-like diuretics, cases of photosensitivity reactions have been reported (see section "Side effects"). If photosensitivity reactions develop while taking the drug, treatment should be discontinued. If it is necessary to continue diuretic therapy, it is recommended to protect the skin from exposure to sunlight or artificial UV rays.

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

Content of potassium ions in blood plasma
Therapy with thiazide and thiazide-like diuretics is associated with a risk of hypokalemia. Hypokalemia (less than 3.4 mmol/l) should be avoided in the following high-risk patients: elderly patients, debilitated patients or those receiving concomitant drug therapy, patients with liver cirrhosis, peripheral edema or ascites, coronary artery disease, heart failure. Hypokalemia in these patients enhances the toxic effect of cardiac glycosides and increases the risk of developing arrhythmias.
Patients with an increased QT interval are also at increased risk, 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 heart rhythm disturbances, especially pirouette-type arrhythmias, which can be fatal.
In all the cases described above, more regular monitoring of the content of potassium ions in the blood plasma is necessary. The first measurement of potassium ion concentration should be carried out within the first week from the start of therapy.
If hypokalemia is detected, appropriate treatment should be prescribed.

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

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). In elderly patients, creatinine clearance is calculated taking into account age, body weight and gender.
At the beginning of treatment with diuretics, patients due to hypovolemia and hyponatremia may experience a temporary decrease in glomerular filtration rate and an increase in the concentration of urea and creatinine in the blood plasma. This transient functional renal failure is not dangerous for patients with unchanged renal function, but its severity may increase in patients with renal failure.

Athletes
Indapamide may give a positive reaction during doping control.

Effect on ability to drive a car
The action of the substances included in the drug Noliprel ® does not lead to impaired psychomotor reactions. However, some patients may develop different individual reactions in response to a decrease in blood pressure, especially at the beginning of therapy or when other antihypertensive drugs are added to the therapy. In this case, the ability to drive a car or operate other machinery may be reduced.

RELEASE FORM
Tablets 2 mg + 0.625 mg.
14 or 30 tablets per blister (PVC/Al). The blister is placed in a protective sachet (polyester/aluminum/polyethylene) containing silica gel desiccant in a plastic wafer with a cardboard lid. 1 blister packed in a sachet with instructions for medical use is placed in a cardboard box.

• Instructions for use Noliprel ® forte a
• Composition of the drug Noliprel ® forte a
• Indications of the drug Noliprel ® forte a
• Storage conditions for the drug Noliprel ® forte a
• Shelf life of the drug Noliprel ® forte a

ATX code: Cardiovascular system (C) > Drugs affecting the renin-angiotensin system (C09) > ACE inhibitors in combination with other drugs (C09B) > ACE inhibitors in combination with diuretics (C09BA) > Perindopril in combination with diuretics (C09BA04)

Release form, composition and packaging

tab., cover film-coated, 5 mg+1.25 mg: 14 or 30 pcs.
Reg. No.: 8649/08/10/13/18 dated 08/30/2018 - Registration period. beat is not limited

Film-coated tablets, white, elongated shape.

Excipients: lactose monohydrate - 71.33 mg, magnesium stearate (E470B), maltodextrin, colloidal anhydrous silicon dioxide (E551), sodium starch glycolate (type A).

Film shell composition: glycerol (E422), hypromellose (E464), macrogol 6000, magnesium stearate (E470B), titanium dioxide (E171).

14 pcs. - polypropylene tubes with dispenser (1) - cardboard packs.
30 pcs. - polypropylene tubes with dispenser (1) - cardboard packs.

Description of the drug NOLIPREL ® FORTE A based on officially approved instructions for use of the drug and made in 2013. Update date: 02/22/2013

pharmachologic effect

A combination drug containing perindopril (ACE inhibitor) and indapamide (thiazide-like diuretic). The pharmacological effect of the drug Noliprel ® forte A is due to the combination of the properties of each component. The combined use of perindopril and indapamide provides a synergistic antihypertensive effect compared to each component separately.

Perindopril

Perindopril is an ACE inhibitor, the enzyme that converts angiotensin I to angiotensin II. In addition, ACE stimulates the secretion of aldosterone by the adrenal glands and enhances the breakdown of bradykinin, which has a vasodilator effect, to an inactive heptapeptide. As a result, perindopril reduces the secretion of aldosterone, according to the principle of negative feedback, increases the activity of renin in the blood plasma, and with long-term use 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 salt and water retention or the development of reflex tachycardia with prolonged use.

The action of perindopril is carried out through the active metabolite perindoprilat. Other metabolites are inactive.

Perindopril also has a hypotensive effect in patients with low or normal renin levels.

Perindopril facilitates the work of the heart due to a vasodilatory effect on the veins (reduced preload), probably due to changes in the metabolism of prostaglandins, as well as due to a decrease in peripheral vascular resistance (reduced afterload).

When studying hemodynamic parameters in patients with heart failure, the following was revealed:

• decreased filling pressure in the left and right ventricles of the heart;
• decrease in OPSS;
• increased cardiac output and increased cardiac index;
• increased peripheral blood flow in muscles.

Exercise tests also showed improved results.

Perindopril acts for arterial hypertension of any degree:

• from mild to moderate to severe. A decrease in diastolic and systolic blood pressure occurs both in the supine and standing positions. The maximum hypotensive effect is observed 4-6 hours after taking a single dose and persists for at least 24 hours. There is a high degree of residual inhibition of ACE activity 24 hours after taking the drug - about 80%. In patients amenable to treatment, normalization of blood pressure is achieved after one month and is maintained without the development of tachyphylaxis. Discontinuation of treatment does not lead to the restoration of arterial hypertension. Perindopril has vasodilatory properties and restores the elasticity of the main arterial vessels, corrects histomorphometric changes in resistant arteries and reduces left ventricular hypertrophy.

If necessary, the addition of a thiazide diuretic results in additive effects.

The combined administration of an ACE inhibitor with a thiazide diuretic reduces the risk of hypokalemia that occurs when taking only one diuretic.

Indapamide

Indapamide belongs to the group of sulfonamides and is a chlorsulfamoyl diuretic. 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 having a hypotensive effect.

Indapamide, when used alone, has a hypotensive effect that lasts for 24 hours. This effect occurs at doses at which the diuretic effect of indapamide is minimal. The effectiveness of the hypotensive effect of indapamide is proportional to its ability to improve arterial elasticity, reduce peripheral vascular resistance and arteriolar resistance. Indapamide helps reduce left ventricular hypertrophy.

When doses of thiazide and thiazide-like diuretics are exceeded, their antihypertensive effectiveness reaches a plateau, and undesirable effects become more pronounced. If treatment is ineffective, then the dose should not be increased.

In addition, it has been shown that in short-, medium- and long-term treatment of patients suffering from arterial hypertension, indapamide does not affect lipid metabolism, i.e. for the content of triglycerides, LDL cholesterol, HDL cholesterol; does not affect carbohydrate metabolism, even in patients with diabetes mellitus and arterial hypertension.

Noliprel ® forte A

Noliprel ® forte A, regardless of the patient's age, has a dose-dependent hypotensive effect on both diastolic and systolic blood pressure in the standing and lying position.

The multicenter, randomized, double-blind PICXEL study assessed the effect of perindopril/indapamide on left ventricular hypertrophy compared with enalapril monotherapy using echocardiography.

In the PICXEL study, patients with hypertension and left ventricular hypertrophy (defined as a left ventricular mass index (LVMI) > 120 g/m2 in men and > 100 g/m2 in women) were randomized to either receive perindopril tert. butylamine 2 mg (equivalent to 2.5 mg perindopril arginine)/indapamide 0.625 mg or in the group receiving enalapril 10 mg, taken once a day for one year. The dose was adapted depending on changes in blood pressure towards an increase:

• up to perindopril tert-butylamine 8 mg (equivalent to 10 mg perindopril arginine)/indapamide 2.5 mg, or up to 40 mg enalapril 1 time/day. Only 34% of patients continued taking perindopril tert-butylamine 2 mg (equivalent to 2.5 mg perindopril arginine)/indapamide 0.625 mg;
• only 20% continued taking enalapril 10 mg.

At the end of treatment, LVMI decreased statistically significantly more in the perindopril/indapamide group (-10.1 g/m2) than in the enalapril group (-1.1 g/m2) in all populations of randomized patients. The difference in these changes between groups was -8.3 (CI 95% (-11.5; -5.0), p< 0.0001).

The most pronounced effect on LVMI was achieved with a dose of perindopril 8 mg (equivalent to 10 mg perindopril arginine)/indapamide 2.5 mg.

When assessing blood pressure, the mean difference between groups in the randomized population was -5.8 mm. rt. Art. (CI 95% (-7.9; -3.7), p< 0.0001) по систолическому АД и -2.3 мм. рт. ст. (ДИ 95% (-3.6;-0.9), р = 0.0004) по диастолическому АД, в пользу группы, получавшей периндоприл/индапамид.

Pharmacokinetics

The pharmacokinetic parameters of perindopril and indapamide when combined do not change compared to their separate use.

Perindopril

Absorption and Metabolism

After oral administration, perindopril is rapidly absorbed. Cmax of perindopril in blood plasma is achieved within 1 hour. T1/2 of perindopril from plasma is 1 hour. Bioavailability of perindopril is 65-70%. Perindopril is a prodrug. 27% of the administered dose of perindopril enters the systemic circulation in the form of the active metabolite perindoprilate. In addition, 5 more inactive metabolites are formed in the body. Cmax of perindoprilate in blood plasma is achieved 3-4 hours after oral administration of perindopril.

When taken with food, the conversion of perindopril to perindoprilat decreases, and therefore its bioavailability, therefore it is recommended to take perindopril arginine on an empty stomach. The correlation between the dose of perindopril and its plasma concentration has been shown to be linear.

Distribution

The binding of perindoprilate to plasma proteins is 20% (mainly with ACE) and depends on its concentration in the blood plasma.

V d of unbound perindoprilate is about 0.2 l/kg. C ss is achieved on average after 4 days.

Removal

Perindoprilat is excreted from the body in the urine. The final half-life of unbound perindoprilate is 17 hours.

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

The clearance of perindoprilate during dialysis is 70 ml/min.

The pharmacokinetics of perindopril changes in patients with liver cirrhosis:

• hepatic clearance of perindopril is reduced by 2 times. However, the concentration of the resulting perindoprilate does not change, so dose adjustment of the drug is not required.

Indapamide

Suction

Indapamide is quickly and completely absorbed from the gastrointestinal tract. Cmax in blood plasma is achieved 1 hour after oral administration.

Distribution

Plasma protein binding - 79%.

Repeated administration of the drug does not lead to its accumulation in the body.

Removal

T1/2 is 14-24 hours (average 18 hours). It is excreted mainly in urine (70% of the administered dose) and in feces (22%) in the form of inactive metabolites.

Pharmacokinetics in special clinical situations

The pharmacokinetics of indapamide do not change in patients with renal failure.

Dosage regimen

The drug should be taken orally, in the morning, preferably before meals.

For adults the drug is prescribed 1 tablet. 1 time/day

A switch to Noliprel ® forte A should be carried out if the effectiveness of the drug Noliprel ® A 2.5 mg/0.625 mg is insufficient. In a stable clinical situation, you can transfer the patient from monotherapy directly to taking Noliprel ® forte A.

U elderly patients Treatment should be started after assessing blood pressure response and renal function.

At severe renal failure (SC< 30 мл/мин) At CC > 60 ml/min

The use of the drug is contraindicated.

Side effects

Perindopril inhibits the activity of the RAAS and tends to reduce the excretion of potassium ions caused by indapamide. In 4% of patients while using the drug Noliprel ® forte A, hypokalemia was observed (potassium level<3.4 ммоль/л).

Determination of the frequency of adverse reactions:

• very often (≥1/10);
• often (≥1/100,<1/10);
• uncommon (≥1/1000,<1/100);
• rare (≥ 1/10,000,<1/1000);
• very rarely (< 1/10 000);
• unknown (impossible to estimate from available data).

From the hematopoietic system: very rarely - thrombocytopenia, leukopenia/neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia. In certain clinical situations (patients after kidney transplantation, patients on hemodialysis), anemia has been observed when taking ACE inhibitors.

From the side of the central nervous system: uncommon - paresthesia, headache, dizziness, asthenia;

infrequently - sleep disturbance, mood disorders;

very rarely - confusion;

unknown - fainting.

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

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

From the cardiovascular system: often - orthostatic or non-orthostatic hypotension;

very rarely - arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation), angina pectoris and myocardial infarction, possibly due to an excessive decrease in blood pressure in high-risk patients;

unknown - atrial fibrillation (potentially dangerous).

From the respiratory system: often - during the use of ACE inhibitors, a dry cough may occur, which persists for a long time while taking drugs of this group and disappears after their withdrawal (the possibility of iatrogenic etiology should be taken into account), shortness of breath;

infrequently - bronchospasm;

very rarely - eosinophilic pneumonia, rhinitis.

From the digestive system: often - dryness of the oral mucosa, nausea, vomiting, pain in the epigastric region, abdominal pain, change in taste, dyspepsia, constipation, diarrhea;

very rarely - pancreatitis, cytolytic or cholestatic hepatitis;

unknown - hepatic encephalopathy in patients with liver failure.

From the skin: often - rash, itching, maculopapular rash;

infrequently - purpura;

very rarely - erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome;

in some cases - photosensitivity.

Allergic reactions: uncommon - angioedema of the face, lips, extremities, mucous membrane of the tongue, glottis and/or larynx;

hives;

hypersensitivity reactions in patients predisposed to broncho-obstructive and allergic reactions.

From the immune system: infrequently - worsening of the course of acute disseminated lupus erythematosus.

From the musculoskeletal system: often - muscle cramps.

From the urinary system: infrequently - renal failure;

very rarely - acute renal failure.

From the reproductive system: infrequently - impotence.

From the side of metabolism: rarely - hypercalcemia;

unknown - decreased potassium levels and hypokalemia in patients at high risk, increased potassium levels (usually transient), hyponatremia with hypovolemia, which contribute to dehydration and the development of orthostatic hypotension.

Laboratory indicators: unknown - prolongation of the QT interval on the ECG, increased concentrations of uric acid and glucose in the blood during treatment, increased activity of liver enzymes, a slight increase in plasma urea and creatinine, reversible after discontinuation of therapy, more often in patients with renal artery stenosis, in the treatment of arterial hypertension with diuretics and in case of renal failure.

Others: often - asthenia;

infrequently - increased sweating.

Contraindications for use

Perindopril

• hereditary/idiopathic angioedema;
• history of angioedema (Quincke's edema) associated with treatment with an ACE inhibitor;
• II and III trimesters of pregnancy;
• hypersensitivity to perindopril and other ACE inhibitors.

Indapamide

• < 30 мл/мин);
• hepatic encephalopathy;
• severe liver failure;
• hypokalemia;
• lactation (breastfeeding);
• hypersensitivity to indapamide and sulfonamides;
• It is not recommended to prescribe in combination with non-antiarrhythmic drugs that cause paroxysmal ventricular tachycardia of the “pirouette” type.

Noliprel ® forte A

• severe renal failure (CK<30 мл/мин);
• dialysis (due to lack of therapeutic experience);
• untreated decompensated heart failure (due to insufficient therapeutic experience);
• hypersensitivity to the components of the drug.

Use during pregnancy and breastfeeding

Pregnancy

The use of Noliprel ® forte A in the first trimester of pregnancy is not recommended; in the second and third trimesters of pregnancy it is contraindicated.

Perindopril

The use of ACE inhibitors in the first trimester of pregnancy is not recommended; in the second and third trimesters of pregnancy it is contraindicated.

Epidemiological data regarding the risk of teratogenicity when taking ACE inhibitors in the first trimester of pregnancy do not allow definite conclusions to be drawn, however, some risk cannot be excluded. Unless continued ACE inhibitor therapy is considered absolutely necessary, patients planning pregnancy should switch to an alternative antihypertensive drug that has been established to have a safe profile in pregnancy. If pregnancy is confirmed, treatment with ACE inhibitors should be stopped immediately and, if necessary, switched to an alternative treatment.

It is known that taking ACE inhibitors in the second and third trimesters of pregnancy in humans has a toxic effect on the fetus (reduced renal function, oligohydramnios, delayed ossification of the skull) and the newborn (renal failure, arterial hypotension, hyperkalemia). If you are taking ACE inhibitors, starting from the second trimester of pregnancy, it is recommended to conduct an ultrasound examination of kidney and skull function.

If the mother took ACE inhibitors during pregnancy, the infant should be closely monitored for the development of arterial hypotension.

Indapamide

Long-term use of a thiazide diuretic in the third trimester of pregnancy can lead to a decrease in blood volume in the mother's body, as well as a decrease in uteroplacental blood flow, which can cause fetoplacental ischemia and fetal growth retardation. In addition, rare cases of hypoglycemia and thrombocytopenia have been reported in newborns.

Breast-feeding

Noliprel ® forte A is contraindicated during breastfeeding. If it is necessary to prescribe the drug Noliprel ® forte A during lactation, the issue of stopping breastfeeding should be decided.

Perindopril

Since there is no data on the use of perindopril during breastfeeding, the use of perindopril is not recommended. During breastfeeding, especially in newborns and premature infants, it is preferable to prescribe alternative treatments whose safety profile is better studied.

Indapamide

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.

Use for liver dysfunction

At moderate liver dysfunction no dose adjustment is required. At severe liver dysfunction the use of the drug is contraindicated.

Use for renal impairment

At severe renal failure (creatinine clearance less than 30 ml/min) moderate renal failure (creatinine clearance 30-60 ml/min) It is recommended to begin treatment with an adequate dose of the free combination. At CC ≥ 60 ml/min no dose adjustment is required. During treatment, serum creatinine and potassium levels should be monitored frequently.

special instructions

Perindopril

Neutropenia, agranulocytosis

Neutropenia/agranulocytosis, thrombocytopenia and anemia were observed while taking ACE inhibitors. In patients with normal liver function and in the absence of other complicating factors, neutropenia rarely develops. Perindopril should be used with extreme caution in patients with diffuse connective tissue diseases, while taking immunosuppressants, allopurinol or procainamide, especially in patients with pre-existing liver dysfunction. Some of these patients developed severe infections, in some cases resistant to intensive antibiotic therapy. When prescribing perindopril to such patients, it is recommended to periodically monitor the number of leukocytes in the blood. Patients should report any signs of infectious diseases (eg, sore throat, fever) to their doctor.

Hypersensitivity/angioedema

When taking ACE inhibitors, incl. and perindopril, in rare cases, the development of angioedema of the face, extremities, lips, mucous membranes, tongue, vocal cords and/or larynx may occur. These reactions may occur at any time during therapy. In such cases, the drug should be stopped immediately and the necessary monitoring should be carried out until the symptoms disappear completely. If the swelling affects only the face and lips, it usually goes away on its own, although antihistamines can be used to treat symptoms.

Angioedema, accompanied by swelling of the larynx, can be fatal. Swelling of the tongue, vocal cords, or larynx can lead to airway obstruction. If these symptoms appear, you should immediately administer epinephrine solution 1:

• 1000 (0.3-0.5 ml) subcutaneously and/or ensure airway patency.

There are reports that black patients are more likely to experience angioedema when taking ACE inhibitors than white patients.

Patients who have had angioedema not associated with taking ACE inhibitors may have an increased risk of developing it when taking drugs of this group.

In rare cases, angioedema of the intestine develops during therapy with ACE inhibitors. In this case, patients experience abdominal pain (with or without nausea and vomiting), in some cases, without previous angioedema of the face and with normal C1-esterase levels. The diagnosis is made using computed tomography of the abdominal region, ultrasound, or at the time of surgery. Symptoms disappear after stopping ACE inhibitors. Therefore, in patients with abdominal pain receiving ACE inhibitors, when carrying out differential diagnosis, it is necessary to take into account the possibility of developing angioedema of the intestine.

Anaphylactoid reactions during desensitization

There are isolated reports of the development of persistent, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy with hymenopteric venom (including bee and aspen). ACE inhibitors should be prescribed with extreme caution to patients prone to allergic reactions and undergoing desensitization; their use should be avoided in patients undergoing immunotherapy with insect venom allergens. However, if the patient requires both treatment with ACE inhibitors and desensitization, then the onset of such reactions can be prevented by temporarily stopping the use of ACE inhibitors at least 24 hours before starting the course of desensitization therapy.

Anaphylactoid reactions during LDL apheresis

In rare cases, life-threatening anaphylactoid reactions may occur in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. To prevent an anaphylactoid reaction, ACE inhibitor therapy should be temporarily discontinued before each apheresis procedure.

Patients on hemodialysis

Anaphylactoid reactions have been reported in some patients undergoing hemodialysis using high-flux membranes (eg, AN69®) and concomitantly receiving one of the ACE inhibitors. For such patients, the use of a different type of membrane or a different class of antihypertensive drug should be considered.

Cough

Taking an ACE inhibitor may cause a dry cough. The cough persists for a long time while taking the drug, but disappears when the drug is discontinued. This symptom may have an iatrogenic etiology. If the need to take an ACE inhibitor remains, then continued treatment should be considered.

Risk of arterial hypotension and/or renal failure (in case of heart failure, water and electrolyte deficiency)

With significant loss of water and electrolytes (strict salt-free diet or long-term treatment with diuretics), especially in patients with initially low blood pressure, with renal artery stenosis, congestive heart failure or cirrhosis of the liver, accompanied by edema and ascites, pronounced stimulation of the RAAS occurs. Therefore, inhibition of RAAS activity when taking an ACE inhibitor may lead to a sudden decrease in blood pressure and/or an increase in serum creatinine, indicating functional renal failure. This is most likely when you first take the drug and during the first 2 weeks of treatment. In some, albeit very rare cases, such a disorder develops acutely, and the onset of the process is difficult to predict. In such cases, treatment should be resumed with a lower dose, gradually increasing it.

Elderly patients

Before starting treatment, kidney function and potassium levels should be monitored. To avoid sudden arterial hypotension, the initial dose of the drug is adjusted depending on the degree of decrease in blood pressure, especially in the case of dehydration and loss of electrolytes.

Patients with established atherosclerosis

The risk of arterial hypotension exists in all patients, but the drug should be used with extreme caution in patients with coronary artery disease or cerebrovascular insufficiency. In such cases, treatment should be started with a low dose.

Renovascular hypertension

Renovascular hypertension is treated by revascularization. However, the use of ACE inhibitors may be beneficial in patients with renovascular hypertension awaiting surgery or when surgery is not available.

In patients with an established diagnosis of renal artery stenosis or if it is suspected, treatment with Noliprel ® forte A should begin in the hospital with a small dose under monitoring of renal function and potassium levels, because Some patients developed renal failure, which was reversible when treatment was discontinued.

Other risk groups

In patients with severe acute heart failure (grade IV) and in patients with insulin-dependent diabetes mellitus (a tendency to spontaneously increase potassium levels), treatment with Noliprel ® forte A should be started with low doses and carried out under constant medical supervision.

Patients with arterial hypertension and coronary insufficiency should not stop taking beta-blockers:

• An ACE inhibitor should be used in addition to a beta blocker.

Diabetes

In diabetic patients already taking oral hypoglycemic agents or insulin, glycemic levels should be carefully monitored, especially during the first month of taking an ACE inhibitor.

Ethnic differences

Perindopril, like other ACE inhibitors, may have a less pronounced hypotensive effect in patients of black race compared to representatives of other races. Perhaps this difference is due to the fact that arterial hypertension in black patients very often occurs against the background of low renin activity.

Surgery/anesthesia

ACE inhibitors can cause a drop in blood pressure during anesthesia, especially if the anesthetic used has a hypotensive effect. Therefore, long-acting ACE inhibitors such as perindopril should, if possible, be discontinued 24 hours before surgery.

Aortic or mitral valve stenosis/hypertrophic cardiomyopathy

Use ACE inhibitors with caution in patients with left ventricular outflow tract obstruction.

Liver dysfunction

In rare cases, ACE inhibitors have been associated with a syndrome that begins with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not yet clear. In patients receiving ACE inhibitors, if jaundice or a marked increase in liver enzyme activity develops, the ACE inhibitor should be discontinued and a thorough medical examination should be performed.

Hyperkalemia

Elevated serum potassium levels have been reported in some patients treated with ACE inhibitors, including perindopril. Risk factors for the development of hyperkalemia include renal failure, deterioration of renal function, age (> 70 years), diabetes mellitus, intercurrent events such as dehydration, acute heart failure, metabolic acidosis, concomitant use of potassium-sparing diuretics (eg, spironolactone, eplerenone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes, or taking other drugs that cause increases in serum potassium (eg, heparin). Taking potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, especially in patients with impaired renal function, may result in significant increases in serum potassium levels. Hyperkalemia can cause serious arrhythmias, sometimes fatal. If concomitant administration of perindopril or the above drugs is considered necessary, they should be taken with caution and with regular monitoring of serum potassium levels.

Indapamide

In patients with impaired liver function, taking thiazide and thiazide-like diuretics can cause hepatic encephalopathy. In this case, the diuretic should be stopped immediately.

Photosensitivity

Cases of photosensitivity have been reported with the use of thiazide and thiazide-like diuretics. If photosensitivity is noted during treatment, it is recommended to stop taking the drug. If re-administration of a diuretic is considered necessary, it is recommended to protect the skin from the sun and artificial UV radiation.

Water and electrolyte balance

Sodium level. Before starting treatment, it is necessary to evaluate the sodium content, and further such studies should be carried out regularly. Taking any diuretic medication can cause a decrease in sodium levels, which sometimes leads to a number of serious complications. Initially, a decrease in sodium levels may be asymptomatic, which is why it is necessary to regularly monitor its content. In elderly patients and patients with liver cirrhosis, monitoring should be carried out even more often.

Potassium level. The main danger when taking thiazide and thiazide-like diuretics is potassium deficiency and, accordingly, hypokalemia. Consider the risk of potassium falling below the permissible level (< 3.4 ммоль/л) необходимо у лиц, входящих в группы повышенного риска, таких как пациенты пожилого возраста или и/или пациенты с нарушенным или недостаточным питанием, независимо от того, принимают они один или несколько лекарственных препаратов, у пациентов с циррозом печени, который сопровождается отеками и асцитом, у пациентов с ИБС и у пациентов с сердечной недостаточностью. В таких случаях гипокалиемия усиливает токсичность сердечных гликозидов и повышает риск развития аритмий. Пациенты с врожденным или ятрогенным увеличением интервала QT также представляют собой группу риска. Гипокалиемия, как и брадикардия, является фактором риска для развития серьезных нарушений сердечного ритма, особенно пароксизмальной желудочковой тахикардии типа "пируэт", которые могут привести к летальному исходу. В любом случае следует как можно чаще контролировать уровень содержания калия. Первое определение содержания калия в плазме следует провести в течение первой недели после начала лечения. В случае снижения уровня калия, необходимо провести коррекцию дозы.

Calcium level. Thiazide and thiazide-like diuretics can reduce the excretion of calcium in the urine, which leads to a temporary and slight increase in the concentration of calcium in the blood. A marked increase in calcium levels may be associated with undiagnosed hyperparathyroidism. In this case, treatment should be stopped until the function of the parathyroid gland is examined.

In patients with diabetes mellitus, it is necessary to constantly monitor blood glucose levels, especially if potassium levels are simultaneously low.

Uric acid

Patients with high levels of uric acid in the blood may be predisposed to developing gout.

Effect on kidney function

Thiazide and thiazide-like diuretics are most effective when renal function is normal or only slightly impaired (serum creatinine is below approximately 2.5 mg/dL, i.e. 220 µmol/L for an adult patient). In elderly patients, plasma creatinine levels should be adjusted for age, weight and gender using the Cockroft formula:

For men: CC (ml/min) = (140 – age) x body weight (kg)/0.814 x serum creatinine (µmol/l)

For women:

• the calculation result should be multiplied by 0.85.

At the beginning of treatment, taking diuretics can lead to loss of water and sodium, which in turn leads to hypovolemia. Hypovolemia causes a decrease in glomerular filtration rate. It may be accompanied by an increase in creatinine and urea in the blood. This renal failure is temporary and does not cause undesirable consequences in patients with normal renal function, but in cases of existing impairment, renal failure may worsen.

Athletes

Please note that indapamide may cause a positive reaction during doping control.

Noliprel ® forte A

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

Kidney failure. In patients with severe renal failure (SC< 30 мл/мин) данная комбинация противопоказана. Лечение следует прекратить, если у пациента, страдающего артериальной гипертензией без видимых поражений почек, но у которого в ходе анализа крови (почечный комплекс) была обнаружена почечная недостаточность. Лечение может быть возобновлено либо данной комбинацией в более низких дозах, либо только с одним компонентов. Таким пациентам обычно следует проводить частый контроль содержания сывороточного креатинина и калия в первый раз – через 2 недели лечения, затем – 1 раз в 2 месяца в период терапевтической стабильности.

Renal failure was mainly observed in patients with acute heart failure and was also observed in renal artery stenosis. This drug is generally not recommended for patients with bilateral renal artery stenosis or for patients with only one kidney.

Arterial hypotension, deficiency of water and electrolytes. The risk of a sudden drop in blood pressure increases with low sodium levels (especially in patients with renal artery stenosis). Therefore, during treatment, the state of water and electrolyte balance should be periodically monitored, which may be disturbed due to diarrhea or vomiting. In case of severe arterial hypotension, intravenous infusion of an isotonic solution may be necessary.

Transient arterial hypotension is not a contraindication for continued treatment. After restoration of adequate blood volume and blood pressure, treatment can be resumed either with this combination at lower doses, or with only one component.

Potassium content. The combination of perindopril and indapamide does not prevent the onset of hypokalemia, especially in patients with diabetes mellitus and in patients with renal failure. As with any antihypertensive drug taken in combination with a diuretic, plasma potassium levels should be regularly monitored during treatment with this combination.

Excipients. Noliprel ® forte A should not be prescribed to patients with lactose intolerance, lapp lactase deficiency or impaired absorption of glucose-galactose.

Use in pediatrics

The effectiveness and tolerability of perindopril in children and adolescents as mono- or as part of combination therapy has not been sufficiently studied.

Impact on the ability to drive vehicles and operate machinery

Perindopril and indapamide in the form of monotherapy or in combination as part of the drug Noliprel ® forte A do not affect the ability to concentrate and the speed of psychomotor reactions. However, in some patients, especially at the beginning of treatment or when combined with another antihypertensive drug, individual reactions may develop with a decrease in blood pressure. This leads to impaired ability to drive vehicles or other mechanisms.

Results of preclinical safety studies

The toxicity of the perindopril/indapamide combination is slightly higher than the toxicity of each component. No renal toxicity was detected in rats. However, this combination causes gastrointestinal toxicity in dogs; in rats, the toxic effect on the maternal body increases (compared to perindopril). These undesirable effects occurred at doses with a very high safety margin compared to the therapeutic doses used.

Preclinical studies conducted separately with perindopril and indapamide revealed neither genotoxic nor teratogenic potential.

Overdose

Symptoms: most likely - arterial hypotension, 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 active substances of the drug from the body - gastric lavage and/or taking activated charcoal with subsequent restoration of water and electrolyte balance. Treatment should be carried out in a specialized hospital. If there is a pronounced decrease in blood pressure, the patient should be placed in a supine position with legs elevated, and, if necessary, correct hypovolemia (for example, intravenous infusion of 0.9% sodium chloride solution). Perindoprilat, the active metabolite of perindopril, can be removed from the body by dialysis.

Drug interactions

Noliprel ® forte A

With the simultaneous use of lithium preparations and ACE inhibitors, a reversible increase in the concentration of lithium in the blood plasma and associated toxic effects is possible. Concomitant use of thiazide diuretics may further increase the risk of lithium toxicity. The simultaneous use of a combination of perindopril and indapamide with lithium preparations is not recommended. If this combination is necessary, the concentration of lithium in the blood plasma should be regularly monitored.

When used simultaneously with baclofen, the hypotensive effect may be enhanced. Blood pressure and renal function should be monitored and the dose of Noliprel ® forte A adjusted if necessary.

When used simultaneously with NSAIDs, including acetylsalicylic acid in high doses (at which an anti-inflammatory effect develops), COX-2 inhibitors and non-selective NSAIDs, the hypotensive effect may be reduced. When combining ACE inhibitors and NSAIDs, there may be an increased risk of deterioration of renal function with the possible development of acute renal failure, and an increase in serum potassium levels, especially in
patients with already impaired renal function. Combinations of these drugs should be prescribed with caution, especially in elderly patients. Adequate hydration of the body should be maintained. At the beginning of combination therapy, as well as periodically during therapy, renal function should be monitored.

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

Corticosteroids, tetracosactide reduce the antihypertensive effect (fluid and sodium ion retention caused by the action of corticosteroids).

Other antihypertensive drugs enhance the antihypertensive effect of the drug.

Perindopril

ACE inhibitors reduce potassium loss caused by diuretics. Concomitant use of 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 the combined use of an ACE inhibitor and the above drugs is necessary (in case of confirmed hypokalemia), special care should be taken and regular monitoring of the content of potassium ions in the blood plasma and ECG parameters should be carried out.

Combinations that require special care

ACE inhibitors (data confirmed for captopril and enalapril) may enhance the hypoglycemic effect of insulin and sulfonylureas in patients with diabetes mellitus. The development of hypoglycemia is very rare (improved glucose tolerance leads to a decrease in the need for insulin).

Combinations that require caution

Allopurinol, cytostatic and immunosuppressive drugs, corticosteroids (when used systemically) and procainamide when used simultaneously with ACE inhibitors increase the risk of developing leukopenia.

The combined use of ACE inhibitors and general anesthesia may lead to an enhanced antihypertensive effect.

In patients receiving thiazide and loop diuretics, at the beginning of therapy with an ACE inhibitor, a decrease in blood volume may be observed, which leads to the risk of developing arterial hypotension.

When prescribing ACE inhibitors, incl. perindopril, patients receiving injectable gold preparations (sodium aurothiomalate) in rare cases, nitrate-like reactions (facial skin flushing, nausea, vomiting, arterial hypotension) were observed.

Indapamide

Combinations that require special care

Due to the risk of hypokalemia, caution should be exercised when co-administering indapamide with drugs that can cause torsades de pointes, such as class I A antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide), class III antiarrhythmic drugs (amiodarone, dofetilide, ibutilide, bretylium tosylate, sotalol), some antipsychotics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, sultopride, tiapride), butyrophenone derivatives (droperidol, haloperidol), other antipsychotics (pimozide), other drugs, incl. h. bepridil, cisapride, diphemanil, erythromycin IV, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, vincamine IV, methadone, astemizole, terfenadine. The development of hypokalemia should be avoided and, if necessary, corrected; monitor the QT interval.

Amphotericin B (iv), gluco- and mineralocorticoids (when administered systemically), tetracosactide, laxatives, stimulant laxatives increase the risk of hypokalemia (additive effect). The content of potassium ions in the blood plasma should be monitored and, if necessary, its correction. Particular attention should be paid to patients simultaneously receiving cardiac glycosides. Laxatives that do not stimulate gastrointestinal motility should be used.

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

Combinations that require caution

Functional renal failure, which can occur while taking diuretics (especially loop diuretics), with simultaneous use of metformin increases the risk of developing lactic acidosis. Metformin should not be used if the plasma creatinine concentration exceeds 1.5 mg/dL (135 µmol/L) in men and 1.2 mg/dL (110 µmol/L) in women.

With significant dehydration of the body caused by taking diuretics, the risk of developing acute renal failure increases, especially when using iodine-containing contrast agents in high doses. Before using iodine-containing drugs, rehydration should be carried out.

It is possible that calcium levels may increase as a result of decreased urinary excretion.

When used simultaneously with cyclosporine, it is possible to increase the creatinine level in the blood serum without changing the concentration of circulating cyclosporine, even with normal water and electrolyte levels.

Contacts for inquiries

Le Laboratoire SERVIER, representative office, (France)

Representative office in the Republic of Belarus
Les Laboratoires Servier Belarus

A drug Noliprel Available in several different types. All variations of the drug include: indapamide . Combination tablets Noliprel contain 2 mg of perindopril and 0.625 mg of indapamide. Ingredients: Noliprel Forte includes 4 mg of perindopril and 1.25 mg of indapamide. Noliprel A contains 2.5 mg of perindopril and 0.625 mg of indapamide. In this drug, perindopril is associated with the amino acid arginine, which has a beneficial effect on the condition of the cardiovascular system.

In tablets Noliprel A Forte - 5 mg perindopril and 1.25 mg indapamide. In the medium Noliprel A Bi-forte - 10 mg perindopril and 2.5 mg indapamide.

As additional substances in the composition of the drug Noliprel there is magnesium stearate, lactose monohydrate, colloidal hydrophobic silicon dioxide, microcrystalline cellulose.

Release form

The drugs are available in the form of white oblong tablets, with a score on both sides of the tablet. Fits in cardboard packaging of 14 and 30 pcs. in blisters.

pharmachologic effect

Noliprel is a combination drug that contains perindopril (an angiotensin-converting factor inhibitor) and indapamide (a diuretic that is part of the sulfonamide group).

The pharmacological effect of a drug is determined by a combination of some of the effects of these components. In this combination, both components mutually increase the effect. Noliprel is an antihypertensive drug that effectively lowers both diastolic and systolic blood pressure. The severity of the effect depends on the dose. After taking the drug, there is no rapid heartbeat. The clinical effect is observed 1 month after treatment was started. The antihypertensive effect lasts for one day. After therapy is suspended, the patient does not experience withdrawal symptoms. During treatment, the severity of left ventricular hypertrophy decreases, and the degree of total precardiac and postcardiac load decreases. Large vessels become more elastic, the walls of small vessels are restored. The medicine has no effect on the metabolic processes that occur in the body.

Perindopril reduces the level of aldosterone secretion, resulting in increased renin activity in the blood. decreases in people with different levels of activity . Under the influence of this component, blood vessels dilate.

When taking the drug, the likelihood of hypokalemia . The mechanism of action of indapamide is similar to thiazide diuretics: urination and excretion of sodium and chloride ions in the urine will increase.

Vascular hyperreactivity decreases under the influence of adrenaline. The amount of lipids in the blood does not change.

Pharmacokinetics and pharmacodynamics

The pharmacokinetics of perindopril and indapamide when used in combination is the same as when used separately. After oral administration, perindopril is rapidly absorbed. Bioavailability level - 65-70%. About 20% of total absorbed perindopril is later converted to perindoprilat (the active metabolite). The maximum concentration of perindoprilate in plasma is observed after 3-4 hours. Less than 30% binds to blood proteins, depending on the concentration in the blood plasma. The half-life is 25 hours. The substance penetrates the placental barrier. Perindoprilat is excreted from the body through the kidneys. Its half-life is 3-5 hours. There is a slower administration of perindoprilate in older people, as well as in patients with heart failure and renal failure.

Before using iodine-containing X-ray contrast agents with Noliprel, the body must be adequately hydrated.

The simultaneous use of calcium salts can provoke hypercalcemia.

Noliprel's analogs

Level 4 ATX code matches:

Analogs of Noliprel, as well as the drugs Noliprel A Bi Forte, Noliprel A Forte, are other drugs that are used to lower blood pressure and contain similar active ingredients, that is, perindopril and indapamide. Such drugs are drugs Co-prenesa , etc. The price of analogues may be lower than the cost of Noliprel and its varieties.

For children

The drug is not prescribed for the treatment of children under 18 years of age, since there is no accurate data on the effectiveness and safety of such treatment.

With alcohol

You should not drink alcohol during Noliprel therapy.

During pregnancy and lactation

And for mothers who are breastfeeding, the use of Noliprel is contraindicated. Systematic treatment with these drugs can lead to the development of abnormalities and diseases in the fetus, as well as lead to fetal death. If a woman finds out she is pregnant during treatment, there is no need to terminate the pregnancy, but the patient should be aware of the possible consequences. If blood pressure increases, other antihypertensive therapy is prescribed. If a woman took this drug in the second and third trimesters, an ultrasound of the fetus should be performed to evaluate the condition of its skull and kidney function.

Newborns whose mothers took the drug may suffer from manifestations of arterial hypotension, so they need to be constantly monitored by specialists.

When feeding with breast milk, the drug is contraindicated, so lactation should be stopped during therapy or another drug should be selected.

Noliprel is a medicine for blood pressure with a combined action, i.e. this tablet contains two different substances that act simultaneously. These substances - and - belong to different classes of drugs for hypertension. Indapamide is a diuretic and perindopril is an ACE inhibitor. They lower blood pressure in different ways, and their combined effect is very powerful.

Noliprel blood pressure tablets - everything you need to know:

• Instructions for use;
• Indications for use, contraindications;
• How to take, in what doses;
• What is the difference between Noliprel Bi-Forte and Noliprel A;
• Reviews from patients and doctors;
• How to treat type 2 diabetes;
• How to replace Noliprel, how to give up harmful “chemicals”.

Read the article!

Prices for Noliprel tablets and their analogues in an online pharmacy with delivery in Moscow and Russia

Name	Active ingredients	Number of tablets per package	Price, rub
perindopril arginine 5 mg + indapamide 1.25 mg
Noliprel A Bi forte	perindopril arginine 10 mg + indapamide 2.5 mg
perindopril arginine 2.5 mg + indapamide 0.625 mg
Ko-Perineva	indapamide 1.25 mg + perindopril erbumine 4 mg
Ko-Perineva	indapamide 2.5 mg + perindopril erbumine 8 mg
Ko-Perineva	indapamide 0.625 mg + perindopril erbumine 2 mg
Ko-Perineva	indapamide 1.25 mg + perindopril erbumine 4 mg, big pack with discount

Noliprel often helps in cases where other medications for hypertension fail, and this justifies its relatively high price.

Along with this medicine, people often search for:

However, if you do not look for and treat the causes of hypertension, but only “extinguish” high blood pressure with pills, then even the most powerful medications will be of little use. You will get a small reprieve, extend your life by several years, but its quality will be low due to constant health problems. Use “chemical” pills as a temporary measure, and direct your main efforts to finding and eliminating the causes of hypertension.

Noliprel is one of the most powerful medications for hypertension that doctors now have at their disposal. This drug is often found to lower blood pressure too much. As a result, patients experience chronic fatigue, lethargy, drowsiness, and sometimes even pain in the heart, because the heart muscle lacks oxygen and nutrition. In such cases, you need to switch to Noliprel tablets with a lower dosage of active ingredients. This is discussed in detail later in the article. If hypertension is mild, and Noliprel turns out to be too effective a medicine, then you need to consult a doctor to replace it with another drug. With a high probability, it will be possible to do without medications at all if you use the method outlined in the block “Cure from hypertension in 3 weeks - it’s real!”

Noliprel - instructions

Our article consists of instructions for the drug Noliprel, including Noliprel Bi-forte, which is supplemented by information from medical journals, as well as reviews from visitors to our website about this medicine. The official instructions for use are written in detail, but are very complex and not understandable for patients.

We have tried to present the information conveniently so that you can quickly find answers to the questions that interest you.

Proven effective and cost-effective supplements for normalizing blood pressure:

Read more about the methodology in the article ““. How to order hypertension supplements from the USA - . Bring your blood pressure back to normal without the harmful side effects that Noliprel and other “chemical” pills cause. Improve your heart function. Become calmer, get rid of anxiety, sleep like a baby at night. Magnesium with vitamin B6 works wonders for hypertension. You will have excellent health, the envy of your peers.

Indications for use

The main indication for prescribing Noliprel blood pressure tablets is considered to be essential hypertension. Essential means primary, not secondary, i.e. the increase in blood pressure in a person is not caused by problems with the kidneys, thyroid gland, adrenal glands or other serious disease.

Also, this drug is often prescribed if the patient has hypertension combined with type 2 diabetes. In all these cases, ours helps. If your blood pressure is above 160/100, then take Noliprel and at the same time follow our simple recommendations. When you feel better and your blood pressure goes down, then, in consultation with your doctor, try lowering the dosage in order to gradually completely abandon the “chemical” pills.

What are the different types of Noliprel?

The blood pressure drug Noliprel is available in several varieties. It is useful for doctors and patients to understand them. Let us recall that Noliprel is a combination medicine for hypertension, the active ingredients of which are perindopril and indapamide.

Types of combined tablets perindopril + indapamide

Noliprel A Bi-forte is the most powerful type of these tablets and is the most commonly prescribed. If it turns out to be too effective, then they switch to tablets with lower dosages of active ingredients.

If Noliprel A Bi-forte is too powerful for you, that is, it lowers your blood pressure excessively, you need to switch to another type of this drug. It is also possible to take perindopril and indapamide separately.

Noliprel A - means that in these tablets perindopril is associated with the amino acid arginine. Regular Noliprel - uses perindopril erbumine (perindopril tertbutylamine). It may be better to use Noliprel A because the amino acid arginine has additional beneficial effects on the cardiovascular system. But this effect is unlikely to be significant because the dosages of arginine are small. Read what arginine is and how it is useful.

How to take these tablets (dosages)

Modern combination tablets for blood pressure need to be taken only once a day, and this is their huge advantage. This mode of administration is the most convenient for patients, especially for absent-minded elderly people. The doctor will prescribe you a more or less powerful version of Noliprel and in this way determine the initial dosage of the medicine. Later, after 4-6 weeks, the doctor adjusts the dose based on the results achieved. If you need to enhance the effect of lowering blood pressure, you can switch to a more powerful variety or add another medicine to Noliprel. As we remember, the Noliprel tablet contains two active ingredients. If they decide to add one more medicine, then there are already three active ingredients. As a rule, it is chosen as an additional medicine.

Noliprel is taken one tablet per day. Patients - do not choose one or another dosage of perindopril and indapamide for yourself! Because an overdose is deadly and can cause a heart attack. And in any case, you will feel bad if you lower the pressure too much.

Overdose symptoms (call an ambulance!):

• Excessive decrease in blood pressure;
• Dizziness, weakness, apathy, drowsiness;
• Nausea, vomiting, convulsions;
• Frequent urge to urinate or, conversely, cessation of urine output;
• Very low pulse - bradycardia;
• Cold sweat, fainting.

You can expect that Noliprel will lower the “upper” pressure by 27 mmHg. Art., and “lower” - by 13 mm Hg. Art. Although it is different for each patient.

Therapeutic effect of Noliprel

Noliprel is a combination medicine for hypertension, which contains perindopril and indapamide. Both active ingredients lower upper and lower blood pressure, and mutually reinforce each other.

Advantages of Noliprel tablets for the treatment of hypertension:

• The effectiveness of the combination of perindopril and indapamide has been widely proven in practice.
• This drug does not have a harmful effect on metabolism, does not worsen blood tests for cholesterol, triglycerides and glucose, and is suitable for diabetes.
• Indapamide is considered one of the safest diuretics and at the same time very effective.
• The effect of each Noliprel tablet lasts 24 hours, so it is enough to take the drug once a day.
• After stopping treatment, withdrawal syndrome does not develop, i.e., the pressure does not rebound.
• The drug powerfully lowers both systolic and diastolic blood pressure in a standing and lying position.
• The degree of hypertrophy of the left ventricle of the heart decreases, i.e., the risk of heart attack decreases. This effect is independent of the reduction in blood pressure.

Contraindications

Noliprel is contraindicated for use during pregnancy and breastfeeding. It is especially undesirable to take this medicine in the 2nd and 3rd trimesters of pregnancy, but it is also not necessary in the first.

It is usually recommended to stop treating hypertension with “chemical” pills several weeks before conception. If pregnancy occurs while taking blood pressure pills, then there is no need to interrupt it, but the woman should immediately stop taking potentially dangerous medications, conduct an ultrasound examination of the fetus and consult with a doctor on how to further treat hypertension.

Noliprel is not suitable for the treatment of hypertension if the patient has had manifestations of hypersensitivity to ACE inhibitors, in particular to perindopril. The most severe of these manifestations is Quincke's edema. If a dry cough becomes intolerable, the drug must be discontinued. The doctor will replace it with a hypertension medicine from a different class.

The drug is not prescribed or used with extreme caution in case of severe kidney problems:

• bilateral renal artery stenosis;
• stenosis of the artery of the only functioning kidney;
• glomerular filtration rate 30 ml/min and below.

Precautions in special cases

Noliprel should be prescribed with extreme caution in the following situations:

• severe heart failure, with or without renal failure;
• cirrhosis of the liver, which is accompanied by edema and ascites;
• The patient has recently had vomiting and/or diarrhea.

In all these cases, the use of the drug can immediately cause a sharp decrease in blood pressure, especially after the first dose of the tablets, and also then during the first 2 weeks of therapy. There is also a risk of excessive reduction in blood pressure in patients who follow a strict salt-free diet.

While taking Noliprel, you should regularly check for clinical signs of dehydration and electrolyte deficiency in the blood plasma. At the same time, a pronounced decrease in blood pressure as a result of the first dose is not an obstacle to further use of this medicine. Your doctor may recommend lowering your dose or switching to taking it alone or without the second component of the combination pills. For elderly patients, it is strongly recommended that blood tests be taken before starting Noliprel to assess the functional activity of the kidneys and the concentration of potassium in the plasma.

A patient who has been prescribed Noliprel or other ACE inhibitors for hypertension should regularly check the concentration of creatinine in the blood plasma. Because blocking the renin-angiotensin-aldosterone system with perindopril or other ACE inhibitors can lead to functional kidney failure, sometimes acute. This complication occurs rarely, however, it is recommended to begin drug therapy for hypertension carefully and increase the dose of tablets gradually. You also need to regularly monitor the concentration of potassium in the blood plasma. Its permissible level is 3.4 mmol/l and above. If the potassium level in the blood falls below normal, this means there is a strong risk of cardiac arrhythmia, which can even be fatal.

Noliprel for blood pressure: patient reviews

Most patient reviews of Noliprel tablets confirm that this drug effectively lowers blood pressure. It usually helps keep blood pressure below 140/90 or even below 130/80 mmHg. Art. and thus reduces the risk of heart attack, stroke, and kidney failure. Noliprel often helps even in cases where other drugs are useless, and this justifies its relatively high price.

Galina Myuzukova

I am 41 years old, height 168 cm, weight 72 kg, until recently I was 79 kg. I have been taking Noliprel A Forte for hypertension for 3 years now. Recently I managed to lose weight, but after that the medicine began to work worse. Pain appeared in the heart area, and sometimes I felt dizzy. The pressure drops excessively. I’m deciding whether to switch to Physiotens, a weaker drug. Perhaps I will take Indapamide or perindopril (Prestarium) separately.

The powerful effect of Noliprel is confirmed not only by patients, but also by doctors in their informal reviews, as well as in studies, the results of which are published in medical journals. Problems that arise in patients with hypertension in connection with taking this medicine appear when patients do not follow the doctor's recommendations and/or the instructions for the drug.

Yuri Bystryakov

Noliprel kept my blood pressure well for 8 years. It practically did not rise above 130/90. Since last week I have been having regular headaches. I measured my blood pressure - 140/100-150/110, this in the morning after sleep. For some reason the medicine stopped working. The body has become accustomed to it or the health condition has worsened with age. Now I’m thinking: should I increase the dose of Noliprel or change to another drug? I am 47 years old and overweight. Office work, managerial, nervous.

Noliprel, like other pills for hypertension, should be taken constantly, every day, and not in courses or when you feel a surge in blood pressure.

Svetlana Shestakova

For several years I have been taking Noliprel A in the morning for hypertension. A couple of months ago, a friend (not a doctor) advised me to add Cardiomagnyl to it before bed. I am very pleased with the result. The pressure did not drop because Noliprel held it well. But it seems that magnesium and aspirin dilate blood vessels, facilitate blood flow through them, and therefore feel better. Perhaps the Noliprel + Cardiomagnil regimen will be useful to someone else.

People often complain of side effects because this drug lowers their blood pressure too much. In such cases, you may feel weakness, lethargy, fatigue, apathy, and lack of energy for work. This means that you need to switch to tablets with a reduced dosage of both active ingredients, which are part of the combination medicine. Or, if hypertension is mild, then Noliprel are too powerful tablets and you need to replace them with softer ones. Do not do this on your own, but consult your doctor.

Dmitry Zheludev

Noliprel is a powerful blood pressure pill, but not a panacea. I have been taking this drug every morning for a long time now - 2 mg of perindopril and 0.625 mg of indapamide in one tablet. For several years everything was fine, but now the pressure began to rise. I went to the doctor - he said to add more Nebilet. I followed the recommendation and it really helped. But I understand that this is a temporary measure. I decided to switch to a healthy lifestyle in order to give up medications. That's how I came to your site. Even the most expensive pills will not be able to lower your blood pressure forever. It's time to take care of your health.

Patients in their reviews often complain about the side effects of powerful combination medications for blood pressure, including Noliprel. Usually these side effects are unpleasant, but not so severe that you need to stop taking the pills. Moreover, they can and should be neutralized by switching to a healthy lifestyle.

As a result of normalization of blood pressure while taking the drug, headaches usually go away and consciousness becomes clearer. This makes you feel better than it gets worse due to side effects. A dry cough is common but is usually a psychosomatic symptom. That is, if patients did not know that perindopril, like other ACE inhibitors, causes a dry cough, then they most likely would not have had this side effect.

Evidence of effectiveness

Many studies have been conducted that have confirmed the effectiveness and relative safety of both separately for the treatment of hypertension. Later, these blood pressure lowering drugs were combined to create the powerful combination drug Noliprel. In the 2000s, it was extensively tested, first in the laboratory and then on real patients, to test its effectiveness and frequency of side effects.

Research on blood pressure tablets Noliprel

Study title	Year of publication of results	Source link
SKIF-2	2010	Mankovsky B.N., Ivanov D.D. The effect of antihypertensive therapy on renal function in patients with type 2 diabetes mellitus: results of the prospective study “SKIF-2” // Faces of Ukraine. - 2010. - No. 8. - P. 50-54.
PIXEL	2005	Dahlof B., Grosse P., Gueret P. et al. Perindopril/indapamide combination more effective than enalapril in reducing blood pressure and left ventricular mass: the PIXEL study // J. Hypertension. - 2005. - Vol. 23. - P. 2063–70
Falco Forte	2010	Safarik R. Total Cardiovascular Risk Level Determines Approach to Antihypertensive Treatment. Results of the Scientific Program Falco Forte: Pp.5.179 // Journal of Hypertension. - 2010. - Vol. 28. - P. 101.
STRATEGY A	2012	Chazova I., Ratova L., Martynyuk T. on behalf of the team of authors. Results of the Russian study STRATEGY A (Russian multicenter program to evaluate the effectiveness of Noliprel A Forte in patients with high-risk arterial hypertension with insufficient blood pressure control) // Consilium Medicum. - 2012. - T. 14, No. 1
PRACTITIONER	2012	Sirenko Yu.N., Mankovsky B.N., Radchenko A.D., Kushnir S.N. on behalf of the study participants. Results of a prospective open study assessing the antihypertensive efficacy and tolerability of Noliprel Bi-Forte in patients with uncontrolled arterial hypertension and type 2 diabetes mellitus (PRACTIC study) // Arterial hypertension. - 2012. - No. 4 (24)

The results of these studies convinced practicing doctors that Noliprel is not only a very effective, but also a fairly safe drug. Therefore, it was often prescribed to patients. Let us separately dwell on the topic of treating hypertension in patients with type 2 diabetes mellitus using these tablets

Treatment of hypertension in patients with type 2 diabetes

In 2012, the results of the Ukrainian PRACTIK study were published. It studied the effectiveness and safety of prescribing Noliprel tablets for blood pressure in patients with hypertension combined with diabetes. The study participants included 762 men and women over 40 years of age with arterial hypertension complicated by type 2 diabetes mellitus. These patients had blood pressure readings of 160/100 mm Hg. up to 200/120 mm Hg. Previously, all of them had not taken blood pressure pills or had taken them, but the drugs could not lower their blood pressure below 140/90 mmHg. Art.

Doctors prescribed Noliprel Bi-forte to all these patients, 1 tablet per day. All blood pressure medications that diabetics had previously taken were discontinued. After a month of therapy with Noliprel Bi-forte, the first control of the result was carried out. If the blood pressure level remained above 140/90 mm Hg, then another 5 mg was added once a day. Later, if necessary, the dose of amlodipine was increased to 10 mg per day.

Treatment of severe hypertension "Triple Strike":

1. The patient is prescribed Noliprel Bi-Forte tablets once a day. Perindopril 10 mg + indapamide 2.5 mg is a double whammy.
2. If after a month the pressure remains above 140/90 mm Hg. Art., then add amlodipine 5 mg once a day.
3. After 2-4 weeks, the dose of amlodipine can be increased to 10 mg per day if the pressure does not decrease to the target.

The average decrease in upper (systolic) pressure among study participants was 44.7 mmHg. Art., and lower (diastolic) pressure - 21.2 mm Hg. Art. After 3 months, 62.4% of patients with hypertension and diabetes were able to achieve target blood pressure levels< 135/85 мм рт.ст., а давление < 140/90 мм рт.ст. зарегистрировали у 74,8% пациентов.

Index	Stages of treatment
	Initially (762 people)	Day 7 (762 people)	Day 30 (762 people)	Day 60 (762 people)	Day 90 (762 people)
Office systolic (upper) pressure, mm Hg. Art.	174.3 ± 0.5	154.0 ± 0.5	143.3 ± 0.5	134.6 ± 0.4	129.6 ± 0.3
Office diastolic (lower) pressure, mm Hg. Art.	100.6 ± 0.4	91.0 ± 0.3	86.0 ± 0.3	81.8 ± 0.3	79.4 ± 0.2
< 140/90 мм рт. ст., кол-во (%)	-	39 (5,1)	201 (26,5)	406 (53,5)	565 (74,8)
Proportion of patients achieving blood pressure level< 135/85 мм рт. ст., кол-во (%)	-	31 (4,1)	150 (19,8)	334 (44,0)	471 (62,4)
Proportion of patients achieving blood pressure level< 130/80 мм рт. ст., кол-во (%)	-	6 (0,8)	31 (4,1)	72 (9,5)	146 (19,3)
The proportion of patients whose upper pressure decreased by 20 and lower pressure by 10 mmHg. Art., %	-	43,6	73,1	89,6	94,6

The proportion of patients who responded by the end of follow-up with a decrease in systolic (upper) blood pressure? 20 mmHg and diastolic (lower) pressure on? 10 mmHg, amounted to 94.6%. This indicates a very high effectiveness of treating hypertension using the method used in the study.

63% of study participants were able to achieve blood pressure< 140/90 мм рт.ст., используя только Нолипрел. Остальным пришлось назначать еще дополнительные лекарства, в подавляющем большинстве случаев - амлодипин. По результатам анализа данных обнаружили, что чем выше исходное артериальное давление у больного, тем сильнее оно снижается в результате приема таблеток.

Before the start of the study, among hypertensive patients with type 2 diabetes, 390 people (51.2%) were characterized as patients at high risk of heart attack and stroke, and 372 (48.8%) were characterized as at very high risk. After 3 months of treatment, the proportion of patients in the high-risk group increased to 69.6% due to the transfer of some patients from the very high-risk group. Also, many study participants were able to move into the moderate risk group. There were 232 people there (30.4%). Thus, a reduction in the risk of cardiovascular disaster was achieved in 604 (79.3%) patients with type 2 diabetes and arterial hypertension.

All 762 patients who started the study completed the study successfully. Some adverse reactions while taking blood pressure tablets Noliprel Bi-forte were noted only in 8 (1.1%) patients. These side effects included:

• dry cough and sore throat (0.3%);
• excessive decrease in blood pressure (0.3%);
• weakness (0.1%);
• character not specified (0.4%).

There were no serious side effects that would require discontinuation or replacement of the drug. Thus, patients with hypertension and type 2 diabetes mellitus tolerated therapy with combined indapamide and perindopril tablets well.

Noliprel does not worsen the results of blood tests for sugar, “good” and “bad” cholesterol, triglycerides, and does not remove potassium from the body.

The authors of the PRACTICE study recommend that doctors prescribe combination blood pressure medications to patients who have hypertension due to type 2 diabetes. One suitable option for combination tablets may be Noliprel. Therapy with this drug reduced blood pressure to< 140/90 мм рт.ст. у 74,8% больных, для которых предыдущее лечение было малоэффективным. С другой стороны, современные клинические руководства рекомендуют поддерживать у диабетиков давление < 130/80 мм рт.ст., а такого результата удалось достигнуть лишь 19% больных. И это несмотря на то, что врачи использовали самые мощные средства из своего арсенала “химических” лекарств.

Side effects

Common side effects of Noliprel:

• excessive decrease in blood pressure, headache;
• increased fatigue, dizziness, mood swings;
• dry cough;
• abdominal pain, nausea, constipation, diarrhea;
• orthostatic hypotension (unpleasant sensations if you stand up suddenly);
• a slight increase in the concentration of creatinine in the urine and blood, which stops after discontinuation of the drug;
• temporary increase in potassium concentration in the blood plasma or, conversely, hypokalemia;
• skin rash, itching

• vomiting, disturbances of appetite and taste perception;
• convulsions, confusion, fainting;
• decreased kidney function, increased protein excretion in the urine;
• difficulty breathing, bronchospasm;
• dry mouth;
• tinnitus;
• deterioration in the results of blood tests for liver tests;
• high levels of uric acid in the blood increase the risk of gout
• urticaria, angioedema.

Severe but extremely rare side effects:

• myocardial infarction, angina pectoris, arrhythmia;
• acute renal failure;
• pancreatitis;
• thrombocytopenia, leukopenia, agranulocytosis, anemia.

Conclusions on side effects:

• Study the contraindications to the treatment of hypertension with Noliprel, as well as in what cases it is prescribed with caution.
• While you are taking this drug, check your potassium regularly with blood tests.

conclusions

Noliprel is a combination tablet for blood pressure containing active ingredients and. This is one of the most powerful medications for hypertension that doctors currently have in their arsenal, and at the same time it is relatively safe. Side effects sometimes occur, but they are not so severe that you have to stop the drug or replace it with another one. Patients quickly experience a beneficial effect on their well-being due to the fact that their blood pressure decreases.

To treat hypertension with a powerful combination medication, it is enough to take just one tablet per day. This is convenient for the patient and increases the chance that the patient will follow the doctor’s recommendations, i.e., remember to take the medicine every day. These tablets are available in several varieties, with different dosages. If the pressure drops too much, you can switch to another version of Noliprel, with a lower content of active ingredients in each tablet, or be treated separately with one of the components - perindopril or indapamide.

The powerful medicine Noliprel often helps even in cases where other blood pressure pills do not work. This justifies the considerable price of the original drug produced by the French company. Also in the article, we covered in detail the issue of treating hypertension, which is combined with type 2 diabetes, with the help of this medicine.

Release form, composition and packaging

Film-coated tablets white, oblong, with a notch on both sides.

Excipients: sodium carboxymethyl starch (type A), colloidal silicon dioxide anhydrous, lactose monohydrate, magnesium stearate, maltodextrin.

Film shell composition: macrogol 6000, SEPIFILM 37781 RBC (glycerol, hypromellose, macrogol-6000, magnesium stearate, titanium dioxide (E171)).

14 pcs. - polypropylene bottles with a dispenser (1) - cardboard packs with first opening control.
30 pcs. - polypropylene bottles with a dispenser (1) - cardboard packs with first opening control.
30 pcs. - polypropylene bottles with a dispenser (3) - cardboard packs with first opening control.

Clinical and pharmacological group

Antihypertensive drug

pharmachologic effect

A combination drug containing perindopril (ACE inhibitor) and indapamide (thiazide-like diuretic). The pharmacological effect of the drug is due to the combination of the individual properties of each component. The combined use of perindopril and indapamide provides a synergistic antihypertensive effect compared to each component separately.

The drug has a pronounced dose-dependent antihypertensive effect on both systolic and diastolic blood pressure in the supine and standing positions. The effect of the drug lasts 24 hours. A persistent clinical effect occurs in less than 1 month from the start of therapy and is not accompanied by tachycardia. Discontinuation of treatment is not accompanied by the development of withdrawal syndrome.

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

Perindopril- inhibitor of the enzyme that converts angiotensin I into angiotensin II. Angiotensin-converting enzyme (ACE), or kinase, is an exopeptidase that carries out both the conversion of angiotensin I to angiotensin II, which has a vasoconstrictor effect, and the destruction of bradykinin, which has a vasodilator effect, to an inactive heptapeptide. As a result, perindopril reduces the secretion of aldosterone, according to the principle of negative feedback, increases the activity of renin in the blood plasma, and with long-term use 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 salt and water retention or the development of reflex tachycardia with prolonged use.

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

With the use of perindopril, there is a decrease in both systolic and diastolic blood pressure in the supine and standing positions. Discontinuation of the drug does not lead to an increase in blood pressure.

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

Perindopril normalizes heart function by reducing preload and afterload.

The combined use of thiazide diuretics enhances the antihypertensive effect. In addition, the combination of an ACE inhibitor and a thiazide diuretic also reduces the risk of hypokalemia while taking diuretics.

In patients with heart failure, perindopril causes a decrease in filling pressure in the right and left ventricle, a decrease in peripheral vascular resistance, an increase in cardiac output and an improvement in the cardiac index, and an increase in regional blood flow in the muscles.

Indapamide- a sulfonamide derivative, its pharmacological properties are close to thiazide diuretics. Inhibits the reabsorption of sodium ions in the cortical segment of the loop of Henle, which leads to increased urinary excretion of sodium, chlorine and, to a lesser extent, potassium and magnesium ions, thereby increasing diuresis. The hypotensive effect occurs in doses that practically do not cause a diuretic effect.

Indapamide reduces vascular hyperreactivity to adrenaline.

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

Indapamide helps reduce left ventricular hypertrophy.

Pharmacokinetics

The pharmacokinetic parameters of perindopril and indapamide when combined do not change compared to their separate use.

Perindopril

Absorption and Metabolism

After oral administration, perindopril is rapidly absorbed. Bioavailability is 65-70%. Cmax of perindoprilat in blood plasma is reached after 3-4 hours. Approximately 20% of the total amount of absorbed perindopril is converted into the active metabolite perindoprilat. When taking the drug with food, the conversion of perindopril to perindoprilat is reduced (this effect does not have significant clinical significance).

Distribution and elimination

Plasma protein binding is less than 30% and depends on the concentration of perindopril in the blood plasma. The dissociation of perindoprilate associated with ACE is slowed down. As a result, T1/2 is 25 hours. Repeated administration of perindopril does not lead to its accumulation, and T1/2 of perindoprilat upon repeated administration corresponds to the period of its activity, thus, an equilibrium state is achieved after 4 days. Perindopril penetrates the placental barrier.

Perindoprilat is excreted from the body in the urine. T 1/2 of perindoprilate is 3-5 hours.

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

The clearance of perindoprilate during dialysis is 70 ml/min.

The pharmacokinetics of perindopril changes in patients with liver cirrhosis: the hepatic clearance of perindopril is reduced by 2 times. However, the concentration of the resulting perindoprilate does not change, so dose adjustment of the drug is not required.

Indapamide

Suction

Indapamide is quickly and completely absorbed from the gastrointestinal tract. Cmax in blood plasma is reached 1 hour after oral administration.

Distribution

Plasma protein binding - 79%.

Repeated administration of the drug does not lead to its accumulation in the body.

Removal

T1/2 is 14-24 hours (average 19 hours). It is excreted mainly in urine (70% of the administered dose) and in feces (22%) in the form of inactive metabolites.

Pharmacokinetics in special clinical situations

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

Indications for use of the drug

- essential arterial hypertension.

Dosage regimen

Prescribed orally, preferably in the morning, before meals, 1 tablet. 1 time/day If 1 month after the start of therapy the desired hypotensive effect has not been achieved, the dose of the drug can be increased to a dose of 5 mg + 1.25 mg (manufactured by the company under the trade name Noliprel ® A forte).

Elderly patients Therapy should be started with 1 tablet. 1 time/day

The drug is contraindicated patients with severe renal failure (CK<30 мл/мин). For patients with moderate renal failure (creatinine clearance 30-60 ml/min) The maximum dose of Noliprel ® A is 1 tablet/day. Patients with CC ≥ 60 ml/min, no dose adjustment is required. During therapy, regular monitoring of creatinine and potassium levels in the blood plasma is necessary.

The drug is contraindicated patients with severe liver failure. At moderate liver failure no dose adjustment is required.

Noliprel ® A should not be prescribed children and teenagers due to the lack of data on efficacy and safety in patients in this age group.

Side effect

Perindopril has an inhibitory effect on the renin-angiotensin-aldosterone system and reduces potassium excretion by the kidneys while taking indapamide. In 2% of patients while using the drug Noliprel ® A, hypokalemia develops (potassium level<3.4 ммоль/л).

The frequency of adverse reactions that may occur during therapy is given in the following gradation: very often (>1/10), often (>1/100,<1/10), нечасто (>1/1000, <1/100), редко (>1/10 000, <1/1000), очень редко (<1/10 000), неуточненной частоты (частота не может быть подсчитана по доступным данным), включая отдельные сообщения.

From the digestive system: often - dry mouth, nausea, loss of appetite, abdominal pain, epigastric pain, taste disturbances, constipation; rarely - angioedema of the intestine, cholestatic jaundice; very rarely - pancreatitis. In patients with liver failure, hepatic encephalopathy may develop.

From the respiratory system: often - during the use of ACE inhibitors, a dry cough may occur, which persists for a long time while taking drugs of this group and disappears after their discontinuation. If a patient develops a dry cough, one should be aware of the possible iatrogenic nature of this symptom.

From the cardiovascular system: infrequently - decreased blood pressure (including orthostatic hypotension).

Dermatological reactions: uncommon - hypersensitivity reactions, mainly in the form of dermatological reactions in patients predisposed to allergic and asthmatic reactions, hemorrhagic rash, skin rashes, maculopapular rash, exacerbation of systemic lupus erythematosus; very rarely - angioedema (Quincke's edema), photosensitivity reactions.

From the nervous system: uncommon - paresthesia, headache, asthenia, sleep disturbance, mood lability, dizziness.

From the musculoskeletal system: infrequently - muscle spasms.

From the hematopoietic system: very rarely - thrombocytopenia, leukopenia, agranulocytosis, aplastic anemia, hemolytic anemia. In certain clinical situations (kidney transplant patients, hemodialysis patients), ACE inhibitors may cause anemia.

Laboratory indicators: 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 (slight increase in the level of urea and creatinine in the blood plasma, which disappears after discontinuation therapy, more often in patients with renal artery stenosis, in the treatment of arterial hypertension with diuretics and in the case of renal failure), hyperkalemia (usually transient); rarely - hypercalcemia.

Contraindications to the use of the drug

- history of angioedema (including while taking other ACE inhibitors);

- hereditary/idiopathic angioedema;

- severe renal failure (CK< 30 мл/мин);

- hypokalemia;

- bilateral renal artery stenosis or stenosis of the artery of a single kidney;

- severe liver failure (including with encephalopathy);

- simultaneous use of drugs that prolong the QT interval;

- simultaneous use of antiarrhythmic drugs that can cause ventricular arrhythmia of the “pirouette” type;

- pregnancy;

- lactation period (breastfeeding);

- hypersensitivity to perindopril and other ACE inhibitors, to indapamide and sulfonamides, as well as to other auxiliary components of the drug.

Due to the lack of sufficient clinical experience, the drug should not be used in patients with untreated decompensated heart failure and in patients on hemodialysis.

WITH caution the drug should be prescribed for systemic diseases of connective tissue (including systemic lupus erythematosus, scleroderma), therapy with immunosuppressants (risk of developing neutropenia, agranulocytosis), inhibition of bone marrow hematopoiesis, reduced blood volume (taking diuretics, salt-free diet, vomiting, diarrhea, hemodialysis) , angina pectoris, cerebrovascular diseases, renovascular hypertension, diabetes mellitus, chronic heart failure (functional class IV according to the NYHA classification), hyperuricemia (especially accompanied by gout and urate nephrolithiasis), blood pressure lability; carrying out hemodialysis using high-flow membranes, desensitization, before the LDL apheresis procedure; in a condition after kidney transplantation; aortic valve stenosis/hypertrophic cardiomyopathy; the presence of lactase deficiency, galactosemia or glucose-galactose malabsorption syndrome; as well as elderly patients or patients under the age of 18 years (efficacy and safety have not been established).

Use of the drug during pregnancy and lactation

The drug should not be used in the first trimester of pregnancy.

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

There have been no adequate controlled studies of ACE inhibitors in pregnant women. The limited available data on the effects of the drug in the first trimester of pregnancy indicate that taking the drug did not lead to malformations associated with fetotoxicity.

Noliprel ® A is contraindicated in the second and third trimesters of pregnancy.

It is known that long-term exposure to ACE inhibitors on the fetus in the second and third trimesters of pregnancy can lead to disruption of its development (decreased renal function, oligohydramnios, slow formation of bone tissue of the skull) 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 the drug Noliprel ® A in the second or third trimesters of pregnancy, it is recommended to conduct an ultrasound examination of the fetus to assess the condition of the skull and kidney function.

Noliprel ® A is contraindicated during lactation.

Use for liver dysfunction

At moderate liver dysfunction no dose adjustment is required. At severe dysfunction liver, the use of the drug is contraindicated.

Use for renal impairment

At severe renal failure (creatinine clearance less than 30 ml/min) the use of the drug is contraindicated. At moderate renal failure (creatinine clearance 30-60 ml/min) The maximum dose of Noliprel A is 1 tablet/day. At CC ≥ 60 ml/min no dose adjustment is required. During treatment, serum creatinine and potassium levels should be monitored frequently.

special instructions

Noliprel ® A

The use of Noliprel ® A 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. When initiating therapy with two antihypertensive drugs that the patient has not previously received, an increased risk of idiosyncrasy cannot be excluded. To minimize this risk, careful monitoring of the patient's condition should be carried out.

Kidney failure

In patients with severe renal failure (SC< 30 мл/мин) данная комбинация противопоказана.

In some patients with arterial hypertension without previous renal impairment during treatment with Noliprel A, laboratory signs of functional renal failure may appear. 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.

The combination of perindopril and indapamide does not prevent the development of hypokalemia, especially in patients with diabetes mellitus or renal failure. As with any antihypertensive drug taken in combination with a diuretic, plasma potassium levels should be regularly monitored during treatment with this combination.

Excipients

It should be taken into account that the excipients of the drug include lactose monohydrate. Noliprel ® A should not be prescribed to patients with hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption.

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 avoid 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 weighed.

Angioedema (Quincke's edema)

In rare cases, during therapy with ACE inhibitors, angioedema of the face, extremities, mouth, tongue, pharynx and/or larynx develops. In such a situation, you should immediately stop taking perindopril and monitor the patient's condition until the swelling completely disappears. If the swelling affects only the face and mouth, the symptoms usually go away without special treatment, but antihistamines can be used to more quickly relieve symptoms.

Angioedema, which is accompanied by swelling of the larynx, can be fatal. Swelling of the tongue, pharynx, or larynx can lead to airway obstruction. In this case, you should immediately administer epinephrine (adrenaline) subcutaneously at a dose of 1:1000 (0.3 to 0.5 ml) and take other emergency measures. Patients with a history of angioedema not associated with taking ACE inhibitors have an increased risk of developing angioedema while taking these drugs.

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

Anaphylactic reactions during desensitization

There are isolated reports of the development of life-threatening anaphylactic reactions in patients receiving ACE inhibitors during desensitizing therapy with hymenoptera insect venom (including bee and aspen). ACE inhibitors should be prescribed with caution to patients prone to allergic reactions and undergoing desensitization procedures. Prescribing the drug to patients receiving immunotherapy with hymenoptera venom should be avoided. However, anaphylactic reactions can be avoided by temporarily discontinuing the drug at least 24 hours before starting a course of desensitizing therapy.

Anaphylactic reactions during LDL apheresis

In rare cases, life-threatening anaphylactic 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 anaphylactic 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.

Risk of arterial hypotension and/or renal failure (including in case of heart failure, water and electrolyte deficiency)

In some pathological conditions, significant activation of the renin-angiotensin-aldosterone system may be observed, especially with severe hypovolemia and a decrease in the level of plasma electrolytes (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.

Patients with established atherosclerosis

The risk of arterial hypotension exists in all patients, but the drug should be used with extreme caution in patients with coronary artery disease or cerebrovascular insufficiency. In such cases, treatment should be started with a low dose.

Renovascular hypertension

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 in patients with diagnosed or suspected bilateral renal artery stenosis or stenosis of the artery of a single kidney should begin 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 patients with severe heart failure (stage IV) and patients with insulin-dependent diabetes mellitus (risk of spontaneous increase in potassium levels), treatment with the drug should be started with low doses and carried out under constant medical supervision.

In patients with arterial hypertension and heart failure, beta-blockers should not be discontinued: ACE inhibitors should be used together with beta-blockers.

Anemia

Anemia may develop in patients who have undergone a kidney transplant or in patients undergoing hemodialysis. The higher the initial hemoglobin level, the more pronounced its decrease. This effect does not appear to be dose-dependent, but may be related to the mechanism of action of ACE inhibitors. The decrease in hemoglobin content is insignificant; it occurs during the first 1-6 months of treatment, and then stabilizes. When treatment is discontinued, hemoglobin levels are completely restored. Treatment can be continued under monitoring of the peripheral blood picture.

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, the patient should stop taking the drug and consult a doctor.

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-electrolyte imbalance

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

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 pirouette-type arrhythmias, which can be fatal. In all the cases described above, more regular monitoring of the content of potassium ions in the blood plasma is necessary. The first measurement of potassium ion concentration should be carried out within the first week from the start of therapy.

If hypokalemia is detected, appropriate treatment should be prescribed.

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.

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

Uric acid

In patients with high levels of uric acid in the blood during treatment with Noliprel A, the risk of developing gout increases.

Kidney function and diuretics

Thiazide and thiazide-like diuretics are fully effective only in patients with normal or slightly impaired renal function (plasma creatinine in adults below 2.5 mg/dL 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 ultraviolet rays.

Athletes

Indapamide may give a positive reaction during doping control.

Use in pediatrics

Noliprel ® A should not be prescribed children and adolescents under 18 years of age, because the effectiveness and safety of use in this category of patients have not been established.

Impact on the ability to drive vehicles and operate machinery

The action of the substances included in the drug Noliprel ® A does not lead to impairment of 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.

Overdose

Symptoms: marked decrease in blood pressure, nausea, vomiting, convulsions, dizziness, drowsiness, confusion, oliguria, which can turn into anuria (as a result of hypovolemia), water and electrolyte imbalance (hyponatremia, hypokalemia).

Treatment: gastric lavage, administration of activated carbon, correction of water and electrolyte balance in a hospital setting. If there is a significant decrease in blood pressure, the patient should be transferred to a horizontal position with legs elevated. If necessary, intravenous infusion of saline solution, measures aimed at restoring bcc.

Perindoprilat can be removed from the body using dialysis.