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

Contraindications

Related to perindopril:

• hypersensitivity to the active substance or to any other ACE inhibitor
• history of angioedema (Quincke's edema) associated with previous treatment with ACE inhibitors
• congenital or idiopathic angioedema
• pregnancy or planning pregnancy;
• simultaneous use with drugs containing aliskiren in patients with diabetes mellitus or impaired renal function (glomerular filtration rate <60 ml/min/1.73 m2);
• simultaneous use with sacubitril/valsartan;
• extracorporeal treatments that bring blood into contact with negatively charged surfaces;
• significant bilateral renal artery stenosis or stenosis of the artery of a single kidney.

Related to indapamide:

• hypersensitivity to the active substance or any other sulfonamides;
• severe to moderate renal impairment (creatinine clearance <60 ml/min)
• hepatic encephalopathy
• severe liver dysfunction;
• hypokalemia
• as a general rule, this drug should not be prescribed in combination with antiarrhythmic drugs that can cause the development of paroxysmal ventricular tachycardia of the “pirouette” type;
• breastfeeding period.

Related to the drug Noliprel® Bi-forte:

• hypersensitivity to any excipient.

Due to the lack of sufficient clinical experience, Noliprel® Bi-forte should not be used:

• patients on hemodialysis;
• patients with untreated decompensated heart failure.

Pharmacokinetics

Noliprel® A Bi-forte

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

Perindopril

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

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

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

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

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

The dialysis clearance of perindoprilate is 70 ml/min.

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

Indapamide

Indapamide is quickly and completely absorbed from the gastrointestinal tract.

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

Connection with blood plasma proteins - 79%.

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

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

Features of application

Pregnancy

The drug is contraindicated for use by pregnant women or women planning pregnancy.

Children

Noliprel® Bi-forte should not be used to treat children and adolescents. The safety and effectiveness of perindopril arginine/indapamide in pediatric patients has not been established. No data available.

Drivers

The two active ingredients, when used separately or in combination as Noliprel® Bi-forte, do not affect the ability to drive vehicles or use other mechanisms, but some patients may experience individual reactions associated with a decrease in blood pressure, especially at the beginning of treatment or when used simultaneously with other antihypertensive drugs. As a result, the ability to drive vehicles or operate other machinery may deteriorate.

Compound

Overdose

In case of overdose, a common adverse reaction is arterial hypotension, which can sometimes be accompanied by nausea, vomiting, convulsions, dizziness, drowsiness, confusion, oliguria, which can progress to anuria (due to hypovolemia), as well as circulatory shock. Disturbances in water and electrolyte balance (decreased levels of potassium and sodium in the blood plasma), renal failure, hyperventilation, tachycardia, rapid heartbeat (palpitation), bradycardia, anxiety, cough may occur.

Side effects

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

Noliprel Bi-Forte No. 30 tablet p.p.o.

Instructions for medical use of the drug NOLIPRELÒ BI-FORTE TRADE NAME NOLIPRELÒ BI-FORTE INTERNATIONAL NON-PROPENTED NAME NO Dosage form Film-coated tablets Composition One tablet contains active substances: perindopril arginine 10 mg (equivalent to 6.790 mg perindopril) and indapamide 2.5 mg excipients: lactose monohydrate, magnesium stearate, maltodextrin, colloidal anhydrous silicon dioxide, sodium starch glycolate (type A). film coating: glycerol, hypromellose, magnesium stearate, macrogol 6000, titanium dioxide (E171). Description Round, white film-coated tablets. Pharmacotherapeutic group Drugs for the treatment of diseases of the cardiovascular system. Drugs affecting the renin-angiotensin system. ACE inhibitors in combination with other drugs. ACE inhibitors in combination with other diuretics. Perindopril in combination with diuretics. ATC code C09BA04 Pharmacological properties Pharmacokinetics The pharmacokinetic properties of perindopril and indapamide do not change compared to their separate use. Related to Perindopril: Absorption and Bioavailability When taken orally, absorption of perindopril is rapid, with maximum concentrations achieved within 1 hour. The half-life of perindopril in plasma is 1 hour. Eating reduces the conversion of perindopril to perindoprilat, and, consequently, its bioavailability, therefore perindopril arginine is recommended to be taken once a day, orally, in the morning before breakfast. Distribution The volume of distribution of unbound perindoprilate is approximately 0.2 l/kg. The binding of perindoprilate to plasma proteins is 20%, mainly binding to the angiotensin-converting enzyme, but depends on the concentration of the drug. Biotransformation Perindopril is a prodrug. 27% of the administered dose of perindopril enters the bloodstream in the form of the active metabolite perindoprilate. In addition to the active perindoprilate, five more inactive metabolites are formed in the body. Peak plasma concentrations of perindoprilate are achieved 3-4 hours after taking the drug. Excretion Perindoprilat is excreted from the body through the kidneys; The half-life (T1/2) of its free fraction is about 17 hours, which allows it to reach a steady state in 4 days. Linearity/non-linearity The relationship between the dose of perindopril and its plasma exposure has been shown to be linear. Special categories of patients Elderly patients: The elimination of perindoprilat is slower in elderly patients, as well as in patients with cardiac or renal failure. Renal failure Dose selection for patients with renal failure is recommended taking into account the degree of renal impairment (creatinine clearance). During dialysis: During dialysis, the clearance of perindopril is 70 ml/min. In cirrhosis: The kinetics of perindopril changes in patients with cirrhosis: hepatic clearance of the parent molecule is slowed by half. However, the amount of perindoprilate formed is not reduced, so dosage adjustment is not required. Associated with indapamide: Adsorption Indapamide is rapidly and completely absorbed from the gastrointestinal tract. Cmax in plasma is achieved approximately 1 hour after administration. Distribution Plasma protein binding is 79%. Repeated administration of the drug does not lead to its accumulation in the body. Biotransformation and excretion T1/2 is 14 -24 hours (average 18 hours). It is excreted mainly in urine (70% of the dose) and feces (22%) in the form of inactive metabolites. Special categories of patients Renal failure: Pharmacokinetics are not changed in patients with renal failure. Pharmacodynamics NOLIPRELÒ BI-FORTE IS A COMBINATION OF PERINDOPRIL ARGININE SALT, AN ANGIOTENSIN-CONVERTING ENZYME INHIBITOR, AND INDAPAMIDE, A CHLOROSULFAMOYL DIURETIC. THE PHARMACOLOGICAL EFFECT OF THE DRUG IS DUE TO THE PHARMACOLOGICAL PROPERTIES OF EACH OF THESE COMPONENTS AND THE ADDITIVE SYNERGIC EFFECT OF BOTH COMPONENTS WHEN THEY ARE COMBINED. MECHANISM OF ACTION RELATED TO PERINDOPRIL: PERINDOPRIL IS AN INHIBITOR OF ANGIOTENSIN CONVERTING ENZYME, WHICH CATALYSTS THE CONVERSION OF ANGIOTENSIN I TO ANGIOTENSIN II, A VASCULAR SUBSTANCE. IN ADDITION TO THIS, ACE STIMULATES THE SECRETION OF ALDOSTERONE BY THE ADRENAL GLANDS AND INCREASES THE DISSOLUTION OF THE vasodilator COMPOUND BRADIKININ TO INACTIVE HEPTAPEPTIDES. THIS RESULTS IN: - A DECREASE IN ALDOSTERONE SECRETION, - AN INCREASE IN PLASMA RENIN ACTIVITY, DUE TO THE LACK OF ALDOSTERONE FEEDBACK, - A DECREASE IN TOTAL PERIPHERAL VASCULAR RESISTANCE, WHICH IS MAINLY DUE TO THE ACTION EAT ON THE VESSELS IN THE MUSCLES AND KIDNEYS, WHICH IS NOT ACCOMPANIED BY SALT AND WATER RETENTION OR REFLEX TACHYCARDIA, WITH PROLONGED USE, PERINDOPRIL ALSO HAS A HYPOTENSIVE EFFECT IN PATIENTS WITH LOW OR NORMAL RENIN CONCENTRATION. THE EFFECT OF PERINDOPRIL IS DUE TO THE ACTIVITY OF ITS METABOLITE PERINDOPRILATE. OTHER METABOLITES ARE INACTIVE. PERINDOPRIL FACILITATES THE FUNCTION OF THE HEART: — DUE TO A VASUDOLATORAL EFFECT ON THE VEINS, PROBABLY DUE TO CHANGES IN PROSTAGLANDIN METABOLISM: DECREASING PRELOAD, — DUE TO A REDUCTION IN TOTAL PERIPHERAL RESISTANCE VASCULAR EFFECTS: REDUCING AFTERLOAD. STUDIES CARRIED OUT WITH PATIENTS SUFFERING WITH HEART FAILURE SHOWED: - DECREASED FILLING PRESSURE IN THE RIGHT AND LEFT VENTRICLE, - DECREASED TOTAL PERIPHERAL VASCULAR RESISTANCE, - INCREASED CARDIAC OUTPUT AND IMPROVEMENT INCREASING THE CARDIAC INDEX IS INCREASING REGIONAL BLOOD FLOW IN THE MUSCLES. EXERCISE TESTS ALSO SHOWED IMPROVED RESULTS. RELATED TO INDAPAMIDE: INDAPAMIDE IS A SULPHANAMIDE DERIVATIVE WITH AN INDOLE RING, PHARMACOLOGICALLY RELATED TO THE THIAZIDE GROUP OF DIURETICS. INDAPAMIDE INHIBITS SODIUM REABSORPTION IN THE CORTICAL SEGMENT OF THE LOOP OF HENLE. IT INCREASES THE EXCRETION OF SODIUM AND CHLORIDE IN THE URINE, AND ALSO, TO A LESSER EXTENT, THE EXCRETION OF POTASSIUM AND MAGNESIUM AND THUS RESULTS IN INCREASED URINE FORMATION, HAVING A HYPOTENSIVE EFFECT. PHARMACODYNAMIC EFFECTS, INDEPENDENT OF THE AGE OF THE PATIENTS, NOLIPREL BI-FORTE HAS A DOSE-DEPENDENT HYPOTENSIVE EFFECT ON SYSTOLIC AND DIASTOLIC BLOOD PRESSURE (BP) IN BOTH LYING AND STANDING POSITIONS. ANTIHYPERTENSIVE EFFECT LASTS 24 HOURS. A REDUCTION IN BLOOD PRESSURE IS ACHIEVED IN LESS THAN 1 MONTH OF NON-TACHYPHYLAXY. DISCONTINUING TREATMENT DOES NOT CAUSE A SHARP EFFECT. PICXEL, A MULTICENTER, RANDOMIZED, DOUBLE-BLINDED, ACTIVE CONTROLLED CLINICAL STUDY, USED ECHOCARDIOGRAPHY TO EVALUATE THE EFFECTS OF PERINDOPRIL/INDAPAMIDE ON LEFT VENTRICULAR HYPERTROPHY VS. WITH ENALAPRIL MONOTHERAPY. IN THE PICXEL STUDY, PATIENTS WITH HYPERTENSION AND LEFT VENTRICLE HYPERTROPHY (LEFT VENTRICLE MASS INDEX (LVMI) > 120 g/m2 IN MEN AND > 100 g/m2 IN WOMEN) WERE RANDOMIZED TO 2 MG PERINDOPRIL TERT-BUTYLAMINE (EQUIVALENT 2 .5 MG PERINDOPRIL ARGININE)/ 0.625 MG INDAPAMINE, OR IN THE GROUP RECEIVED 10 MG ENALAPRIL, ONCE A DAY FOR ONE YEAR OF TREATMENT. THE DOSE WAS ADJUSTED ACCORDING TO BLOOD PRESSURE CONTROL DATA TO 8 MG PERINDOPRIL TERT-BUTYLAMINE (EQUIVALENT OF 10 MG PERINDOPRIL ARGININE) AND 2.5 INDAPAMINE OR 40 MG ENALAPRIL ONCE DAILY. ONLY 34% OF STUDY PARTICIPANTS STAYED ON THE ORIGINAL DOSE OF 2 MG PERINDOPRIL TERT-BUTYLAMINE (EQUIVALENT OF 2.5 MG PERINDOPRIL ARGININE)/0.625 MG INDAPAMINE (COMPARED TO 20% STAYED ON THE ENALAPRIL DOSE 10 MG). AT THE END OF TREATMENT, IN THE ENTIRE POPULATION OF RANDOMIZED PATIENTS, LVMI DECREASED SIGNIFICANTLY MORE IN THE PERINDOPRIL/INDAPAMIDE GROUP (-10.1 G/M2) THAN IN THE ENALAPRIL GROUP (-1.1 G/M2). THE DIFFERENCE BETWEEN GROUP IN LVMI CHANGE WAS -8.3 (95% CI (-11.5, -5.0), P < 0.0001). RELATED TO PERINDOPRIL: PERINDOPRIL IS EFFECTIVE FOR ANY GRADE OF HYPERTENSION: MILD, MODERATE AND SEVERE. A REDUCTION IN DIASTOLIC AND SYSTOLIC BLOOD PRESSURE OCCURS BOTH IN A LYING POSITION AND IN A STANDING POSITION. THE MAXIMUM HYPOTENSIVE EFFECT IS OBSERVED 4-6 HOURS AFTER A SINGLE USE AND RETAINS FOR 24 HOURS. A HIGH DEGREE OF RESIDUAL INHIBITION OF ANGIOTENSIN-CONVERTING ENZYME ACTIVITY IS NOTED AFTER 24 HOURS AFTER TAKING THE DRUG - 80%. IN TREATABLE PATIENTS, NORMALIZATION OF BLOOD PRESSURE IS ACHIEVED IN ONE MONTH AND IS SUSTAINED WITHOUT THE DEVELOPMENT OF TACHYPHYLAXIA. DISCONTINUATION OF TREATMENT DOES NOT LEAD TO RESTORATION OF HYPERTENSION. PERINDOPRIL HAS VASCODILATING PROPERTIES AND RESTORES THE ELASTICITY OF THE MAIN ARTERIAL VESSELS, CORRECTS HISTOMORPHOMETRIC CHANGES IN RESISTANT ARTERIES AND REDUCES LEFT VENTRICLE HYPERTROPHY. IF REQUIRED, ADDING A THIAZIDE DIURETIC WILL RESULT IN ADDITIONAL SYNERGY. COMBINED PRESCRIPTION OF AN ANGIOTENSIN CONVERTING ENZYME INHIBITOR WITH A THIAZIDE DIURETIC REDUCES THE RISK OF HYPOKALEMIA ARISING FROM TAKEN ONLY ONE DIURETIC. RELATED TO INDAPAMIDE: INDAPAMIDE IN MONOTHERAPY HAS A HYPOTENSIVE EFFECT THAT RESTRIDES FOR 24 HOURS. THIS EFFECT OCCURS AT DOSES AT WHICH THE DIURETIC EFFECT OF INDAPAMIDE IS MINIMUM. THE EFFECTIVENESS OF THE HYPOTENSIVE ACTION OF INDAPAMIDE IS PROPORTIONAL TO ITS ABILITY TO IMPROVE ARTERY ELASTICITY, REDUCE BPSS AND ARTERIOLE RESISTANCE. INDAPAMIDE HELPS TO REDUCE LEFT VENTRICLE HYPERTROPHY. WHEN THE DOSE OF THIAZIDE AND THIAZIDE-LIKE DIURETICS IS EXCEEDED, THEIR HYPOTENSIVE EFFECTIVENESS REACHES A PLATEAU, WHILE ADVERSE EFFECTS BECOME MORE AND MORE PRONECTED. IF THE TREATMENT IS NOT EFFECTIVE, THE DOSE SHOULD NOT BE INCREASED. IN ADDITION, INDAPAMIDE HAS BEEN SHOWN THAT IN THE SHORT-, MEDIUM-TERM AND LONG-TERM TREATMENT OF PATIENTS WITH HYPERTENSION, INDAPAMIDE: - DOES NOT AFFECT THE METABOLISM OF LIPIDS: TRIGLYCERIDES, LDL CHOLESTEROL AND HDL CHOLESTEROL - DOES NOT AFFECT ON CARBOHYDRATE METABOLISM, EVEN IN DIABETICS WITH HYPERTENSION. CLINICAL TRIAL DATA ON DOUBLE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) BLOCKDE: TWO LARGE RANDOMIZED CONTROLLED TRIALS (ONTARGET (ONGOING TELMISARTAN ALONE AND IN COMBINATION WITH RAMIPRIL GLOBAL ENDPOINT TRIAL, INTERNATIONAL NATIONAL STUDY COMPARING THE EFFECTIVENESS OF TELMISARTAN IN MONOTHERAPY AND IN COMBINATION WITH RAMIPRIL) AND VA NEPHRON-D (VETERANS AFFAIRS NEPHROPATHY IN DIABETES, VETERANS AFFAIRS DIABETIC NEPHROPATHY STUDY) WERE DEDICATED TO STUDYING THE COMBINED USE OF AN ACE INHIBITOR AND A RECEPTOR BLOCKER ANGIOTENSIN II: THE ONTARGET STUDY WAS CONDUCTED IN PATIENTS WITH A HISTORY OF CARDIOVASCULAR OR CEREBROVASCULAR DISEASES OR TYPE 2 DIABETES WITH SIGNS OF TARGET ORGAN DAMAGE. THE VA NEPHRON-D STUDY WAS CONDUCTED IN PATIENTS WITH TYPE 2 DIABETES AND DIABETIC NEPHROPATHY. THESE STUDIES INDICATED NO SIGNIFICANCE WHAT BENEFITABLE EFFECT ON RENAL AND/OR CARDIOVASCULAR OUTCOMES AND MORTALITY AND AT THE SAME TIME THE PRESENCE OF AN INCREASED RISK OF HYPERKALEMIA, ACUTE RENAL FAILURE AND/OR HYPOTENSION COMPARED WITH MONOTHERAPY. CONSIDERING SIMILAR PHARMACODYNAMIC PROPERTIES, THE RESULTS OBTAINED ALSO EXTEND TO OTHER ACE INHIBITORS AND ANGIOTENSIN II RECEPTOR BLOCKERS. THEREFORE, ACE INHIBITORS AND ANGIOTENSIN II RECEPTOR BLOCKERS SHOULD NOT BE USED SIMULTANEOUSLY IN PATIENTS WITH DIABETIC NEPHROPATHY. ALTITUDE STUDY (ALISKIREN TRIAL IN TYPE 2 DIABETES USING CARDIOVASCULAR AND RENAL DISEASE ENDPOINTS, STUDYING THE BENEFITS OF ALISKIREN IN REDUCING THE RISK OF CARDIOVASCULAR AND RENAL COMPLICATIONS IN PATIENTS WITH TYPE 2 DIABETES TYPE) WAS DEDICATED TO STUDYING THE BENEFITS OF ADDING ALISKIREN TO STANDARD ACE INHIBITOR THERAPY OR AN ANGIOTENSIN II RECEPTOR BLOCKER IN PATIENTS WITH TYPE 2 DIABETES AND CHRONIC KIDNEY DISEASE, CARDIOVASCULAR DISEASE, OR BOTH. THE STUDY WAS TERMINATED DUE TO AN INCREASED RISK OF ADVERSE OUTCOMES. CARDIOVASCULAR DEATH AND STROKE WERE MUCH MORE ENCOUNTERED IN THE ALISKIREN GROUP COMPARED WITH THE PLACEBO GROUP, ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS OF SPECIAL INTEREST (HYPERKALEMIA, HYPOTENSION I AND RENAL DYSFUNCTION) WERE ALSO MORE FREQUENTLY RECORDED IN THE ALISKIREN GROUP THAN IN THE PLACEBO GROUP. USE IN CHILDREN NO DATA AVAILABLE FOR USE OF NOLIPREL BI-FORTEU IN CHILDREN. INDICATIONS FOR USE · ESSENTIAL ARTERIAL HYPERTENSION Method of administration and dosage Oral administration. NoliprelÒ Bi-forte take 1 tablet per day, preferably in the morning before meals. If blood pressure does not decrease within 1 month of treatment, then the dosage must be doubled. Elderly patients: In elderly patients, plasma creatinine levels should be adjusted based on age, weight and gender. In elderly patients, the drug is prescribed if renal function is normal, and the degree of blood pressure reduction should be monitored. Patients with renal failure The drug is contraindicated in patients with moderate to severe renal failure (creatinine clearance (CC) less than 60 ml/min). Patients with CC ≥ 60 ml/min during therapy require regular monitoring of the concentration of creatinine and potassium in the blood plasma. Patients with impaired liver function The drug is contraindicated in patients with severe liver failure. For moderately severe liver failure, no dose adjustment is required. Children and adolescents Noliprel Bi-forte should not be prescribed to children and adolescents under 18 years of age due to the lack of data on the effectiveness and safety of the drug in patients in this age group. Side effects: Perindopril inhibits the activity of the renin-angiotension-aldosterone system and tends to reduce potassium loss caused by indapamide. Hypokalemia (potassium level < 3.4 mmol/l) is observed in 6% of patients treated with Noliprel® Bi-forte. The most common adverse reactions are: - associated with perindopril: dizziness, headache, paresthesia, impaired taste, visual disturbances, vertigo, tinnitus, hypotension, cough, shortness of breath, abdominal pain, constipation, indigestion, diarrhea, nausea, vomiting, itching, rash, muscle cramps and asthenia. - associated with indapamide: hypersensitivity reactions, mainly dermatological, in patients with a predisposition to allergic and asthmatic reactions, and maculopapular rash. 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); uncommon (>1/1000, <1/100); rare (>1/10,000, <1/1000); very rare (<1/10,000); frequency not established (frequency cannot be calculated from available data). Often - Hypersensitivity reactions (mainly of a dermatological nature, in patients with a predisposition to allergic and asthmatic reactions) - Dizziness, headache, paresthesia, dysgeusia, - Visual disturbances - Vertigo, tinnitus - Hypotension (and effects associated with hypotension) - Cough , shortness of breath - Abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting, - Itching, rash, maculopapular rash - Muscle cramps - Asthenia Uncommon - Eosinophilia* -Hypoglycemia*, hyperkalemia, reversible with cessation of treatment*, Hyponatremia* - Mood swings , sleep disturbances - Drowsiness*, fainting* - Palpitations*, tachycardia* - Vasculitis* - Bronchospasm - Dry mouth - Urticaria, angioedema, purpura, hyperhidrosis, photosensitivity reactions*, pemphigoid* - Arthralgia*, myalgia* - Renal failure — Erectile dysfunction — Chest pain*, malaise*, peripheral edema*, hyperthermia* - Increased blood urea*, increased blood creatinine* — Fall* Rare — Exacerbation of psoriasis* — Fatigue — Increased bilirubin in the blood — Increase liver enzyme levels Very rare - Rhinitis - Agranulocytosis, aplastic anemia, pancytopenia, leukopenia, neutropenia, hemolytic anemia, thrombocytopenia - Hypercalcemia - Confusion - Stroke, possibly caused by very severe hypotension in high-risk patients - Angina, arrhythmia (including bradycardia , ventricular tachycardia, atrial fibrillation), myocardial infarction, possibly caused by very severe hypotension in high-risk patients - Eosinophilic pneumonia - Pancreatitis - Hepatitis, liver dysfunction - Erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome - Acute renal failure - Decreased hemoglobin and hematocrit levels Not known - Decreased potassium with hypokalemia, particularly significant in some high-risk populations - Potential for hepatic encephalopathy in case of liver failure - Myopia, blurred vision - Torsade de pointes (possibly fatal) - Possible deterioration The currents of the existing acute disseminated red lupus - an increase in blood glucose - an increase in uric acid in the blood - lengthening of the QT interval on the electrocardiogram * The frequency is calculated according to the results of clinical studies for side effects detected from spontaneous messages. Contraindications associated with perindopril:-increased sensitivity to the active substance or any other ACE inhibitor is an anamnesa of angioedema (Quincke's edema), associated with the treatment of ACE inhibitor-hereditary or idiopathic angiourotic edema-the second and third trimester-the simultaneous use of nolipre With drugs containing aliskirene in patients with diabetes or impaired renal function (SKF <60ml/min/1.73m²) associated with indapamide: - increased sensitivity to active substance or any other sulfanilamic drug - severe and moderate impaired renal function (clearance Creatinine below 60 ml/min)-liver encephalopathy-severe liver failure-hypokalemia-as a rule, this drug is not recommended in combination with non-antiarhythmic agents causing paroxysmal ventricular tachycardia of the Piruet type. -breastfeeding-due to insufficiency of therapeutic experience, the abolitions should not be used in the following cases:-in patients who need to conduct dialysis-in patients with untreated decompensated heart failure-childhood and adolescence up to 18 years of age of general instructions, general instructions, Associated with perindopril and indapamide: Neft -recommended combinations: lithium: with combined reception of lithium and ACE inhibitors, cases of a reversible increase in the concentration of lithium in serum and toxicity. The combined technique of perindopril and lithium is not recommended, but if it is necessary, then careful monitoring of lithium levels in the blood serum of the combination, which require special caution: Baclofen: enhances the severity of the hypotensive effect (it is necessary to control the level of blood pressure and adjust the dose of noliprele bi-medium). Non-steroidal anti-inflammatory drugs (NSAIDs) (including aspirin ≥ 3g/day): With the simultaneous use of ACE inhibitors together with non-steroidal anti-inflammatory drugs (for example, taking acetylsalicylic acid according to the scheme and doses necessary for anti-inflammatory treatment, the receipt of TsOG-2 inhibitors and the reception Non -? NSAIDs) may observe a weakening of the antihypertensive effect. The simultaneous use of ACE and NSAID inhibitors increases the risk of deterioration of renal function, including the development of acute renal failure, and can also cause an increase in the serum levels of potassium, especially in patients with existing kidney function disorders. The combination of these drugs should be used with caution, especially in the elderly. Patients should receive sufficient fluid volume; You should also control the function of the kidneys when prescribing combined therapy and periodically after its completion. Combinations that require caution: Imiprama-like antidepressants (tricyclic), antipsychotics: increased hypotensive action and an increase in the risk of development of orthostatic hypotension (additive effect). Associated with perindopril: data from clinical studies have shown that the double blockade of the renin-angiotensininzinzinzinin system (RAAS) by combined use of ACE inhibitors, Angiotensin II or Aliskiren receptor blockers are accompanied by an increase in the frequency of undesirable phenomena, such as hypotension, hypercalemia and reducing the function of the kidney (including The development of acute renal failure) in comparison using one drug acting on RAS (see Contraindications, Special Instructions and Pharmacodynamic Redness. Medicines that cause hypercalemia: some drugs or therapeutic groups of drugs can increase the likelihood of hypercalemia: Aliskiren , Potassium salts, potassium -saving diuretics, ACE inhibitors, angiotensin II, NSAIDs, heparin, immunosuppressants, such as cyclosporin, takrolimus, trimetrome. Combined taking these drugs, increases the risk of hypercalemia. The combined technique is contraindicated: Aliskiren: in patients with diabetes or renal failure, the risk of hyperkalemia, the deterioration of renal function, the development of cardiovascular diseases and mortality from cardiovascular diseases increases. Setter-recommended combinations: Aliskiren: In patients, in addition to patients with diabetes or renal failure, the risk of hyperkalemia, the deterioration of renal function, the development of cardiovascular diseases and mortality from cardiovascular diseases increases. Combined therapy with an ACE inhibitor and an angiotensin receptor blocker: in literary data it is indicated that in patients with severe atherosclerotic disease, heart failure or diabetes with damage to the target organ, combined therapy with an ACE inhibitor and an angiotensin receptor blocker are related to a higher frequency of hypotension, hypotension. Fainting, hyperkalemia and deterioration of the renal function (including acute renal failure) in comparison with taking one drug that affects the renin-angiotensin-aldosterone system. Double blockade (for example, by combining the ACE inhibitor with an angiotensin II receptor blocker) should be limited to individual cases and is accompanied by careful monitoring of the renal function, potassium and blood pressure (see “special instructions”). Estrustin: increased risk of undesirable reactions, such as angioedema (angiootek). Potassium -saving diuretics (for example, triamteren, amyloride, etc.), potassium (salt): hypercalemia (potentially death), especially in combination with renal failure (additive hypercalemic effect). The combined intraindopril intake with these drugs is not recommended. If the concomitant use of these drugs is still shown, then when taking them, special caution should be carried out and frequent monitoring of potassium content in blood serum. Information on the use of spironolactone for heart failure see in the section “Combinations that require special care”. Combinations that require special caution: antiabetics (insulin, oral hypoglycemic prescriptions): epidemiological studies have shown that the combined use of ACE inhibitors and antidiabetic drugs (insulins, oral hypoglycemic drugs) can lead to an increase in the effect of reducing the level of glucose in the blood with the risk of hypoglycemia. The onset of such events is most likely in the first weeks of combined treatment and in patients with impaired renal function. Potassium -saving diuretics: in patients taking diuretics, especially in patients with reduced BCCs and/or salts, there may be a significant decrease in blood pressure at the beginning of therapy for the ACE inhibitor. The likelihood of a hypotensive effect can be reduced by the cessation of diuretics, increasing the BCC or salt consumption before therapy with perindopril in a low dose with its subsequent gradual increase. With arterial hypertension, if the previous treatment with diuretics caused a deficiency of salt/decrease in the BCC, it is necessary to either stop taking a diuretic before the therapy for the therapy with an ACE inhibitor with the subsequent introduction of a potassium -saving diuretic, or the receipt of the ACE inhibitor must begin with a low dose with its subsequent increase. With congestive heart failure, requiring the use of diuretics, the reception of the ACE inhibitor should begin with a very low dose, if possible after a preliminary reduction in the dose of the concomitant potassium -saving diuretic. In all cases, during the first few weeks after the start of therapy, the APF inhibitor, careful monitoring of the kidney function (creatinine level) is necessary. Potassium-saving diuretics (eplerenon, spironolactone): when taking an epleinone or spironolactone in doses from 12.5 mg/day to 50 mg/day and low doses of ACE inhibitors: in the treatment of heart failure of class II-IV (according to the classification of nyha) with the emission faction < 40%, with the preceding therapy with ACE inhibitors and loop diuretics, there is a risk of hyperkalemia, with a potential death, especially in case of non -compliance with recommendations for the purpose of this combination of drugs. Before prescribing this combination of drugs, you should make sure that there is no hyperkalemia and renal failure in the patient. During the first month of therapy once a week, and then once a month it is recommended to monitor Kaliyia and creatimia. Ratsecadotril: It is known that ACE inhibitors (for example, perindopril) are the reason for the occurrence of angioedema. This risk increases when they are used in combination with Ratsecadotril (a drug used in acute diarrhea). MTOR-Ingibrators (for example, sylolymus, Everolymus, Temsirolymus): patients undergoing combined therapy of MTOR-Ingitors may be increased in the risk of angioedema. Combinations that require caution: antihypertensive and vasodilating drugs: combined intake of these drugs can lead to increased the hypotensive effect of perindopril. The accompanying technique of nitroglycerin and other nitrates or other vasodilators can lead to a further decrease in blood pressure. Allopurinol, cytostatic or immunosuppressive substances, systemic corticosteroids or prokaamine: with combined use of these drugs with ACE inhibitors, the risk of leukopenia increases: ACE inhibitors can enhance the hypotensive effect of some anesthetic substances (see “special instructions”). Glyptines (linagliptin, saksagliptin, sitagliptin, vildagliptin): in patients taking ACE inhibitor, the risk of developing angioedema due to a decrease in the activity of dipeptidylpeptidase IV associated with glyptine intake is increased. Sympatomymetics: sympathomy can reduce the hypotensive effect of ACE inhibitors. Gold: In rare cases, in patients who simultaneously receive treatment with gold injections (sodium aurotiomalat) and ACE inhibitors, including perindopril, vasomotor reactions (such symptoms as a rush of blood, nausea, vomiting and hypotension) occurred. A related to Indapamide: combinations that require special caution: drugs that can cause paroxysmal ventricular tachycardia type “Piruet”: due to the risk of hypokalemia, caution should be observed when taking indapamide in combination with drugs that can cause paroxysmal ventricular tachycardia type Piruet ТАКИМИ КАК АНТИАРИТМИЧЕСКИЕ ПРЕПАРАТЫ КЛАССА IA (ХИНИДИН, ГИДРОХИНИДИН, ДИЗОПИРАМИД), АНТИАРИТМИЧЕСКИЕ ПРЕПАРАТЫ КЛАССА III (АМИОДАРОН, ДОФЕТИЛИД, ИБУТИЛИД, БРЕТИЛИЙ, СОТАЛОЛ), НЕКОТОРЫЕ НЕЙРОЛЕПТИКИ (ХЛОРПРОМАЗИН, ЦИАМЕМАЗИН, ЛЕВОМЕПРОМАЗИН, ТИОРИДАЗИН, ТРИФЛУОПЕРАЗИН), БЕНЗАМИДЫ (АМИСУЛЬПРИД, СУЛЬПИРИД, Sultopride, tiapid), botirophenone derivatives (Dropeidol, haloperidol), other antipsychotics (Pimoside); Other drugs, such as Beledil, Sisapride, Difemanil, Erythromycin in/B, halophantrin, mizolastin, moxifloxacin, pentamidine, sparfloxacin, vincamine, methadone, astemizole, terphenin. Prevention of potassium levels and correction, if necessary: ​​monitoring the QT interval. Potassium -saving preparations: amphotericin B (intravenously), glucocorticoids and mineralocorticoids (systemic administration), tetracosactide, stimulating laxatives: increased risk of potassium levels (additive effect). Monitoring of potassium content and, if necessary, dose correction; Special attentiveness is required in the treatment of a one. Non -fingering lamps should be used. Putting drugs: low potassium can enhance the toxic effects of the lines. Monitoring ECG and potassium levels should be carried out, and if necessary, review the treatment. Combinations that require caution: potassium -saving diuretics (amyloride, spironolactone, triamteren): Despite the fact that rational combinations are useful for some patients, hypokalemia or hyperkalemia (especially in patients with renal failure or diabetes), can still be manifested. It is necessary to monitor the level of potassium of blood plasma and ECG, and if necessary, you need to review the treatment. Metformin: lactic acidic acidosis against the background of metformin is, apparently, with functional renal failure, which is due to the action of diuretics, especially the loop. Do not use metformin if the content of creatinine in plasma exceeds 15 mg/l (135 μmol/l) in men and 12 mg/l (110 μmol/l) in women.

Interaction

Potassium-sparing diuretics (amiloride, spironolactone, triamterene). Despite the rationality of prescribing this combination to some patients, hypokalemia or hyperkalemia may occur (especially in patients with renal failure or diabetes mellitus). Plasma potassium levels should be monitored, ECG monitoring should be performed, and therapy should be reviewed if necessary.

Metformin. May lead to lactic acidosis due to the development of functional renal failure associated with taking diuretics, especially loop diuretics. 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.

Iodine contrast agents. In case of dehydration caused by the use of diuretics, there is a risk of developing acute renal failure, especially when using large doses of iodine contrast agents. Before using iodine contrast agents, it is necessary to restore the water balance.

Calcium (salts). There is a risk of increased calcium levels in the blood due to decreased excretion in urine.

Cyclosporine, tacrolimus. There is a risk of an increase in blood creatinine without changing the concentration of circulating cyclosporine, even in the absence of water and sodium deficiency.

Corticosteroids, tetracosactide (systemic action). Reduce the antihypertensive effect (retention of water and sodium ions under the influence of corticosteroids).

Pharmacodynamics

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

1. Mechanism of action

Noliprel® A Bi-forte

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

Perindopril

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

- reduces the secretion of aldosterone;

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

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

Perindopril normalizes myocardial function, reducing preload and afterload.

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

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

— decrease in OPSS;

- increased cardiac output and increased cardiac index;

- increased muscle peripheral blood flow.

Indapamide

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

2. Antihypertensive effect

Noliprel® A Bi-forte

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

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

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

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

Perindopril

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

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

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

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

Indapamide

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

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

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

Note!

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