Noliprel A Bi-forte, 10 mg+2, 5 mg 30 pcs.

Noliprel ^® A Bi-Forte is a combined preparation containing perindopril arginine and indapamide. The pharmacological properties of Noliprel^® A Bi-Forte combine the individual properties of each of its active ingredients.

1. Mechanism of Action

Noliprel ^® A Bi-forte

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

Perindopril

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

– reduces aldosterone secretion;

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

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

Perindopril normalizes myocardial function by reducing preload and postload.

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

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

– decreased PPSS;

– increased cardiac output and increased cardiac index;

– increased muscular peripheral blood flow.

Indapamide

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

2. Antihypertensive effects

Noliprel^® A Bi-forte

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

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

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

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

Perindopril

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

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

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

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

Indapamide

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

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

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

Pharmacokinetics

Noliprel ^® A Bi-forte

. The combined use of perindopril and indapamide does not alter their pharmacokinetic characteristics compared with the separate administration of these agents.

Perindopril

Perindopril is rapidly absorbed when taken orally. C_max in plasma is reached 1 h after oral administration. T_1/2 is 1 h. Perindopril has no pharmacological activity. Approximately 27% of the total amount of perindopril taken orally enters the bloodstream as the active metabolite, perindoprilate.

In addition to perindoprilat, 5 other metabolites with no pharmacological activity are formed. C_max of perindoprilat in blood plasma is reached 3-4 hours after oral administration. Food intake slows down the conversion of perindopril to perindoprilat, thus affecting bioavailability. Therefore, the drug should be taken once a day, in the morning, before meals.

There is a linear dependence of plasma concentration of perindopril on its dose. The V_d of unbound perindoprilat is approximately 0.2 L/kg. Binding of perindoprilat to plasma proteins, mainly to ACE, depends on the concentration of perindopril and is about 20%.

Perindoprilat is excreted by the kidneys. The effective T_1/2 unbound fraction is about 17 h, the equilibrium state is reached within 4 days.

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

The dialysis clearance of perindoprilat is 70 ml/min.

The pharmacokinetics of perindopril is altered in patients with cirrhosis: its hepatic clearance is reduced by half. However, the amount of perindoprilat produced is not decreased, which does not require dose adjustment (see “Dosage and administration” and “Special indications”).

Indapamide

Indapamide is rapidly and completely absorbed from the gastrointestinal tract.

The C_max of indapamide in plasma is observed 1 h after oral administration.

The binding to plasma proteins is 79%.

T_1/2 is 14-24 h (mean 18 h). Reuptake of the drug does not lead to its cumulation in the body. It is eliminated mainly by the kidneys (70% of the administered dose) and through the intestine (22%) in the form of inactive metabolites.

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

Indications

Essential hypertension (patients who require therapy with perindopril at a dose of 10 mg and indapamide at a dose of 2.5 mg).

Active ingredient

Composition

Active ingredients:

Perindopril arginine 10 mg;

Indapamide 2.5 mg;

Associates:

Lactose monohydrate, 142.66 mg;

Magnesium stearate, 0.9 mg;

Maltodextrin, 18 mg;

Colloidal anhydrous silica – 0.54 mg;

sodium carboxymethyl starch (type A) – 5.4 mg;

Film coating:

macrogol 6000, 0.27828 mg; magnesium stearate, 0.2622 mg; titanium dioxide (E171), 0.83902 mg; glycerol, 0.2622 mg; hypromellose, 4.3583 mg).

How to take, the dosage

Overly, 1 tablet once daily, preferably in the morning, before meals.

Elderly patients

In elderly patients, creatinine Cl is calculated taking into account age, body weight and sex. Elderly patients with normal renal function should take Noliprel ® A Bi-Forte 1 tablet once daily and the degree of BP decrease should be controlled.

Renal failure (see

Recommendations

The drug is contraindicated in patients with moderate to severe renal insufficiency (Csl-creatinine

Patients with blood plasma creatinine Cl equal or greater than 60 ml/min must have regular monitoring of creatinine and potassium concentrations during therapy.

Hepatic failure

The drug is contraindicated in patients with severe hepatic failure.

In moderately severe hepatic insufficiency, no dose adjustment is required.

Children and adolescents

Noliprel ® A Bi-forte should not be administered to children and adolescents less than 18 years of age because of lack of data about effectiveness and safety of the drug in patients in this age group.

Interaction

Noliprel ® A Bi-Forte

1. Undesirable combinations of drugs

Lithium drugs: Concomitant use of lithium drugs and ACE inhibitors may cause reversible increase in plasma lithium and associated toxic effects. Additional administration of thiazide diuretics may contribute to further increase in lithium content and increase the risk of manifestation of toxicity. Simultaneous use of the combination of perindopril and indapamide with lithium preparations is not recommended. In case of such therapy, regular monitoring of plasma lithium is required (see “Special Precautions”).

2. combinations of drugs requiring special attention

Baclofen: possible increase in hypotensive effect. BP and renal function should be monitored; if necessary, correction of the dose of hypotensive drugs is required.

NSAIDs, including high doses of acetylsalicylic acid (more than 3 g/day): simultaneous use of ACE inhibitors and NSAIDs (acetylsalicylic acid in dose with anti-inflammatory effect, COX-2 inhibitors and non-selective NSAIDs) may lead to decreased antihypertensive effect. Concomitant use of ACE inhibitors and NSAIDs may lead to worsening of renal function, including the development of acute renal failure and increased serum potassium, especially in patients with reduced renal function. Caution should be exercised when prescribing this combination, especially in elderly patients. Patients should compensate fluid loss and monitor renal function regularly, both at the beginning of treatment and during treatment.

3. Drug combinations requiring attention

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

GCS, tetracosactide: decreased antihypertensive effect (fluid and sodium ion retention due to GCS action).

Other hypotensive agents: may increase the antihypertensive effect.

Perindopril

1. Undesirable combinations of drugs

Potassium-saving diuretics (amiloride, spironolactone, triamterene, both as monotherapy and in combination therapy) and potassium preparations: during ACE inhibitor therapy, serum potassium is usually within normal limits, but hyperkalemia may develop (rarely). Concomitant use of potassium-saving diuretics (e.g., spironolactone, triamterene, amiloride), potassium preparations and potassium-containing salt substitutes can lead to a significant increase in serum potassium ions up to death. If concomitant use of ACE inhibitor and the above mentioned drugs is necessary (in case of confirmed hypokalemia), caution should be exercised and plasma potassium and ECG parameters should be regularly monitored.

2. combinations of drugs requiring special attention

Hypoglycemic oral medications (sulfonylureas) and insulin: the following effects have been described for captopril and enalapril. ACE inhibitors may increase the hypoglycemic effect of insulin and sulfonylurea derivatives in patients with diabetes. The development of hypoglycemia is very rare (due to increased glucose tolerance and reduced insulin requirement).

Special Instructions

Noliprel ® A Bi-Forte

Lithium preparations

The simultaneous use of the combination of perindopril and indapamide with lithium preparations is not recommended (see “Interactions”).

Renal dysfunction

The therapy with Noliprel ® A Bi-forte is contraindicated in patients with moderate to severe renal impairment (Cl creatinine® A Bi-forte should be stopped. In the future, the combination therapy can be resumed using low-dose combination of perindopril and indapamide, or the drugs can be used in monotherapy mode.

Such patients require regular monitoring of serum potassium ions and creatinine – 2 weeks after the start of therapy and every 2 months thereafter. Renal insufficiency occurs more frequently in patients with severe chronic heart failure or initial renal dysfunction, including renal artery stenosis.

Noliprel ® A Bi-forte is not recommended in patients with bilateral renal artery stenosis or artery stenosis of the only functioning kidney.

Arterial hypotension and water-electrolyte imbalance

Hyponatremia is associated with a risk of sudden development of arterial hypotension (especially in patients with renal artery stenosis, including bilateral). Therefore, when monitoring patients, attention should be paid to possible symptoms of dehydration and decreased plasma electrolyte content, such as after diarrhea or vomiting. These patients require regular monitoring of plasma electrolytes.

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 continuation of therapy. After restoration of the RBC and BP, therapy may be resumed using low-dose combinations of perindopril and indapamide, or the drugs may be used as monotherapy.

Contraindications

Perindopril

Side effects

Blood and lymphatic system disorders: very rarely – thrombocytopenia, leukopenia/neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia.

In certain clinical situations (patients after kidney transplantation, patients on hemodialysis) ACE inhibitors may cause anemia (see “Special Precautions”).

CNS disorders: common – paresthesia, headache, dizziness, vertigo; infrequent – sleep disturbance, mood swings; very rare – confusion; unspecified frequency – fainting.

An organ of vision: often – visual impairment.

Hearing organ: often – tinnitus.

Particularly – significant decrease of BP, including orthostatic hypotension; very rarely – cardiac pacing disorders, including bradycardia, ventricular tachycardia, atrial fibrillation, as well as angina and myocardial infarction, possibly due to excessive reduction in patients in high risk group (see “Indications. “

Precautions

In an unspecified frequency, pirouette arrhythmias (possibly fatal – see “Interactions” and “Precautions”).

The respiratory system, thoracic and mediastinal organs: often – with ACE inhibitors use dry cough may occur, which persists for a long time while taking the drugs of this group and disappears after discontinuation, shortness of breath; rarely – bronchospasm; very rarely – eosinophilic pneumonia, rhinitis.

Digestive system disorders: frequent – dry oral mucosa, nausea, vomiting, abdominal pain, epigastric pain, taste disorder, decreased appetite, dyspepsia, constipation, diarrhea; very rare – pancreatitis; angioneurotic edema of the bowel, cholestatic jaundice; unspecified frequency – hepatic encephalopathy in patients with liver failure (see “Contraindications and Special Indications).

Skin and subcutaneous fat: frequently – skin rash, itching, maculopapular rash; infrequently – angioedema of face, lips, extremities, mucous membrane of tongue, vocal folds and/or larynx, urticaria (see “Special Indications”). “Special indications”), hypersensitivity reactions in patients predisposed to bronchoobstructive and allergic reactions; hemorrhagic vasculitis. In patients with acute forms of systemic lupus erythematosus, a deterioration of the course of the disease is possible. Very rarely – erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome. There have been cases of photosensitivity reactions (see “Cautions”).

Musculoskeletal and connective tissue disorders: often – muscle cramps.

The urinary system: infrequent – renal failure; very rare – acute renal failure.

Reproductive system disorders: infrequent – impotence.

General disorders and symptoms: frequent – asthenia; infrequent – increased sweating.

Laboratory measures: rare – hypercalcemia; unspecified frequency – prolongation of QT-interval on ECG (see “Interaction”). Interaction” and “Special Indications”), increase of uric acid and glucose concentration in blood during the drug administration, increase of liver enzymes activity, slight increase of creatinine concentration in urine and in plasma, passing after cancellation of therapy, more often in patients with renal artery stenosis, when treating with diuretics and in case of renal failure, hypokalemia, especially significant for patients belonging to the risk group (see “Interaction” and “Particular information”). “Special Indications”); hyperkalemia, more often transient; hyponatremia and hypovolemia, leading to dehydration and orthostatic hypotension.

Overdose

Symptoms: the most likely symptom of overdose is a marked decrease in BP, sometimes combined with nausea, vomiting, seizures, dizziness, drowsiness, confusion and oliguria, which may turn into anuria (as a result of hypovolemia). Electrolyte disorders may also occur (hyponatremia, hypokalemia).

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

In case of significant BP decrease the patient should be transferred to the supine position with elevated legs, and if necessary, correction of hypovolemia should be performed (e.g., intravenous infusion of 0.9% sodium chloride solution). Perindoprilat, the active metabolite of perindopril, can be removed from the body by dialysis.

Pregnancy use

Pregnancy

Noliprel ® A Bi-Forte is contraindicated in pregnancy (see “Contraindications”).

If pregnancy is planned or if pregnancy occurs while taking the drug, the drug should be stopped immediately and other hypotensive therapy should be prescribed. Appropriate controlled studies of ACE inhibitors in pregnant women have not been conducted. The limited data available on the effects of the drug in the first trimester of pregnancy indicate that the drug did not lead to malformations associated with fetotoxicity.

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

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

Long-term use of thiazide diuretics in the third trimester of pregnancy may cause hypovolemia in mother and decrease uterine-placental blood flow, which leads to feto-placental ischemia and delayed fetal development. In rare cases, against the background of taking diuretics shortly before delivery, hypoglycemia and thrombocytopenia develop in newborns.

If the patient received Noliprel ® A Bi-Forte during the second or third trimester of pregnancy, an ultrasound examination of the newborn is recommended to evaluate the cranial bones and renal function.

In newborns whose mothers have received therapy with ACE inhibitors may have arterial hypotension, therefore, newborns should be closely monitored medically.

Breastfeeding period

Noliprel ® A Bi-forte is contraindicated during breastfeeding.

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

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

The significance of therapy for the mother must be assessed and a decision must be made whether to stop breastfeeding or to discontinue the drug.

Similarities