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

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

Pharmacodynamics

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

1. Mechanism of action

Noliprel® A forte

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

Perindopril

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

– reduces aldosterone secretion;

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

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

Perindopril normalizes myocardial function by reducing preload and postload.

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

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

– decreased ROSS;

– increased cardiac output;

– increased muscular peripheral blood flow.

Indapamide

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

2. Antihypertensive effects

Noliprel® A forte

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

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

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

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

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

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

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

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

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

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

Perindopril

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

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

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

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

Indapamide

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

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

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

Pharmacokinetics

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

Perindopril

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

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

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

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

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

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

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

The dialysis clearance of perindoprilat is 70 ml/min.

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

Perindopril penetrates the placenta.

Indapamide

Indapamide is rapidly and completely absorbed from the gastrointestinal tract.

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

The binding to plasma proteins is 79%.

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

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

Indications

Active ingredient

Composition

Active ingredients:

Perindopril arginine5 mg;

Indapamide 1.25 mg;

Supplementary substances:

sodium carboxymethyl starch (type A) – 2.7 mg;

silica colloidal anhydrous silica – 0.27 mg;

lactose monohydrate – 71.33 mg;

magnesium stearate – 0.45 mg;

maltodextrin – 9 mg;

film jacket:

macrogol 6000 – 0.087 mg;

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

How to take, the dosage

Orally, preferably in the morning, before meals.

Essential hypertension

1 tablet of Noliprel® A forte once daily.

If possible, the drug should be started with a single-component dose selection. If clinically necessary, Noliprel® A forte combination therapy may be considered immediately after monotherapy.

In patients with arterial hypertension and type 2 diabetes mellitus, to decrease the risk of microvascular complications (renal side) and macrovascular complications from cardiovascular disease/p>

It is recommended that therapy be initiated with the perindopril/indapamide combination at a dose of 2.5/0.625 mg (Noliprel® A) once daily. After 3 months of therapy, if tolerated well, the dose may be increased by 1 tablet of Noliprel® A forte once daily.

Perienced patients

The drug should be started after monitoring renal function and BP.

Renal failure

The drug is contraindicated in patients with severe renal failure (creatinine Cl less than 30 ml/min). For patients with moderately severe renal insufficiency (creatinine Cl 30-60 ml/min) it is recommended to start therapy with the required doses of drugs (in monotherapy) included in Noliprel® A forte.

Patients with creatinine Cl equal to or greater than 60 ml/min do not require dose adjustment. Regular monitoring of creatinine and potassium concentrations in plasma is necessary during therapy.

Hepatic failure (see “Contraindications”, “Caution” and “Pharmacokinetics”)

The drug is contraindicated in patients with severe hepatic failure. No dose adjustment is required in moderately severe hepatic impairment.

Children and adolescents

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

Interaction

1. Recommended combinations

Lithium preparations: Concomitant use of lithium preparations and ACE inhibitors may cause reversible increase in plasma lithium concentration and associated toxic effects. Additional administration of thiazide diuretics may contribute to further increase in lithium concentration and increase the risk of toxicity. Concomitant use of the combination of perindopril and indapamide with lithium preparations is not recommended. If such therapy is necessary, plasma lithium levels should be monitored continuously (see “Special Precautions”).

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

Baclofen: It is possible to increase the 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): administration of NSAIDs may decrease diuretic, natriuretic and hypotensive effects. If significant fluid loss occurs, acute renal failure may develop (due to decreased glomerular filtration rate). Before initiating treatment with the drug it is necessary to replenish the fluid loss and regularly monitor renal function at the beginning of 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).

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

Other hypotensive drugs: possible increase of the antihypertensive effect.

Perindopril

1. Combinations not recommended

Potassium-saving diuretics (amiloride, spironolactone, triamterene) and potassium preparations:ACE inhibitors reduce diuretic-induced renal potassium loss. Potassium-saving diuretics (e.g., spironolactone, triamterene, amiloride), potassium preparations, and potassium-containing salt substitutes can lead to a significant increase in serum potassium, up to and including 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 agents (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

The use of Noliprel® A forte 5 mg + 1.25 mg is not accompanied by a significant decrease in the incidence of side effects, except hypokalemia, compared to perindopril and indapamide at the lowest authorized doses (see “Side effects”). At the beginning of therapy with two hypotensive drugs that the patient has not received before, an increased risk of idiosyncrasy cannot be excluded. Close monitoring of the patient minimizes this risk.

Renal dysfunction

The therapy is contraindicated in patients with significant renal impairment (creatinine Cl less than 30 ml/min). Some patients with arterial hypertension without previous obvious impairment of renal function during the therapy may have laboratory signs of functional renal insufficiency. In this case, the treatment should be discontinued. Thereafter, combination therapy may be resumed using lower doses of drugs, or monotherapy may be used.

Such patients require regular monitoring of serum potassium and creatinine levels – 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 underlying renal dysfunction, including renal artery stenosis.

Arterial hypotension and water-electrolyte balance disorders

Hyponatremia is associated with the risk of sudden development of arterial hypotension (especially in patients with arterial stenosis of the sole renal artery and bilateral renal artery stenosis). Therefore, during dynamic monitoring of patients, attention should be paid to possible symptoms of dehydration and decreased plasma electrolyte levels, e.g., after diarrhea or vomiting. These 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 continuation of therapy. After recovery of the RBC and BP, therapy may be resumed using lower doses of medications, or the drugs may be used as monotherapy.

Potassium levels

The combined use of perindopril and indapamide does not prevent hypokalemia, especially in patients with diabetes mellitus or renal insufficiency. As in the case of combined use of a hypotensive drug and a diuretic, regular monitoring of plasma potassium levels is necessary.

Auxiliary substances

Please note that the excipients of the drug include lactose monohydrate. Noliprel® A forte should not be administered to patients with hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption.

Lithium preparations

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

Perindopril

Neutropenia/agranulocytosis

The risk of neutropenia with 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 with systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma). After withdrawal of ACE inhibitors, signs of neutropenia disappear on their own.

In order to prevent the development of such reactions, it is recommended to strictly follow the recommended dose. The benefit/risk factor should be carefully evaluated when prescribing ACE inhibitors in this group of patients.

Angeoneurotic edema (Quincke’s edema)

In rare cases, angioedema of the face, extremities, lips, tongue, vocal cleft, and/or larynx may occur when taking ACE inhibitors, including perindopril. If symptoms occur, perindopril should be stopped immediately, and the patient should be observed until the signs of edema disappear completely. If only the face and lips are affected, the swelling usually resolves on its own, although antihistamines may be used to treat the symptoms.

Contraindications

Side effects

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

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, asthenia, vertigo; infrequent – sleep disturbance, mood swings; very rare – mental confusion; unspecified frequency – fainting.

An organ of vision: often – visual impairment.

Hearing organ: often – tinnitus.

Systemic system disorders: often – marked decrease of BP, including orthostatic hypotension; very rarely – cardiac rhythm disorders, including bradycardia, ventricular tachycardia, atrial fibrillation, as well as angina and myocardial infarction, possibly due to excessive reduction of BP in high-risk patients (see “Indications”); unspecified frequency – “pirouette” arrhythmia (possibly with lethal outcome – see “Interaction”).

The respiratory system, thoracic and mediastinal organs: frequently – with ACE inhibitors use dry cough may occur, which is prolonged during use of the drugs of this group and disappears after discontinuation of them, 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 – angioedema of the intestine, cholestatic jaundice, pancreatitis; unspecified frequency – hepatic encephalopathy in patients with liver failure (see “Contraindications” and “Special Indications”), hepatitis.

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”). “Cautions”); hypersensitivity reactions in patients predisposed to bronchoobstructive and allergic reactions; purpura, in patients with an acute form of systemic lupus 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: hyperkalemia, more frequently – transient; slight increase of creatinine concentration in urine and plasma, passing after discontinuation of therapy, more often in patients with renal artery stenosis, in treatment of arterial hypertension by diuretics and in case of renal failure; rarely – hypercalcemia; of unspecified frequency – increase of QT interval on ECG (see “Indications. “Particular indications”), increased concentration of uric acid and glucose in blood, increased activity of liver enzymes, hypokalemia, especially significant for patients at risk (see “Particular indications”), hyponatremia and hypovolemia, leading to dehydration and orthostatic hypotension. Simultaneous hypochloremia may lead to compensatory metabolic alkalosis (the probability and severity of this effect is low).

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

Pregnancy use

The drug is contraindicated in pregnancy.

If pregnancy is planned or if pregnancy occurs while taking Noliprel® A forte, the drug should be stopped immediately and other hypotensive therapy should be prescribed.

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

There have been no relevant controlled studies on the use of ACE inhibitors in pregnant women. The limited data available on the effects of ACE inhibitors in the first trimester of pregnancy suggest that ACE inhibitors administration has not led to fetotoxicity related fetal malformations, but fetotoxic effects of the drug cannot be completely excluded.

Noliprel® A forte is contraindicated in II and III trimesters of pregnancy. It is known that long term exposure of fetus to ACE inhibitors in II and III trimesters of pregnancy may cause abnormal development of fetus (decreased renal function, oligohydramnios, delayed ossification of skull bones) and development of complications in newborn (renal failure, arterial hypotension, hyperkalemia). Prolonged use of thiazide diuretics in the third trimester of pregnancy may cause hypovolemia in the mother and decrease uterine-placental blood flow, which leads to fetoplacental ischemia and fetal growth retardation. In rare cases, against the background of taking diuretics shortly before delivery, hypoglycemia and thrombocytopenia develop in newborns. If the patient received Noliprel® A forte during the second or third trimester of pregnancy, an ultrasound examination of the newborn is recommended to evaluate the skull and renal function.

In newborns whose mothers were treated with ACE inhibitors may have arterial hypotension, and therefore newborns should be under close medical supervision.

Noliprel® A forte is contraindicated during lactation. It is not known whether perindopril is excreted with breast milk. Indapamide is excreted with breast milk. Thiazide diuretics cause a decrease in the amount of breast milk or suppression of lactation. The newborn may develop hypersensitivity to sulfonamide derivatives, hypokalemia, and nuclear jaundice.

Because the use of perindopril and indapamide during lactation may cause severe complications in the breastfed infant, the significance of therapy to the mother should be assessed and a decision should be made to discontinue breastfeeding or to discontinue the drug.

Similarities