Noliprel A, 2.5mg+0.625 mg 30 pcs.

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

1. Mechanism of Action

Noliprel ^® A

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).

The 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, to an inactive heptapeptide. As a result, perindopril:

– reduces aldosterone secretion;

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

– with prolonged use, it reduces 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, it was found:

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

– decreased PPSS;

– 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 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

Noliprel^® A has dose-dependent antihypertensive effects on both BP and cPH, both standing and lying down. 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 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 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

At 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 lead-in period during which patients received perindopril/indapamide therapy, they were allocated to the standard glycemic control group or to the IGC group (Diabeton^® MB with the 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 10% significant reduction in the relative risk of combined incidence of macrovascular 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. Taking the drug with meals is accompanied by a decrease in metabolism of perindopril to perindoprilat (this effect is not of significant clinical significance).

The C_max 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 perindoprilat bound to ACE is delayed. As a consequence, the effective T_1/2 is 25 h. Repeated administration of perindopril does not result in its cumulation, and the T_1/2 of perindoprilat on repeated administration corresponds to its period of activity, so that the equilibrium state is reached after 4 days.

Perindoprilat is excreted by the kidneys. T_1/2 metabolite is 3-5 h.

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, 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.

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

The binding to plasma proteins is 79%.

T_1/2 is 14-24 h (mean 19 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 with arterial hypertension and type 2 diabetes mellitus to reduce the risk of microvascular complications (from the kidneys) and macrovascular complications from cardiovascular disease.

Active ingredient

Composition

1 tablet contains:

How to take, the dosage

Orally, preferably in the morning, before meals.

Essential hypertension

1 tablet of Noliprel ® A once daily.

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

Patients with arterial hypertension and type 2 diabetes mellitus to decrease risk of microvascular complications (renal side) and macrovascular complications from cardiovascular disease

Noliprel® A 1 tablet once daily. After 3 months of therapy, if tolerated well, the dose may be increased to 2 tablets Noliprel® A once daily (or 1 tablet Noliprel® A forte once daily).

Patients in the elderly

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).

In patients with moderate renal insufficiency (creatinine Cl 30-60 ml/min) it is recommended to start therapy with the required doses of drugs (as monotherapy) included in Noliprel ® A.

Patients with a creatinine Cl equal to or greater than 60 ml/min do not require dose adjustment. Regular monitoring of creatinine and plasma potassium levels is required 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 should not be indicated in children and adolescents less than 18 years of age because of lack of data about the effectiveness 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 antihypertensive 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 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 concentration 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

Noliprel ® A

The use of Noliprel ® A 2.5 mg + 0.625 mg containing a low dose of indapamide and perindopril arginine is not associated with a significant reduction in the incidence of side effects, with the exception of hypokalemia, compared to perindopril and indapamide in 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 should not be administered in 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 avoid the development of such reactions, it is recommended to follow the recommended dose strictly. When prescribing ACE inhibitors in this group of patients, the benefit/risk factor should be carefully balanced.

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

Hepatopoietic 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: often – with ACE inhibitors use dry cough may occur, which is prolonged during use of 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 disturbances, 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”, “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 – QT interval prolongation 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).

The side effects noted in clinical trials

The side effects noted in the ADVANCE study are consistent with the previously established safety profile of the combination of perindopril and indapamide. Serious adverse events were noted in some patients in the study groups: hyperkalemia (0.1%), acute renal failure (0.1%), arterial hypotension (0.1%), and cough (0.1%).

In 3 patients in the perindopril/indapamide group, angioedema was noted (versus 2 in the placebo group).

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, the drug should be stopped immediately and other hypotensive therapy should be prescribed.

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

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

Noliprel ® A is contraindicated in the second and third trimester of pregnancy (see “Contraindications”).

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 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 have received therapy with ACE inhibitors may experience arterial hypotension, so newborns should be closely monitored by medical personnel.

Lactation period

Noliprel ® A is contraindicated during lactation.

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.

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 made to discontinue breastfeeding or administration of the drug.

Similarities