Perindopril PLUS, tablets 1.25mg+4 mg 30 pcs

Perindopril PLUS is a combined drug containing indapamide and perindopril erbumin. Pharmacological properties of the drug Perindopril PLUS combine individual properties of each of its active components.

Mechanism of Action

Perindopril PLUS

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

Perindopril

Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II (angiotensin-converting enzyme (ACE) inhibitor). ACE, or kininase II, is an exopeptidase that performs both the conversion of angiotensin I vasoconstrictor angiotensin II and the degradation of bradykinin, which has a vasodilatory effect, to an inactive heptapeptide.

The result is perindopril:

• reduces aldosterone secretion;
• by the principle of negative feedback, it increases plasma renin activity;
with long-term use reduces total peripheral vascular resistance (TPRR), 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 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:

• reduced filling pressures in the left and right ventricles of the heart;
• reduced PPS;
• increased cardiac output and increased cardiac index;
• increased muscle peripheral blood flow.

Indapamide

Indapamide belongs to the group of sulfonamides and has pharmacological properties similar to thiazide diuretics.

Indapamide inhibits reabsorption of sodium ions in the cortical segment of the Genle loop, which leads to increased renal excretion of sodium ions, chloride ions and to a lesser extent sodium and magnesium ions, thereby increasing diuresis and reducing blood pressure (BP).

Antihypertensive effects

Perindopril PLUS

The drug Perindopril PLUS has dose-dependent antihypertensive effects on both diastolic and systolic BP in both standing and lying positions.

The antihypertensive effect lasts for 24 h. Stable therapeutic effect develops in less than 1 month from the beginning of therapy and is not accompanied by tachyphylaxis. Discontinuation of therapy does not cause “withdrawal” syndrome.

The drug Perindopril PLUS reduces the degree of left ventricular hypertrophy (LVH), improves arterial elasticity, decreases PEEP, has no effect on lipid metabolism (total cholesterol, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, triglycerides).

The combination of perindopril and indapamide has been shown to have an effect on HLV compared with enalapril. In patients with arterial hypertension and HLV treated with perindopril erbumin 2 mg/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 and indapamide to 2,5 mg, or enalapril to 40 mg once daily, there was a more significant reduction in left ventricular mass index (LVMI) of the perindopril/indapamide group compared with 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. Its antihypertensive effect reaches its maximum 4-6 hours after a single oral dose and lasts for 24 hours. Twenty-four 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. 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.

Double blockade of the renin-angiotensin-aldosterone system (RAAS)

There are data from clinical studies of combined therapy with ACE inhibitor with angiotensin II receptor antagonists (ARA II).

There have been clinical studies involving patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes with confirmed target organ damage, and studies involving patients with type 2 diabetes and diabetic nephropathy.

These studies found no significant positive effect on the occurrence of renal and/or cardiovascular events and mortality rates in patients receiving combination therapy, while the risk of hyperkalemia, acute renal failure and/or arterial hypotension increased compared to patients receiving monotherapy.

With consideration of the similar within-group pharmacodynamic properties of ACE inhibitors and ARA II, these results would be expected for any other drug interaction between ACE inhibitors and ARA II classes.

The use of ACE inhibitors in combination with angiotensin II receptor antagonists is therefore contraindicated in patients with diabetic nephropathy.

There are data from a clinical trial examining the beneficial effects of adding aliskiren to standard therapy with an ACE inhibitor or ARA II in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease, or who have a combination of these conditions.

The study was stopped early due to an increased risk of adverse outcomes. Cardiovascular death and stroke occurred more often in the group of patients receiving aliskiren compared to the placebo group. Also adverse events and serious adverse events of special interest (hyperkalemia, arterial hypotension and renal dysfunction) were reported more frequently in the aliskiren group than in the placebo group.

Indapamide

The antihypertensive effect is seen when the drug is used in doses that have minimal diuretic effect. The antihypertensive effect of indapamide is associated with improvement of elastic properties of large arteries, reduction of PPS.

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

Indications

Active ingredient

Composition

excipients: microcrystalline cellulose 102 – 70.75 mg; croscarmellose sodium (primellose) – 3.0 mg; corn starch pregelatinized (starch 1500) – 15.0 mg; sodium hydrocarbonate – 4.0 mg; magnesium stearate – 1.0 mg; colloidal silicon dioxide anhydrous (aetherless) – 1.0 mg.

How to take, the dosage

Overly, once daily, preferably in the morning before breakfast, with plenty of fluid.

If possible, the drug should be started with a selection of single-component doses. If clinically necessary, combined therapy with Perindopril PLUS may be prescribed immediately after monotherapy with one of the components of the drug (perindopril and indapamide).

Doses are given for the indapamide/perindapril ratio.

The starting dose is 1 tablet of Perindopril PLUS (0.625 mg/2mg) once daily. If adequate BP control is not achieved after 1 month of therapy, the dose should be increased to 1 tablet of Perindopril PLUS (1.25 mg/4 mg) once daily.

If necessary to achieve a more significant hypotensive effect, the dose of Perindopril PLUS may be increased to maximum daily dose of 1 tablet (2.5 mg/8 mg) once daily.

Perindopril PLUS elderly patients

The starting dose is 1 tablet of 0.625 mg/2 mg of Perindopril PLUS once daily.

The therapy with the drug should be started under monitoring of renal function and BP.

Patients with impaired renal function

Perindopril PLUS is contraindicated in patients with severe renal impairment (CKG less than 30 ml/min).

Patients with moderate renal impairment (CKD 30-60 ml/min) are recommended to start therapy with the required doses of Perindopril PLUS (in monotherapy); the maximum daily dose of Perindopril PLUS is 1.25 mg/4 mg.

Patients with a CK of 60 ml/min or more do not require dose adjustment. Creatinine and serum potassium concentrations should be monitored regularly during therapy.

Patients with impaired liver function

The drug is contraindicated in patients with severe hepatic impairment.

There is no need to adjust doses in moderately severe hepatic impairment.

Children and adolescents

Perindopril PLUS should not be used in children and adolescents less than 18 years of age because of insufficient data on efficacy and safety.

Interaction

General for perindopril and indapamide

Combinations not recommended

Lithium drugs: Concomitant use of lithium drugs and ACE inhibitors has reported a reversible increase in plasma lithium concentration and associated toxic effects. Concomitant use of the combination of perindopril and indapamide with lithium preparations is not recommended. Plasma lithium levels should be monitored regularly if such therapy is necessary.

Combinations of drugs requiring special attention and caution

Baclofen: Increased antihypertensive effect. BP should be monitored and, if necessary, doses of hypotensive drugs should be adjusted.

Patients should receive adequate fluid intake and it is recommended to monitor renal function both at the beginning of co-therapy and periodically during treatment.

Combinations of drugs requiring attention

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

Perindopril

. Data from clinical studies demonstrate that dual RAAS blockade resulting from concomitant use of ACE inhibitors, ARA II or aliskiren leads to an increased incidence of adverse events such as arterial hypotension, hyperkalemia and renal dysfunction (including acute renal failure) compared to situations where only one RAAS-acting medication is used.

Drugs that cause hyperkalemia

The combination of these drugs increases the risk of hyperkalemia.

Simultaneous use is contraindicated

Aliskiren and medicinal products containing aliskiren

Combinations not recommended for use

Aliskiren: In patients without diabetes mellitus or renal dysfunction, there is an increased risk of hyperkalemia, impaired renal function, and increased incidence of cardiovascular morbidity and mortality.

Combination of therapy with ACE inhibitors and ARA II: In patients with established atherosclerotic disease, heart failure, or diabetes mellitus with target organ damage, concomitant administration of ACE inhibitors and ARA II has been reported in the literature to increase the incidence of arterial hypotension, syncope, hyperkalemia, and renal function impairment (including acute renal failure), compared with situations in which only one drug acting on RA AC is used. The use of dual ACE RA blockade (e.g., concomitant administration of an ACE inhibitor and ARA II) should be limited to single cases with strict monitoring of renal function, plasma potassium, and BP.

Estramustine: Simultaneous use may increase the risk of side effects such as angioedema.

Kalium-saving diuretics (e.g., triamterene, amiloride) and potassium salts: hyperkalemia (possibly fatal), especially in impaired renal function (additional effects associated with hyperkalemia).

The combination of perindopril with the above-mentioned drugs is not recommended. However, if concomitant use is indicated, they should be used with caution and serum potassium levels should be monitored regularly.

The specifics of spironolactone use in chronic heart failure are described in the sub-section “Drug combinations requiring special attention”.

Combinations of drugs requiring special attention

Hypoglycemic oral agents and insulin: Epidemiologic studies have shown that the combined use of ACE inhibitors and hypoglycemic agents (insulin, oral hypoglycemic agents) may increase the hypoglycemic effect of insulin and oral hypoglycemic agents to the point of developing hypoglycemia. This effect is most likely to be observed during the first weeks of concomitant therapy, as well as in patients with impaired renal function.

Potassium-saving diuretics: In patients receiving diuretics, especially in patients with hypovolemia and/or reduced salt concentration, an excessive decrease in BP may be observed at the beginning of perindopril therapy. The risk of hypotension can be reduced by withdrawal of the diuretic, by replenishing fluid or salt loss before starting perindopril therapy, and by prescribing perindopril at a low dose with further gradual increase.

In patients with arterial hypertension with hypovolemia or reduced salt concentration on diuretic therapy, diuretics should either be discontinued before starting an ACE inhibitor, (and the potassium-intolerant diuretic may be prescribed again later), or the ACE inhibitor should be given at a low dose with further gradual increase in dose.

When diuretics are used in cases of chronic heart failure, the ACE inhibitor should be prescribed at a very low dose, possibly after reducing the dose of a concomitantly used potassium-uncontaining diuretic.

In all cases, renal function (creatinine concentration) should be monitored during the first weeks of ACE inhibitor use.

Kaliberating diuretics (eplerenone, spironolactone): use of eplerenone or spironolactone in doses from 12.5 mg to 50 mg per day and low doses of ACE inhibitors:

In therapy of chronic heart failure NYHA functional class II-IV with left ventricular ejection fraction < 40% and previously used ACE inhibitors and “loop” diuretics, there is a risk of hyperkalemia (with possible fatal outcome), especially if recommendations regarding this drug combination are not followed.

Before using this drug combination, it is necessary to ensure that hyperkalemia and renal dysfunction are absent. We recommend regular monitoring of creatinine and potassium concentrations in blood: weekly in the first month of treatment and monthly thereafter.

MTOR inhibitors (mammalian target of rapamycin) (e.g., sirolimus, everolimus, temsirolimus)

Patients receiving concurrent therapy with mTOR inhibitors may have an increased risk of angioedema.

Racecadotril

Combinations of drugs requiring attention

Hypotensive agents and vasodilators: concomitant use of these drugs may increase the antihypertensive effect of perindopril. When concomitant administration with nitroglycerin, other nitrates or other vasodilators, additional BP reduction is possible.

Allopurinol, cytostatic and immunosuppressive agents, corticosteroids for systemic use and procainamide: concomitant use with ACE inhibitors may be accompanied by an increased risk of leukopenia.

Medications for general anesthesia: ACE inhibitors may increase the antihypertensive effect of a number of agents for general anesthesia.

Glyptins (linagliptin, saxagliptin, sitagliptin, vildagliptin): co-administration with ACE inhibitors increases the risk of angioedema due to inhibition of dipeptide dilpeptidase-4 (DPP-IV) activity by griptin.

Sympathomimetics: may impair the antihypertensive effect of ACE inhibitors.

Gold preparations: when using ACE inhibitors, including perindopril, patients receiving intravenous gold (sodium aurothiomalate) have been described with nitrite reactions manifested by facial hyperemia, nausea, vomiting, arterial hypotension.

Indapamide

Combinations of drugs requiring special attention

Cardiac glycosides: hypokalemia increases toxic effects of cardiac glycosides. In concomitant use of indapamide and cardiac glycosides, plasma potassium and ECG parameters should be monitored and, if necessary, therapy should be adjusted.

Combinations of drugs requiring attention

Iodine-containing contrast agents: dehydration of the body against the background of diuretic drugs increases the risk of acute renal failure, especially when using high doses of iodine-containing contrast agents. Patients should compensate for fluid loss before using iodine-containing contrast agents.

Calcium salts: concomitant use may lead to hypercalcemia due to reduced renal excretion of calcium ions.

Cyclosporine, tacrolimus: increased plasma creatinine concentration is possible without changing the plasma concentration of cyclosporine, even when water and sodium ion levels are normal.

Corticosteroids, tetracosactide (when used systemically): reduction of antihypertensive effect (salt and water retention with corticosteroids).

Special Instructions

Kidney function impairment

The therapy is contraindicated in patients with moderate to severe renal impairment (CKI less than 60 ml/min). In some patients with arterial hypertension without previous obvious impairment of renal function during the therapy, laboratory signs of functional renal insufficiency may appear. In this case, the treatment should be discontinued. Subsequently, combination therapy may be resumed with a low-dose combination of indapamide and perindopril, or only one of the drugs may be used.

Such patients require regular monitoring of potassium and serum creatinine concentration – two 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. The drug Perindopril PLUS is not recommended in cases of bilateral renal artery stenosis or artery stenosis of the only functioning kidney.

Arterial hypotension and water-electrolyte imbalance

In cases of initial hyponatremia, there is a risk of sudden development of arterial hypotension, especially in patients with renal artery stenosis. Therefore, during dynamic monitoring of patients, attention should be paid to possible symptoms of dehydration and decreased plasma electrolyte content, e.g., 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 recovery of circulating blood volume and BP, therapy may be resumed using lower doses of the drugs, or only one of the drugs may be used.

Potassium content

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

Auxiliary substances

Please note that the excipients of the drug include lactose monohydrate. Perindopril PLUS should not be used in patients with hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption.

Lithium preparations

The concomitant use of Perindopril PLUS with lithium preparations is not recommended.

Perindopril PLUS should not be used in children and adolescents less than 18 years of age because of lack of data about the effectiveness and safety of indapamide and perindopril, either alone or together, in this age group of patients.

Perindopril

Double blockade of the angiotensin-aldosterone system (RAAS)

. There is evidence for an increased risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure) when ACE inhibitors are used concomitantly with ARA II or aliskiren. Therefore, dual blockade of the RAAS by combining an ACE inhibitor with ARA II or aliskiren is not recommended.

If dual blockade is absolutely necessary, it should be performed under close professional supervision with regular monitoring of renal function, plasma electrolytes and BP.

The use of ACE inhibitors in combination with ARA II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Potassium-saving diuretics, potassium preparations, potassium salt substitutes, and dietary supplements

Perindopril should not be used with potassium-saving diuretics or with potassium preparations, potassium salt substitutes, or dietary supplements.

Neutropenia / agranulocytosis / thrombocytopenia

Some patients had severe infectious diseases, in some cases resistant to intensive antibiotic therapy. When prescribing perindopril to such patients, it is recommended to periodically monitor the number of leukocytes in the blood. Patients should inform the physician of any signs of infectious diseases (e.g., sore throat, fever).

Contraindications

Perindopril

Indapamide

Side effects

The incidence of side effects is estimated on the basis of: often – 1-10%; rarely – 0.1-1%; extremely rare, including isolated reports – less than 0.1%.

Cardiovascular system: often – excessive decrease in blood pressure and related symptoms, rarely – arrhythmia, angina pectoris, myocardial infarction and stroke.

Urinary system disorders: decreased renal function and acute renal failure.

Respiratory system disorders: often – “dry” cough, difficulty in breathing; rarely – bronchospasm, rhinorrhea.

Gastrointestinal system: frequently – nausea, vomiting, abdominal pain, change in taste, diarrhea or constipation, dry mouth, decreased appetite, cholestatic jaundice, pancreatitis, intestinal edema.

The central nervous system: often – headache, asthenia, fatigue, dizziness, tinnitus, visual disturbances, muscle cramps, paresthesias; rarely – decreased mood, insomnia; extremely rare – confusion.

Allergic reactions: common – skin rash, itching, rarely – urticaria, angioedema; very rare – erythema multiforme.

Laboratory indices: frequent – hypercreatininemia, proteinuria, hyperkalemia; hyperuricemia; rare (with prolonged use in high doses) – neutropenia, leukopenia, hypogemoglobinemia, thrombocytopenia, decreased hematocrit; Very rarely – agranulocytosis, pancytopenia, increased “liver” enzymes activity, hyperbilirubinemia, hemolytic anemia (with glucose-6-phosphate dehydrogenase deficiency).

Others: increased sweating, impaired sexual function.

Overdose

Symptoms: marked BP decrease, nausea, vomiting, muscle cramps, dizziness, drowsiness, confusion, oliguria up to anuria (due to reduction of the blood circulation); disorders of water-electrolyte balance (low plasma levels of sodium and potassium) are possible.

Treatment: gastric lavage and/or administration of activated charcoal, restoration of water-electrolyte balance in hospital. With a pronounced BP decrease the patient should be transferred to the “supine” position with elevated legs; then measures should be taken to increase the blood circulation (intravenous injection of 0.9% sodium chloride solution). Perindoprilat, the active metabolite of perindopril, can be eliminated from the body by dialysis.

Similarities