A Prestarium

Active material: Perindopril
When ATH: C09AA04
CCF: ACE inhibitor
ICD-10 codes (testimony): G45, I10, i20, I50.0, I63
When CSF: 01.04.01.03
Manufacturer: Servier Laboratories (France)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Pills, Film-coated white, round, lenticular.

Excipients: lactose monohydrate, magnesium stearate, maltodextrin, hydrophobic colloidal silicon dioxide, sodium carboxymethyl starch, glycerol, gipromelloza, macrogol 6000, Titanium dioxide.

30 PC. – vials made of polypropylene (1) – packs cardboard to control the first opening.

Pills, Film-coated light green, oblong, rounded with two sides, notched on both sides and engraved as a company logo on one of the faces of the.

Excipients: lactose monohydrate, magnesium stearate, maltodextrin, hydrophobic colloidal silicon dioxide, sodium carboxymethyl starch, glycerol, gipromelloza, macrogol 6000, Titanium dioxide, dye copper chlorophyllin (E141ii).

14 PC. – vials made of polypropylene (1) – packs cardboard to control the first opening.
30 PC. – vials made of polypropylene (1) – packs cardboard to control the first opening.

Pills, Film-coated green color, round, lenticular, engraved heart-shaped on one side and the company logo – another.

Excipients: lactose monohydrate, magnesium stearate, maltodextrin, hydrophobic colloidal silicon dioxide, sodium carboxymethyl starch, glycerol, gipromelloza, macrogol 6000, Titanium dioxide, dye copper chlorophyllin (E141ii).

30 PC. – vials made of polypropylene (1) – packs cardboard to control the first opening.

Pharmacological action

Antihypertensive drugs, ACE inhibitor. ACE, or kininaza, It is an exopeptidase, that carries out both the conversion of angiotensin I to the vasoconstrictor compound angiotensin II, and the destruction of bradykinin, having a vasodilating action, to inactive heptapeptyda.

Inhibition of ACE results in a reduction of angiotensin II in plasma, as a result, increases plasma renin activity (due to inhibition of the negative feedback, which prevents the release of renin) and reduced secretion of aldosterone. Since ACE inactivates bradykinin, ACE inhibition is accompanied by increased activity of the circulating, and tissue kallikrein-kinin system, This activates the prostaglandin system. Perindopril reduces peripheral vascular resistance, which leads to a decrease in blood pressure. Thus peripheral blood accelerates, However, heart rate does not increase.

Perindopril has a therapeutic effect due to the active metabolite, peryndoprylatu. Other metabolites of the drug did not have inhibitory effect on ACE in vitro.

Arterial hypertension

When hypertension against the background of the drug there is a decrease in both systolic, and diastolic blood pressure in the supine position and standing. The decrease in blood pressure is achieved quickly enough. Patients with a positive response to treatment normalization of blood pressure occurs within a month. This habituation effect is not observed.

Discontinuation of treatment is not accompanied by the development of withdrawal. Perindopril has vasodilatory effect, It helps to restore the elasticity of the large arteries and the structure of the vascular wall of small arteries, and It reduces left ventricular hypertrophy. Concomitant administration of thiazide diuretics enhances the antihypertensive effect. Besides, combining an ACE inhibitor and a thiazide diuretic and reduces the risk of hypokalemia in patients receiving diuretics.

Heart failure

Perindopril normalizes heart function, reducing preload and afterload. In patients with chronic heart failure, treated with perindopril, There was a reduction of filling pressure in the left and right ventricles of the heart; reduction in systemic vascular resistance; increase in cardiac output and an increase in cardiac index. Study drug compared with placebo showed, changes in blood pressure after the first administration of the drug Prestarium^® A dose 2.5 mg in patients with heart failure of mild to moderate severity did not differ significantly from the change in blood pressure, observed after placebo.

Cerebrovascular disease

In the process of the international multicenter study (PROGRESS) evaluated the effect of active treatment with perindopril (monotherapy or in combination with indapamidom) during 4 age on the risk of recurrent stroke in patients, with a history of cerebrovascular disease. After the introductory period, the use of perindopril t-butylamine 2 mg (equivalent perindopril arginine 2.5 mg) 1 times / day for 2 weeks and then 4 mg (equivalent perindopril arginine 5 mg) 1 time / day over the next two weeks, 6105 Patients were randomized into two groups: placebo (n=3054) and perindopril t-butylamine at 4 mg (matches 5 mg perindopril arginine) (monotherapy) or in combination with indapamide (n=3051). Indapamide additionally administered to patients, no direct indications or contraindications to the use of diuretics. This therapy was administered in addition to standard therapy of stroke and / or hypertension or other pathological conditions. All randomized patients had a history of cerebrovascular disease (stroke or transient ischemic attack) during the last 5 years. The magnitude of blood pressure was not an inclusion criterion: 2916 patients had hypertension and 3189 – normal blood pressure. After 3.9 years of therapy, the magnitude of blood pressure (systolic / diastolic) decreased by an average of 9/4 mmHg. It was also shown a significant reduction in the risk of recurrent stroke (both ischemic, and hemorrhagic nature) order 28% (95% CI (17; 38), p< 0.0001) compared to placebo (10.1% vs 13.8%). In addition, it was shown a significant reduction in the risk of fatal or disabling stroke lead; major cardiovascular events, including myocardial infarction, incl. fatal; dementias, associated with stroke; serious deterioration of cognitive functions.

These therapeutic advantages are observed both in patients with hypertension, and with normal blood pressure, irrespective of age, gender, the presence or absence of diabetes and the type of stroke.

Stable coronary artery disease

An international multicenter, randomized,, double-blind, placebo-controlled study lasting EUROPA 4 year, He studied the efficacy of perindopril in patients with stable coronary artery disease. In a clinical study involved 12218 older patients 18 years: 6110 patients received perindopril t-butylamine at 8 mg (equivalently 10 mg perindopril arginine) and 6108 patients – placebo.

The main outcome measures were cardiovascular mortality, nonfatal myocardial infarction and / or cardiac arrest with successful resuscitation followed. To participate in the study were selected patients with established coronary artery disease myocardial infarction at least 3 months prior to screening, undergoing coronary revascularization at least 6 months prior to screening, anhyohrafychesky vыyavlennыy stenosis (least 70% narrowing of one or more major coronary arteries) or a positive stress test with a history of chest pain. The drug was administered in addition to standard therapy, used for hyperlipidemia, hypertension and diabetes.

Most patients taking antiplatelet agents, lipid-lowering agents and beta-blockers. By the end of the study the ratio of patients, taking these groups of drugs, was 91%, 69% and 63% respectively. Through 4.2 the result of years of therapy at a dose of perindopril t-butylamine 8 mg 1 time / day had a significant reduction in the relative risk 20% (95% CI) Development predetermined complications: in 488 (8%) patients from the group, receiving perindopril t-butylamine, and 603 (9.9 %) patients in the placebo group (p = 0.0003).

The result is not dependent on sex, age, Blood pressure and the presence of myocardial infarction.

Pharmacokinetics

Absorption

After oral administration, perindopril is rapidly absorbed from the gastrointestinal tract, C_max plasma levels achieved after 1 no. About 27% total amount absorbed is converted into perindopril perindoprilat – active metabolite. Furthermore perindoprilat formed during the metabolism of more 5 metabolites – they are inactive substances.

T_1/2 perindopril from plasma is 1 no. C_max perindoprilat plasma levels achieved through 3-4 no.

Taking the drug during the meal is accompanied by a decrease in the conversion of perindopril to perindoprilat, thus reducing the bioavailability of the drug.

Distribution

Binding of perindoprilat to plasma proteins is 20%, mainly ACE, and is dose-dependent. V_d free perindoprilat is about 0.2 l / kg.

Deduction

Perindoprilat excreted by the kidneys and total T_1/2 unbound fraction of 17 no, providing an equilibrium condition within 4 d.

Pharmacokinetics in special clinical situations

Withdrawal perindoprilat slowed down in the elderly, as well as in patients with heart and kidney failure. When kidney failure correction of the dose is preferably carried out according to the degree of renal impairment.

Dialysis clearance of perindoprilat is 70 ml / min.

In patients with liver cirrhosis hepatic clearance of perindopril reduced by half. Nonetheless, number perindoprilat formed is not reduced and does not change the dose required.

Testimony

- Arterial hypertension;

- Congestive heart failure;

- Prevention of recurrent stroke (Combination therapy with indapamide) patients, stroke or transient ischemic attack of ischemic;

- Stable coronary artery disease: to reduce the risk of cardiovascular complications.

Dosage regimen

The drug is prescribed inside 1 time / day in the morning, before meals.

Arterial hypertension

The recommended starting dose is 5 mg 1 time / day, morning. When treatment failure within a month, the dose may be increased to 10 mg 1 time / day.

In the appointment of ACE inhibitors in patients with severe activated renin-angiotensin-aldosterone system (if renovascular hypertension, violation of water-salt balance, diuretic therapy, severe hypertension, cardiac decompensation) there may be unpredictable sharp decline in blood pressure, for the prevention of which it is recommended to stop taking the diuretic for 2-3 days prior to the expected start of therapy with Prestarium^® A.

If it is impossible to cancel diuretics, initial dose Prestarium^® A is 2.5 mg. It is necessary to monitor the kidney function and the content of potassium in blood serum. Subsequently, if necessary, the dose may be increased.

In elderly patients Treatment should start with a dose 2.5 mg / day, and thereafter, if necessary, gradually increase it up to a maximum dose 10 mg / day.

Heart failure

Treatment with Prestarium^® And in combination with nekaliysberegayuschimi diuretic and / or digoxin and / or beta-blockers, It recommended to start under close medical supervision, was prescribed in an initial dose 2.5 mg 1 time / day, morning. Subsequently, depending on tolerance and response to therapy, through 2 week of treatment dose can be increased to 5 mg 1 time / day.

Patients at high risk of symptomatic hypotension, eg, with a reduced content of salts with or without hyponatremia, hypovolemia or taking diuretics, before taking the drug Prestarium^® A, possibly, listed status must be corrected. Such indicators as the amount of blood pressure, renal function and potassium content of the plasma should be monitored both before, and during therapy.

Prevention of recurrent stroke

In patients with cerebrovascular disease history, therapy with Prestarium^® And should start with a dose 2.5 mg during the first 2 weeks before the administration of indapamide.

Therapy should be initiated at any (from 2 weeks to years) after stroke.

Reducing the risk of cardiovascular complications

At stable coronary artery disease therapy with Prestarium^® And should start with a dose 5 mg 1 times / day for 2 weeks. Then, the daily dose should be increased to 10 mg 1 time / day (depending on renal function).

Elderly patients therapy should be initiated at a dose of 2.5 mg 1 time / day for one week, then 5 mg 1 time / day for the next week before increasing the dose to 10 mg 1 time / day (depending on renal function).

At impaired renal function dose Prestarium^® A should be selected according to the degree of renal insufficiency and under regular monitoring of potassium and CK.

* dialysis clearance of perindoprilat: 70 ml / min

In appointing the drug patients with impaired liver function, changes in dose is required.

Side effect

Cardio-vascular system: excessive reduction of blood pressure and associated symptoms; rarely – arrhythmia, angina, myocardial infarction and stroke; at-risk patients may develop severe hypotension secondary.

From the laboratory parameters: rarely – reduction of the concentration of hemoglobin and hematocrit, thrombocytopenia, leukopenia / neutropenia, edinichnыe cases agranulocytosis or pantsitopenii; the likelihood of developing hemolytic anemia against deficiency of glucose-6-phosphate dehydrogenase; rarely – increase of urea and creatinine blood plasma, passing hyperkalemia, especially in patients with renal insufficiency, increase in liver enzymes and bilirubin liver.

Contraindications

- A history of angioedema (congenital / idiopathic or related to previous treatment with an ACE inhibitor reaction);

- Pregnancy;

- Lactation (breast-feeding);

- Hypersensitivity to the drug;

- Hypersensitivity to other ACE inhibitors;

- Lactase deficiency, galactosemia, syndrome glucose / galactose malabsorption (because, that in the preparation of auxiliary substances include lactose monohydrate).

FROM caution used in reducing BCC (diuretics, salt-free diet, vomiting, diarrhea, hemodialysis), giponatriemii, cerebrovascular diseases, angina – the risk of a sharp decrease in blood pressure; if renovascular hypertension, bilateral renal artery stenosis, or there is only one functioning kidney – risk of severe hypotension and renal insufficiency; in chronic renal failure; in systemic connective tissue diseases (SLE, scleroderma) and immunosuppressive therapy – the risk of agranulocytosis and neutropenia; when hyperkalemia; stenosis of the aortic valve, hypertrophic obstructive cardiomyopathy; during hemodialysis using membranes polyacrylic vysokoprotochnyh; LDL apheresis before treatment; in patients after renal transplantation (there is no clinical experience); concurrently with the desensitizing therapy allergens; surgery (general anesthesia); in patients with diabetes mellitus, receiving hypoglycemic drugs or insulin (recommended to control blood glucose levels); patients aged 18 years (efficacy and safety have not been studied).

Pregnancy and lactation

It is not recommended to use the drug Prestarium^® And in the I trimester of pregnancy. When planning your pregnancy is confirmed or you must go to alternative therapy. Adequate well-controlled clinical studies on the effect of ACE inhibitors in the I trimester of pregnancy has not been. In a limited number of cases the use of ACE inhibitors in the I trimester of pregnancy was not observed any malformations, related fetotoxic.

Perindopril is contraindicated in II and III trimesters of pregnancy, tk. there is evidence of the manifestation of fetotoxicity (decreased kidney function, oligogidramnion (a pronounced decrease in amniotic fluid), delay in the formation of the skull bones) and neonatal toxicity (impairment of renal function, gipotenziya, hyperkalemia). If therapy with perindopril was conducted in the II and / or III trimesters of pregnancy, necessary to carry out ultrasound of the kidneys and the skull of the fetus.

Unknown, whether perindopril is allocated with breast milk in humans, it is not recommended to use the drug during lactation (breast-feeding).

Cautions

In patients with stable coronary artery disease in the event of an episode of unstable angina (No significant or) during the first month of therapy Prestarium^® A, should evaluate the benefits and risks of continuing treatment to.

ACE inhibitors can cause a sharp decrease in blood pressure. Symptomatic hypotension is rarely seen in patients without comorbidities. The risk of excessive reduction of blood pressure is elevated in patients with reduced BCC, that can be observed during therapy with diuretics, under strict salt-free diet, gemodialize, as well as vomiting and diarrhea. In most cases, episodes of significant decrease in blood pressure have been reported in patients with severe heart failure both in the presence of concomitant renal failure, and in the absence of se. Most often this side effect observed in patients, receiving “loop” diuretics at higher doses, as well as on the background of hyponatremia or renal dysfunction. In these patients, treatment should start under close medical supervision, preferably in a hospital. This drug is given in small doses, followed by careful titration. Possibly, should temporarily discontinue therapy diuretics. This approach is also used in patients with angina pectoris or cerebrovascular disease, which marked hypotension may cause myocardial infarction or cerebrovascular complications.

Before the appointment of the drug Prestarium^® A, as well as other ACE inhibitors, and during the reception should be carefully monitored blood pressure, renal function and the concentration of potassium ions in serum.

In order to reduce the likelihood of symptomatic hypotension in patients, receiving diuretic therapy in high doses, dose diuretics, possibly, should be reduced for a few days before the start of the drug Prestarium^® A.

In the case of hypotension the patient should be placed in the supine position. If necessary, make replenishment BCC using on / in a saline solution. Marked decrease in blood pressure when first taking the drug is not an obstacle for the further administration of the drug. After the restoration of the bcc and blood pressure treatment can be continued with careful selection of the dose.

In patients with symptomatic heart failure, hypotension, developing in the initial period of therapy with ACE inhibitors, It can lead to a deterioration of renal function. Sometimes while developing acute renal failure is, usually, reversible.

In patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney (especially in the presence of renal failure) during therapy with ACE inhibitors may increase concentrations of urea and creatinine in the blood serum.

The use of ACE inhibitors in patients with renovascular hypertension is accompanied by an increased risk of severe hypotension and renal insufficiency. Treatment of these patients start under close medical supervision with the appointment of the drug in small doses, and further an adequate selection of doses. During the first few weeks of therapy is necessary to temporarily discontinue diuretics and monitoring of renal function.

In some patients,, suffering from hypertension, in the presence of previously undetected renal failure, especially when concomitant administration of diuretics, may increase the concentration of urea and creatinine in the blood serum. These changes are usually expressed slightly and are reversible. In this case, we recommend reducing the dose of the drug Prestarium^® A and / or cancellation of a diuretic.

Patients, hemodialysis using membranes vysokoprotochnyh, there were a few cases of persistent, life-threatening anaphylactic reactions. Avoid ACE inhibitors when using this type of membrane.

Data on the use of the drug Prestarium^® And with no kidney transplantation.

Angioedema persons, limbs, lips, mucosas, language, glottis and / or larynx may develop in patients, receiving ACE inhibitors, especially during the first few weeks of therapy. In rare cases, severe angioedema may occur against a background of long-term use of an ACE inhibitor. In such cases, treatment with ACE inhibitors should be stopped immediately, as a replacement should be appointed medications other pharmacotherapeutic group.

Angioedema language, glottis or larynx may be fatal. When its development emergency treatment includes, among other appointments, immediate p / administration of epinephrine solution (adrenaline) 1:1000 (1 mg / ml) 0.3-0.5 ml or slow / in its administration (in accordance with the instructions for the preparation of infusion solution) under the control of ECG and blood pressure. The patient must be hospitalized for observation and treatment of not less than 12-24 hours until complete disappearance of the symptoms of this reaction.

During the apheresis procedure by a LDL-dextran sulfate absorption, the appointment of ACE inhibitors in patients may develop anaphylactic reactions.

There are some reports about the development of life-threatening anaphylactic reactions in patients, receiving ACE inhibitors during desensitizing treatment with bee venom (Bees, this). ACE inhibitors must be used with caution in patients with a predisposition to allergic reactions, undergoing desensitization treatments. Should be avoided in patients receiving ACE inhibitors, receiving bee venom immunotherapy. Nonetheless, This reaction can be avoided by temporarily canceling the ACE inhibitor before the procedure.

ACE inhibitors is sometimes associated with the syndrome, starting with the development of cholestatic jaundice, progressing to fulminant hepatic necrosis, and (sometimes) fatal. The mechanism of this syndrome is not clear. If you have symptoms of jaundice or increase in liver enzymes in patients, taking ACE inhibitors, discontinue drug therapy of a survey.

Neutropenia, agranulocytosis, thrombocytopenia, Anemia can develop during therapy with ACE inhibitors. In normal renal function and no other complications of neutropenia occurs rarely. ACE inhibitors are assigned only in case of emergency in the presence of systemic vasculitis, carrying immunosuppressive therapy, taking allopurinol or procainamide, as well as by combining all of these factors, especially against the background of previous renal failure. There is a risk of serious infectious diseases, resistant to intensive antibiotic. During the therapy with perindopril in patients with the above factors should regularly monitor the number of white blood cells and warn the patient of the need to inform the doctor about any symptoms of infection.

It should be taken into account, that patients blacks risk of angioedema higher. Like other ACE inhibitors, perindopril less effective as antihypertensive agents patients Blacks. This effect is probably associated with a marked prevalence of low-renin status in patients blacks with hypertension.

The therapy with an ACE inhibitor may occur dry non-productive cough, which after the drug is stopped.

The use of ACE inhibitors in patients, condition which requires surgical intervention and / or optionally general anesthesia, It can lead to hypotension or collapse, due to a sharp increase in antihypertensive action. Receiving perindopril discontinue the day before surgery. With the development of arterial hypotension necessary to maintain blood pressure by filling the BCC.

The therapy with ACE inhibitors may develop hyperkalemia, especially when the patient has renal and / or heart failure, uncontrolled diabetes. Usually, it is not recommended to prescribe drugs potassium, potassium-sparing diuretics and other drugs, associated with the risk of increasing the content of potassium (eg, Heparin) because of the possibility of severe hyperkalemia. If co-administration of these drugs is necessary, the therapy should be accompanied by regular monitoring of serum potassium.

Patients, receiving hypoglycemic agents for oral or insulin, During the first month of therapy with ACE inhibitors should be carefully monitored blood glucose.

Not recommended for use in conjunction with perindopril lithium preparations, potassium-sparing diuretics, potassium supplements, kalisodergaszczye products and nutritional supplements.

Because, that in the preparation of auxiliary substances include lactose monohydrate, Prestarium^® A is contraindicated in patients with lactase deficiency, galactosemia or syndrome glucose / galactose malabsorption. In tablets, the drug Prestarium^® And 2.5 mg, 5 mg 10 mg contains 36.29 mg, 72.58 mg 145.16 mg lactose monohydrate respectively.

Effects on ability to drive vehicles and management mechanisms

ACE inhibitors should be used with caution in patients, drive vehicles and engage in activities, require high concentration and speed of psychomotor reactions, because of the risk of hypotension and dizziness.

Overdose

Symptoms: marked reduction in blood pressure, shock, electrolyte imbalance (such as increasing the concentration of potassium ions, reduced sodium); renal failure, hyperventilation, tachycardia, dizziness, bradycardia, anxiety and cough.

Treatment: with a significant decrease in blood pressure should be transferred to the patient in the supine position and can immediately replenishing BCC, possibly, hold infusion of angiotensin II and / or type I / catecholamine. With the development of a stable bradycardia may be required artificial pacemaker. Constant monitoring of vital body functions, Serum electrolytes and QC. Perindopril may be removed from the systemic circulation by hemodialysis. If dialysis is necessary to avoid the use of polyacrylic vysokoprotochnyh membranes.

Drug Interactions

IN the initial period of treatment in some patients during therapy with diuretics, especially when excess fluid excretion and / or salts, there may be an excessive reduction of blood pressure, the risk of which can be reduced by eliminating a diuretic, introduction of increased amounts of water and / or sodium chloride, and assigning an ACE inhibitor at lower doses. Further increase of the dose of perindopril should be performed with caution.

Against the background of ACE inhibitor therapy, usually, content of potassium in serum is within the normal range, but sometimes may develop hyperkalemia. The combined use of ACE inhibitors and potassium-sparing diuretics (spironolactone, triamterene and amiloride) and preparations of potassium, potassium-based products and food additives can lead to a significant increase in the concentration of potassium in blood serum. In this regard co-administration of ACE inhibitors is not recommended. These combinations should be used only in the case of hypokalemia, observing precautions and constantly monitoring the content of potassium in the blood serum.

Co-administration of ACE inhibitors and drugs lithium may lead to a reversible increase in the concentration of lithium in blood serum and the development of lithium toxicity. Additional administration of thiazide diuretics on the background of combined use of lithium and ACE inhibitors increases the risk of existing lithium toxicity. Joint ACE inhibitors and lithium is not recommended. If this combination can not be avoided, it is necessary to carry out regular monitoring of serum lithium.

Appointment of NSAIDs may be associated with the weakening of the antihypertensive effect of ACE inhibitors. Furthermore, found, NSAIDs and ACE inhibitors have an additive effect in increasing the content of potassium in blood serum, thus it is also possible deterioration of kidney function. Usually, These effects are reversible. In rare cases may develop acute renal failure, arising, usually, when an existing impaired renal function in elderly patients or in the background of dehydration.

The antihypertensive effect of the drugs can be enhanced on the background of combined use with ACE inhibitors. The use of nitroglycerin and / or other vasodilators may result in additional hypotensive effect.

While the use of ACE inhibitors allopurinol, immunosuppressants, incl. cytostatic drugs and systemic corticosteroids, procainamide may increase the risk of leucopenia.

ACE inhibitors may enhance the hypoglycemic effect of insulin and oral hypoglycemic agents up to the development of hypoglycemia. Usually, This phenomenon is observed in the first weeks of combined use of these drugs in patients with renal insufficiency.

Co-administration with ACE inhibitors tricyclic antidepressants, antipsychotics (neuroleptics), funds for general anesthesia may lead to enhanced hypotensive effect.

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors. In the appointment of such a combination should regularly assess the effectiveness of ACE inhibitors.

Antacids reduce the bioavailability of ACE inhibitors.

Perindopril can be administered in conjunction with acetylsalicylic acid (as thrombolytic), thrombolytic agents, beta-blockers and / or nitrates.

Ethanol enhances the hypotensive effect of ACE inhibitors.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

The drug should be stored out of reach of children. Special conditions for storage of the drug is not required. Shelf life – 3 year.