Perindopril

PERINDOPRES® tablets 4 mg, tablets 8 mg

Instruction manual

For medical use of the drug

Structure:

Active ingredient: perindopril;

1 tablet contains 4 mg or 8 mg of perindopril tert-butylamine, which corresponds to 3.338 mg or 6.676 mg of perindopril;

excipients: lactose monohydrate; microcrystalline cellulose; silicon dioxide, colloidal hydrophobic; magnesium stearate.

Dosage form.

Tablets.

Basic physico-chemical properties: tablets of white or almost white color, flat-cylindrical in shape, with chamfer and risk.

Pharmacotherapeutic group.

Inhibitors of angiotensin-converting enzyme (APF), monocomponent. perindopril. code atx c09a a04.

Pharmacological properties.

Pharmacodynamics

Perindopril is an enzyme inhibitor that converts angiotensin I to angiotensin II (angiotensin converting enzyme - ACE). A conversion enzyme, or kinase, is an exopeptidase that makes it possible to convert angiotensin I into a vasoconstrictor angiotensin II, and also causes the bradykinin vasodilator to break down to an inactive heptapeptide. ACE inhibition leads to a decrease in the concentration of angiotensin II in blood plasma, which increases the activity of renin in blood plasma (by the feedback mechanism) and reduces the secretion of aldosterone. Since ACE inactivates bradykinin, ACE inhibition also leads to increased activity of the circulating and local kallikrein-kinin system (and, thus, also leads to activation of the prostaglandin system). This mechanism of action leads to a decrease in blood pressure by ACE inhibitors and is partially responsible for the appearance of some side effects (for example, cough).

Perindopril tert-butylamine acts through its active metabolite - perindoprilat. Other metabolites do not show activity in ACE inhibition under experimental conditions.

Arterial hypertension.

Perindopril effectively reduces blood pressure at all degrees of arterial hypertension: mild, moderate and severe; a decrease in systolic and diastolic blood pressure is observed in the patient both in the supine position and in the standing position.

Perindopril reduces the resistance of peripheral vessels, which leads to a decrease in blood pressure. As a consequence, peripheral blood flow increases without affecting the heart rate.

As a rule, renal blood flow also increases, while the glomerular filtration rate usually does not change.

The maximum antihypertensive effect develops 4–6 hours after a single dose and persists for at least 24 hours: the T / P ratio (minimum efficiency / maximum effectiveness during the day) of perindopril is 87–100%.

Blood pressure decreases rapidly. In patients who responded to treatment, normalization of blood pressure occurs within a month and persists without tachyphylaxis.

In the case of discontinuation of perindopril, a withdrawal effect does not occur.

Perindopril reduces left ventricular hypertrophy.

Clinical studies have shown that perindopril has vasodilating properties. It improves the elasticity of large arteries and reduces the ratio of wall thickness to the lumen of the vessel for small arteries.

Combination therapy with thiazide diuretics exhibits an additive synergistic effect. The combination of an ACE inhibitor and a thiazide diuretic also reduces the risk of developing hypokalemia caused by a diuretic.

Heart failure.

Perindopril tert-butylamine facilitates the work of the heart by reducing pre- and afterload on the heart.

A study in patients with heart failure demonstrated:

• decrease in filling pressure of the right and left ventricles;
• decreased systemic peripheral resistance;
• increased cardiac index and improved cardiac output;
• increased regional blood flow in the muscles of the myocardium.

In comparative studies, the first administration of 2 mg perindopril to patients with mild to moderate heart failure was not associated with any significant decrease in blood pressure compared with that with placebo.

Pharmacokinetics

Absorption.

After oral administration, perindopril is rapidly absorbed, the maximum plasma concentration is reached within 1 hour. The half-life of perindopril in blood plasma is 1 hour.

Perindopril is a prodrug. 27% of the total amount taken perindopril is determined in the blood as an active metabolite - perindoprilat. In addition to the active metabolite - perindoprilat, the drug forms 5 metabolites that are inactive. The maximum concentration of perindoprilat in blood plasma is achieved 3-4 hours after administration.

Eating reduces the conversion of perindopril to perindoprilat, therefore, its bioavailability decreases, therefore, it is recommended to take the daily dose of perindopril tert-butylamine once in the morning before meals.

A linear relationship between the dose of perindopril and its concentration in blood plasma is noted.

Distribution.

The volume of distribution of unbound perindoprilat is approximately 0.2 l / kg. The binding of perindoprilat to plasma proteins is 20%, mainly with the angiotensin-converting enzyme, but this indicator is dose-dependent.

Breeding.

Perindoprilat is excreted in the urine. The final half-life of the unbound fraction is approximately 17 hours. The stage of equilibrium plasma concentration is reached after 4 days from the start of treatment.

Special patient groups.

Excretion of perindoprilat slows down in elderly patients, as well as in patients with heart or kidney failure. It is recommended to select a dose for patients with renal failure, taking into account the degree of insufficiency (creatinine clearance).

Dialysis clearance of perindoprilat - 70 ml / min.

The kinetics of perindopril changes in patients with cirrhosis: the hepatic clearance of perindopril is halved. However, the amount of perindoprilat formed does not decrease. Therefore, such patients do not need to adjust the dose.

Clinical characteristics.

Indications.

• Arterial hypertension; heart failure; prevention of re-stroke in patients with cerebrovascular disease; prevention of cardiovascular complications in patients with documented stable coronary heart disease.

Long-term treatment reduces the risk of myocardial infarction and heart failure (according to the EUROPA study).

Contraindications

• Hypersensitivity to the active substance or to any of the excipients, or to any other inhibitor of APF; a history of angioedema after the use of an APF inhibitor; idiopathic or hereditary angioedema; concomitant administration with drugs containing the active substance aliskiren to patients with diabetes mellitus or with renal failure (glomerular filtration rate 2) (see sections "application features" and "interaction with other drugs and other types of interactions"); pregnancy or the period of pregnancy planning (see the section "use during pregnancy or lactation").

Interaction with other drugs and other types of interactions.

Medicines causing hyperkalemia.

Some drugs or therapeutic classes of drugs can cause hyperkalemia, namely: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory drugs (NSAIDs), heparins, immunosuppressants such as cyclosporin or tacoprimol. The simultaneous use of these drugs increases the risk of hyperkalemia.

It is contraindicated (see section "Contraindications") the simultaneous use of perindopril with aliskiren for patients with diabetes mellitus or patients with impaired renal function, given the increased risk of hyperkalemia, impaired renal function, cardiovascular morbidity and mortality, and is not recommended (see section " Features of use ") to all other groups of patients.

The simultaneous use of ACE inhibitors and angiotensin receptor blockers. Data have been published that in patients with established atherosclerosis, heart failure or diabetes mellitus with target organ damage, the simultaneous use of ACE inhibitors and angiotensin receptor blockers was accompanied by an increase in the incidence of arterial hypotension, fainting, hyperkalemia, and impaired renal function (including acute renal deficiency) compared with those of monotherapy with drugs that affect the renin-angiotensin-aldosterone system. Double blockade (i.e., a combination of an ACE inhibitor with angiotensin II receptor antagonists) can be used in individual cases and under close monitoring of kidney function, potassium levels and blood pressure.

Estramustine. The risk of adverse reactions, such as angioedema (angioedema), is increased.

Potassium-sparing diuretics (e.g. triamteren, amiloride), potassium salts. Hyperkalemia (including lethal) may occur, especially in patients with renal failure (additive hyperkalemia). The above medicines are not recommended for simultaneous use with perindopril (see section "Features of use"). However, if simultaneous administration of the aforementioned substances is necessary, they should be used with caution and frequent monitoring of potassium in blood plasma should be carried out.

Lithium. When using ACE inhibitors with lithium preparations, a reversible increase in the concentration of lithium in blood plasma and, accordingly, an increase in the risk of its toxic effect are possible. It is not recommended to use perindopril with lithium preparations. In the case of the proven need for such an appointment, it is necessary to carefully monitor the level of lithium in the blood plasma (see the section "Features of use").

Simultaneous use, which requires special attention.

Antidiabetic agents (insulin, oral hypoglycemic agents). Epidemiological studies suggest that the simultaneous use of ACE inhibitors and hypoglycemic agents (insulin, oral hypoglycemic agents) can lead to an increase in the hypoglycemic effect with a risk of hypoglycemia. Most likely, this phenomenon can occur in the first weeks of combination treatment and in patients with renal failure.

Baclofen. The antihypertensive effect is enhanced. If necessary, you should monitor blood pressure and adapt the dose of antihypertensive drugs.

Diuretics. In patients taking diuretics, and especially those who have impaired water-electrolyte metabolism, an excessive decrease in blood pressure after treatment with ACE inhibitors is possible.The likelihood of developing a hypotensive effect is reduced due to the cancellation of the diuretic, an increase in the volume of circulating blood, or the consumption of salt before starting perindopril therapy with tert-butylamine. Treatment should begin with low doses and gradually increase them.

In case of arterial hypertension, when a previously prescribed diuretic could cause water / electrolyte insufficiency, it must be canceled before treatment with an ACE inhibitor (in such cases, taking a diuretic can be resumed over time) or an ACE inhibitor in a low dose should be prescribed with a gradual increase.

With congestive heart failure while taking a diuretic, an ACE inhibitor should be started with a minimum dose, possibly after a dose reduction of the diuretic.

In any case, it is necessary to monitor renal function (creatinine level) during the first weeks of treatment with an ACE inhibitor.

Potassium-sparing diuretics (eplerenone, spironolactone). In the case of simultaneous use of eplerenone or spironolactone in doses from 12.5 mg to 50 mg per day with low doses of an ACE inhibitor, it must be borne in mind that:

• in case of non-compliance with the recommendations for the purpose of this combination, there is a risk of hyperkalemia (possibly fatal) in the treatment of patients with heart failure II-IV class according to NYHA and ejection fraction

  - before the appointment of such a combination, you should make sure that there is no hyperkalemia and renal failure;

• careful monitoring of potassium and creatininemia is recommended weekly during the first month of treatment and monthly thereafter.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid ≥ 3 g / day. It is possible to weaken the antihypertensive effect while using ACE inhibitors with NSAIDs, such as: acetylsalicylic acid in anti-inflammatory doses, COX-2 inhibitors, non-selective NSAIDs. The simultaneous use of ACE inhibitors and NSAIDs can lead to an increased risk of impaired renal function, including the likelihood of developing acute renal failure, increased levels of potassium in the blood plasma, especially in patients with a history of impaired renal function. Such a combination should be prescribed with caution, in particular for elderly patients. Patients should restore water balance, and it is also necessary to pay attention to monitoring kidney function immediately after the appointment of combination therapy and periodically in the future.

Simultaneous use, which requires some attention.

Antihypertensive agents and vasodilators. The simultaneous use of antihypertensive agents can increase the hypotensive effect of perindopril tert-butylamine. The simultaneous use with nitroglycerin and other nitrates, or other vasodilators can contribute to an additional decrease in blood pressure.

Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin). In patients who are prescribed a combination of gliptin and an ACE inhibitor, an increased risk of angioedema is possible due to the fact that gliptin reduces the activity of dipeptyl peptidase-IV (DPP-IV).

The simultaneous use of anesthetics, tricyclic antidepressants or antipsychotropic drugs with ACE inhibitors can lead to a further decrease in blood pressure (see section "Features of use").

Sympathomimetics may attenuate the hypotensive effect of ACE inhibitors.

Gold. A nitrate-like reaction (symptoms include facial flushing, nausea, vomiting, and arterial hypotension) is rare in patients who take ACE inhibitors, including perindopril, and gold injectable drugs (sodium aurothiomalate) at the same time.

Features of the application.

Stable ischemic heart disease.

If during the first month of perindopril treatment there was an episode of unstable angina (of any severity), the benefit / risk ratio must be carefully weighed before deciding whether to continue therapy.

Arterial hypotension.

Taking ACE inhibitors can cause a decrease in blood pressure. Symptomatic arterial hypotension is less common in patients with uncomplicated arterial hypertension and is more likely in patients with hypovolemia, those who take diuretics, are on a salt-limited diet, in patients on dialysis, in patients with diarrhea or vomiting, or in patients with severe renin-dependent arterial hypertension (see sections "Interaction with other drugs and other types of interactions" and "Adverse reactions"). Symptomatic hypotension is more likely in patients with symptomatic heart failure, with or without concomitant renal failure. The occurrence of symptomatic arterial hypotension is most likely in patients with a more severe degree of heart failure, who take large doses of loop diuretics, have a history of hyponatremia, or renal failure of a functional nature. To reduce the risk of symptomatic arterial hypotension at the beginning of therapy and at the stage of dose selection, patients should be under the supervision of a physician (see sections "Dosage and Administration" and "Adverse Reactions"). The same warnings exist for patients with coronary heart disease or cerebrovascular disease, in whom an excessive decrease in blood pressure can cause myocardial infarction or stroke.

If arterial hypotension occurs, the patient should take a horizontal position and, if necessary, inject intravenously 0.9% (9 mg / ml) sodium chloride solution. Transient hypotension is not a contraindication for the further use of the drug, which can usually be used without any obstacles after restoring blood volume and increasing blood pressure.

In some patients with congestive heart failure with normal or low blood pressure of perindopril, tert-butylamine can cause an additional decrease in systemic blood pressure. This effect is predictable and usually does not require discontinuation of the drug. If arterial hypotension becomes symptomatic, it may be necessary to reduce the dose or discontinue the drug.

Aortic and mitral valve stenosis / hypertrophic cardiomyopathy.

Like other ACE inhibitors, perindopril tert-butylamine should be prescribed with caution to patients with mitral valve stenosis or obstruction of the exit from the left ventricle (aortic stenosis or hypertrophic cardiomyopathy).

Renal failure.

In case of renal failure (creatinine clearance

In patients with symptomatic heart failure, arterial hypotension, which occurs at the beginning of the use of ACE inhibitors, can lead to impaired renal function, in some cases with the occurrence of acute renal failure, which is usually reversible.

In some patients with bilateral renal artery stenosis or stenosis of a single kidney artery, when using ACE inhibitors, an increase in serum urea and creatinine levels were observed, which usually returned to normal after discontinuation of treatment. This is especially true for patients with renal failure. In the presence of concomitant renovascular hypertension, the risk of severe arterial hypotension and renal failure increases.Treatment of such patients should begin under close medical supervision, with small doses and with careful titration of doses. Given the above, treatment with diuretics can contribute to the occurrence of arterial hypotension, so they need to be canceled and kidney function monitored in the first weeks of perindopril treatment with tert-butylamine.

Some patients with arterial hypertension, who did not have any renovascular disease before treatment, developed an increase in blood urea and serum creatinine, usually insignificant and temporary, especially when perindopril tert-butylamine is prescribed simultaneously with a diuretic. But this is more common in patients with pre-existing renal failure. Dose reduction and / or withdrawal of a diuretic and / or perindopril tert-butylamine may be required.

Patients on hemodialysis.

In patients undergoing hemodialysis using high-flow polyacrylic membranes and taking concomitant therapy with ACE inhibitors, anaphylactic reactions occurred. Therefore, for such patients, it is necessary to decide on the use of another type of dialysis membranes or another class of antihypertensive drugs.

Patients after kidney transplantation.

There is no experience in prescribing perindopril tert-butylamine to patients after a recent kidney transplant operation.

Hypersensitivity / angioedema.

Rare cases of the occurrence of angioedema of the face, limbs, lips, mucous membranes, tongue, glottis and / or larynx in patients with ACE inhibitors, including perindopril tert-butylamine, have been reported (see section “Adverse Reactions”). This can happen at any time during treatment. In such cases, it is necessary to urgently discontinue the drug and establish appropriate supervision of the patients condition until the symptoms disappear completely. In those rare cases when edema spreads only in the area of ​​the face and lips, the patients condition, as a rule, improves without treatment. Prescribing antihistamines may be helpful in relieving symptoms.

Angioedema associated with laryngeal edema can be fatal. In cases where the swelling extends to the tongue, glottis or larynx, causes airway obstruction, urgent emergency treatment is necessary, which may include the administration of adrenaline and / or airway patency. Patients should be under close medical supervision until the symptoms that have arisen disappear and the condition stabilizes.

Patients with a history of angioedema that was not associated with an ACE inhibitor are at increased risk for angioedema while taking an ACE inhibitor (see section “Contraindications”).

Rare cases of intestinal angioedema have been reported in patients during treatment with ACE inhibitors. In such patients, abdominal pain was observed (with or without nausea or vomiting); in some cases, no previous angioedema of the face was observed and the level of C-1 esterase was normal. The diagnosis of intestinal angioedema was established during computed tomography of the abdominal cavity or ultrasound, or during surgery. After the withdrawal of the ACE inhibitor, the symptoms of angioedema disappeared. Intestinal angioedema should be ruled out in the differential diagnosis in patients with abdominal pain taking ACE inhibitors.

Anaphylactoid reactions during plasmapheresis of low density lipoproteins (LDL).

Rarely, in patients taking ACE inhibitors, life-threatening anaphylactoid reactions can occur during plasmapheresis of low-density lipoprotein (LDL) using dextransulfate. The development of anaphylactoid reactions can be avoided if treatment with ACE inhibitors is temporarily discontinued before each plasmapheresis.

Anaphylactoid reactions during desensitizing therapy.

In patients taking ACE inhibitors, anaphylactoid reactions may occur during desensitized treatment with drugs that contain bee venom. These reactions can be avoided by temporarily stopping the use of an ACE inhibitor, but reactions can occur again if careless provocative tests are performed.

Liver failure.

Cases when, against the background of taking an ACE inhibitor, a syndrome develops that begins with cholestatic jaundice and progresses to transient liver necrosis and sometimes death, rarely occur. The mechanism of development of this syndrome is unknown. Patients who develop jaundice or a significant increase in liver enzymes while taking an ACE inhibitor should stop using it and undergo an appropriate medical examination and receive treatment (see section “Adverse Reactions”).

Neutropenia / agranulocytosis / thrombocytopenia / anemia.

Among patients taking ACE inhibitors, cases of neutropenia / agranulocytosis, thrombocytopenia, and anemia have been reported. In patients with normal renal function and in the absence of other risk factors, neutropenia occurs rarely. Perindopril should be prescribed very carefully to patients with collagenoses, during therapy with immunosuppressants, allopurinol or procainamide or with a combination of these aggravating factors, especially against the background of existing renal dysfunction. Serious infections can sometimes develop in the aforementioned patients, which in some cases do not respond to intensive antibiotic therapy. If perindopril is prescribed to such patients, it is recommended to periodically monitor the number of white blood cells and patients should be aware that it is necessary to notify of any manifestation of an infectious disease (sore throat, fever).

Racial factor.

ACE inhibitors are more likely to cause angioedema in patients of the Negroid race than in other races. Like other ACE inhibitors, perindopril is less effective in lowering blood pressure in patients of the Negroid race than in patients of other races. This may be explained by the low level of renin in the blood of patients with arterial hypertension from the African American population.

Cough.

Reported on the occurrence of cough during therapy with ACE inhibitors. According to the characteristics of the cough is unproductive, persistent and stops after the drug is withdrawn. Cough caused by taking ACE inhibitors should be considered when making a differential diagnosis of cough.

Surgical intervention / anesthesia.

The drug can block the secondary formation of angiotensin II in response to the compensatory release of renin in patients during surgery or during anesthesia with drugs that cause hypotension. The drug should be discontinued one day before surgery. In the event of arterial hypotension, if it is believed that it is caused by the indicated mechanism, the patients condition can be normalized by increasing the volume of circulating blood.

Hyperkalemia

In some patients, while taking ACE inhibitors, including perindopril, there was an increase in the concentration of potassium in the blood serum.Risk factors for hyperkalemia include renal failure, impaired renal function, age (> 70 years), diabetes mellitus, intercurrent conditions such as dehydration, acute cardiac decompensation, metabolic acidosis, and the simultaneous use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene, or amilirid ), food additives containing potassium, or its salt with potassium, or other drugs that cause an increase in the concentration of potassium in the blood serum (for example eparina). The use of potassium supplements, potassium-sparing diuretics, or salt substitutes with potassium, especially for patients with impaired renal function, can lead to a significant increase in serum potassium levels. Hyperkalemia can cause serious, sometimes fatal arrhythmia. If the simultaneous use of perindopril and any of the above substances is considered appropriate, they should be used with caution and with frequent monitoring of the level of potassium in the blood serum (see section "Interaction with other drugs and other types of interactions").

Patients with diabetes.

Patients with diabetes who take oral hypoglycemic agents or receive insulin should carefully monitor their glycemia during the first month of treatment with ACE inhibitors (see section “Interaction with other drugs and other types of interactions”).

Lithium.

The simultaneous use of lithium and perindopril is usually not recommended (see section "Interaction with other drugs and other types of interactions").

Potassium-sparing drugs, food supplements containing potassium or salt substitutes with potassium.

The simultaneous use of perindopril with potassium-sparing drugs or food additives containing potassium is not recommended (see section "Interaction with other drugs and other types of interactions").

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

There is information about the occurrence of arterial hypotension, fainting, stroke, hyperkalemia and impaired renal function (including acute renal failure), especially while taking medications that affect RAAS. The combination of an ACE inhibitor (ACE inhibitor) with an angiotensin II receptor blocker (ARB) or aliskiren, given the double blockade of the renin-angiotensin-aldosterone system, is not recommended.

For patients with diabetes mellitus, or with renal failure (glomerular filtration rate 2), simultaneous use with aliskiren is contraindicated (see sections "Contraindications" and "Interaction with other drugs and other types of interactions").

Excipients.

This medicine contains 59.0 / 118.0 mg of lactose monohydrate. Use with caution in patients with diabetes. Perindopril tert-butylamine is not recommended for patients with rare hereditary galactose intolerance, glucose-galactose malabsorption syndrome, Lapp lactase deficiency.

Use during pregnancy or lactation.

Pregnancy. the use of APF inhibitors is contraindicated during pregnancy (see section "contraindications"). the drug should not be used by pregnant women or women who plan to become pregnant. if pregnancy is confirmed during treatment, the use of the drug should be stopped immediately and replaced with another drug approved for use in pregnant women.

Epidemiological data on the risk of a teratogenic effect as a result of taking ACE inhibitors during the first trimester of pregnancy are not final, therefore a slight increase in risk cannot be ruled out.It is known that taking ACE inhibitors during the second and third trimesters of pregnancy leads to fetotoxicity and neonatal toxicity.

If a woman took an ACE inhibitor during the second trimester of pregnancy, it is recommended that the child undergo an ultrasound examination of the kidney and skull bones. Newborns whose mothers took ACE inhibitors during pregnancy should be closely monitored because of the possibility of arterial hypotension.

Lactation. The use of perindopril tert-butylamine during breastfeeding is not recommended due to the lack of data on its penetration into breast milk. During breastfeeding, it is advisable to prescribe an alternative treatment with a more investigated safety profile, especially during the period of feeding a newborn or premature baby.

Fertility. There is no effect on reproductive ability or fertility.

The ability to influence the speed of reactions when driving vehicles or other mechanisms.

Perindopril tert-butylamine does not directly affect the ability to drive vehicles or work with other mechanisms. but in some patients, individual reactions may occur associated with a decrease in blood pressure, especially at the beginning of treatment or when used simultaneously with other antihypertensive drugs. as a result, the ability to drive vehicles or work with other mechanisms can be reduced.

Dosage and administration.

For oral use.

Perindopres tablets^® 4 mg and 8 mg can be divided in half to achieve a dose of 2 mg and 4 mg.

Tablets are recommended to be taken once a day in the morning before meals.

The dose should be selected individually, depending on the indicators of blood pressure (see section "Features of use").

Arterial hypertension.

Perindopril tert-butylamine can be prescribed as monotherapy or in combination with drugs of other classes of antihypertensive drugs.

The recommended starting dose is 4 mg once daily in the morning