Prestarium A tab disperg 5mg N30 (Servier)

Compound

Dosage form and composition

Prestarium is produced in the form of tablets for oral use. The active ingredient of the product is perindopril salt. The substance blocks the activity of the enzyme hormone angiotensin, which provokes an increase in blood pressure. The drug has several varieties, differing in dosage and content of auxiliary compounds:

• Prestarium tablets: containing 2, 4 and 8 mg. perindopril;
• Prestarium A: with an increased dosage: 2.5, as well as 5 and 10 mg;
• Bi-Prestarium: tablets in double dosage containing amlodipine, a calcium channel blocker.

All types of Prestarium have a similar effect, but they are prescribed for varying severity of hypertension.

Pharmacodynamics

Mechanism of action

Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II.

ACE, or kininase II, is an exopeptidase that carries out both the conversion of angiotensin I into the vasoconstrictor substance angiotensin II, and the destruction of bradykinin, which has a vasodilatory effect, into an inactive heptapeptide. As a result, perindopril reduces the secretion of aldosterone.

Since ACE inactivates bradykinin, suppression of ACE is accompanied by an increase in the activity of both the circulating and tissue kallikrein-kinin system, and the PG system is also activated. It is possible that this effect is part of the mechanism of the antihypertensive effect of ACE inhibitors, as well as the mechanism of development of some side effects of drugs of this class (for example, cough).

Perindopril has a therapeutic effect due to the active metabolite perindoprilat. Other metabolites do not have an ACE inhibitory effect in vitro.

Clinical efficacy and safety

Arterial hypertension

Perindopril is effective in the treatment of arterial hypertension of any severity. With the use of the drug, there is a decrease in both SBP and DBP in the supine and standing positions.

Perindopril reduces peripheral vascular resistance, which leads to a decrease in blood pressure, while peripheral blood flow accelerates without changing heart rate.

As a rule, perindopril leads to an increase in renal blood flow, while the glomerular filtration rate does not change.

The antihypertensive effect of the drug reaches its maximum 4–6 hours after a single oral dose and persists for 24 hours. 24 hours after oral administration, pronounced (about 80%) residual ACE inhibition is observed.

A decrease in blood pressure is achieved quite quickly. In patients with a positive response to treatment, normalization of blood pressure occurs within a month and is maintained without the development of tachycardia.

Discontinuation of treatment is not accompanied by the development of withdrawal syndrome.

Perindopril has a vasodilating effect, helps restore the elasticity of large arteries and the structure of the vascular wall of small arteries, and also reduces left ventricular hypertrophy.

The simultaneous administration of thiazide diuretics increases the severity of the antihypertensive effect. In addition, the combination of an ACE inhibitor and a thiazide diuretic also reduces the risk of hypokalemia while taking diuretics.

Heart failure

Perindopril normalizes heart function by reducing preload and afterload.

In patients with chronic heart failure treated with perindopril, the following was found:

- decrease in filling pressure in the left and right ventricles of the heart;

— decrease in OPSS;

- increased cardiac output and increased cardiac index.

A study of the drug compared with placebo showed that changes in blood pressure after the first dose of Prestarium® A 2.5 mg in patients with chronic heart failure (functional class II–III according to the NYHA classification) were not statistically significantly different from the changes in blood pressure observed after taking placebo.

Cerebrovascular diseases

Results of the PROGRESS study, which assessed the effect of active therapy with perindopril (monotherapy or in combination with indapamide) for 4 years on the risk of recurrent stroke in patients with a history of cerebrovascular disease. After an introductory period of perindopril tert-butylamine 2 mg (equivalent to perindopril arginine 2.5 mg) once daily for two weeks and then 4 mg (equivalent to perindopril arginine 5 mg) once daily for the next two weeks, 6105 patients were randomized into two groups: placebo (n = 3054) and perindopril tert-butylamine 4 mg (corresponding to 5 mg perindopril arginine) (monotherapy) or in combination with indapamide (n = 3051).

Indapamide was additionally prescribed to patients who did not have direct indications or contraindications for the use of diuretics. This therapy was prescribed in addition to standard therapy for stroke and/or arterial hypertension or other pathological conditions. All randomized patients had a history of cerebrovascular disease (stroke or transient ischemic attack) within the past 5 years. Blood pressure was not an inclusion criterion: 2916 patients had arterial hypertension and 3189 had normal blood pressure. After 3.9 years of therapy, blood pressure (sBP/dBP) decreased by an average of 9/4 mmHg. Art. It also showed a significant reduction in the risk of recurrent stroke (both ischemic and hemorrhagic) of the order of 28% (95% CI (17; 38), p < 0.0001) compared with placebo (10.1 and 13.8%) .

Additionally, significant risk reductions have been shown:

- fatal or disabling strokes;

- major cardiovascular complications, including myocardial infarction, incl. with fatal outcome;

- dementia associated with stroke;

- serious deterioration of cognitive functions.

This was noted both in patients with arterial hypertension and with normal blood pressure, regardless of age, gender, presence or absence of diabetes mellitus and type of stroke.

Stable ischemic heart disease

It has been shown that when taking perindopril tertbutylamine at a dose of 8 mg/day (equivalent to 10 mg perindopril arginine) in patients with stable coronary artery disease, there is a significant reduction in the absolute risk of complications provided for by the main criterion of effectiveness (mortality from cardiovascular diseases, incidence of non-fatal myocardial infarction and/or cardiac arrest followed by successful resuscitation), by 1.9%. In patients who had previously had a myocardial infarction or coronary revascularization procedure, the absolute risk reduction was 2.2% compared with the placebo group.

Pharmacokinetics

Suction. When taken orally, perindopril is rapidly absorbed from the gastrointestinal tract, Cmax in blood plasma is reached after 1 hour. T1/2 of perindopril from blood plasma is 1 hour.

Perindopril has no pharmacological activity. Approximately 27% of the total amount of absorbed perindopril enters the bloodstream in the form of the active metabolite perindoprilate. In addition to perindoprilate, 5 more metabolites are formed that do not have pharmacological activity. Cmax of perindoprilate in blood plasma is achieved 3–4 hours after oral administration.

Eating slows down the conversion of perindopril to perindoprilat, thereby affecting bioavailability. Therefore, the drug should be taken orally once a day, in the morning, before meals.

Distribution. The Vd of free perindoprilate is approximately 0.2 l/kg. The association of perindoprilate with plasma proteins, mainly with ACE, is insignificant and dose-dependent.

Excretion. Perindoprilat is excreted by the kidneys. T1/2 of the free fraction is 3–5 hours. Effective T1/2 is approximately 17 hours, the equilibrium state is reached within 4 days.

Special groups of patients. The elimination of perindoprilate is slowed down in old age, as well as in patients with heart and renal failure. The dialysis clearance of perindoprilate is 70 ml/min.

In patients with liver cirrhosis, the hepatic clearance of perindopril is reduced by 2 times. However, the amount of perindoprilate formed does not decrease, and dose adjustment of the drug is not required (see “Dosage and Administration” and “Special Instructions”).

Contraindications

hypersensitivity to the active substance, other ACE inhibitors and excipients (see “Composition”) included in the drug;

history of angioedema (Quincke's edema) associated with taking an ACE inhibitor;

hereditary/idiopathic angioedema;

pregnancy (see “Use during pregnancy and lactation”);

period of breastfeeding (see “Use during pregnancy and lactation”);

simultaneous use with aliskiren and aliskiren-containing drugs in patients with diabetes mellitus or impaired renal function (glomerular filtration rate (GFR) <60 ml/min/1.73 m2) (see “Special Instructions” and “Interaction”);

lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome;

age under 18 years (efficacy and safety have not been established).

With caution: (see also “Special Instructions” and “Interaction”): bilateral renal artery stenosis or the presence of only one functioning kidney, renal failure, systemic connective tissue diseases (systemic lupus erythematosus, scleroderma), therapy with immunosuppressants, allopurinol, procainamide ( risk of developing neutropenia, agranulocytosis), reduced blood volume (taking diuretics, salt-free diet, vomiting, diarrhea), angina pectoris, cerebrovascular diseases, renovascular hypertension, diabetes mellitus, chronic heart failure functional class IV according to the NYHA classification, simultaneous use of potassium-sparing diuretics, potassium supplements, potassium-containing substitutes for table salt and lithium, hyperkalemia, surgery/general anesthesia, hemodialysis using high-flow membranes, desensitization therapy, LDL apheresis, condition after kidney transplantation, aortic stenosis/mitral stenosis/hypertrophic obstructive cardiomyopathy, use in black patients.

Use during pregnancy and breastfeeding

Pregnancy

Prestarium® A is contraindicated for use during pregnancy (see “Contraindications”).

Prestarium® A should not be used in the first trimester of pregnancy. If you are planning pregnancy or if it occurs while using the drug Prestarium® A, you should immediately stop taking the drug and, if necessary, prescribe other antihypertensive therapy with a proven safety profile for use during pregnancy.

It is known that the effect of ACE inhibitors on the fetus in the second and third trimesters of pregnancy can lead to disruption of its development (decreased renal function, oligohydramnios, delayed ossification of the skull bones) and the development of complications in the newborn (renal failure, arterial hypotension, hyperkalemia).

If the patient received ACE inhibitors during the second or third trimester of pregnancy, it is recommended to conduct an ultrasound examination of the newborn to assess the condition of the skull bones and renal function.

Breastfeeding period

It is not known whether perindopril passes into breast milk. Therefore, the use of Prestarium® A during breastfeeding is not recommended. If the use of the drug is necessary during lactation, then breastfeeding should be discontinued.

Fertility

Preclinical studies have shown no effect of perindopril on reproductive function in rats of both sexes.

How does Prestarium work?

The drug reduces the production of the hormone aldosterone, the breakdown of bradykinin and renin activity. The decrease in blood pressure as a result of taking it is not accompanied by a disturbance in heart rate. The use of Prestarium has a beneficial effect on renal blood flow. In this case, the main functions of the organs are not affected. During treatment, the size of the enlarged left ventricle is normalized, and the elasticity of the coronary and other large vessels improves. Prestarium containing amlodipine has a complex effect:

• dilates blood vessels;
• normalizes blood flow in the heart vessels and capillaries;
• reduces the load on the myocardium, improves its blood supply.

The medicine does not affect cholesterol metabolism and does not lead to metabolic disorders. The therapeutic effect develops within 1 hour after taking the tablets. It has a cumulative mechanism of action, the maximum is observed on days 4–5 from the start of the course and persists throughout its entire duration. Metabolites of the drug are excreted in the urine. Its remains do not accumulate inside the body. After withdrawal, patients do not exhibit addiction syndrome.

Side effects

The safety profile of perindopril is consistent with the safety profile of ACE inhibitors.

The most common adverse events reported in clinical studies and observed with perindopril are: dizziness, headache, paresthesia, vertigo, visual disturbances, tinnitus, excessive decrease in blood pressure, cough, shortness of breath, abdominal pain, constipation, diarrhea, taste disturbance, dyspepsia, nausea, vomiting, itching, skin rash, muscle spasms and asthenia.

The frequency of adverse reactions that were noted during clinical trials and/or post-registration use of perindopril is given in the following gradation: very often (≥1/10); often (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); unspecified frequency (frequency cannot be calculated from available data). The classification of frequency indicators is recommended by WHO.

From the circulatory and lymphatic system: infrequently* - eosinophilia; very rarely - decreased hemoglobin and hematocrit, thrombocytopenia, leukopenia/neutropenia, agranulocytosis, pancytopenia, hemolytic anemia in patients with congenital deficiency of glucose-6-phosphate dehydrogenase (see "Special Instructions").

Metabolic disorders: uncommon* - hypoglycemia (see "Special Instructions" and "Interactions"), hyperkalemia, reversible after discontinuation of the drug (see "Special Instructions"), hyponatremia.

From the side of the central nervous system: often - paresthesia, headache, dizziness, vertigo; uncommon - sleep disturbance, mood lability, drowsiness*, fainting*; very rarely - confusion.

From the side of the organ of vision: often - visual impairment.

On the part of the hearing organ: often - tinnitus.

From the cardiovascular system: often - excessive decrease in blood pressure and associated symptoms; uncommon* - vasculitis, tachycardia, palpitations; very rarely - cardiac arrhythmias, angina pectoris, myocardial infarction and stroke, possibly due to an excessive decrease in blood pressure in high-risk patients (see "Special Instructions").

From the respiratory system: often - cough, shortness of breath; uncommon - bronchospasm; very rarely - eosinophilic pneumonia, rhinitis.

From the digestive system: often - constipation, nausea, vomiting, abdominal pain, taste disturbance, dyspepsia, diarrhea; infrequently - dryness of the oral mucosa; very rarely - pancreatitis.

From the liver and biliary tract: very rarely - hepatitis (cholestatic or cytolytic) (see "Special Instructions").

On the part of the skin and subcutaneous fat: often - skin itching, rash; uncommon - angioedema of the face, lips, upper and lower extremities, mucous membranes, tongue, vocal folds and/or larynx; urticaria (see “Special Instructions”); very rarely - erythema multiforme; uncommon* - photosensitivity, pemphigus, increased sweating.

From the musculoskeletal system and connective tissue: often - muscle spasms; infrequently* - arthralgia, myalgia.

From the kidneys and urinary tract: infrequently - renal failure; very rarely - acute renal failure.

From the reproductive system: infrequently - erectile dysfunction.

General disorders and symptoms: often - asthenia; Uncommon: chest pain*, peripheral edema*, weakness*, fever*, falls*.

Laboratory indicators: rarely - increased activity of liver transaminases and bilirubin in the blood serum; infrequently* - increased concentrations of urea and creatinine in the blood plasma.

*Evaluation of the frequency of adverse reactions identified by spontaneous reports was based on data from the results of clinical studies.

Adverse events noted in clinical studies

The EUROPA study recorded only serious adverse events. Serious adverse events were reported in 16 (0.3%) patients in the perindopril group and 12 (0.2%) patients in the placebo group. In the perindopril group, a marked decrease in blood pressure was observed in 6 patients, angioedema in 3 patients, and sudden cardiac arrest in 1 patient. The rate of drug discontinuation due to cough, severe decrease in blood pressure, or other cases of intolerance was higher in the perindopril group compared with the placebo group.

Side effects

Prestarium can cause the following undesirable reactions from the body:

• nausea, dry mouth, loss of appetite;
• dry cough;
• increased uric acid levels;
• dizziness, headaches;
• physical weakness, apathy, increased drowsiness;
• depression;
• swelling of the ankles;
• thrombocytopenia, decreased hemoglobin, red blood cells and other blood count disorders.

Allergic reactions may cause skin itching, rashes, swelling of the mucous membranes and skin, and respiratory problems. Men may experience decreased libido. In case of overdose, vascular collapse, bradycardia, and impaired coordination of movements are likely.

Interaction

Drugs that cause hyperkalemia

Certain drugs or drugs from other pharmacological classes may increase the risk of developing hyperkalemia: aliskiren and aliskiren-containing drugs, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists (ARAs), NSAIDs, heparin, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim. Combining these drugs increases the risk of hyperkalemia.

Concomitant use is contraindicated (see section "Contraindications")

Aliskiren. Patients with diabetes mellitus or impaired renal function (GFR <60 ml/min) are at increased risk of hyperkalemia, deterioration of renal function, and increased incidence of cardiovascular morbidity and mortality.

Simultaneous use is not recommended (see section "Special instructions")

Aliskiren. In patients without diabetes mellitus or renal impairment, there may be an increased risk of hyperkalemia, worsening renal function, and increased incidence of cardiovascular morbidity and mortality.

Double blockade of the RAAS

The literature has reported that in patients with established atherosclerotic disease, heart failure, or diabetes mellitus with end-organ damage, concomitant therapy with an ACE inhibitor and an ARB II is associated with a higher incidence of hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure). ) compared to the use of only one drug that affects the RAAS. Dual blockade (for example, when combining an ACE inhibitor with an ARB II) should be limited to selected cases with careful monitoring of renal function, potassium levels and blood pressure.

Estramustine. Concomitant use may result in an increased risk of adverse effects such as angioedema.

Potassium-sparing diuretics (such as triamterene, amiloride, spironolactone and its derivative eplerenone), potassium salts

Hyperkalemia (possibly fatal), especially if renal function is impaired (additional effects associated with hyperkalemia).

The combination of perindopril with the above-mentioned drugs is not recommended (see "Special Instructions"). If, however, concomitant use is indicated, they should be used with caution and regular monitoring of serum potassium levels.

Features of the use of spironolactone in heart failure are described below.

Lithium preparations. With the simultaneous use of lithium preparations and ACE inhibitors, a reversible increase in the concentration of lithium in the blood serum and associated toxic effects may be observed. The simultaneous use of perindopril and lithium preparations is not recommended. If such therapy is necessary, the concentration of lithium in the blood plasma should be regularly monitored (see “Special Instructions”).

Concomitant use requiring extreme caution

Hypoglycemic agents (insulin, hypoglycemic agents for oral administration). The use of ACE inhibitors may enhance the hypoglycemic effect of insulin and oral hypoglycemic agents, leading to the development of hypoglycemia. As a rule, this is observed in the first weeks of simultaneous therapy and in patients with impaired renal function.

Baclofen. Enhances the antihypertensive effect of ACE inhibitors. Blood pressure levels and, if necessary, dosage of antihypertensive drugs should be carefully monitored.

Potassium-sparing diuretics. In patients receiving diuretics, especially those that remove fluid and/or salts, an excessive decrease in blood pressure may be observed at the beginning of perindopril therapy, the risk of which can be reduced by discontinuing the diuretic, replacing fluid or salt loss before starting perindopril therapy, as well as prescribing perindopril at low levels. dose with further gradual increase.

For arterial hypertension in patients receiving diuretics, especially those that remove fluid and/or salts, the diuretics should either be discontinued before starting the ACE inhibitor (in this case, a potassium-sparing diuretic can be reintroduced later), or the ACE inhibitor should be prescribed at a low dose with further gradual increase.

When using diuretics in the case of chronic heart failure, an ACE inhibitor should be prescribed at a low dose, possibly after reducing the dose of a concomitantly used potassium-sparing diuretic. In all cases, renal function (creatinine concentration) should be monitored in the first weeks of using ACE inhibitors.

Potassium-sparing diuretics (eplerenone, spironolactone). Use of eplerenone or spironolactone in doses of 12.5 to 50 mg/day and low doses of ACE inhibitors:

- when treating heart failure of functional class II-IV according to the NYHA classification with a left ventricular ejection fraction <40% and previously used ACE inhibitors and loop diuretics, there is a risk of hyperkalemia (with possible death), especially if the recommendations for this combination of drugs are not followed.

Before using this combination of drugs, you must ensure that there is no hyperkalemia or impaired renal function.

It is recommended to regularly monitor the concentration of creatinine and potassium in the blood: weekly in the first month of treatment and monthly thereafter.

NSAIDs, including high doses of acetylsalicylic acid (more than 3 g/day). The simultaneous use of ACE inhibitors with NSAIDs (acetylsalicylic acid in a dose that has an anti-inflammatory effect, COX-2 inhibitors and non-selective NSAIDs) may lead to a decrease in the antihypertensive effect of ACE inhibitors. Concomitant use of ACE inhibitors and NSAIDs may lead to deterioration of renal function, including the development of acute renal failure, and an increase in serum potassium, especially in patients with reduced renal function. Caution should be exercised when prescribing this combination, especially in elderly patients. Patients should receive adequate amounts of fluids, and close monitoring of renal function is recommended, both at the beginning and during treatment.

Concomitant use which requires some caution

Antihypertensive drugs and vasodilators. The antihypertensive effect of perindopril may be enhanced when used simultaneously with other antihypertensive and vasodilating agents, including short- and long-acting nitrates.

Gliptins (linagliptin, saxagliptin, sitagliptin, vitagliptin). Concomitant use with ACE inhibitors may increase the risk of angioedema due to inhibition of dipeptidyl peptidase IV (DPP-IV) activity by gliptin.

Tricyclic antidepressants, antipsychotics (neuroleptics) and general anesthesia. Concomitant use with ACE inhibitors may lead to increased antihypertensive effects (see "Special Instructions").

Sympathomimetics. May weaken the antihypertensive effect of ACE inhibitors.

Gold preparations. When using ACE inhibitors, incl. perindopril, patients receiving intravenous gold (sodium aurothiomalate) were described to have a symptom complex including facial skin flushing, nausea, vomiting, and arterial hypotension.

How to use Prestarium: instructions

The doctor prescribes the exact treatment regimen depending on the type of disease and the age of the patient. General recommendations:

• The tablets must be taken on an empty stomach, in the morning, with plenty of water; there is no need to chew the drug;
• the prescribed dose is taken once: it can range from 2 to 8 mg per day;
• in acute conditions, the drug is taken no earlier than complete normalization and remission.

For elderly people and other risk groups, the dosage is adjusted downwards. It is prohibited to change the number of tablets on your own. The course of treatment is continued until the physical condition is stabilized and the existing pathologies are normalized. If necessary, Prestarium is taken for several months in a row or continuously. It is allowed to combine it with diuretic medications.

The drug is incompatible with narcotic analgesics, corticosteroid hormones, immunosuppressants, cytostatics, diabetes treatments, antipsychotics, since when taken simultaneously, the risk of side effects mutually increases.