Prestans pills 5mg + 10mg №30

Mechanism of action

Combined antihypertensive and antianginal drug.

Perindopril

Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II (ACE inhibitor). ACE, or kininase II, is exopeptidase, which carries out both the conversion of angiotensin I into a vasoconstrictor substance angiotensin II, and the destruction of bradykinin, which has a vasodilator, to an inactive heptapeptide.

Since ACE inactivates bradykinin, ACE suppression is accompanied by an increase in the activity of both the circulating and tissue kallikrein-kinin system, and the prostaglandin system is also activated.

Perindopril has a therapeutic effect due to its active metabolite, perindoprilat. Other metabolites have no inhibitory effect on ACE in vitro.

Arterial hypertension

Perindopril is a drug for treating hypertension of any severity. Against the background of its use, a decrease in both systolic and diastolic blood pressure in the prone and standing position is noted. Perindopril reduces OPSS, which leads to a decrease in elevated blood pressure and improvement of peripheral blood flow without changing heart rate.

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

The antihypertensive effect of the drug reaches a maximum after 4-6 hours after a single dose and remains for 24 hours.

The antihypertensive effect 24 hours after a single dose is about 87-100% of the maximum antihypertensive effect. Reduced blood pressure is achieved quite quickly.

The therapeutic effect occurs less than 1 month from the start of therapy and is not accompanied by tachycardia. Discontinuation of treatment does not cause withdrawal syndrome. Perindopril has a vasodilating effect, helps to restore the elasticity of large arteries and the structure of the vascular wall of small arteries, and also reduces left ventricular hypertrophy.

Stable ischemic heart disease

The efficacy of perindopril in patients (12,218 patients over 18 years old) with stable coronary artery disease without the clinical symptoms of chronic heart failure was studied during a 4-year study (EUROPA). 90% of study participants previously had acute myocardial infarction or coronary revascularization.Therapy with perindopril tertbutylamine at a dose of 8 mg / (equivalent to 10 mg of perindopril arginine) resulted in a significant reduction in the absolute risk of complications by 1.9%, in patients who previously had myocardial infarction or coronary revascularization, the absolute risk decreased by 2.2% compared to the placebo group.

Amlodipine

Amlodipine is a blocker of slow Calcium channels, a derivative of the dihydropyridine series. Amlodipine inhibits the transmembrane transition of calcium ions into cardiomyocytes and smooth muscle cells of the vascular wall.

The antihypertensive effect of amlodipine is due to a direct effect on the smooth muscle cells of the vascular wall. It is established that amlodipine causes expansion of peripheral arterioles, reducing OPSS (afterload), since the heart rate does not change, and the need of myocardium for oxygen decreases. It causes the expansion of coronary arteries and arterioles in both ischemic and intact areas. In patients with Prinzmetal angina, coronary blood flow is improved.

In patients with arterial hypertension, amlodipine is administered 1 time / provides a clinically significant reduction in blood pressure while standing and lying down for 24 hours. The antihypertensive effect develops slowly, and therefore the development of acute arterial hypotension is not typical.

In patients with angina, taking amlodipine 1 time / increases exercise tolerance, delaying the onset of an attack of angina and "ischemic" depression of the ST segment, and also reduces the frequency of attacks of angina and Nitroglycerin (short-acting form).

Amlodipine does not affect the lipid profile and does not cause changes in the hypolipidemic parameters of blood plasma.

The drug can be used in patients with concomitant bronchial asthma, diabetes mellitus and gout.

The efficacy and safety of using amlodipine at a dose of 2.5-10 mg /, an ACE inhibitor lisinopril at a dose of 10-40 mg / and thiazide diuretic chlortalidone at a dose of 12.5-25 mg / as a first-line drug was studied in a 5-year study ALLHAT (involving 33 357 patients aged 55 years and older) in patients with mild or moderate arterial hypertension and at least one of the additional risk factors for coronary complications,such as: myocardial infarction or stroke, transferred more than 6 months before being included in the study, or another confirmed cardiovascular disease of atherosclerotic genesis; diabetes; HDL cholesterol levels of less than 35 mg / dL; left ventricular hypertrophy according to ECG or echocardiography; smoking.

The main criterion for evaluating the effectiveness is a combined indicator of the frequency of deaths from IHD and the frequency of nonfatal myocardial infarction. There were no significant differences between the amlodipine and chlorthalidone groups in the main evaluation criteria. The incidence of heart failure in the amlodipine group was significantly higher than in the chlorthalidone group — 10.2% and 7.7%, respectively; the overall incidence of deaths in the amlodipine and chlorthalidone groups did not differ significantly.

Perindopril and Amlodipine

Effectiveness with long-term use of amlodipine in combination with perindopril and Atenolol in combination with bendroflumethiazide in patients aged 40 to 79 years with arterial hypertension and at least 3 of the additional risk factors: left ventricular hypertrophy according to ECG or echocardiography; type 2 diabetes; peripheral artery atherosclerosis; previous stroke or transient ischemic attack; male; age 55 years and older; microalbuminuria or proteinuria; smoking; total cholesterol / HDL cholesterol ≥ 6; The early development of coronary artery disease in next of kin was studied in an ASCOT-BPLA study.

The main criterion for evaluating the effectiveness is a combined indicator of the frequency of nonfatal myocardial infarction (including painless) and deaths of IHD. The incidence of complications provided for by the main evaluation criteria in the amlodipine / perindopril group was 10% lower than in the atenolol / bendroflumethiazide group, but this difference was not statistically significant. In the amlodipine / perindopril group, there was a significant decrease in the incidence of complications, provided by additional criteria of effectiveness (except for fatal and nonfatal heart failure).

Pharmacokinetics

The amount of absorption of perindopril and amlodipine when using the drug Prestanc does not significantly differ from that when using monopreparations.

Perindopril

Suction

When taken perindopril is rapidly absorbed, Cmax in the blood plasma is reached within 1 hour. Perindopril does not possess pharmacological activity. Approximately 27% of the total amount of perindopril ingested enters the bloodstream as an active metabolite of perindoprilat. In addition to perindoprilat, 5 more metabolites are formed that do not possess pharmacological activity. Cmax of perindoprilat in plasma is reached 3-4 h after ingestion. Eating slows down the conversion of perindopril to perindoprilat, thereby affecting bioavailability. Therefore, the drug should be taken 1 time / in the morning before eating.

Distribution

There is a linear dependence of the concentration of perindopril in plasma from its dose. Vd of free perindoprilat is approximately 0.2 l / kg. Binding of perindoprilat with plasma proteins , mainly with ACE, is about 20% and is dose-dependent.

Removal

T1 / 2 perindopril from plasma is 1 hour.

Perindoprilat is excreted by the kidneys. The final T1 / 2 of the free fraction is about 17 hours, so an equilibrium state is reached within 4 days.

Pharmacokinetics in special clinical situations

Removal of perindoprilat is delayed in old age, as well as in patients with cardiac and renal failure. Therefore, in these groups of patients, it is necessary to regularly monitor the concentration of creatinine and potassium in the blood plasma.

The dialysis clearance of perindoprilat is 70 ml / min.

The pharmacokinetics of perindopril changed in patients with cirrhosis of the liver: its hepatic clearance is reduced by 2 times. However, the amount of perindoprilat formed does not decrease, which does not require dose adjustment.

Amlodipine

Suction

Cmax of amlodipine in the blood plasma is achieved 6-12 hours after ingestion. Absolute bioavailability is about 64-80%.

Distribution

Eating does not affect the bioavailability of amlodipine. Vd - approximately 21 l / kg. In vitro studies have shown that about 97.5% of circulating amlodipine is associated with plasma proteins.

Metabolism and excretion

Amlodipine is metabolized in the liver to form inactive metabolites. The final T1 / 2 of amlodipine from plasma is 35-50 h, which allows you to take the drug 1 time / About 60% of the received dose of amlodipine is excreted by the kidneys, 10% - unchanged.

Pharmacokinetics in special clinical situations

The time from taking the drug to reaching Cmax of amlodipine does not differ in patients of elderly and younger age.In elderly patients, there is a slowdown in the clearance of amlodipine, which leads to an increase in AUC. Elderly patients do not require dose adjustment of the drug, but it is necessary to increase the dose of amlodipine with caution.

In patients with hepatic insufficiency, T1 / 2 amlodipine is increased.

- arterial hypertension;

- IHD: stable exertional angina in patients requiring perindopril and amlodipine.

The drug is administered orally, 1 tablet 1 time per day, preferably in the morning before a meal. The dose of the drug Prestants is selected after a previously performed titration of doses of individual components of the drug: perindopril and amlodipine in patients with arterial hypertension and stable angina pectoris.

When therapeutic, the dose of Prestans can be changed, based on individual selection of doses of individual components: 5 mg perindopril + 5 mg amlodipine or 5 mg perindopril + 10 mg amlodipine or 10 mg perindopril + 5 mg amlodipine or 10 mg perindopril + 10 mg amlodipine .

Prestans in doses of 10 mg of perindopril + 10 mg of amlodipine is the maximum daily dose of the drug, which is not recommended to exceed.

The elimination of perindoprilat in elderly patients and patients with renal insufficiency is slow. Therefore, in such patients, it is necessary to regularly monitor the concentration of creatinine and potassium in the blood plasma. Prestans may be administered to patients with a CC ≥ 60 mL / min. Prestanc is contraindicated in patients with CC <60 ml / min. Such patients are recommended individual selection of doses of perindopril and amlodipine. Changes in the concentration of amlodipine in the blood plasma do not correlate with the severity of renal failure.

Caution should be exercised in the appointment of the drug Prestan in patients with hepatic insufficiency due to the lack of recommendations on the dosing of the drug in these patients.

Prestanza should not be prescribed to children and adolescents under 18 years of age due to the lack of data on the efficacy and safety of perindopril and amlodipine in these groups of patients, both as monotherapy and as combination therapy.

The frequency of adverse reactions that were noted during monotherapy with perindopril and amlodipine is given in the form of the following gradation: very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10,000, <1/1000); very rarely (<1/10 000), including individual messages; unspecified frequency (frequency cannot be calculated from available data).

On the part of the hematopoietic system: very rarely - leukopenia, neutropenia, agranulocytosis, pancytopenia, thrombocytopenia, hemolytic anemia in patients with congenital glucose-6-phosphate dehydrogenase deficiency, a decrease in hemoglobin and hematocrit.

Allergic reactions: infrequently - urticaria.

Metabolic disorders: infrequently - weight gain, weight loss; very rarely - hyperglycemia.

From the side of the central nervous system: often - drowsiness, dizziness, headache, paresthesia; infrequently - insomnia, mood lability, sleep disturbance, tremor, hypoesthesia; very rarely - peripheral neuropathy, confusion.

On the part of the organ of vision: often - visual disturbances.

From the organ of hearing: often - tinnitus.

Since the cardiovascular system: often - heartbeat, flushing of blood to the skin of the face, pronounced decrease in blood pressure; infrequently - fainting; rarely - pain behind the sternum; very rarely - stenocardia, myocardial infarction, possibly due to an excessive decrease in blood pressure in patients from the high-risk group, arrhythmias (including bradycardia, ventricular tachycardia and atrial fibrillation), stroke, possibly due to an excessive decrease in blood pressure in patients from the high risk, vasculitis.

On the part of the respiratory system: often - shortness of breath, cough; infrequently - rhinitis, bronchospasm; very rarely - eosinophilic pneumonia.

On the part of the digestive system: often - abdominal pain, nausea, vomiting, dyspepsia , a violation of taste perception, diarrhea, constipation; infrequently - constipation, dryness of the oral mucosa; rarely, increased bilirubin levels; very rarely - pancreatitis, gum hyperplasia, gastritis, hepatitis, cholestatic jaundice, cytolytic or cholestatic hepatitis, increased activity of liver enzymes ACT, ALT (most often in combination with cholestasis).

On the part of the skin: often - itching,rash; infrequently - angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and / or larynx, alopecia, hemorrhagic rash, photosensitization, increased sweating; very rarely - angioedema, erythema multiforme, Stevens-Johnson syndrome.

From the musculoskeletal system: often - muscle spasms; infrequently - arthralgia, myalgia, back pain.

On the part of the kidneys and urinary tract: infrequently - violation of urination, nocturia, frequent urination, renal failure; very rarely - severe renal failure.

On the part of the reproductive system: infrequently - impotence, gynecomastia.

On the part of the body as a whole: often - peripheral edema, asthenia, increased fatigue; infrequently - chest pain, malaise.

Laboratory indicators: unspecified frequency - increased concentration of urea and serum creatinine, hyperkalemia.

Perindopril

- angioedema (angioedema) in history (including against the background of taking other ACE inhibitors);

- hereditary / idiopathic angioedema;

- age up to 18 years (efficiency and safety have not been established);

- Hypersensitivity to perindopril or other ACE inhibitors.

Amlodipine

- severe arterial hypotension (systolic blood pressure less than 90 mm Hg);

- obstruction of the output tract of the left ventricle (for example, severe aortic stenosis);

- unstable angina (with the exception of Prinzmetal stenocardia);

- age up to 18 years (efficiency and safety have not been established);

- Hypersensitivity to amlodipine or other dihydropyridine derivatives.

Prestants

- renal failure (CC less than 60 ml / min);

- age up to 18 years (efficiency and safety have not been established);

- hereditary lactose intolerance , lactase deficiency and glucose / galactose malabsorption syndrome;

- Hypersensitivity to excipients that are part of the drug.

Carefully

Renal artery stenosis (including bilateral), the only functioning kidney, liver failure, renal failure, systemic diseases of the connective tissue (includingsystemic lupus erythematosus, scleroderma), immunosuppressive therapy, Allopurinol , procainamide (risk of neutropenia, agranulocytosis), reduced BCC (diuretics, salt-free diet, vomiting, diarrhea), atherosclerosis, cerebrovascular disease, renovascular hypertension, diabetes, chronic heart failure, use of dantrolene, estramustine, potassium-sparing diuretics, potassium preparations, potassium-containing substitutes for edible salt and lithium preparations, hyperkalemia, surgical intervention / general anesthesia, elderly, hemodialysis using vysokoprotochnyh membranes (e.g., AN69®), desensitizing therapy, LDL aphaeresis, aortic stenosis / mitral stenosis / hypertrophic cardiomyopathy patients blacks.

The drug is contraindicated for use in pregnancy.

Except for cases when therapy with Prestans is necessary for health reasons, when planning a pregnancy, the drug should be discontinued and other antihypertensive agents prescribed for pregnancy should be prescribed. If pregnancy occurs, you should immediately discontinue taking Prestans and, if necessary, prescribe another therapy.

It is known that the effect of ACE inhibitors on the fetus in the II and III trimesters of pregnancy can lead to a violation of its development (reduced 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 in the II or III trimester of pregnancy, it is recommended to conduct an ultrasound examination of the fetus to assess the state of the skull and kidney function.

Newborns whose mothers received ACE inhibitors during pregnancy need careful medical supervision because of the risk of arterial hypotension, oliguria and hyperkalemia. The limited data available on taking amlodipine and other slow calcium channel blockers during pregnancy indicate that the drug does not adversely affect the fetus. However, there is a risk of prolonged delivery.

It is not recommended to take Prestans in the period of lactation due to the lack of appropriate clinical experience in the use of perindopril and amlodipine, both in monotherapy and in combination. If you need to take the drug, you should stop breastfeeding.

Application for violations of the liver

Caution should be exercised in the appointment of the drug Prestan in patients with hepatic insufficiency due to the lack of recommendations on the dosing of the drug in these patients.

Application for violations of kidney function

Removal of perindoprilat in patients with renal insufficiency is slow. Therefore, in such patients, it is necessary to regularly monitor the concentration of creatinine and potassium in the blood plasma. Prestans may be administered to patients with a CC ≥ 60 mL / min. Prestanc is contraindicated in patients with CC <60 ml / min. Such patients are recommended individual selection of doses of perindopril and amlodipine. Changes in the concentration of amlodipine in the blood plasma do not correlate with the severity of renal failure.

special instructions

Special instructions relating to perindopril and amlodipine, apply to the drug Prestanc.

Perindopril

Hypersensitivity / Angioedema

When taking ACE inhibitors, incl. and perindopril, in rare cases, angioedema of the face, extremities, lips, mucous membranes, tongue, vocal cords and / or larynx may develop. When symptoms appear, the drug should be immediately discontinued, and the patient should be observed until the signs of edema disappear completely. If the edema affects only the face and lips, then its manifestations usually disappear on their own, although antihistamines may be used to treat the symptoms. Angioedema, accompanied by swelling of the larynx, can be fatal. Swelling of the tongue, vocal cords or larynx can lead to airway obstruction. If these symptoms appear, epinephrine (adrenaline) should be injected subcutaneously and / or ensure airway patency. The patient must be under medical supervision until the symptoms disappear completely and permanently. In patients with a history of angioedema, not associated with the use of ACE inhibitors, the risk of its development may be increased when taking drugs in this group.

In rare cases, against the background of therapy with ACE inhibitors, angioedema of the intestines develops.At the same time, patients have abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases, without prior angioedema of the face and at a normal level of C1-esterase. The diagnosis is established using computed tomography of the abdominal area, ultrasound, or at the time of surgery. Symptoms disappear after discontinuation of ACE inhibitors. Therefore, in patients with abdominal pain, receiving ACE inhibitors, when conducting a differential diagnosis, it is necessary to take into account the possibility of developing angioedema.

Anaphylactoid reactions during LDL apheresis

In rare cases, patients receiving ACE inhibitors may experience life-threatening anaphylactoid reactions when performing an apheresis of LDL using dextran. To prevent an anaphylactoid reaction, the ACE inhibitor therapy should be temporarily discontinued before each apheresis procedure.

Anaphylactoid reactions during desensitization

There are separate reports on the development of anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy (for example, from hymenoptera). In these same patients, the anaphylactoid reaction was avoided by the temporary discontinuation of ACE inhibitors, and when accidentally taking the drug, the anaphylactoid reaction occurred again.

Neutropenia, agranulocytosis, thrombocytopenia, anemia

Neutropenia / agranulocytosis, thrombocytopenia and anemia can occur while taking ACE inhibitors. In patients with normal renal function and in the absence of other aggravating factors, neutropenia rarely develops. Patients with diffuse diseases of the connective tissue should be treated with particular caution when taking immunosuppressants, allopurinol or procainamide, especially in patients with impaired renal function.

Some patients had severe infectious lesions, in some cases, resistant to intensive antibiotic therapy. When prescribing perindopril in such patients, it is recommended to periodically monitor the number of leukocytes in the blood. Patients should inform the doctor about any signs of infectious diseases.

Hypotension

ACE inhibitors can cause a sharp decrease in blood pressure. Symptomatic arterial hypotension rarely develops in patients without concomitant diseases. The risk of an excessive decrease in blood pressure is increased in patients with reduced BCC, which can be observed during diuretic therapy, with a strict salt-free diet, hemodialysis, diarrhea and vomiting, as well as in patients with severe arterial hypertension with high renin activity. In patients with an increased risk of developing symptomatic arterial hypotension, blood pressure, kidney function and serum potassium should be carefully monitored during treatment with Prestans.

A similar approach is used in patients with angina pectoris and cerebrovascular diseases in whom severe hypotension can lead to myocardial infarction or impaired cerebral circulation.

If arterial hypotension develops, the patient should be placed in a supine position with the legs elevated. If necessary, the BCC should be replenished with IV injection of a 0.9% sodium chloride solution. Transient arterial hypotension is not an obstacle to further administration of the drug. After the restoration of BCC and blood pressure treatment can be continued.

Mitral stenosis, aortic stenosis, hypertrophic cardiomyopathy

Prestanz, like other ACE inhibitors, should be used with caution in patients with obstruction of the left ventricular output tract (aortic stenosis, hypertrophic cardiomyopathy), as well as in patients with mitral stenosis.

Renal dysfunction

Patients with renal insufficiency (QA less than 60 ml / min) are recommended to select individual doses of perindopril and amlodipine. Such patients need regular monitoring of serum potassium and creatinine.

In patients with bilateral renal artery stenosis or single kidney artery stenosis during therapy with ACE inhibitors, there may be an increase in serum urea and creatinine, usually occurring when therapy is canceled. More often, this effect is observed in patients with renal insufficiency. The additional presence of renovascular hypertension causes an increased risk of developing severe arterial hypotension and renal failure in these patients.In some patients with arterial hypertension without signs of kidney vascular lesions, an increase in serum urea and creatinine may be increased, especially with co-administration of perindopril with a diuretic, usually minor and transient. Most often, this effect is observed in patients with previous kidney dysfunction.

Liver failure

In rare cases, cholestatic jaundice occurs with the use of ACE inhibitors. With the progression of this syndrome fulminant necrosis of the liver develops, sometimes with a fatal outcome. The mechanism for the development of this syndrome is unclear. With the appearance of jaundice or a significant increase in the activity of liver enzymes in the background of taking ACE inhibitors, you should stop taking the drug and consult a doctor.

Ethnic differences

Patients of the Negroid race are more likely to develop angioedema than on other races while taking ACE inhibitors.

Perindopril, like other ACE inhibitors, may have a less pronounced hypotensive effect in patients of the Negroid race compared to other races. Perhaps this difference is due to the fact that patients with arterial hypertension of the Negroid race are more likely to have low renin activity.

Cough

During therapy with an ACE inhibitor, a dry cough may occur. Coughing persists while taking this group of drugs and disappears after they are canceled. When a patient has a dry cough, you should be aware of the possible iatrogenic nature of this symptom.

Surgical intervention / general anesthesia

The use of ACE inhibitors in patients undergoing extensive surgery and / or general anesthesia can lead to a pronounced decrease in blood pressure if agents are used for general anesthesia with hypotensive action. This is due to the blocking of the formation of angiotensin II against the background of a compensatory increase in renin activity. If the development of arterial hypotension is associated with the described mechanism, the volume of circulating plasma should be increased. It is recommended to stop taking the drug 24 hours before surgery.

Hyperkalemia

Hyperkalemia can develop during treatment with ACE inhibitors, including and perindopril.Risk factors for hyperkalemia are renal failure, advanced age (older than 70 years), diabetes mellitus, some concomitant conditions (dehydration, acute decompensation of chronic heart failure, metabolic acidosis), simultaneous use of potassium-sparing diuretics (such as spironolactone and its derivative eplerenone, triamterene, amine ), as well as preparations of potassium or potassium-containing substitutes for edible salt, as well as the use of other drugs that contribute to an increase in the content of potassium in the blood plasma (e.g. heparin). The use of potassium preparations, potassium-sparing diuretics, potassium-containing salt substitutes can lead to a significant increase in the level of potassium in the blood, especially in patients with reduced kidney function. Hyperkalemia can lead to serious, sometimes fatal heart rhythm disturbances. If simultaneous administration of perindopril and the above preparations is necessary, treatment should be carried out with caution against the background of regular monitoring of the content of potassium in the blood serum.

Patients with diabetes

When prescribing the drug to patients with diabetes mellitus, receiving hypoglycemic agents for oral administration or insulin , during the first month of therapy, it is necessary to carefully monitor the concentration of glucose in the blood.

Amlodipine

Liver failure

In patients with impaired liver function, amlodipine T1 / 2 is increased. In appointing the drug in such patients, care should be taken to regularly monitor the activity of liver enzymes.