Triplixam tabs 10mg + 2.5mg + 10mg #30

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pharmachologic effect

Triplixam is a combination drug that includes three antihypertensive components, each of which complements the action of the others on controlling blood pressure in patients with arterial hypertension. Amlodipine is a “slow” calcium channel blocker (BMCC), a dihydropyridine derivative, indapamide is a sulfonamide diuretic, perindopril arginine is an inhibitor of the enzyme that converts angiotensin I to angiotensin II (an ACE inhibitor)
The pharmacological properties of Triplixam combine the properties of each of its active ingredients. In addition, the combination of amlodipine, indapamide and perindopril arginine enhances the antihypertensive effect of each of the components.

Mechanism of action

Amlodipine

Amlodipine - BMCC, a dihydropyridine derivative. Amlodipine inhibits the transmembrane transition of calcium ions into cardiomyocytes and smooth muscle cells of the vascular wall.

Indapamide

Indapamide is a derivative of a sulfonamide with an indole ring and, by its pharmacological properties, is close to thiazide diuretics, which inhibit the reabsorption of sodium ions in the cortical segment of the nephron loop. At the same time, kidneys excrete sodium, chlorine and, to a lesser extent, potassium and magnesium ions, which is accompanied by an increase in diuresis and an antihypertensive effect.

Perindopril

Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II (an inhibitor of the angiotensin-converting enzyme (ACE)). APF. or kininase II, is an exopeptidase that converts angiotensin I into a vasoconstrictor angiotensin II. In addition, the enzyme stimulates the production of aldosterone by the adrenal cortex and the destruction of bradykinin, which has a vasodilating effect, to inactive heptapeptide. As a result, perindopril:
- reduces the secretion of aldosterone;
- by the principle of negative feedback increases the activity of renin in the blood plasma;
- with prolonged use reduces the total peripheral vascular resistance (OPS), which is mainly due to the effect on the vessels in the muscles and kidneys. These effects are not accompanied by the retention of sodium ions or liquids or the development of reflex tachycardia with prolonged use.
Perindopril has an antihypertensive effect in patients with both low and normal renin activity in the blood plasma.
Perindopril has a therapeutic effect due to the active metabolite perindoprilat. Other metabolites do not possess pharmacological activity. Perindopril normalizes the work of the heart, reducing preload and afterload due to:
- vasodilator effect on veins, possibly associated with the activation of the prostaglandin system;
- decrease in the general peripheral vascular resistance (OPSS)
A study of hemodynamic parameters in patients with chronic heart failure (CHF) revealed:
- reduction of filling pressure in the left and right ventricles of the heart; a decrease in fsr;
- an increase in cardiac output and an increase in cardiac index;
- increased muscle peripheral blood flow.
Also increased exercise tolerance.

Pharmacodynamic effects

Amlodipine

The antihypertensive effect of amlodipine is due to the direct effect on the smooth muscle cells of the vascular wall. The detailed mechanism by which amlodipine performs an antianginal effect is not fully established, but it is known that amlodipine reduces the overall ischemic load through two actions:
- causes expansion of peripheral arterioles, reducing the total peripheral vascular resistance (afterload). This reduction in the load on the heart reduces energy consumption, and myocardial oxygen demand.
- causes expansion of the coronary arteries and arterioles in both the ischemic and intact zones. At the same time, in patients with spasm of the coronary arteries (Prinzmetal angina pectoris), coronary blood flow and oxygen supply to the myocardium improves.
In patients with arterial hypertension (AH), taking amlodipine 1 time per day provides a clinically significant reduction in blood pressure in the “standing” and “lying” position for 24 hours.
Amlodipine does not have undesirable metabolic effects and does not affect lipid metabolism, does not cause changes in blood plasma lipid-lowering parameters and can be used in patients with concomitant bronchial asthma, diabetes and gout.

Indapamide

When indapamide was used in monotherapy, a 24-hour antihypertensive effect was demonstrated. The antihypertensive effect is manifested when Triplixam is used in doses that have minimal diuretic effect.
The antihypertensive activity of indapamide is associated with an improvement in the elastic properties of large arteries, a decrease in arteriolar and general peripheral vascular resistance.
Indapamide reduces left ventricular hypertrophy.
Thiazide and thiazide-like diuretics at a certain dose reach a plateau of therapeutic effect, while the frequency of side effects continues to increase with a further increase in the dose of Triplixam. Therefore, you should not increase the dose of Triplixam, if at the reception of the recommended dose is not achieved therapeutic effect.
In short, medium and long-term studies involving patients with arterial hypertension, it has been shown that indapamide:
does not affect lipid metabolism, including the level of triglycerides, cholesterol, low density lipoproteins and high density lipoproteins; does not affect the indicators of carbohydrate metabolism, including in patients with diabetes mellitus.

Perindopril

Perindopril is effective in the treatment of hypertension of any degree of severity. Against the background of its use, a decrease in both systolic and diastolic blood pressure (BP) in the "lying" and "standing" positions is noted.
The antihypertensive effect of Triplixam reaches a maximum after 4-6 hours after a single dose and remains for 24 hours.
24 hours after ingestion, a pronounced (about 80%) residual ACE inhibition is observed.
In patients with a positive response to treatment, normalization of blood pressure occurs within a month and persists without developing tachycardia.
Cessation of treatment is not accompanied by the development of the effect of "rebound".
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.
The simultaneous appointment of thiazide diuretics increases the severity of the antihypertensive effect.
In addition, the combination of an ACE inhibitor and a thiazide diuretic also leads to a reduction in the risk of hypokalemia in patients receiving diuretics.

Perindopril / Indapamide

In patients with arterial hypertension, regardless of age, the combination of perindopril and indapamide has a dose-dependent antihypertensive effect on both diastolic and systolic blood pressure in the "standing" and "lying" position. In clinical studies, a more pronounced antihypertensive effect was shown on the background of combined therapy with perindopril and indapamide compared with monotherapy with individual components.

Clinical efficacy and safety

The effect of Triplixam on morbidity and mortality has not been studied.

Amlodipine

The efficacy and safety of using amlodipine at a dose of 2.5–10 mg / day, an ACE inhibitor lisinopril at a dose of 10–40 mg / day as a first-line drug, and thiazide diuretic chlortalidone at a dose of 12.5–25 mg / day were studied in 5-year study of ALLHAT (involving 33357 patients aged 55 years and older) in patients with mild or moderate degrees of hypertension and. At least one of the additional risk factors for coronary complications, such as: myocardial infarction or stroke more than 6 months prior to enrollment, or otherwise confirmed cardiovascular disease of atherosclerotic genesis; type 2 diabetes; high-density lipoprotein cholesterol (HDL-C) cholesterol is less than 35 mg / dL; left ventricular hypertrophy by electrocardiography 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%, however, the overall incidence of deaths in the amlodipine and chlorthalidone groups did not differ significantly.

Perindopril / Indapamide

In a study involving patients with arterial hypertension and left ventricular hypertrophy (left ventricular mass index> 120 g / m2 in men and> 100 g / m2 in women), the effectiveness of treatment with 2 mg of perindopril tertbutylamine (which corresponds to 2.5 mg of perindopril arginine) in combinations with 0.625 mg of indapamide compared with monotherapy with 10 mg of enalapril, when taken once a day for 1 year, were evaluated by echocardiography. If necessary, to maintain adequate monitoring of blood pressure indicators, doses of perindopril tertbutylamine up to 8 mg (which corresponds to 10 mg of perindopril arginine) and indapamide up to 2.5 mg once a day or enalapril up to 40 mg once a day were titrated. In the group of patients taking perindopril / indapamide, 34% of patients did not need to increase the dose compared to 20% in the group treated with enalapril.
At the end of treatment, the values ​​of the left ventricular mass index decreased more significantly in the perindopril / indapamide group (-10.1 g / m2) compared with the enalapril group (-1.1 g / m2).
The best effect in relation to the values ​​of the mass index of the left ventricle was achieved with the use of higher doses of the combination of perindopril and indapamide.
In terms of lowering blood pressure values, the difference between the groups was 5.8 mm Hg. Art. for systolic pressure and 2.3 mm Hg. Art. for diastolic pressure, respectively, in favor of the perindopril / indapamide group.
A study involving patients with type 2 diabetes studied the effect of lowering blood pressure on the incidence of macrovascular (death due to cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke) and microvascular complications (occurrence or worsening of nephropathy and eye diseases) in patients taking the combination perindopril / indapamide compared with placebo, on the background of standard therapy, as well as taking modified release gliclazide in comparison with standard therapy to maintain normal blood glucose levels.
After 4.3 years of therapy, the relative risk of macro-and microvascular complications decreased by 9% in the group taking the perindopril / indapamide combination. The advantage was achieved by significantly reducing the relative risk of mortality by 14%, death due to cardiovascular causes by 18% and the development of renal complications by 21% in the group of patients receiving a combination of perindopril / indapamide compared with placebo.
In the subgroup of patients with arterial hypertension, a significant 9% reduction in the relative risk of the combined frequency of macro- and microvascular complications in the perindopril / indapamide combination compared with placebo was shown.
In this group, the relative risk of mortality (by 16%), death due to cardiovascular causes (by 20%) and the development of renal complications (by 20%) in patients receiving a combination of perindopril / indapamide compared with patients receiving placebo also significantly decreased.
The benefits of antihypertensive therapy did not depend on the benefits achieved against the background of intensive glycemic control.

Double blockade of the reiin-angiotezin-aldosterone system (RAAS)

There is evidence of clinical studies of combination therapy with the use of an ACE inhibitor with ARA II.
Clinical studies were conducted with patients with a history of cardiovascular or cerebrovascular disease, or diabetes mellitus 2 tin, accompanied by confirmed lesion of the target organ, as well as studies with patients with diabetes type 2 and diabetic nephropathy.
These studies did not reveal a significant positive effect on the occurrence of renal and / or cardiovascular complications and mortality in patients receiving combined therapy, while the risk of hyperkalemia, acute renal failure and / or hypotension increased compared with patients who received monotherapy.
Taking into account the similar intragroup pharmacodynamic properties of ACE inhibitors and ARA II, these results can be expected for the interaction of any other drugs, representatives of the ACE inhibitor classes and ARA II.
Therefore, ACE inhibitors and ARA II should not be used simultaneously in patients with diabetic nephropathy.
There is evidence from a clinical study examining the positive effects of adding aliskiren to standard therapy with an ACE inhibitor or ARA II in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease, or with a combination of these diseases. The study was terminated early due to the increased risk of undesirable outcomes. Cardiovascular death and stroke occurred more frequently in the group of patients receiving aliskiren compared with the placebo group. Also, adverse events and serious adverse events of particular interest (hyperkalemia, hypotension and renal dysfunction) were recorded more often in the aliskiren group than in the placebo group.

Pharmacokinetics of Triplixam

The combined use of perindopril / indapamide and amlodipine does not change their pharmacokinetic characteristics compared with the separate administration of these agents.
Amlodipine

Suction

After oral administration, amlodipine is well absorbed from the gastrointestinal tract. The maximum concentration of amlodipine in the blood plasma is achieved 6–12 hours after ingestion.

Distribution

Absolute bioavailability is about 64–80%, volume of distribution is about 21 l / kg. In vitro studies have shown that about 97.5% of circulating amlodipine is associated with plasma proteins. Simultaneous food intake does not affect the bioavailability of amlodipine.

Metabolism

Amlodipine is metabolized in the liver to form inactive metabolites; the kidneys excrete 10% of the taken dose of amlodipine unchanged and 60% as metabolites.

Removal

The final half-life (T½) of amlodipine from blood plasma is 35-50 hours, which allows you to take Triplixam 1 time per day.

Special patient groups

In elderly patients, there is a slowdown in the clearance of amlodipine, which leads to an increase in the area under the concentration-time curve (AUC) and T½. An increase in AUC and T½ in patients with chronic heart failure (CHF) corresponds to the expected value for this age group.
Data on the use of amlodipine in patients with hepatic insufficiency is limited. In patients with hepatic insufficiency, there is a decrease in the clearance of amlodipine, which leads to an increase in T½ and AUC by approximately 40-60%.
Indapamide

Suction

Indapamide is rapidly and completely absorbed in the gastrointestinal tract.
The maximum concentration of indapamide in the blood plasma is observed 1 hour after ingestion.

Distribution

Communication with plasma proteins - 79%.

Metabolism and excretion

The half-life is 14-24 hours (average, 18 hours). When re-taking Triplixam is not observed its accumulation.
Indapamide is excreted in the form of inactive metabolites, mainly by the kidneys (70% of the administered dose) and through the intestines (22%).

Special patient groups

In patients with renal insufficiency, the pharmacokinetics of indapamide does not change.
Perindopril

Suction

When administered perindopril is rapidly absorbed in the gastrointestinal tract, the maximum concentration (Cmax) in the blood plasma is reached after 1 h (the active metabolite of perindopril is perindopril). The half-life (T½) of perindopril from blood plasma is 1 hour. Eating slows down the conversion of perindopril to perindoprilat, thus affecting bioavailability. Therefore, Triplixam should be taken 1 time per day, in the morning, before eating.

Distribution

The volume of distribution of free perindoprilat is approximately 0.2 l / kg. Connection of perindoprilat with plasma proteins, mainly with ACE. is about 20% and is dose-dependent.

Metabolism

Perindopril does not possess pharmacological activity. Approximately 27% of the total amount taken inside perindopril enters the bloodstream as an active metabolite of perindoprilat. In addition to perindoprilat, 5 more metabolites are formed that do not possess pharmacological activity. The maximum concentration of perindoprilat in plasma is reached 3-4 hours after ingestion.

Removal

Perindoprilat is excreted by the kidneys. The final T½ of the free fraction is about 17 hours, so an equilibrium state is reached within 4 days. There is a linear dependence of the concentration of perindopril in plasma from its dose.

Elderly age

Removal of perindoprilat is delayed in old age, as well as in patients with cardiac and renal failure.

Renal failure

Selection of the dose should be carried out taking into account the severity of renal failure (creatinine clearance in plasma).

Dialysis

The dialysis clearance of perindoprilat is 70 ml / min.

Cirrhosis of the liver

The pharmacokinetics of perindopril is impaired in patients with cirrhosis of the liver: its hepatic clearance decreases by 2 times. However, the amount of perindoprilat formed does not decrease, which does not require dose adjustment (see the sections “Dosage and Administration” and “Special Instructions”).

Indications

As therapy in patients with arterial hypertension while reducing blood pressure while taking amlodipine, indapamide and perindopril in the same doses.

Contraindications for Triplixam

Hypersensitivity to the active and auxiliary substances that are part of Triplixam, sulfonamide derivatives, dihydropyridine derivatives, other ACE inhibitors, any other substances that are part of Triplixam;
Patients on hemodialysis;
Untreated heart failure in the decompensation stage;
Severe renal failure (creatinine clearance (CC) less than 30 ml / min);
Moderate renal failure (creatinine clearance (CC) less than 60 ml / min) for dosing the perindopril / indapamide combination 10 mg / 2.5 mg (i.e. Triplixam 5 mg + mg + 10 mg and Triplixam 10 mg + 2 , 5 mg + 10 mg);
Angioedema (angioedema) in the background of taking ACE inhibitors in history (see section "Special instructions");
Hereditary / idiopathic angioedema;
Pregnancy (see section “Use during pregnancy and during breastfeeding”);
Breastfeeding period (see the section “Use during pregnancy and during breastfeeding”);
Hepatic encephalopathy:
Severe hepatic impairment;
Hypokalemia;
Severe arterial hypotension (systolic blood pressure less than 90 mm Hg);
Shock (including cardiogenic);
Obstruction of the outflow tract of the left ventricle (for example, clinically significant stenosis of the aortic mouth);
Hemodynamically unstable heart failure after acute myocardial infarction;
Simultaneous use with aliskiren-containing drugs in patients with diabetes mellitus or impaired renal function (glomerular filtration rate (GFR) <60 ml / min / 1.73m2 body surface area) (see sections "Interaction with other drugs" and "Pharmacodynamics ");
Bilateral renal artery stenosis, single kidney artery stenosis;
The simultaneous use of drugs that can cause polymorphic ventricular tachycardia type "pirouette";
Simultaneous use with drugs that extend the QT interval;
Simultaneous use with potassium-sparing diuretics, potassium and lithium preparations, in patients with an increased content of potassium in the blood plasma;
Age up to 18 years (efficacy and safety have not been established).
With care (see also sections "Special Instructions" and "Interaction with Other Medicines")
The presence of only one functioning kidney, impaired water and electrolyte balance, systemic connective tissue diseases, therapy with immunosuppressants, allopurinol, procainamide (risk of developing neutropenia, agranulocytosis), acute myocardial infarction (and within 1 month after myocardial infarction), sinus node syndrome ( severe tachy and bradycardia), with simultaneous appointment with inhibitors or inducers of the CYP3A4 isoenzyme, hepatic failure, mild to moderate severity, bone marrow suppression vorheniya, reduced circulating blood volume (diuretic intake, diet with restricted salt, vomiting, diarrhea, hemodialysis), hyperuricemia (especially accompanied by gouty and active nephrolithiasis), simultaneous use of dantrolene, estramustine, blood pressure lability, before the procedure, after the treatment of lipid flu, imitation lipopathy (LDL) with dextran sulfate, condition after kidney transplantation, Negroid patients, ischemic heart disease, cerebrovascular diseases, renovascular hypertension I, diabetes mellitus, chronic heart failure (NYHA class III and IV), simultaneous use of potassium-saving diuretics, potassium preparations, potassium-containing salt and lithium substitutes, surgery / general anesthesia, hemodialysis using high-flow membranes (for example, AN69® ), simultaneous desensitization therapy with allergens (for example, hymenoptera poison), aortic stenosis / mitral stenosis / hypertrophic obstructive cardiomyopathy, lived age.

Dosage and administration

Inside, on 1 tablet once a day, preferably in the morning before meals.
The dose of Triplixam is selected after the previously titrated doses of individual components. The maximum daily dose - 1 tablet at a dosage of 10.0 mg + 2.5 mg + 10.0 mg.

Special patient groups

Patients with renal insufficiency (see the sections “Pharmacokinetics”, “Contraindications” and “Special Instructions”)
Triplixam is contraindicated in patients with severe renal insufficiency (CC less than 30 ml / min) (see section “Contraindications”). Patients with moderate renal insufficiency (CC 30-60 ml / min) Triplixam is contraindicated in a dosage of 5.0 mg + 2.5 mg + 10.0 mg and 10.0 mg + 2.5 mg + 10.0 mg. It is recommended to begin therapy with the selection of single-component doses.
Continuous medical monitoring should include regular monitoring of plasma creatinine and potassium concentrations. Simultaneous use with aliskiren is contraindicated in patients with impaired renal function (GFR <60 ml / min / 1.73 m2 of body surface area) (see section "Contraindications").
Patients with a liver failure (see the sections "Pharmacokinetics" "Contraindications" and "Special Instructions")
Triplixam is contraindicated in patients with severe liver failure.
For patients with mild or moderate hepatic insufficiency, dose selection should be carried out with caution, since there are no definite recommendations for the dosage of amlodipine for this group of patients.

Elderly patients (see section "Special instructions")

Elimination of perindoprilat in elderly patients is delayed (See the Pharmacokinetics section). Therapy should be based on kidney function.

Pediatric patients

Currently, there are no data on the safety and efficacy of the use of Triplixam in children and adolescents.

Side effects of Triplixam

The most frequent adverse reactions reported in the treatment of perindopril, indapamide and amlodipine as monotherapy were: dizziness, headache, paresthesias, vertigo, drowsiness, visual disturbances, tinnitus, palpitations, flushing of blood to the skin of the face, lowering blood pressure (and effects associated with hypotension), cough, shortness of breath, gastrointestinal disorders (abdominal pain, constipation, diarrhea, taste perversion, nausea, dyspepsia, vomiting), pruritus, rash, maculopapular rash, muscle spasms, swelling in the area ankles as well taenia, swelling and fatigue.

special instructions

All precautions associated with the intake of individual components of the drug should be considered when using their fixed combination as part of Triplixam.
Amlodipine

Chronic heart failure

Patients with chronic heart failure should be treated with caution.
When using amlodipine in patients with chronic heart failure III and functional class according to the NYHA classification, pulmonary edema may develop. “Slow” calcium channel blockers, including amlodipine, should be used with caution in patients with chronic heart failure, due to the possible increased risk of cardiovascular events and mortality.
In patients with severe chronic heart failure (NYHA class IV), treatment should begin with lower doses and under close medical supervision.
Patients with arterial hypertension and coronary heart disease should not stop taking beta-blockers: an ACE inhibitor should be used in conjunction with beta-blockers.

Hypertensive crisis

The efficacy and safety of the use of amlodipine in hypertensive crisis has not been established.
Indapamide

Hepatic encephalopathy

In the presence of impaired liver function, the administration of thiazide and thiazide-like diuretics can lead to the development of hepatic encephalopathy. In this case, you should immediately stop taking diuretic.

Photosensitivity

While taking thiazide and thiazide-like diuretics, photosensitivity reactions have been reported (see the “Side Effects” section). In the case of the development of photosensitivity reaction in patients receiving Triplixam should stop treatment. If necessary, continue diuretic therapy is recommended to protect the skin from exposure to sunlight or artificial ultraviolet rays.

The content of calcium ions in the blood plasma

Thiazide and thiazide-like diuretics can reduce the excretion of calcium ions by the kidneys and lead to a slight and temporary increase in the content of calcium ions in the blood plasma. Severe hypercalcemia may be a consequence of previously undiagnosed hyperparathyroidism. In such cases, diuretic drugs should be discontinued and a study of the function of the parathyroid glands should be conducted (see the “Side Effects” section).

Uric acid

In patients with elevated plasma uric acid concentrations during therapy, the incidence of gout attacks may increase.
Perindopril
Potassium-sparing diuretics, potassium preparations, potassium-containing salt substitutes and food additives
The simultaneous administration of perindopril and potassium-saving diuretics, as well as potassium preparations, potassium-containing food salt substitutes and food additives is not recommended (see the section "Interaction with Other Medicines").

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

There is evidence of an increased risk of arterial hypotension, hyperkalemia, and renal dysfunction (including acute renal failure) with simultaneous use of ACE inhibitors with ARA II or aliskiren. Therefore, a double blockade of RAAS as a result of a combination of an ACE inhibitor with ARA II or aliskiren is not recommended (see the sections “Interaction with other drugs” and “Pharmacodynamics”). If a double blockade is necessary, this should be carried out under the strict supervision of a specialist with regular monitoring of renal function, electrolyte levels in blood plasma and blood pressure. ACE inhibitors should not be used simultaneously with ARA II in patients with diabetic nephropathy.

Neutropenia / agranulocytosis / thrombocytopenia / anemia

There are reports of the development of neutropenia / agranulocytosis, thrombocytopenia and anemia in patients receiving ACE inhibitors. In patients with normal renal function and in the absence of other aggravating factors, neutropenia rarely develops. With particular caution should be used perindopril in patients with systemic diseases of the connective tissue, in patients receiving immunosuppressants, allopurinol or procainamide, or in their combination, especially in patients with impaired renal function.
Some of these patients experienced severe infections, in some cases resistant to intensive antibiotic therapy. When prescribing perindopril, such patients are recommended to periodically monitor leukocytes in the blood, and patients should inform the doctor about any signs of infectious diseases (for example, sore throat, fever) (see the section "Side Effects").

Hypersensitivity / Angioedema

When taking ACE inhibitors, including perindopril, in rare cases, angioedema of the face, extremities, lips, tongue, glottis and / or larynx may develop. This can occur during any period of therapy. When symptoms appear, Triplixam 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 symptoms.
Angioedema, accompanied by swelling of the larynx, can be fatal. Swelling of the tongue, glottis or larynx can lead to airway obstruction, in which case intensive therapy should be carried out immediately. If these symptoms appear, you should immediately inject a solution of epinephrine (adrenaline) 1: 1000 (0.3–0.5 ml) and / or provide airway patency. The patient must be under medical supervision until the symptoms disappear completely and permanently.
In patients of the Negroid race, there was a higher incidence of angioedema associated with the use of ACE inhibitors compared with other races.
In patients with a history of angioedema, not associated with taking ACE inhibitors. the risk of its development when taking Triplixam may be increased (see section "Contraindications"). There are reports of rare cases of angioedema of the intestine during therapy with ACE inhibitors. At the same time, patients had 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 was established using computed tomography of the abdominal area, ultrasound, or at the time of surgical intervention. Symptoms passed 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 desensitization

There are separate reports on the development of long-term, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy with hymenoptera venom (bees, wasps). ACE inhibitors should be used with caution in patients with allergic history or susceptibility to allergic reactions undergoing desensitization procedures, and the use of an ACE inhibitor should be avoided in patients receiving immunotherapy with hymenoptera. However, the anaphylactoid reaction can be avoided by temporarily canceling the ACE inhibitor no less than 24 hours before the desensitization procedure begins.

Anaphylactoid reactions during LDL apheresis

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

Hemodialysis

In patients receiving ACE inhibitors, anaphylactoid reactions were noted during hemodialysis using high-flow membranes (for example, AN69®). Therefore, it is desirable to use a different type of membrane or use an antihypertensive agent of another pharmacotherapeutic group.

Pregnancy

Do not take ACE inhibitors during pregnancy. If continuation of therapy with ACE inhibitors is necessary, patients should switch to other types of antihypertensive therapy with an established safety profile when taken during pregnancy. When pregnancy occurs, the use of ACE inhibitors should be immediately stopped and, if necessary, alternative antihypertensive therapy should be initiated (see the sections "Contraindications" and "Use during pregnancy and during breastfeeding").

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. If the doctor believes that therapy with an ACE inhibitor is necessary for the patient, you can consider the possibility of continuing Triplixam.
Mitral stenosis / aortic stenosis / hypertrophic obstructive cardiomyopathy
ACE inhibitors should be used with caution in patients with obstruction of the outflow tract of the left ventricle.

Ethnic differences

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

Surgical intervention / General anesthesia

The use of ACE inhibitors in patients undergoing surgery using general anesthesia can lead to a pronounced decrease in blood pressure, especially when using agents for general anesthesia that have an antihypertensive effect.
It is recommended, if possible, to stop taking long-acting ACE inhibitors, including perindopril, one day before surgery.

Patients with renovascular hypertension

The treatment of renovascular hypertension is revascularization. However, the use of ACE inhibitors has a beneficial effect in patients, both awaiting surgery, and in the case when surgery is not possible.
When using Triplixam in patients with existing or suspected renal artery stenosis, treatment should be started in the hospital with low doses with constant monitoring of the kidney and potassium levels in the blood, since such patients may develop functional renal failure, which disappears when discontinuation of therapy.

Atherosclerosis

The risk of arterial hypotension exists in all patients, however, special care should be taken when using Triplixam in patients with coronary heart disease and cerebrovascular insufficiency. In such patients, treatment should begin with low doses of the drug.
Perindopril / indapamide.

Lithium preparations

The simultaneous use of a combination of perindopril and indapamide with lithium preparations is not recommended (see the section "Interaction with other drugs").

Hypotension and impaired water-electrolyte balance

The presence of initial hyponatremia is associated with the risk of sudden development of arterial hypotension (especially in patients with renal artery stenosis). Therefore, when monitoring patients, one should pay attention to possible symptoms of dehydration and reduction of electrolytes in the blood plasma, for example, after diarrhea or vomiting. Such patients require regular monitoring of plasma electrolytes. In severe hypotension, intravenous administration of 0.9% sodium chloride solution may be required.
Transient arterial hypotension is not a contraindication for continued therapy. After restoring the BCC and AD, you can resume therapy using low doses of the combination, or use the components of Triplixam in monotherapy mode.
All diuretics can cause hyponatremia. which sometimes leads to serious complications. At the initial stage, hyponatremia may not be accompanied by clinical symptoms; therefore, regular laboratory monitoring is necessary. More frequent monitoring of the content of sodium ions is indicated for elderly patients and patients with liver cirrhosis (see the “Side Effects” and “Overdose” sections).

Patients with diabetes

In patients with type 1 diabetes (the danger of a spontaneous increase in the content of potassium ions), treatment should begin with lower doses and under close medical supervision.
When prescribing Triplixam to patients with diabetes mellitus receiving hypoglycemic agents for ingestion or insulin, during the first month of therapy, regular monitoring of plasma glucose concentration is necessary. It is necessary to control blood glucose levels in patients with diabetes mellitus, especially in the presence of hypokalemia.
Amlodipine / Perindopril

Liver failure

In rare cases, cholestatic jaundice occurs in the presence 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. If jaundice occurs or a significant increase in the activity of “liver” enzymes in patients taking ACE inhibitors, you should stop taking the ACE inhibitor and consult a doctor (see the “Side Effects” section).
In patients with impaired liver function, T½ and amlodipine AUC increases. It is necessary to begin reception of an amlodipin with the lowest doses and to observe precautionary measures, both at the beginning of treatment, and at an increase in a dose. Patients with severe hepatic insufficiency should be gradually increased in dose, ensuring careful monitoring of the clinical condition.
No trials of Triplixam have been conducted in patients with liver failure. Considering the influence of each component included in the preparation, separately, Triplixam is contraindicated in patients with severe hepatic insufficiency, and also requires special care when prescribing patients with moderate and mild hepatic insufficiency.
Amlodipine / indapamide / perindopril

Renal dysfunction

The drug is contraindicated in patients with severe renal insufficiency (CC less than 30 ml / min) (see section "Contraindications").
In patients with moderately severe renal failure (CK 30–60 ml / min), use of Triplixam in dosages containing 10 mg of perindopril and 2.5 mg of indapamide is contraindicated (ie, Triplixam dosage of 5 mg + 2.5 mg + 10 mg and 10 mg + 2.5 mg + 10 mg).
In some patients with arterial hypertension without previous obvious impaired renal function, laboratory signs of functional renal failure may appear during therapy. In this case, treatment with Triplixam should be discontinued with a further opportunity to resume the combination therapy using low doses of the drug, or use the components of the drug in monotherapy. Such patients need regular monitoring of the content of potassium ions and creatinine in the blood serum - 2 weeks after the start of therapy and every 2 months thereafter. Renal failure often occurs in patients with severe chronic heart failure or an initial renal dysfunction, including in renal artery stenosis.
Triplixam is not recommended for patients with bilateral renal artery stenosis or arterial stenosis of a single functioning kidney.
There is a risk of arterial hypotension and / or renal failure (in the presence of chronic heart failure, dehydration and reduction of electrolytes in the blood plasma, etc.): in some pathological conditions, a significant activation of the RAAS may be observed, especially with severe hypovolemia and a decrease in the content of electrolytes blood plasma (on the background of a salt-free diet or long-term use of diuretics), in patients with initially low blood pressure, renal artery stenosis (including bilateral), chronic heart disease sufficiency or cirrhosis with edema and ascites.
The blockade of RAAS with ACE inhibitors may be accompanied by a sharp decrease in blood pressure and / or an increase in plasma creatinine concentration, indicating the development of functional renal failure. These phenomena are more often observed when taking the first dose of Triplixam or during the first two weeks of therapy. Sometimes these conditions develop acutely and the time of their onset may vary. In such cases, it is recommended to resume therapy from lower doses, gradually increasing them. In patients with coronary artery disease and cerebrovascular diseases, a sharp decrease in blood pressure can lead to myocardial infarction or impaired cerebral circulation.
Thiazide and thiazide-like diuretics are fully effective only in patients with normal or slightly impaired renal function (plasma creatinine concentration in adult patients is below 25 mg / l or 220 μmol / l). In elderly patients, creatinine levels should be evaluated based on age, body weight, and gender.
At the beginning of diuretic treatment, patients may experience a temporary decrease in the glomerular filtration rate and an increase in the concentration of urea and creatinine in blood plasma due to hypovolemia and hyponatremia. This transient functional renal failure is not dangerous for patients with unchanged kidney function, however, in patients with initial renal insufficiency, its severity may increase. Patients with renal insufficiency can take amlodipine in standard doses. Changes in plasma concentrations of amlodipine do not correlate with the degree of renal failure.
Special studies on the use of the drug Triplixam in renal failure has not been conducted. When using Triplixam for renal failure, the effects noted when taking the individual components of the drug should be considered.

The content of potassium ions in the blood plasma

Combined therapy with indapamide, perindopril and amlodipine does not prevent the development of hypokalemia, especially in patients with diabetes mellitus or renal failure. As in the case of the use of other antihypertensive drugs in combination with a diuretic, regular monitoring of the content of potassium ions in the blood plasma is necessary.
Hyperkalemia may develop in some patients during treatment with ACE inhibitors, including perindopril. Risk factors for hyperkalemia are renal failure, impaired renal function, advanced age (> 70 years), diabetes mellitus, some associated conditions (dehydration, acute decompensation of cardiac activity, metabolic acidosis), simultaneous administration of potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene, amiloride), preparations of potassium or potassium-containing substitutes for edible salt, as well as the use of other means that increase the content of potassium ions in the blood plasma (for example, heparin). The use of nutritional supplements / potassium preparations, potassium-sparing diuretics, potassium-containing substitutes for edible salt can lead to a significant increase in the content of potassium in the blood, especially in patients with reduced kidney function. Hyperkalemia can lead to serious, sometimes fatal heart rhythm disturbances. If you need a combined reception of the above funds, treatment should be carried out with caution, against the background of regular monitoring of the content of potassium ions in the serum (see the section "Interaction with other drugs"). Therapy with thiazide and thiazide-like diuretics is associated with the risk of hypokalemia. It is necessary to avoid hypokalemia (less than 3.4 mmol / l) in the following categories of patients from the high-risk group: elderly patients and / or exhausted patients (even if they do not receive combined drug therapy), cirrhosis patients with edema and ascites, patients with ischemic heart disease, chronic heart failure. Hypokalemia in these patients increases the toxic effect of cardiac glycosides and increases the risk of developing arrhythmias.
The risk group also includes patients with an extended QT interval, and it does not matter if this increase is caused by congenital causes or the effect of drugs.
Hypokalemia, like bradycardia, contributes to the development of severe cardiac arrhythmias, in particular, polymorphic ventricular tachycardia of the "pirouette" type, which can be fatal. In all the cases described above, regular monitoring of the content of potassium ions in the blood plasma is necessary. The first measurement of the content of potassium ions should be carried out during the first week from the start of therapy.
If hypokalemia is detected, appropriate treatment should be prescribed.

Elderly patients

Before taking Triplixam, it is necessary to evaluate the functional activity of the kidneys and the content of potassium ions in the blood plasma. At the beginning of therapy, the dose of the drug is selected, taking into account the degree of reduction in blood pressure, especially in the case of a decrease in circulating blood volume (BCC) and electrolyte loss. Such measures help to avoid a sharp decrease in blood pressure.
In elderly patients, increasing the dose should be carried out with caution (see sections "Dosage and administration" and "Pharmacokinetics").

Influence on ability to steer vehicles, mechanisms

Due to the possibility of weakness, dizziness due to the use of Triplixam, care must be taken when driving and working with other technical devices that require high concentration of attention and speed of psychomotor reactions.

Overdose

Information about drug overdose Triplixam is missing.

Amlodipine

Information on overdose of amlodipine is limited.

Symptoms

There is evidence of the development of excessive peripheral vasodilation with the possible development of reflex tachycardia. It was reported about the risk of severe and persistent arterial hypotension, incl. with the development of shock and death.
Methods of providing medical care.
When clinically significant hypotension arises due to an overdose of amlodipine, it is necessary to carry out activities aimed at maintaining the function of the cardiovascular system, including placing limbs in an elevated position, monitoring of BCC and diuresis, monitoring of cardiac and respiratory activity.
To normalize vascular tone and blood pressure, you can use vasoconstrictor drugs, provided that there are no contraindications to their use. To eliminate the effects of calcium channel blockages, intravenous administration of calcium gluconate is possible.
In some cases, gastric lavage may be effective. In healthy volunteers, it was demonstrated that the use of activated carbon within 2 hours after ingestion of 10 mg of amlodipine reduces the absorption rate of amlodipine.
Because amlodipine binds to proteins, hemodialysis is ineffective.
Perindopril / Indapamide Combination

Symptoms

For the combination of perindopril / indapamide, the most likely symptom of overdose is arterial hypotension, sometimes in combination with nausea, vomiting, seizures, dizziness, drowsiness, confusion and oligouria, which can turn into anuria (as a result of hypovolemia). Electrolyte disturbances may also occur (hyponatremia, hypokalemia).

Methods of care

Emergency measures are reduced to the removal of Triplixam from the body: gastric lavage and / or reception of activated carbon, followed by restoration of water and electrolyte balance.
With a significant decrease in blood pressure, the patient should be placed in the "lying" position on the back with raised legs, if necessary, correction of hypovolemia (for example, intravenous infusion of 0.9% sodium chloride solution) should be performed. Perindopril, the active metabolite of perindopril, can be removed from the body through dialysis (see Pharmacokinetics section)

Release form and composition

Film Coated Tablets
1 tablet 5 mg + 0.625 mg + 2.5 mg: contains the active ingredients amlodipine besilate 6.935 mg, corresponds to 5.0 mg amlodipine, 0.625 mg indapamide and perindopril arginine 2.5 mg.
1 tablet 5 mg + 1.25 mg + 5 mg: contains the active ingredients amlodipine besilate 6.935 mg, corresponds to 5.0 mg amlodipine, 1.25 mg indapamide and perindopril arginine 5 mg.
1 tablet 10 mg + 1.25 mg + 5 mg: contains the active ingredients amlodipine besilate 13.87 mg, corresponds to 10.0 mg amlodipine, 1.25 mg indapamide and perindopril arginine 5 mg.
1 tablet 5 mg + 2.5 mg + 10 mg: contains the active ingredients amlodipine besilate 6.935 mg, corresponds to 5.0 mg amlodipine, 2.5 mg indapamide and perindopril arginine 10.0 mg.
1 tablet 10 mg + 2.5 mg + 10 mg: contains the active ingredients amlodipine besilate 13.87 mg, corresponds to 10.0 mg amlodipine, 2.5 mg indapamide and perindopril arginine 10.0 mg.
Excipients: calcium carbonate + corn starch, pregelatinized1 35 / 53.5 / 70 / 90.5 / 107 mg, microcrystalline cellulose 35.04 / 53.465 / 70.08 / 90.315 / 106.93 mg, croscarmellose sodium 3 / 4.5 / 6 / 7.5 / 9 mg, magnesium stearate 0.5 / 0.75 / 1 / 1.25 / 1.5 mg, colloidal silicon dioxide 0.4 / 0.6 / 0.8 / 1/1, 2 mg, pregelatinized starch 16/24/32/40/48 mg.
The composition of the film shell: glycerol2 0.1512 / 0.2268 / 0.3024 / 0.378 / 0.4536 mg, hypromellose2 2.51328 / 3.76992 / 5.02656 / 6.2832 / 7.53984 mg, macrogol-60002 3 0.16048 / 0.24072 / 0.32096 / 0.4012 / 0.48144 mg, magnesium stearate2 0.1512 / 0.2268 / 0.3024 / 0.378 / 0.4536 mg, titanium dioxide2 0.48384 / 0, 72576 / 0.9678 / 1.2096 / 1.45152 mg
1 Calcium carbonate 90% + Pregelatinized corn starch 10%.
2 Ingredient of dry premix for white film coating 37781 RBC (glycerol 4.5%, hypromellose 74.8%, macrogol-6000 1.8%, magnesium stearate 4.5%, titanium dioxide 14.4%).
3 Ingredient for film coating and polishing.

Terms of sell

You can buy Triplixam without a prescription.