Triplixam® (Tripliksam)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Dosage form: & nbspFilm-coated tablets.
Composition:1 tablet 5 mg + 0.625 mg + 2.5 mg: contains active substances amlodipine besylate 6,935 mg, corresponds to 5,0 mg of amlodipine, 0.625 mg of indapamide and perindopril arginine 2.5 mg.
1 tablet 5 mg + 1.25 mg + 5 mg: contains active substances amlodipine besylate 6.935 mg, corresponds to 5.0 mg of amlodipine, 1.25 mg of indapamide and perindopril arginine 5.0 mg.
1 tablet 10 mg + 1.25 mg + 5 mg: contains active substances amlodipine besylate 13.87 mg, corresponds to 10.0 mg of amlodipine, 1.25 mg of indapamide and perindopril arginine 5.0 mg.
1 tablet 5 mg + 2.5 mg + 10 mg: contains active substances amlodipine besylate 6,935 mg, corresponds to 5,0 mg of amlodipine, 2.5 mg of indapamide and perindopril of arginine 10.0 mg.
1 tablet 10 mg + 2.5 mg + 10 mg: contains active substances amlodipine besylate 13.87 mg, corresponds to 10.0 mg of amlodipine, 2.5 mg of 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 / 90.31 / 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, silicon dioxide colloid 0.4 / 0.6 / 0.8 / 1 / 1.2 mg, pregelatinized starch 16 / 24/32/40/48 mg.
Composition of the film shell: glycerol2 0,1512 / 0,2268 / 0,3024 / 0,378 / 0,4536 mg, hypromellose2 2.51328 / 3.76992 / 5.02656 / 6.283 / 7.53984 mg, Macrogol-60002,3 0.16048 / 0.24072 / 0.32096 / 0.4012 / 0.448144 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% + Corn starch pregelatinized 10%.
2 Ingredient 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 and polishing shells.
Description:5 mg + 0.625 mg + 2.5 mg: oblong biconvex tablets of white color, engraved on one side and company logo - another.
5 mg + 1.25 mg + 5 mg: oblong biconvex tablets of white color with engraving on one side and company logo - another.
10 mg + 1.25 mg + 5 mg: oblong biconvex tablets of white color, engraved on one side and company logo - another.
5 mg + 2.5 mg + 10 mg: oblong biconvex tablets of white color, engraved on one side and company logo - another.
10 mg + 2.5 mg + 10 mg: oblong biconvex tablets of white color, engraved on one side and company logo - another.
Pharmacotherapeutic group:Hypotensive combination.
Pharmacodynamics:Triplicum® is a combined preparation that includes three antihypertensive components, each of which complements the action of others in controlling blood pressure in patients with hypertension. Amlodipine - a blocker of "slow" calcium channels (BCCC), a dihydropyridine derivative, indapamide - a sulfonamide diuretic, perindopril arginine - inhibitor of the enzyme converting angiotensin I to angiotensin II (ACE inhibitor).
Pharmacological properties of the drug Triplicum ® combine the properties of each of its active substances. In addition, the combination of amlodipine, indapamide and perindopril arginine enhances the antihypertensive effect of each of the components.
Mechanism of action
Amlodinin
Amlodipine - BCCC, a derivative of dihydropyridine. Amlodipine inhibits the transmembrane transition of calcium ions to cardiomyocytes and smooth muscle cells of the vascular wall.
Indapamide
Indapamide refers to sulfonamide derivatives with an indole ring and by pharmacological properties is similar to thiazide diuretics that inhibit the reabsorption of sodium ions in the cortical segment of the nephron loop. This increases the release of kidney ions of sodium, chlorine and, to a lesser extent, potassium and magnesium ions, which is accompanied by an increase in diuresis and antihypertensive effect.
Perindopril
Perindopril is an inhibitor of the enzyme converting angiotensin I to angiotensin II (an angiotensin-converting enzyme (ACE) inhibitor). ACE, or kininase II, is an exopeptidase that converts angiotensin I into an angiotensin II vasoconstrictor. In addition, the enzyme stimulates the production of aldosterone by the adrenal cortex and the destruction of bradykinin, which has a vasodilating action, to an inactive heptapeptide. As a result, perindopril:
- reduces the secretion of aldosterone;
- on the principle of negative feedback increases the activity of renin in the blood plasma;
- with prolonged use reduces the overall peripheral vascular resistance (OPSS), which is mainly due to the effect on the vessels in the muscles and kidneys. These effects are not accompanied by a delay in sodium or liquid ions or the development of reflex tachycardia with prolonged use.
Perindopril has an antihypertensive effect in patients with both low and normal renin activity in blood plasma.
Perindopril has a therapeutic effect due to the active metabolite perindoprilatu.Other metabolites do not have pharmacological activity. Perindopril normalizes the work of the heart, reducing preload and postloading due to:
- vasodilator action on the veins, possibly associated with the activation of the prostaglandin system;
- decrease in total peripheral vascular resistance (OPSS)
When studying the parameters of hemodynamics in patients with chronic heart failure (CHF), it was found:
- decrease of filling pressure in the left and right ventricles of the heart;
- reduction of the OPSS;
- an increase in cardiac output and an increase in the cardiac index;
- Increased muscle peripheral blood flow.
Tolerance of exercise was also increased.
Pharmacodynamic effects
Amlodipine
The antihypertensive effect of amlodipine is due to direct action on the smooth muscle cells of the vascular wall. A detailed mechanism by which amlodipine has an antianginal effect, is not fully established, but it is known that amlodipine reduces the total ischemic load by two actions:
- causes the expansion of peripheral arterioles,reducing overall peripheral vascular resistance (afterload). This reduction in heart burden reduces energy consumption, and the need for myocardium in oxygen.
- causes the expansion of the coronary arteries and arterioles both in the ischemic and intact zones. In patients with coronary artery spasm (prinzmetal angina), coronary blood flow and oxygen supply to the myocardium improve.
In patients with arterial hypertension (AH), amlodipine once a day provides a clinically significant decrease in blood pressure in the "standing" and "lying" for 24 hours. Antihypertensive effect develops slowly, and therefore, the development of acute arterial hypotension is uncharacteristic.
Amlodipine does not have undesirable metabolic effects and does not affect lipid metabolism, does not cause changes in lipid-lowering plasma parameters and can be used in patients with concomitant bronchial asthma, diabetes and gout.
Indapamide
When using indapamide in monotherapy mode, a 24-hour antihypertensive effect was demonstrated. Antihypertensive effect is manifested when the drug is used in doses that have a minimal diuretic effect.
Antihypertensive activity of indapamide is associated with improving the elastic properties of large arteries, reducing arteriolar and general peripheral vascular resistance.
Indapamide reduces hypertrophy of the left ventricle.
Thiazide and thiazide-like diuretics at a certain dose reach a plateau of therapeutic effect, while the incidence of side effects continues to increase with a further increase in the dose of the drug. Therefore, do not increase the dose of the drug, if the recommended dose does not achieve a therapeutic effect.
In short, medium duration and long-term studies involving patients with hypertension, it was shown that indapamide:
- does not affect lipid metabolism, including triglycerides, cholesterol, low-density lipoproteins and high-density lipoproteins;
- does not affect the metabolism of carbohydrates, including in patients with diabetes mellitus.
Perindopril
Perindopril is effective in the treatment of arterial hypertension of any severity. Against the background of its use, there is a decrease in both systolic and diastolic arterial pressure (BP) in the "lying" and "standing" positions.
Antihypertensive effect of the drug reaches a maximum in 4-6 hours after a single oral intake and is maintained for 24 hours.
After 24 hours after ingestion, a residual (about 80%) residual inhibition of ACE is observed.
In patients with a positive response to treatment, BP normalization occurs within a month and persists without the development of tachycardia.
The cessation of treatment is not accompanied by the development of the "rebound" effect.
Perindopril has vasodilating effect, contributes to the restoration of elasticity and large arteries of the vascular wall structure of small arteries and reduces left ventricular hypertrophy.
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 developing hypokalemia with diuretics. Perindopril / Indapamide
In patients with 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" positions.In the course of clinical studies, a more pronounced antihypertensive effect was shown against combined therapy with perindopril and indapamide compared to single-agent monotherapy.
Clinical efficacy and safety
The effect of Triplicum® on morbidity and mortality was not studied.
Amlodipine
The efficacy and safety of the use of amlodipine in a dose of 2.5-10 mg / day, an inhibitor of ACE lisinopril at a dose of 10-40 mg / day as a "first line" drug and a thiazide diuretic chlorthalidone at a dose of 12.5-25 mg / day was studied in A 5-year study of ALLHAT (involving 33,357 patients aged 55 years and older) in patients with mild to moderate AH and. at least one of the additional risk factors for coronary events, such as: myocardial infarction or stroke, which was carried out more than 6 months before enrollment, or other confirmed cardiovascular disease of atherosclerotic origin; type 2 diabetes mellitus; the concentration of high-density lipoprotein cholesterol (HDL-C) is less than 35 mg / dL; hypertrophy of the left ventricle according to electrocardiography or echocardiography; smoking.
The main criterion for assessing efficacy is a combined index of the frequency of deaths from ischemic heart disease and the incidence of non-fatal myocardial infarction. There were no significant differences between the groups of amlodipine and chlorthalidone according to the main evaluation criterion. 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 death rate in the amlodipine and chlorthalidone group did not differ significantly.
Perindopril / Indapamide
In a study involving patients with hypertension and left ventricular hypertrophy (left ventricular mass index> 120 g / m2 for men and> 100 g / m2 in women), the efficacy of 2 mg perindopril therapy with terbutylamine (corresponding to 2.5 mg perindopril arginine) in combination with 0.625 mg indapamide compared with 10 mg enalapril monotherapy, once a day for 1 year, was assessed by echocardiography. If necessary, titration of perindopril tertbutylamine up to 8 mg (corresponding to 10 mg perindopril arginine) and indapamide to 2.5 mg once daily or enalapril up to 40 mg once a day was performed to maintain adequate blood pressure monitoring.In the group of patients taking perindopril / indapamide, dose increases were not required in 34% of patients compared with 20% in the group taking enalapril.
At the end of treatment, the left ventricular mass index values ​​decreased more significantly in the perindopril / indapamide group (-10.1 g / m2) in comparison with the enalapril group (-1.1 g / m2).
The best effect on the values ​​of the left ventricular mass index was achieved with higher doses of a combination of perindopril and indapamide.
With respect to the reduction in 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.
In a study involving patients with type 2 diabetes mellitus, the effect of lowering blood pressure on the incidence of macrovascular disease (death due to cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke) and microvascular complications (the onset or worsening of nephropathy and eye disease) in patients taking combination perindopril / indapamide compared with placebo, on a background of standard therapy, and also taking glycazide modified release in comparison with standard therapy aimed at maintaining blood glucose levels in the norm.
After 4.3 years of therapy, the relative risk of macrovascular and microvascular complications decreased by 9% in the group taking the perindopril / indapamide combination. The advantage was achieved through a significant reduction in the relative risk of mortality by 14% and death from cardiovascular causes by 18% and the development of kidney complications by 21% in the group of patients receiving the combination of perindopril / indapamide combination compared with placebo.
In the subgroup of patients with hypertension, a significant 9% decrease in the relative risk of the combined frequency of macro- and microvascular complications in the group taking the perindopril / indapamide combination was shown, compared with placebo.
In this group also significantly reduced mortality relative risk (16%), death from cardiovascular causes (20%) and development of renal complications (20%) in patients receiving combination perindopril / indapamide compared to patients receiving placebo.
The advantages of antihypertensive therapy did not depend on the benefits achieved against intensive glycemic control.
Double blockade of the renin-angiotensin-aldosterone system (RAAS)
There are data from clinical trials of combined therapy with the use of an ACE inhibitor with APA II.
Clinical studies have been conducted with patients with a history of cardiovascular or cerebrovascular disease, or diabetes mellitus 2, accompanied by confirmed damage to the target organ, as well as studies involving patients with type 2 diabetes and diabetic nephropathy.
These studies did not reveal a significant positive effect on the occurrence of renal and / or cardiovascular complications and mortality rates in patients receiving combination therapy, while the risk of developing hyperkalemia, acute renal failure, and / or hypotension increased compared with patients receiving monotherapy.
Taking into account the similar intra-group pharmacodynamic properties of ACE inhibitors and APA II, these results can be expected for the interaction of any other drugs, representatives of ACE inhibitors and APA II classes.
Therefore, ACE inhibitors and ARA II should not be used simultaneously in patients with diabetic nephropathy.
There is evidence from a clinical trial to study the beneficial effects of the addition of 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 a combination of these diseases. The study was terminated early due to the increased risk of unwanted outcomes. Cardiovascular death and stroke occurred more often in the group of patients receiving aliskiren, compared with the placebo group. Also, adverse events and serious adverse events of special interest (hyperkalemia, arterial hypotension, and renal dysfunction) were more frequent in the aliskiren group than in the placebo group.
Pharmacokinetics:Triplixam®
The combined use of perindopril / indapamide and amlodipine does not change their pharmacokinetic characteristics as compared to the separate administration of these agents.
Amlodipine
Suction
After oral administration amlodipine well absorbed from the gastrointestinal tract.The maximum concentration of amlodipine in the blood plasma is reached 6-12 hours after ingestion.
Distribution
Absolute bioavailability is about 64-80%, the volume of distribution is about 21 l / kg. In vitro studies, it was 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 with the formation of inactive metabolites; 10% of the accepted dose of amlodipine is unchanged in the unchanged form and 60% in the form of metabolites.
Excretion
The final half-life (T1/2) of amlodipine from the blood plasma is 35-50 h, which allows taking the drug 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 T1/2. Increase in AUC and T1/2 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 impairment are limited.In patients with hepatic insufficiency, there is a decrease in clearance of amlodipine, which leads to an increase T1/2 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
Relationship with blood plasma proteins - 79%.
Metabolism and excretion
The half-life is 14-24 hours (on average, 18 hours). When you re-take the drug is not observed its cumulation.
Indapamide is excreted as inactive metabolites, mainly by the kidneys (70% of the administered dose) and through the intestine (22%).
Special patient groups
In patients with renal insufficiency, the pharmacokinetics of indapamide does not change.
Perindopril
Suction
Ingestion perindopril quickly absorbed in the gastrointestinal tract, the maximum concentration (Cmax) in the blood plasma is achieved after 1 hour (the active metabolite of perindopril is perindoprilat). Half-life (T1/2) of perindopril from plasma is 1 hour. Food intake slows the conversion of perindopril to perindoprilat, thus affecting bioavailability.Therefore, the drug should be taken 1 time per day, in the morning, before eating.
Distribution
The volume of distribution of free perindoprilata is approximately 0.2 l / kg. The association of perindoprilat with plasma proteins, mainly with ACE, is about 20% and is dose-dependent.
Metabolism
Perindopril does not have pharmacological activity. Approximately 27% of the total amount of perindopril ingested enters the bloodstream as an active metabolite of perindoprilate. In addition to perindoprilata, another 5 metabolites are formed that do not have pharmacological activity. The maximum concentration of perindoprilat in the blood plasma is reached 3-4 hours after ingestion.
Excretion
Perindoprilat is excreted from the body by the kidneys. Finite T1/2 free fraction is about 17 hours, so the equilibrium state is reached within 4 days. There is a linear dependence of the concentration of perindopril in the blood plasma from its dose.
Special patient groups
Elderly age
The excretion of perindoprilat is delayed in old age, as well as in patients with cardiac and renal insufficiency.
Renal insufficiency
The dose should be selected taking into account the severity of renal failure (creatinine clearance in the blood plasma).
Dialysis
The dialytic clearance of perindoprilat is 70 ml / min.
Cirrhosis of the liver
The pharmacokinetics of perindopril is disrupted in patients with cirrhosis of the liver: its hepatic clearance is reduced by a factor of 2. Nevertheless, 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 a therapy in patients with arterial hypertension with a decrease in blood pressure on the background of amlodipine, indapamide and perindopril in the same doses.
Contraindications:Hypersensitivity to the active and auxiliary substances included in the preparation, derivatives of sulfonamide, dihydropyridine derivative, other ACE inhibitors, any other substances included in the preparation;
- Patients on hemodialysis;
- Unhealed heart failure in the stage of decompensation;
- Severe renal failure (creatinine clearance (CK) less than 30 ml / min);
- Moderate renal insufficiency (creatinine clearance less than 60 ml / min) for the dosage of a combination of perindopril / indapamide 10 mg / 2.5 mg (ie, Triplicum® 5 mg + 2.5 mg + 10 mg and Triplicum®® 10 mg + 2.5 mg + 10 mg);
- Angioedema (angioedema) on the background of taking ACE inhibitors in the anamnesis (see section "Special instructions");
- Hereditary / idiopathic angioedema;
- Pregnancy (see the section "Application during pregnancy and during breastfeeding");
- The period of breastfeeding (see the section "Application 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 (eg, clinically significant stenosis of the aortic estuary);
- Hemodynamically unstable heart failure after acute myocardial infarction;
- Simultaneous use with aliskiren-containing drugs in patients with diabetes mellitus or renal dysfunction (glomerular filtration rate (GFR) <60 ml / min / 1.73 m2 surface area of ​​the body) (see Fig.sections "Interaction with other medicinal products" and "Pharmacodynamics");
- bilateral stenosis of the renal arteries, stenosis of the artery of a single kidney;
- Simultaneous use with drugs that can cause a polymorphic ventricular tachycardia such as "pirouette";
- Simultaneous use with drugs that extend the QT interval;
- Simultaneous use with potassium-sparing diuretics, potassium and lithium preparations, in patients with elevated potassium levels in blood plasma;
- Age under 18 years (efficiency and safety not established).
Carefully:(see also the sections "Special instructions" and "Interaction with other medicinal products")
The presence of only one functioning kidney, disturbance of the water-electrolyte balance, systemic connective tissue diseases, immunosuppressor therapy, allopurinol, procainamide (risk of neutropenia, agranulocytosis), acute myocardial infarction (and within 1 month after myocardial infarction), sinus node weakness syndrome pronounced tachy- and bradycardia), with simultaneous administration with inhibitors or inducers of the isoenzyme CYP3A4,hepatic insufficiency of mild and moderate severity, oppression of bone marrow hematopoiesis, decreased volume of circulating blood (diuretics, diet with restriction of table salt, vomiting, diarrhea, hemodialysis), hyperuricemia (especially accompanied by gout and urate nephrolithiasis), simultaneous use of dantrolene, estramustine, lability blood pressure, before the procedure of apheresis of low-density lipoproteins (LDL) with dextran sulfate, the condition after kidney transplantation, patients Negroid race, ischemic heart disease, cerebrovascular disease, renovascular hypertension, diabetes mellitus, chronic heart failure (NYHA class III and IV functional class), concomitant use of potassium-sparing diuretics, potassium preparations, potassium-containing substitutes for dietary salt and lithium, surgery / general anesthesia, hemodialysis using high-permeability membranes (for example, AN69®), simultaneous desensitizing therapy with allergens (for example, Hymenoptera venom ), aortic stenosis / mitral stenosis / hypertrophic obstructive cardiomyopathy, advanced age.
Pregnancy and lactation:The use of Trnplixam® during pregnancy is contraindicated. When planning a pregnancy or when it occurs while taking Trnplixam®, you should immediately stop taking and prescribe an alternative antihypertensive therapy with a proven safety profile.
Trnplixam® is contraindicated during breastfeeding. It is necessary to evaluate the importance of therapy for the mother and decide whether to stop breastfeeding or stop taking the drug.
Pregnancy
Amlodipine
The safety of the use of amlodipine in pregnancy is not established.
In experimental animal studies, the fetotoxic and embryotoxic effects of the drug have been established when applied in high doses.
Indapamide
At the moment, there is insufficient data on the use of indapamide during pregnancy (less than 300 cases have been described). Long-term use of thiazide diuretics in the III trimester of pregnancy can cause hypovolemia in the mother and a decrease in uteroplacental blood flow, which leads to fetoplacental ischemia and delayed fetal development.In rare cases, against the background of diuretics shortly before delivery, neonates develop hypoglycemia and thrombocytopenia.
Studies in animals have not revealed direct or indirect effects on reproductive toxicity.
Perindopril
The use of ACE inhibitors is not recommended for use in the first trimester of pregnancy (see section "Special instructions"). The use of ACE inhibitors is contraindicated in the second and third trimester of pregnancy (see the sections "Contraindications" and "Special instructions").
At the moment, there is no conclusive epidemiological evidence of teratogenic risk when taking ACE inhibitors in the first trimester of pregnancy. However, a slight increase in the risk of fetal development disorders can not be ruled out. When planning pregnancy, you should cancel the drug and prescribe other antihypertensive drugs that are approved for use in pregnancy. When pregnancy is detected, therapy with ACE inhibitors should be discontinued immediately and, if necessary, another antihypertensive therapy should be prescribed.
It is known that the effect of ACE inhibitors on the fetus in the II and III trimesters of pregnancy can lead to a disruption of its development (decreased kidney function, oligohydramnion,slowing ossification of the skull bones) and development of complications in the newborn (renal failure, arterial hypotension, hyperkalemia).
If the patient has received an ACE inhibitor during II or III trimester of pregnancy, it is recommended to conduct ultrasound newborn to assess the status of the skull and renal function.
Newborns whose mothers received ACE inhibitors during pregnancy should be under close medical supervision because of the risk of developing arterial hypotension (see the sections "Contraindications" and "Special instructions").
Breastfeeding period
Triplicum® is contraindicated during breastfeeding.
Amlodipine
There is no information on the excretion of amlodipine in breast milk.
Indapamide
At the moment there is no reliable information about the isolation of indapamide or its metabolites with breast milk. Taking thiazide diuretics causes a decrease in the amount of breast milk or suppression of lactation. A newborn can develop hypersensitivity to sulfonamide derivatives and hypokalemia. The risk to the fetus / newborn can not be ruled out.
Perindopril
Due to the lack of information regarding the use of perindopril during breastfeeding, the use of perindopril is not recommended, it is preferable to follow an alternative treatment during breastfeeding with a more studied safety profile, especially when feeding newborns and premature babies.
Fertility
Amlodipine
In some patients treated with blockers of "slow" calcium channels, a reversible decrease in sperm motility was noted. Clinical data concerning the potential effect of amlodipine on reproductive function is not enough.
Periidopril / Indapamide
Pre-clinical studies have shown no effect on reproductive function in rats of both sexes. Presumably, there is no effect on fertility in humans.
Dosing and Administration:Inside, 1 tablet 1 time per day, preferably in the morning before eating.
The dose of Triplixam® is selected after the previously titrated doses of individual components. The maximum daily dose is 1 tablet in 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")
Triplicum® is contraindicated in patients with severe renal failure (QC less than 30 mL / min) (see "Contraindications"). Patients with renal insufficiency of moderate severity (CK 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 mono-component doses.
Continuous medical surveillance should include regular monitoring of the concentration of creatinine and potassium in the blood plasma. Simultaneous use with aliskiren is contraindicated in patients with impaired renal function (GFR <60 mL / min / 1.73 m2 body surface area) (see section "Contraindications").
Patients with hepatic insufficiency (see the sections "Pharmacokinetics" "Contraindications" and "Special instructions")
Patients with severe hepatic impairment of Triplicum® are contraindicated.
For patients with mild or moderate hepatic insufficiency, dose selection should be carried out with caution, since there are no unambiguous recommendations for dosage of amlodipine for this group of patients.
Patients of advanced age (see section "Special instructions")
The excretion of perindoprilat in elderly patients is slowed down (See section "Pharmacokinetics"). Therapy should be performed taking into account the function of the kidneys.
Patients of childhood
Currently, there is no data on the safety and efficacy of Triplicum® in children and adolescents.
Side effects:Security Profile
The most frequent adverse reactions reported in the treatment with perindopril, indapamide and amlodipine as a monotherapy were: dizziness, headache, paresthesia, vertigo, drowsiness, visual impairment, ringing in the ears, palpitation, blood flushes to the skin of the face, (and effects associated with hypotension), cough, shortness of breath, gastrointestinal disorders (abdominal pain, constipation, diarrhea, taste distortion, nausea, dyspepsia, vomiting), itching, rash, maculopapular rash, muscle cramps, swelling in the area ankles, as eniya, swelling and fatigue.
The list of adverse reactions is given in the table.
The incidence of adverse reactions that were noted in perindopril, indapamide or amlodipine therapy is given in the following gradation (WHO classification by frequency of development): very often (≥ 1/10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10000,<1/1000); very rarely (<1/10000); frequency (frequency can not be calculated from available data).

MedDRA

Classes and systems of organs

Undesirable reactions

Frequency

Amlodipine

Indapamide

Perindopril

Infectious and

parasitic

diseases

Rhinitis

Infrequently

-

Rarely

Violations of the blood and lymphatic system

Eosinophilia

-

-

Infrequently*

Agranulocytosis (see section "Special instructions")

-

Rarely

Rarely

Aplastic anemia


Rarely

-

Pancytopenia

-

-

Rarely

Leukopenia (see section "Special instructions")

Rarely

Rarely

Rarely

Neutropenia (see section "Special instructions")

-

-

Rarely

Hemolytic anemia

-

Rarely

Rarely

Thrombocytopenia (see section "Special instructions")

Rarely

Rarely

Rarely

Thrombocytopenic purpura

Rarely

-

-

Immune system disorders

Hypersensitivity reactions

Rarely

Infrequently


Disorders from the metabolism and nutrition

Hypoglycemia (see sections "Special instructions" and "Interaction with other medicinal products")

-

-

Infrequently*

Hyperkalemia reversible after drug withdrawal (see Fig.section "Special instructions")

-

-

Infrequently*

Hyponatremia (see section "Special instructions")


Frequency

unknown

Infrequently*

Hyperglycaemia

Rarely

-

-

Hypercalcemia

-

Rarely

-

Reduction of potassium content and development of hypokalemia, especially significant for patients at risk (see section "Special instructions")

-

Frequency

unknown

-

Anorexia

Infrequently

-

-

Increased appetite

Rarely

-

-

Violations

psyche

Insomnia

Infrequently

-

-

Lability of mood (including anxiety)

Infrequently

-

Infrequently

Depression

Infrequently

-

-

Sleep disturbance

-

-

Infrequently

Confusion of consciousness

Rarely

-

Rarely

Unusual dreams

Infrequently

-

-

Increased excitability

Infrequently

-

-

Disturbances from the nervous system

Dizziness

Often

-

Often

Headache

Often

Rarely

Often

Paresthesia

-

Rarely

Often

Vertigo

-

Rarely

Often

Drowsiness

Often

-

Infrequently*

Hypesesia

Infrequently

-

-

Dysgeusia (perversion of taste)

Infrequently

-

Often

Parosmia (perversion of the sense of smell)

Rarely

-

-

Tremor

Infrequently

-

-

Fainting

Infrequently*

Frequency

unknown

Infrequently

Hypertonus

Rarely

-

-

Peripheral Neuropathy

Rarely

-

-

Stroke, possibly due to excessive blood pressure lowering in patients at high risk (see section "Special instructions")

-

-

Rarely

Migraine

Rarely

-

-

Apathy

Rarely

-

-

Agitation

Rarely

-

-

Ataxia

Rarely

-

-

Amnesia

Rarely

-

-

Extrapyramidal

violations

Frequency

unknown

-

-

Disturbances on the part of the organ of sight

Visual impairment (including diplopia)

Infrequently

Frequency

unknown

Often

Myopia

-

Frequency

unknown

-

Blurred vision

-

Frequency

unknown

-

Violation of accommodation

Infrequently

-

-

Xerophthalmia

Infrequently

-

-

Conjunctivitis

Infrequently

-

-

Pain in the eyes

Infrequently

-

-

Hearing disorders and labyrinthine disorders

Tinnitus

Infrequently

-

Often

Heart Disease

Heart palpitations

Often

-

Infrequently*

Tachycardia

-

-

Infrequently*

Angina pectoris (see section "Special instructions")

-

-

Rarely

Heart rhythm disturbances (including bradycardia, ventricular tachycardia and atrial fibrillation)

Rarely

Rarely

Rarely

Myocardial infarction, possibly due to excess BP reduction in patients at high risk (see section "Special instructions")

Rarely

-

Rarely

Polymorphic ventricular tachycardia of the "pirouette" type (possibly fatal) (see the sections "Interaction with other medicinal products" and "Special instructions")

-

Frequency

unknown

-

Development or aggravation of the course of chronic heart failure

Rarely

-

-

Vascular disorders

"Tides" of blood to the skin of the face

Often

-

-

Arterial hypotension (excessive BP reduction) and symptoms associated with this (see section "Special instructions")

Infrequently

Rarely

Often

Vasculitis

Rarely

-

Infrequently*

Orthostatic hypotension

Rarely

-

-

Disturbances from the respiratory system, chest and mediastinal organs

Cough (see section "Special instructions")

Rarely

-

Often

Dyspnea

Infrequently

-

Often

Bronchospasm

-

-

Infrequently

Eosinophilic pneumonia

-

-

Rarely

Nose bleed

Infrequently

-

-

Disorders from the gastrointestinal tract

Abdominal pain

Often

-

Often

Constipation

Infrequently

Rarely

Often

Diarrhea

Infrequently

-

Often

Dyspepsia

Infrequently

-

Often

Nausea

Often

Rarely

Often

Vomiting

Infrequently

Infrequently

Often

Dryness of the oral mucosa

Infrequently

Rarely

Infrequently

Changing the rhythm of defecation

Infrequently

-

-

Hyperplasia of gums

Rarely

-

-

Pancreatitis

Rarely

Rarely

Rarely

Gastritis

Rarely

-

-

Flatulence

Infrequently

-

-

Angioedema of the intestine

-

-

Rarely

Disturbances from the liver and bile ducts

Hepatitis (see section "Special instructions")

Rarely

Frequency

unknown

Rarely

Cholestatic jaundice

Rarely

-

Rarely

Impaired liver function

-

Rarely

-

Possible development of hepatic encephalopathy in the case of liver failure (see the sections "Contraindications" and "Special instructions")

-

Frequency

unknown

-

Disturbances from the skin and subcutaneous tissues

Itchy skin

Infrequently

-

Often

Skin rash

Infrequently

-

Often

Maculopapular rash

-

Often


Hives (see section "Special instructions")

Rarely

Rarely

Infrequently

Angioneurotic edema (see section "Special instructions"), angioedema

Rarely

Rarely

Infrequently

Alopecia

Infrequently

-

-

Purpura

Infrequently

Infrequently

-

Skin discoloration

Infrequently

-

-

Dermatitis

Rarely

-

-

Exanthema

Infrequently

-

-

Increased sweating

Infrequently

-

Infrequently

Reaction

photosensitivity

Rarely

Frequency is unknown (see section "Special instructions")

Infrequently*

Pemphigoid



Infrequently*

Erythema multiforme

Rarely

-

Rarely

Stevens-Johnson syndrome

Rarely

Rarely

-

Exfoliative dermatitis

Rarely

-

-

Toxic epidermal necrolysis

-

Rarely

-

Xeroderma

Rarely

-

-

Cold sweat

Rarely

-

-

Possible exacerbation of already existing systemic lupus erythematosus

-

Frequency unknown

-

Disturbances from the musculoskeletal and connective

Muscle Cramps

Infrequently

-

Often

Osteoarthritis

Infrequently

-

-

Myasthenia gravis

rarely

-

-

arthralgia

infrequently

-

infrequently*

myalgia

infrequently

-

infrequently*

backache

infrequently

-

-

disorders of the kidneys and urinary tract

violation of urination, nocturia, pollakiuria (frequent urination)

infrequently

-

-

acute renal failure

-

-

rarely

painful urination

infrequently

-

-

renal insufficiency

-

rarely

infrequently

disorders of the genitals and breast

erectile disfunction

infrequently

-

infrequently

gynecomastia

infrequently

-

-

common disorders and symptoms

asthenia

infrequently

-

often

increased fatigue

often

rarely

-

peripheral edema (ankle and foot)

often


infrequently

edema

often

-

-

pain

infrequently

-

-

chest pain

infrequently

-

-

malaise

infrequently

-

infrequently*

chills

infrequently

-

-

thirst

infrequently

-

-

fever

-

-

infrequently*

laboratory and instrumental data

increased urea concentration in the blood

-

-

infrequently*

increase in the concentration of creatinine in the blood

-

-

infrequently*

increased activity of hepatic transaminases

rarely

frequency unknown

rarely

hyperbilirubinemia

rarely

-

rarely

reduction of hemoglobin and hematocrit (see section "special instructions")

-

-

rarely

interval lengthening qt per ek (see "special instructions" and "interactions with other medicinal products")

-

frequency unknown

-

increased concentration of uric acid in the blood

-

frequency unknown

-

increase / decrease in body weight

infrequently

-

-

trauma, poisoning, complications after interventions

falls

-

-

infrequently*
* An estimate of the incidence of adverse reactions identified by spontaneous reports was performed based on the results of clinical trials.
Overdose:Information on the overdose of Triplixam® is not available.
Amlodipia
Information about an overdose of amlodipine is limited.
Symptoms.
There are data on the development of excessive peripheral vasodilation with possible development of reflex tachycardia. The risk of developing severe and persistent arterial hypotension was reported, incl.with the development of shock and death.
Methods of medical care.
With clinically significant hypotension due to an overdose of amlodipine, it is necessary to carry out activities aimed at maintaining the function of the cardiovascular system, including placing the limbs in an elevated position, monitoring bcc and diuresis, monitoring cardiac and respiratory activity.
To normalize vascular tone and arterial pressure, vasoconstrictive medications can be used provided that there are no contraindications to their use. To eliminate the effects of calcium channel blockade, intravenous calcium gluconate is possible.
In some cases, gastric lavage may be effective. In healthy volunteers it was demonstrated that the use of activated charcoal within 2 hours after taking 10 mg of amlodipine reduces the rate of absorption of amlodipine.
Because the amlodipine it binds to proteins, hemodialysis is ineffective.
Combination perindopril / indapamide
Symptoms
For the combination of periidopril / indapamide the most likely symptom of an overdose is arterial hypotension,sometimes in combination with nausea, vomiting, convulsions, dizziness, drowsiness, confusion and oliguria, which can
go to anuria (as a result of hypovolemia). Also, electrolyte disorders (hyponatremia, hypokalemia) may occur.
Methods of medical care
Emergency measures are reduced to removing the drug from the body: washing the stomach and / or taking activated charcoal with the subsequent restoration of the water electrolyte balance.
With a significant reduction in blood pressure, the patient should be placed in the "lying" position on the back with raised legs, if necessary, correction of hypovolemia (eg, intravenous infusion of 0.9% sodium chloride solution). Perindoprilat, an active metabolite of perindopril, can be removed from the body by dialysis (see section "Pharmacokinetics").
Interaction:Clinical studies show that the double blockade of the renin-angiotensin-aldosterone system (RAAS) as a result of simultaneous administration of ACE inhibitors, APA II or aliskiren leads to an increase in the incidence of adverse events such as hypotension,hyperkalemia and renal dysfunction (including acute renal failure), compared to situations where only one drug is used that affects RAAS (see "Contraindications", "Special instructions" and "Pharmacodynamics").
Drugs that cause hyperkalemia
Some drugs may increase the risk of hyperkalemia: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists (ARA II), non-steroidal anti-inflammatory drugs (NSAIDs), heparin, immunosuppressants such as ciclosporin or tacrolimus, trimethoprim. Simultaneous use of the drug Triplicum ® with these agents increases the risk of hyperkalemia.
Contraindicated combinations of medicines (see section "Contraindications")
Aliskiren
In patients with diabetes mellitus or renal insufficiency (glomerular filtration rate (GFR) <60 ml / min / 1.73 m2 surface area of ​​the body) increases the risk of hyperkalemia, impaired renal function, increased incidence of adverse cardiovascular events and mortality from cardiovascular diseases.
Unsuitable combinations of drugs

Active substance

Medicinal preparation with which interaction is established

Description of the mechanism of interaction

Amlodipine

Dantrolene (intravenous administration)

In laboratory animals, cases of ventricular fibrillation with a lethal outcome and collapse on the background of verapamil and intravenous dantrolene were observed, accompanied by hyperkalemia. Due to the risk of hyperkalemia, simultaneous administration of "slow" calcium channel blockers, including amlodipine, in patients prone to malignant hyperthermia, as well as in the treatment of malignant hyperthermia, should be avoided.

Grapefruit or grapefruit juice

Simultaneous reception of amlodipine and the use of grapefruit or grapefruit juice is not recommended due to the possible increase in the bioavailability of amlodipine in some patients, which in turn can lead to an increase in the effects of lowering blood pressure.

Perindopril

Aliskiren

In patients without diabetes mellitus or renal dysfunction (glomerular filtration rate (GFR) <60 ml / mii / 1.73m2 surface area of ​​the body), there may be an increased risk of hyperkalemia, impaired renal function, and an increased incidence of cardiovascular morbidity and mortality (see section "Specific guidance").

Joint therapy with ACE inhibitors and angiotensin receptor blockers

In the literature, it was reported that in patients with established atherosclerotic disease, chronic heart failure or diabetes with target organ damage, simultaneous therapy with an ACE inhibitor and ARA II is associated with a higher incidence of hypotension, syncope, hyperkalemia, and impaired renal function (including acute renal insufficiency) compared with the use of only one drug that affects RA AS. Double blockade (for example, with the combination of an ACE inhibitor with APA II) should be limited to individual cases with careful monitoring of kidney function, potassium and blood pressure (see section "Special instructions").

Estramustine

Simultaneous application can lead to an increased risk of side effects, such as angioedema.

Potassium-sparing diuretics (such as triamterene, amiloride), potassium salts

Hyperkalemia (with a possible fatal outcome), especially in cases of impaired renal function (additional effects associated with hyperkalemia).

The combination of perindopril with the above medicines is not recommended (see section "Special instructions").If, however, simultaneous application is shown, they should be used, observing safety precautions and regularly monitoring the potassium content in serum.

Features of the use of spironolactone in chronic heart failure are described further in the text.

Perindopril / Indapamide

Lithium preparations

With simultaneous use of lithium drugs and ACE inhibitors, a reversible increase in lithium levels in the blood plasma and related toxic effects can occur. Simultaneous application of the combination

Perindopril and indapamide with lithium preparations is not recommended. If necessary, such therapy should be regularly monitored by lithium in blood plasma (see section "Special instructions").
Combinations of medicines requiring special attention

The current

substance

Medicinal preparation with which interaction is established

Description of the mechanism of interaction

Amlodipine

Inductors of cytochrome isoenzyme CYP3A4

Data on the effect of inducers of isoenzyme CYP3A4 on amlodipine, are absent. Simultaneous reception of isoenzyme inducers CYP3A4 (eg, rifampicin, St. John's wort products) can lead to a decrease in plasma concentrations of amlodipine. Caution should be exercised while using amlodipine and isoenzyme inducers CYP3A4.


Inhibitors of cytochrome isoenzyme CYP3A4

Simultaneous reception of amlodipine and powerful or moderate inhibitors CYP3A4 (protease inhibitors, antifungal agents of the azole group, macrolides, for example, erythromycin or clarithromycin, verapamil or diltiazem, tacrolimus) can lead to a significant increase in the concentration of amlodipine. Clinical manifestations of these pharmacokinetic abnormalities may be more pronounced in elderly patients. In this regard, monitoring of clinical status and dose adjustment may be required.

Indapamide

Preparations that can cause a polymorphic ventricular tachycardia such as "pirouette"

Because of the risk of developing hypokalemia, caution should be exercised when concomitant administration of indapamide with drugs capable of inducing polymorphic ventricular tachycardia such as pirouettes, for example, antiarrhythmic drugs of the class IA (quinidine, hydroquinidine, disopyramide) and class III (amiodarone, dofetilide, ibutilide, brethil tosylate, sotalol); some neuroleptics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine); benzamides (amisulpride, sulpiride, sultopride, tiapride); butyrophenones (droperidol, haloperidol); other neuroleptics (pimozide); other drugs, such as bepridil, cisapride, difemanyl methyl sulfate, erythromycin in / in, halofantrine, misolastine, moxifloxacin, pentamidine, sparfloxacin, wincamine in / in, methadone, astemizole, terfenadine.

It is necessary to prevent the development of hypokalemia, if necessary, to correct it; monitor the interval QT.

Amphotericin B (iv), gluco- and mperalocorticosteroids (for systemic administration), tetracosactide, laxatives, stimulating bowel motility

Increased risk of hypokalemia (additive effect).

It is necessary to constantly monitor the level of potassium in the blood plasma, if necessary - its correction. Particular attention should be given to patients who simultaneously receive cardiac glycosides.It is recommended to use laxatives that do not stimulate intestinal motility.

Cardiac glycosides

Hypokalemia increases the toxic effect of cardiac glycosides. With the simultaneous use of indapamide and cardiac glycosides, it is necessary to monitor the potassium content in the blood plasma and the parameters of the ECG and, if necessary, adjust the therapy.

Allopuriyol

The simultaneous use with indapamide may be accompanied by an increased risk of reactions of hypersensitivity to allopurinol.

Perindopril

Hypoglycemic agents (insulins, hypoglycemic agents for oral administration)

Epidemiological studies have shown that the combined use of ACE inhibitors and hypoglycemic agents (insulins, hypoglycemic agents for oral administration) can enhance the hypoglycemic effect of insulin and hypoglycemic agents for oral administration until the development of hypoglycemia. This effect is most likely to be observed during the first weeks of simultaneous therapy, as well as in patients with impaired renal function.

Potassium-sparing

diuretics

In patients receiving diuretics, especially those taking out fluid and / or salts, at the beginning of perindopril therapy, there may be an excessive decrease in blood pressure, the risk of which can be reduced by eliminating the diuretic, replenishing fluid loss or salts before starting perindopril therapy, and prescribing perindopril in low dose with a further gradual increase.

When hypertension patients receiving diuretics, especially leading out liquid and / or salts, diuretics must either be canceled before the application of an ACE inhibitor (in this case kaliynesberegayuschy diuretic can later be re-assigned), or ACE inhibitor should be assigned a low dose with its further gradual increase. In the application of diuretics in the case of chronic heart failure, ACE inhibitor should be assigned a low dose, optionally after reducing the dose applied simultaneously kaliynesberegayuschego diuretic.

In all cases, renal function (creatinine concentration) should be monitored in the first weeks of the use of ACE inhibitors.

Potassium-sparing diuretics (eplerenone, spironolactone)

The use of eplerenone or spironolactone in doses from 12.5 mg to 50 mg per day and low doses of ACE inhibitors:

When treating chronic heart failure II-IV functional class by classification NYHA with a left ventricular ejection fraction <40% and previous ACE inhibitors and loop diuretics, there is a risk of hyperkalemia (possibly fatal), especially in the case of non-compliance with recommendations for this combination of drugs. Before using this combination of drugs, you need to make sure there is no hyperkalemia and renal dysfunction.

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

Perindopril / Indapamide

Baclofen

Possible strengthening of antihypertensive

actions. It is necessary to monitor blood pressure and kidney function, if necessary, correction of the dose of antihypertensive drugs is required.


Non-steroidal anti-inflammatory drugs (NSAIDs), including

Acetylsalicylic acid in a dose> 3 g per day

Simultaneous administration of ACE inhibitors and NSAIDs (acetylsalicylic acid in a dose of anti-inflammatory effect, inhibitors of cyclooxygenase-2 (COX-2) and non-selective NSAIDs) can lead to a decrease in antihypertensive effect. The concomitant use of ACE inhibitors and NSAIDs can lead to impaired renal function, including the development of acute renal failure and an increase in serum potassium, especially in patients with initially decreased renal function. Care should be taken when prescribing this combination, especially in elderly patients. Patients should receive an adequate amount of fluid, should regularly monitor kidney function, both at the beginning and during treatment.
A combination of drugs that requires attention

The current

substance

Medicinal preparation with which interaction is established

Description of the mechanism of interaction

Amlodipine

Atorvastatin, digoxin, warfarin or cyclosporin

In clinical studies, the effect of amlodipine on the pharmacokinetics of atorvastatin, digoxin, warfarin, or cyclosporine has not been demonstrated.

Simvastatin

With the simultaneous administration of several doses of amlodipine 10 mg and simvastatin 80 mg, an increase in the concentration of simvastatin by 77% was observed compared with the isolated intake of simvastatin.In patients receiving amlodipine, it should limit the intake of simvastatin up to 20 mg per day.

Antiviral drugs (ritonavir)

Increases plasma concentrations of BCCC, including amlodipine.

Lithium preparations

When combined with lithium preparations, it is possible to intensify the manifestations of their neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, ringing in the ears).

Indapamide

Metformin

Functional renal failure, which can occur against the background of diuretics, especially "loop", with the simultaneous appointment of metformin increases the risk of lactic acidosis.

Do not use metformin, if the level of creatinine in the plasma exceeds 15 mg / L (135 μmol / L) in men and 12 mg / L (110 μmol / L) in women.

Iodine-containing contrast agents

Dehydration of the body against the background of taking diuretics increases the risk of acute renal failure, especially when using high doses of iodine-containing contrast agents. Before using iodine-containing contrast agents, patients must compensate for fluid loss.


Salts of calcium

With simultaneous application, it is possible to develop hypercalcemia due to decreased calcium excretion by the kidneys.


Cyclosporin

It is possible to increase the concentration of creatinine in the blood plasma without changing the concentration of cyclosporine, even with normal water content and sodium ions.

Perindonyl

Antihypertensive agents and vasodilators

With simultaneous administration with nitroglycerin, other nitrates or other vasodilators, an additional reduction in blood pressure is possible.

Allopurinol, cytostatic and immunosuppressive agents, corticosteroids (for systemic use), and procainamide

Simultaneous use with ACE inhibitors may be accompanied by an increased risk of leukopenia.

Means for general anesthesia

ACE inhibitors can lead to an increase in the antihypertensive effect of some agents for general anesthesia.

Diuretics (thiazide and "loop")

The use of diuretics in high doses can lead to hypovolemia, and the addition of perindopril to arterial hypotension.

Glyptins (linaglyptin, saxagliptin, sitagliptin,

vildagliptin)

When combined with ACE inhibitors, the risk of angioedema due to inhibition of dipeptidyl peptidase-4 (DPP-IV) glyptin.

Sympathomimetics

Sympathomimetics can weaken the antihypertensive effect of ACE inhibitors.

Preparations of gold

With the use of ACE inhibitors, including perindopril patients receiving intravenously a preparation of gold (sodium aurotomy malate), a symptom complex of nitrite reactions was described, including facial flushing, nausea, vomiting and arterial hypotension.

Perindopril

/ Indapamide

/ Amlodipine

Imipramine-like (tricyclic) antidepressants, antipsychotics

Preparations of these classes increase the antihypertensive effect and increase the risk of orthostatic hypotension (additive effect).

Other antihypertensive agents

It is possible to increase the antihypertensive effect leading to an additional decrease in blood pressure.

Corticosteroids, tetracosactide

Reduction of antihypertensive action (fluid retention and sodium ions due to the action of corticosteroids).
Other drug interactions

Active substance

Medicinal preparation with which interaction is established

Description of the mechanism of interaction

Amlodipine

Sildenafil

With the simultaneous use of amlodipine and sildenafil, there was no increase in the antihypertensive effect of each drug.

Cyclosporin

Amlodipine does not significantly affect the pharmacokinetic parameters of cyclosporine.

Aluminum/

Magnesium-containing antacids

A single dose of Aluminum / Magnesium-containing antacids does not significantly affect the pharmacokinetics of amlodipine.
Special instructions:All precautions associated with the use of individual components of the drug should be taken into account when using their fixed combination in the preparation of Triplixam®.
Amlodipine
Chronic heart failure
Treatment of patients with chronic heart failure should be conducted with caution.
With the use of amlodipine in patients with chronic cardiac insufficiency III and IV functional class according to the classification of NYHA, the development of pulmonary edema is possible. Blocks of "slow" calcium channels, including amlodipine, should be used with caution in patients with chronic heart failure, due to the possible increase in the risk of development of adverse events from the cardiovascular system and mortality.
In patients with severe chronic heart failure (NYHA functional class IV) treatment should begin with lower doses and under careful medical supervision.
Patients with 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 is not established.
Indapamide
Hepatic encephalopathy
In the presence of violations of the liver, the use of thiazide and thiazide-like diuretics can lead to the development of hepatic encephalopathy. In this case, you should immediately stop taking a diuretic.
Photosensitivity
In patients receiving thiazide and thiazide diuretics reported cases of photosensitivity reactions (see. Section "Side effects"). In the case of developing photosensitivity reaction against the background of taking the drug should stop treatment. If it is necessary to continue therapy with diuretics, it 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.Expressed hypercalcemia may be a consequence of previously not diagnosed hyperparathyroidism. In such cases, diuretic drugs should be withdrawn and parathyroid gland function examined (see "Side effect" section).
Uric acid
In patients with elevated uric acid concentrations in blood plasma, the frequency of gout attacks may increase with therapy.
Perindopril
Potassium-sparing diuretics, potassium preparations, potassium-containing substitutes for edible salt and food additives
The simultaneous administration of perindopril and potassium-sparing diuretics, as well as preparations of potassium, potassium-containing substitutes for edible salt and food additives, is not recommended (see section "Interaction with Other Drugs"). 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 concomitant use of ACE inhibitors with APA II or aliskiren. Therefore, a double blockade of RAAS due to a combination of an ACE inhibitor with APA II oraliskiren is not recommended (see the sections "Interaction with other medicinal products" and "Pharmacodynamics"). If a double blockade is necessary, then this should be done under the strict supervision of a specialist with regular monitoring of kidney function, electrolyte levels in blood plasma and blood pressure. ACE inhibitors should not be used concurrently with ARA II in patients with diabetic nephropathy. Neutropenia / agranulocytosis / thrombocytopenia / anemia
There are reports of the development of neutropenia / agranulocytosis, thrombocytopenia and anemia with the administration of ACE inhibitors. In patients with normal renal function and in the absence of other aggravating factors, neutropenia develops rarely. With extreme caution should be applied perindopril in patients with systemic connective tissue diseases, with the use of immunosuppressants, allopurinol or procainamide, or in combination, especially in patients with impaired renal function.
Some of these patients had severe infections, in some cases, resistant to intensive antibiotic therapy. When prescribing perindopril to such patients, it is recommended to periodically monitor leukocytes inand patients should inform the doctor of any signs of infectious diseases (eg, sore throat, fever) (see section "Side effect").
Hypersensitivity / angioedema
When taking ACE inhibitors, including perindopril, in rare cases, development of angioedema of the face, limbs, lips, tongue, glottis and / or larynx can be observed. This can occur at any time of therapy. When symptoms appear, taking the drug should be stopped immediately, and the patient should be observed until the signs of edema disappear completely. If the swelling affects only the face and lips, then its manifestations usually pass on their own, although antihistamines can be used to treat the symptoms.
Angioedema, accompanied by swelling of the larynx, can lead to death. Swelling of the tongue, glottis or larynx can lead to airway obstruction, in which case intensive therapy should be immediately performed. If such symptoms occur, immediately inject a solution of epinephrine (adrenaline) 1: 1000 (0.3-0.5 ml) and / or provide airway patency. The patient should be under medical supervision until the symptoms disappear completely and persistently.
In patients of the Negroid race, a higher incidence of angioedema developed with ACE inhibitors compared with other races was noted.
Patients with a history of Quinck's edema who are not associated with taking ACE inhibitors may have a higher risk of developing it when taking the drug (see "Contraindications"). There are reports of rare cases of development of angioedema of the intestine against the background of therapy with ACE inhibitors. In this case, patients had abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without a previous angioedema and at a normal level of C1-esterase. The diagnosis was established using computed tomography of the abdominal region, ultrasound or at the time of surgery. Symptoms occurred after discontinuation of ACE inhibitors. Therefore, patients with abdominal pain receiving ACE inhibitors should take into account the possibility of developing angioedema of the intestine during differential diagnosis.
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 Hepaticoptera insects (bees, wasps). ACE inhibitors should be used with caution in patients with a history of allergic anamnesis or susceptibility to allergic reactions undergoing desensitization procedures, and the use of an ACE inhibitor should be avoided in patients receiving immunotherapy with venom of Hymenoptera. However, the anaphylactoid reaction can be avoided by temporarily lifting the ACE inhibitor at least 24 hours before the desensitization procedure begins.
Anaphylactoid reactions during apheresis of LDL
In rare cases, patients receiving ACE inhibitors may develop life-threatening anaphylactoid reactions during LDL-apheresis with dextran sulfate. To prevent anaphylactoid reaction, therapy with an ACE inhibitor should be temporarily discontinued before each apheresis procedure.
Hemodialysis
In patients receiving ACE inhibitors, anaphylactoid reactions were noted in hemodialysis using high-flow membranes (eg AN69®).Therefore, it is desirable to use a different type of membrane or to use an antihypertensive agent of another pharmacotherapeutic group.
Pregnancy
Contraindicated in the administration of ACE inhibitors during pregnancy. If further treatment with ACE inhibitors is necessary, patients should switch to other types of antihypertensive therapy with established safety profile during admission during pregnancy. At the onset of pregnancy, the taking of ACE inhibitors should be stopped immediately and, if necessary, started an alternative antihypertensive therapy (see "Contraindications" and "Pregnancy and lactation" sections).
Cough
Against the background of therapy with an ACE inhibitor, dry cough may occur. Cough persists for a long time against the background of taking this group's drugs and disappears after their withdrawal. When a patient has a dry cough, remember the possible iatrogenic nature of this symptom. If the doctor believes that ACE inhibitor therapy is necessary for the patient, you may consider continuing the drug.
Mitral stenosis / aortic stenosis / hypertrophic obstructive cardiomyopathy
ACE inhibitors should be administered with caution to patients with obstruction of the outflow tract of the left ventricle.
Ethnic differences
Perindopril, like other ACE inhibitors, obviously has a less pronounced hypotensive effect in patients of the Negroid race compared with representatives of other races. Perhaps this difference is due to the fact that in patients with arterial hypertension of the Negroid race, low activity of renin is more often observed.
Surgery / General Anesthesia
The use of ACE inhibitors in patients undergoing surgery with general anesthesia can lead to a marked decrease in blood pressure, especially when using means 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 method of treating reninvascular hypertension is revascularization. Nevertheless, the use of ACE inhibitors has a beneficial effect in patients, both waiting for surgery, and in the case when surgical intervention is impossible.
If Triplixam® is used in patients with existing or suspected renal artery stenosis, treatment should begin in a hospital setting with low doses, with constant monitoring of the kidney and potassium levels in the blood, as these patients may develop functional kidney failure that disappears when discontinuation of therapy.
Atherosclerosis
The risk of arterial hypotension exists in all patients, but special care should be taken when applying the drug in patients with coronary heart disease and cerebral circulatory insufficiency. In such patients, treatment should begin with low doses of the drug.
Perindopril / indapamide.
Lithium preparations
Simultaneous use of a combination of perindopril and indapamide with lithium preparations is not recommended (see section "Interaction with other drugs"). Arterial hypotension and disturbance of 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 observing patients, attention should be paid to the possible symptomsdehydration and reduction of electrolytes in the blood plasma, for example, after diarrhea or vomiting. Such patients need regular monitoring of the content of plasma electrolytes. With severe arterial hypotension, intravenous administration of 0.9% sodium chloride solution may be required.
Transient arterial hypotension is not a contraindication for the continuation of therapy. After the recovery of bcc and blood pressure, one can resume therapy using low doses of the combination, or use the components of the drug in the monotherapy regimen.
All diuretics can cause hyponatraemia, which sometimes leads to serious complications. Hyponatremia at the initial stage may not be accompanied by clinical symptoms, so regular laboratory monitoring is necessary. More frequent monitoring of sodium ions is indicated in elderly patients and patients with cirrhosis of the liver (see "Side effects" and "Overdose" sections).
Patients with diabetes mellitus
In patients with type 1 diabetes mellitus (the risk of a spontaneous increase in potassium ion content) treatment should begin with lower doses and under careful medical supervision.
When the drug is prescribed for patients with diabetes mellitus, who receive hypoglycemic agents for ingestion or insulin, during the first month of therapy, regular monitoring of the glucose concentration in the blood plasma is necessary. It is necessary to monitor the blood glucose level in patients with diabetes mellitus, especially in the presence of hypokalemia.
Amlodipine / Perindopril
Liver failure
In rare cases, when taking ACE inhibitors, cholestatic jaundice occurs. With the progression of this syndrome, fulminant liver necrosis develops, sometimes with a fatal outcome. The mechanism of development of this syndrome is unclear. If there is jaundice or a significant increase in the activity of "liver" enzymes in patients taking ACE inhibitors, stop taking the ACE inhibitor and consult a doctor (see the "Side effect" section).
In patients with impaired liver function T1/2 and AUC of amlodipine increases. Admission of amlodipine should start with the lowest doses and observe precautions, both at the beginning of treatment, and with increasing doses. Patients with severe hepatic insufficiency should increase the dose gradually, ensuring thorough monitoring of the clinical condition.
Triplixam® was not studied in patients with hepatic insufficiency. Taking into account the influence of each component included in the preparation separately, the Triplixam® preparation is contraindicated in patients with severe hepatic insufficiency, and also requires special caution in appointing patients with mild and mild liver failure.
Amlodipine / indapamide / perindopril
Impaired renal function
The drug is contraindicated in patients with severe renal failure (CC less than 30 ml / min) (see section "Contraindications").
In patients with moderate renal insufficiency (CK 30-60 ml / min), the use of Triplixam® in dosages containing 10 mg of perindopril and 2.5 mg of indapamide (ie, the dose of Triplixam® 5 mg + 2.5 mg + 10 mg and 10 mg + 2.5 mg + 10 mg).
In some patients with hypertension without a previous obvious violation of kidney function, there may be laboratory signs of functional renal failure on the background of therapy. In this case, treatment with the drug should be discontinued with the further opportunity to resume 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 and creatinine ions in the blood serum - 2 weeks after the start of therapy and then every 2 months. Renal failure often occurs in patients with severe chronic heart failure or an initial impairment of kidney function, including with renal artery stenosis.
Triplixam® is not recommended for patients with bilateral stenosis of the renal arteries or stenosis of the artery 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 states, there may be a significant activation of RAAS, especially with pronounced hypovolemia and a decrease in the electrolyte content blood plasma (against a background of a salt-free diet or long-term diuretics), in patients with initially low blood pressure, stenosis of the renal artery (including bilateral), chronic heart disease sufficiency or cirrhosis with edema and ascites.
Blockade of RAAS with ACE inhibitors can be accompanied by a sharp decrease in blood pressure and / or an increase in the concentration of creatinine in the blood plasma, indicating the development of functional renal failure. These phenomena are more often observed with the first dose of the drug or during the first two weeks of therapy. Sometimes these conditions develop sharply and the time of their onset can vary. In such cases, resumption of therapy is recommended starting with lower doses, gradually increasing them. In patients with ischemic heart 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 effective only in patients with normal or slightly impaired renal function (creatinine concentration in
blood plasma in adult patients below 25 mg / l or 220 μmol / L). In elderly patients, the level of creatinine should be evaluated in terms of age, body weight and sex.
At the beginning of diuretic treatment in patients due to hypovolemia and hyponatremia, a temporary decrease in the glomerular filtration rate and an increase in the concentration of urea and creatinine in the blood plasma can be observed.This transient functional renal failure is not dangerous for patients with unchanged kidney function, however, in patients with initial renal failure, 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 Triplicum ® in renal failure have not been conducted. When using Triplixam® with renal failure, the effects noted when taking individual components of the drug should be considered.
The content of potassium ions in the blood plasma
Joint therapy with indapamide, perindopril and amlodipine does not prevent the development of hypokalemia, especially in patients with diabetes mellitus or renal insufficiency. As with the use of other antihypertensive agents in combination with a diuretic, regular monitoring of the potassium ion content in the blood plasma is necessary.
Hyperkalemia can develop in some patients during treatment with ACE inhibitors, including perindopril.Risk factors for hyperkalemia include renal failure, impaired renal function, elderly age (> 70 years), diabetes mellitus, certain concomitant conditions (dehydration, acute cardiac decompensation, metabolic acidosis), concomitant 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 agents that increase the content of potassium ions in the blood plasma (for example, heparin). The use of dietary supplements / potassium preparations, potassium-sparing diuretics, potassium-containing substitutes for edible salt can lead to a significant increase in potassium in the blood, especially in patients with reduced renal function. Hyperkalemia can lead to serious, sometimes fatal heart rhythm disturbances. If combined use of the aforementioned agents is required, treatment should be conducted with caution, against a background of regular monitoring of potassium ions in the blood serum (see section "Interaction with other drugs").Therapy with thiazide and thiazide-like diuretics is associated with a risk of hypokalemia. It is necessary to avoid hypokalemia (less than 3.4 mmol / L) in the following categories of patients at high risk: elderly patients and / or depleted patients (even if they do not receive concomitant medication), patients with cirrhosis 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 arrhythmia.
Patients with an extended QT interval are also at risk, but it does not matter whether this increase is due to congenital causes or effects of drugs.
Hypokalemia, like bradycardia, contributes to the development of severe heart rhythm disturbances, in particular, polymorphic ventricular tachycardia such as pirouette, which can be fatal. In all cases described above, regular monitoring of the potassium ion content in the blood plasma is necessary. The first measurement of the content of potassium ions should be carried out during the first week after the start of therapy.
If hypokalemia is detected, appropriate treatment should be prescribed.
Elderly patients
Before starting the drug, 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 BP reduction, especially in case of a decrease in the volume of circulating blood (BCC) and loss of electrolytes. Such measures allow to avoid a sharp decrease in blood pressure.
In elderly patients, an increase in the dose should be carried out with caution (see the sections "Dosing and Administration" and "Pharmacokinetics").
Effect on the ability to drive transp. cf. and fur:In connection with the possibility of weakness, dizziness against the background of the use of the drug Trylixam®, care must be taken when driving vehicles and working with other technical devices that require a high concentration of attention and speed of psychomotor reactions.
Form release / dosage:Tablets coated with a film coat, 5 mg + 0.625 mg + 2.5 mg, 5 mg + 1.25 mg + 5 mg, 10 mg + 1.25 mg + 5 mg, 5 mg + 2.5 mg + 10 mg, 10 mg + 2.5 mg + 10 mg.
Packaging:In the production of "Servier (Ireland) Industries Ltd.". Ireland.
For 29 or 30 tablets in a bottle of polypropylene, equipped with a dispenser and a stopper containing a moisture absorbing gel (silica gel).
1 bottle with instructions for medical use in a pack of cardboard with the control of the first autopsy.
In production at LLC "Serdiks", Russia.
For 29 or 30 tablets in a bottle of polypropylene, equipped with a dispenser and a stopper containing a moisture absorbing gel (silica gel).
1 bottle with instructions for medical use in a pack of cardboard with the control of the first autopsy.
Packaging for hospitals: 30 tablets per bottle of polypropylene, equipped with a dispenser and a stopper containing a moisture absorbing gel.
For 3 bottles of 30 tablets with instructions for medical use in the amount corresponding to the number of bottles, in a pack of cardboard with the control of the first autopsy.
Storage conditions:At a temperature of no higher than 25 ° C. Keep out of the reach of children.
Shelf life:2 years.
Do not use after the expiration date.
Terms of leave from pharmacies:On prescription
Registration number:LP-003905
Date of registration:17.10.2016
Expiration Date:17.10.2021
The owner of the registration certificate:Servier LaboratoriesServier Laboratories France
Manufacturer: & nbsp
Representation: & nbspServier Laboratories Servier Laboratories France
Information update date: & nbsp2016-11-11
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