Triplixam^® (Tablets) Instructions for Use

Instructions
Dosage forms

ATC Code

C09BX01 (Perindopril and amlodipine and indapamide)

Active Substances

Indapamide (Rec.INN registered by WHO)

Amlodipine (Rec.INN registered by WHO)

Perindopril (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antihypertensive combination drug

Pharmacotherapeutic Group

Antihypertensive combination agent

Pharmacological Action

A combined antihypertensive agent, it includes three antihypertensive components, each of which complements the action of the others in controlling blood pressure in patients with arterial hypertension. Amlodipine is a slow calcium channel blocker (CCB), a dihydropyridine derivative. Indapamide is a sulfonamide diuretic. Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II ( ACE inhibitor). The pharmacological properties of the combination combine the properties of each of its active substances. In addition, the combination of amlodipine, indapamide and perindopril enhances the antihypertensive effect of each component.

Mechanism of action

Amlodipine is a CCB, a dihydropyridine derivative. Amlodipine inhibits the transmembrane influx of calcium ions into cardiomyocytes and vascular smooth muscle cells.

Indapamide belongs to sulfonamide derivatives with an indole ring and is pharmacologically close to thiazide diuretics, which inhibit the reabsorption of sodium ions in the cortical segment of the nephron loop. This increases the renal excretion of sodium and chloride ions and, to a lesser extent, potassium and magnesium ions, which is accompanied by an increase in diuresis and an antihypertensive effect.

Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II (ACE inhibitor). ACE, or kininase II, is an exopeptidase that carries out the conversion of angiotensin I to the vasoconstrictor substance angiotensin II. In addition, the enzyme stimulates the production of aldosterone by the adrenal cortex and the breakdown of bradykinin, which has a vasodilating effect, into an inactive heptapeptide. As a result, perindopril

Reduces the secretion of aldosterone;
Increases plasma renin activity by the principle of negative feedback;
With long-term use, reduces total peripheral vascular resistance (TPR), which is mainly due to its effect on blood vessels in muscles and kidneys. These effects are not accompanied by sodium or fluid retention or the development of reflex tachycardia with long-term use.

Perindopril has an antihypertensive effect in patients with both low and normal plasma renin activity.

Perindopril exerts its therapeutic effect through the active metabolite perindoprilat. Other metabolites do not have pharmacological activity.

Perindopril normalizes heart function, reducing preload and afterload due to

Vasodilating effect on veins, possibly associated with the activation of the prostaglandin system;
Reduction of TPR.

When studying hemodynamic parameters in patients with chronic heart failure (CHF), the following was revealed

Decrease in filling pressure in the left and right ventricles of the heart;
Decrease in TPR;
Increase in cardiac output and increase in cardiac index;
Enhancement of muscular peripheral blood flow.

Exercise tolerance also increased.

Pharmacodynamic effects

Amlodipine

The antihypertensive effect of amlodipine is due to a direct effect on vascular smooth muscle cells. The detailed mechanism by which amlodipine exerts its antianginal action is not fully established, but it is known that amlodipine reduces total ischemic load through two actions

Causes dilation of peripheral arterioles, reducing TPR (afterload). This reduction in cardiac load reduces energy expenditure and myocardial oxygen demand;
Causes dilation of coronary arteries and arterioles in both ischemic and intact areas. This improves coronary blood flow and myocardial oxygen supply in patients with coronary artery spasm (Prinzmetal’s angina).

In patients with arterial hypertension (AH), taking amlodipine once a day provides a clinically significant reduction in blood pressure in the standing and lying positions over 24 hours. The antihypertensive effect develops slowly, so the development of acute arterial hypotension is not typical.

Amlodipine does not have undesirable metabolic effects and does not affect lipid metabolism parameters, does not cause changes in plasma lipid-lowering parameters and can be used in patients with concomitant bronchial asthma, diabetes mellitus and gout.

Indapamide

A 24-hour antihypertensive effect was demonstrated when using indapamide in monotherapy. The antihypertensive effect is manifested when using the drug in doses that have a minimal diuretic effect.

The antihypertensive activity of indapamide is associated with an improvement in the elastic properties of large arteries and a decrease in arteriolar and total peripheral vascular resistance.

Indapamide reduces left ventricular hypertrophy.

Thiazide and thiazide-like diuretics reach a plateau of therapeutic effect at a certain dose, while the frequency of side effects continues to increase with a further increase in the drug dose. Therefore, the dose of the drug should not be increased if the therapeutic effect is not achieved at the recommended dose.

In short-term, medium-term and long-term studies involving patients with arterial hypertension, it was shown that Indapamide

Does not affect lipid metabolism parameters, including the level of triglycerides, cholesterol, LDL and HDL;
Does not affect carbohydrate metabolism parameters, including in patients with diabetes mellitus.

Perindopril

Perindopril is effective in the treatment of arterial hypertension of any severity. Its use results in a decrease in both systolic and diastolic blood pressure in the lying and standing positions.

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

24 hours after oral administration, a pronounced (about 80%) residual inhibition of ACE is observed.

In patients with a positive response to treatment, normalization of blood pressure occurs within one month and is maintained without the development of tachycardia.

Discontinuation of treatment is not accompanied by the development of a rebound effect.

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

Concomitant administration of thiazide diuretics enhances 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 developing hypokalemia while taking 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 positions. Clinical studies have shown a more pronounced antihypertensive effect with combination therapy with perindopril and indapamide compared with monotherapy with individual components.

Pharmacokinetics

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

Amlodipine

Absorption

After oral administration, amlodipine is well absorbed from the gastrointestinal tract. C_max of amlodipine in plasma is reached 6-12 hours after oral administration of the drug.

Distribution

Absolute bioavailability is about 64-80%. V_d is approximately 21 L/kg. In vitro studies have shown that about 97.5% of circulating amlodipine is bound to plasma proteins. Simultaneous food intake does not affect the bioavailability of amlodipine.

Metabolism

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

Excretion

The terminal T_1/2 of amlodipine from plasma is 35-50 hours, which allows the drug to be taken once a day.

Special patient groups

Elderly patients experience a slowdown in the clearance of amlodipine, leading to an increase in AUC and T_1/2. The increase in AUC and T_1/2 in patients with chronic heart failure (CHF) corresponds to the expected value for this age group.

Data on the use of amlodipine by patients with hepatic insufficiency are limited. In patients with hepatic insufficiency, a decrease in the clearance of amlodipine is observed, leading to an increase in T_1/2 and AUC by approximately 40-60%.

Indapamide

Absorption

Indapamide is rapidly and completely absorbed from the gastrointestinal tract. C_max of indapamide in plasma is observed 1 hour after oral administration.

Distribution

Binding to plasma proteins is 79%.

Metabolism and excretion

T_1/2 is 14-24 hours (average 18 hours). No accumulation of the drug is observed upon repeated administration. Indapamide is excreted as 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 do not change.

Perindopril

Absorption

When taken orally, perindopril is rapidly absorbed from the gastrointestinal tract, C_max in plasma is reached in 1 hour (the active metabolite of perindopril is perindoprilat). T_1/2 of perindopril from plasma is 1 hour. Food intake slows down the conversion of perindopril to perindoprilat, thus affecting bioavailability. Therefore, the drug should be taken once a day, in the morning, before meals.

Distribution

V_d of free perindoprilat is approximately 0.2 L/kg. The binding of perindoprilat to plasma proteins, mainly to ACE, is about 20% and is dose-dependent.

Metabolism

Perindopril does not have pharmacological activity. Approximately 27% of the total amount of perindopril taken orally enters the bloodstream in the form of the active metabolite perindoprilat. In addition to perindoprilat, 5 more metabolites are formed that do not have pharmacological activity. C_max of perindoprilat in plasma is reached 3-4 hours after oral administration.

Excretion

Perindoprilat is excreted from the body by the kidneys. The terminal T_1/2 of the free fraction is about 17 hours, so the steady state is reached within 4 days.

There is a linear relationship between the plasma concentration of perindopril and its dose.

Special patient groups

Elderly age. The excretion of perindoprilat is slowed down in the elderly, as well as in patients with cardiac and renal insufficiency.

Renal insufficiency. Dose selection should be carried out taking into account the severity of renal insufficiency (plasma creatinine clearance).

Dialysis. The dialysis clearance of perindoprilat is 70 ml/min.

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

Indications

Treatment of arterial hypertension when blood pressure decreases while taking amlodipine, indapamide and perindopril in the same doses.

ICD codes

Open the list of ICD codes

ICD-10 code	Indication
I10	Essential [primary] hypertension

ICD-11 code	Indication
BA00.Z	Essential hypertension, unspecified

Dosage Regimen

The method of application and dosage regimen for a specific drug depend on its form of release and other factors. The optimal dosage regimen is determined by the doctor. It is necessary to strictly adhere to the compliance of the dosage form of a specific drug with the indications for use and dosage regimen.

Tablets

Orally, 1 single dose once a day, preferably in the morning before meals.

The dose of the drug containing this combination is selected after previous titration of the doses of the individual components. The maximum daily dose of the amlodipine + Indapamide + perindopril combination is 10 mg + 2.5 mg + 10 mg.

Special patient groups

This combination is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 ml/min). This combination is contraindicated in patients with moderate renal impairment (creatinine clearance 30-60 ml/min) in the dosage of 5 mg + 2.5 mg + 10 mg and 10 mg + 2.5 mg + 10 mg. It is recommended to start therapy by selecting doses of monocomponents.

Constant medical supervision should include regular monitoring of plasma creatinine and potassium concentrations. Concomitant use with aliskiren is contraindicated in patients with renal impairment (GFR <60 ml/min/1.73m² body surface area).

This combination is contraindicated in patients with severe hepatic impairment. For patients with mild or moderate hepatic impairment, dose selection should be carried out with caution, since there are no clear recommendations on the dose of amlodipine for this group of patients.

The excretion of perindoprilat in elderly patients is slowed down. Therapy should be carried out taking into account renal function.

Currently, there are no data on the safety and efficacy of using this combination in children and adolescents.

Adverse Reactions

Safety profile

The most frequent adverse reactions reported during treatment with perindopril, indapamide and amlodipine as monotherapy were: dizziness, headache, paresthesia, drowsiness, taste disturbance, visual impairment, diplopia, tinnitus, vertigo, palpitations, flushing, decreased blood pressure (and effects associated with arterial hypotension), cough, dyspnea, gastrointestinal disorders (abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting, change in stool frequency and character), skin itching, rash, maculopapular rash, muscle cramps, ankle swelling, asthenia, edema and fatigue.

The list of adverse reactions is given in the table.

The frequency of adverse reactions that were noted in therapy with perindopril, indapamide or amlodipine is given in the following gradation (WHO classification by frequency of occurrence): very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency not known (frequency cannot be calculated from available data).

Adverse reactions	Frequency
Adverse reactions	Amlodipine	Indapamide	Perindopril
Infections and infestations
Rhinitis	Uncommon	–	Very rare
Blood and lymphatic system disorders
Eosinophilia	–	–	Uncommon*
Agranulocytosis	–	Very rare	Very rare
Aplastic anemia		Very rare	–
Pancytopenia	–	–	Very rare
Leukopenia	Very rare	Very rare	Very rare
Neutropenia	–	–	Very rare
Hemolytic anemia	–	Very rare	Very rare
Thrombocytopenia	Very rare	Very rare	Very rare
Thrombocytopenic purpura	Very rare	–	–
Immune system disorders
Hypersensitivity reactions	Very rare	Uncommon	–
Metabolism and nutrition disorders
Hypoglycemia	–	–	Uncommon *
Hyperkalemia, reversible after drug withdrawal	–	–	Uncommon *
Hyponatremia		Frequency unknown	Uncommon *
Hyperglycemia	Very rare	–	–
Hypercalcemia	–	Very rare	–
Decrease in potassium content and development of hypokalemia, especially significant for patients at risk	–	Frequency unknown	–
Anorexia	Uncommon	–	–
Increased appetite	Rare	–	–
Psychiatric disorders
Insomnia	Uncommon	–	–
Mood lability (including anxiety)	Uncommon	–	Uncommon
Depression	Uncommon	–	–
Sleep disorder	–	–	Uncommon
Confusion	Rare	–	Very rare
Unusual dreams	Uncommon	–	–
Increased excitability	Uncommon	–	–
Nervous system disorders
Dizziness	Common	–	Common
Headache	Common	Rare	Common
Paresthesia	Uncommon	Rare	Common
Drowsiness	Common	–	Uncommon *
Hypoesthesia	Uncommon	–	–
Dysgeusia (taste perversion)	Uncommon	–	Common
Parosmia (smell perversion)	Very rare	–	–
Tremor	Uncommon	–	–
Syncope	Uncommon*	Frequency unknown	Uncommon
Hypertonia	Very rare	–	–
Peripheral neuropathy	Very rare	–	–
Stroke, possibly due to excessive blood pressure reduction in high-risk patients	–	–	Very rare
Migraine	Very rare	–	–
Apathy	Very rare	–	–
Agitation	Very rare	–	–
Ataxia	Very rare	–	–
Amnesia	Very rare	–	–
Extrapyramidal disorders	Frequency unknown	–	–
Possible development of hepatic encephalopathy in case of hepatic insufficiency	–	Frequency unknown	–
From the organ of vision
Vision disorders (including diplopia)	Common	Frequency unknown	Common
Diplopia	Common	–	–
Myopia	–	Frequency unknown	–
Blurred vision	–	Frequency unknown	–
Accommodation disorder	Uncommon	–	–
Xerophthalmia	Uncommon	–	–
Conjunctivitis	Uncommon	–	–
Eye pain	Uncommon	–	–
From the ear and labyrinth disorders
Tinnitus	Uncommon	–	Common
Vertigo	–	Rare	Common
From the heart
Palpitations	Common	–	Uncommon *
Tachycardia	–	–	Uncommon *
Angina pectoris	–	–	Very rare
Cardiac arrhythmias (including bradycardia, ventricular tachycardia and atrial fibrillation)	Uncommon	Very rare	Very rare
Myocardial infarction, possibly due to excessive BP reduction in high-risk patients	Very rare	–	Very rare
Polymorphic ventricular tachycardia of the "torsades de pointes" type (possibly fatal)	–	Frequency unknown	–
Development or worsening of chronic heart failure	Very rare	–	–
From the vascular system
Flushing	Common	–	–
Arterial hypotension (excessive BP reduction) and associated symptoms	Uncommon	Very rare	Common
Vasculitis	Very rare	–	Uncommon *
Orthostatic hypotension	Very rare	–	–
Raynaud’s phenomenon	–	–	Frequency unknown
From the respiratory system, thoracic and mediastinal disorders
Cough	Uncommon	–	Common
Dyspnea	Common	–	Common
Bronchospasm	–	–	Uncommon
Eosinophilic pneumonia	–	–	Very rare
Epistaxis	Uncommon	–	–
From the gastrointestinal tract
Abdominal pain	Common	–	Common
Constipation	Common	Rare	Common
Diarrhea	Common	–	Common
Dyspepsia	Common	–	Common
Nausea	Common	Rare	Common
Vomiting	Uncommon	Uncommon	Common
Dry mouth	Uncommon	Rare	Uncommon
Change in bowel habits	Common	–	–
Gingival hyperplasia	Very rare	–	–
Pancreatitis	Very rare	Very rare	Very rare
Gastritis	Very rare	–	–
Flatulence	Uncommon	–	–
Intestinal angioedema	–	–	Very rare
From the hepatobiliary system
Hepatitis	Very rare	Frequency unknown	Very rare
Cholestatic jaundice	Very rare	–	Very rare
Liver function impairment	–	Very rare	–
From the skin and subcutaneous tissues
Pruritus	Uncommon	–	Common
Skin rash	Uncommon	–	Common
Maculopapular rash	–	Common	–
Urticaria	Uncommon	Very rare	Uncommon
Angioedema, Quincke’s edema	Very rare	Very rare	Uncommon
Alopecia	Uncommon	–	–
Purpura	Uncommon	Uncommon	–
Skin discoloration	Uncommon	–	–
Dermatitis	Rare	–	–
Exanthema	Uncommon	–	–
Hyperhidrosis	Uncommon	–	Uncommon
Photosensitivity reaction	Very rare	Frequency unknown	Uncommon *
Psoriasis exacerbation	–	–	Rare
Pemphigoid	–	–	Uncommon *
Erythema multiforme	Very rare	–	Very rare
Stevens-Johnson syndrome	Very rare	Very rare	–
Exfoliative dermatitis	Very rare	–	–
Toxic epidermal necrolysis	Frequency unknown	Very rare	–
Xeroderma	Very rare	–	–
Cold sweat	Very rare	–	–
From the musculoskeletal system and connective tissue
Muscle spasms	Common	–	Common
Arthrosis	Uncommon	–	–
Myasthenia	Rare	–	–
Arthralgia	Uncommon	–	Uncommon *
Myalgia	Uncommon	–	Uncommon *
Back pain	Uncommon	–	–
Possible exacerbation of pre-existing systemic lupus erythematosus	–	Frequency unknown	–
From the renal and urinary system
Micturition disorder	Uncommon	–	–
Nocturia	Uncommon	–	–
Pollakiuria (frequent urination)	Uncommon	–	–
Acute renal failure	–	–	Very rare
Painful urination	Uncommon	–	–
Renal failure	–	Very rare	Uncommon
From the reproductive system and breast
Erectile dysfunction	Uncommon	–	Uncommon
Gynecomastia	Uncommon	–	–
General disorders and administration site conditions
Asthenia	Common	–	Common
Fatigue	Common	Rare	–
Peripheral edema (ankles and feet)	–	–	Uncommon
Edema	Very common	–	–
Pain	Uncommon	–	–
Chest pain	Uncommon	–	Uncommon *
Malaise	Uncommon	–	Uncommon *
Chills	Uncommon	–	–
Thirst	Uncommon	–	–
Fever	–	–	Uncommon *
Laboratory and instrumental data
Increased blood urea	–	–	Uncommon *
Increased blood creatinine	–	–	Uncommon *
Increased liver transaminases	Very rare	Frequency unknown	Rare
Hyperbilirubinemia	–	–	Rare
Decreased hemoglobin and hematocrit	–	–	Very rare
Prolongation of QT interval on ECG	–	Frequency unknown	–
Increased blood uric acid	–	Frequency unknown	–
Weight increased	Uncommon	–	–
Weight decreased	Uncommon	–	–
Injury, poisoning and procedural complications
Falls	–	–	Uncommon *

* The frequency assessment of adverse reactions identified from spontaneous reports is based on data from clinical study results.

Cases of syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported with the use of other ACE inhibitors. The syndrome of inappropriate antidiuretic hormone secretion is classified as a very rare but possible complication of therapy with ACE inhibitors, including perindopril.

Contraindications

Hypersensitivity to the active substances of the combination, sulfonamide derivatives, dihydropyridine derivatives, other ACE inhibitors, any other components of the drug;
Patients undergoing hemodialysis;
Untreated decompensated heart failure;
Severe renal impairment (CrCl less than 30 ml/min);
Moderate renal impairment (CrCl less than 60 ml/min) for the perindopril/Indapamide 10 mg/2.5 mg combination dosage;
History of angioedema (Quincke’s edema) associated with previous ACE inhibitor therapy;
Hereditary/idiopathic angioedema;
Hepatic encephalopathy;
Severe hepatic impairment;
Hypokalemia;
Severe arterial hypotension (systolic BP less than 90 mm Hg);
Shock (including cardiogenic);
Obstruction of the left ventricular outflow tract (e.g., clinically significant aortic stenosis);
Hemodynamically unstable heart failure after acute myocardial infarction;
Concomitant use with aliskiren-containing drugs in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR <60 ml/min/1.73 m² body surface area);
Concomitant use with ARBs in patients with diabetic nephropathy;
Concomitant use with the combination of valsartan + sacubitril;
Extracorporeal treatments leading to blood contact with negatively charged surfaces;
Severe bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney;
Concomitant use with drugs that can induce polymorphic ventricular tachycardia of the "torsades de pointes" type;
Concomitant use with drugs that prolong the QT interval;
Concomitant use with potassium-sparing diuretics, potassium supplements and lithium, in patients with elevated plasma potassium levels;
Pregnancy;
Breastfeeding period;
Age under 18 years (efficacy and safety not established).

Use in Pregnancy and Lactation

Contraindicated during pregnancy and breastfeeding.

When planning pregnancy or if pregnancy occurs during the use of this combination, the drug should be discontinued immediately and alternative antihypertensive therapy with a proven safety profile should be prescribed.

The significance of therapy for the mother should be assessed and a decision should be made to either discontinue breastfeeding or discontinue the drug containing this combination.

Pregnancy

Amlodipine

The safety of amlodipine during pregnancy has not been established.

In experimental studies in animals, fetotoxic and embryotoxic effects of the drug were established when used in high doses.

Indapamide

Currently, there is insufficient data on the use of indapamide during pregnancy (less than 300 cases described). Long-term use of thiazide diuretics in the third trimester of pregnancy may cause maternal hypovolemia and reduced uteroplacental blood flow, leading to fetoplacental ischemia and fetal growth retardation. In rare cases, newborns developed hypoglycemia and thrombocytopenia when diuretics were taken shortly before delivery.

Animal studies did not reveal any direct or indirect effects on reproductive toxicity.

Perindopril

The use of ACE inhibitors is not recommended in the first trimester of pregnancy (see section “Special Precautions”) and is contraindicated in the second and third trimesters of pregnancy (see sections “Contraindications” and “Special Precautions”).

Currently, there is no conclusive epidemiological data on the teratogenic risk of ACE inhibitors in the first trimester of pregnancy. However, a small increased risk of fetal developmental disorders cannot be excluded. When planning pregnancy, the drug should be discontinued and other antihypertensive agents approved for use during pregnancy should be prescribed. If pregnancy is detected, ACE inhibitor therapy should be discontinued immediately and, if necessary, other antihypertensive therapy should be prescribed.

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

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

Newborns whose mothers received ACE inhibitors during pregnancy should be under close medical supervision due to the risk of developing arterial hypotension (see sections “Contraindications” and “Special Precautions”).

Breastfeeding period

Triplixam^® is contraindicated during breastfeeding.

Amlodipine

Amlodipine is excreted in human breast milk. The infant’s dose as a proportion of the maternal dose was determined to be in the range of 3-7%, with a maximum of 15%. The effect of amlodipine on infants is unknown.

Indapamide

Currently, there is no reliable information on the excretion of indapamide or its metabolites into breast milk. Hypersensitivity to sulfonamide derivatives and hypokalemia may develop; the risk to the newborn/infant cannot be excluded.

Since Indapamide is similar in properties to thiazide diuretics, its use causes a decrease in the amount of breast milk or suppression of lactation.

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 use alternative treatment with a more studied safety profile during breastfeeding, especially when feeding newborns and preterm infants.

Fertility

Amlodipine

Some patients treated with calcium channel blockers have experienced reversible reduction in sperm motility. There is insufficient clinical data regarding the potential effect of amlodipine on reproductive function. In one study in rats, a negative effect on male fertility was found.

Perindopril/Indapamide

Preclinical studies showed no effect on reproductive function in rats of both sexes. It is presumed that there is no effect on human fertility.

Use in Hepatic Impairment

Contraindicated in severe hepatic insufficiency, hepatic encephalopathy.

Use with caution in mild to moderate hepatic insufficiency.

Use in Renal Impairment

Contraindicated in severe renal impairment (CrCl less than 30 ml/min), moderate renal impairment (CrCl less than 60 ml/min) for the perindopril/Indapamide 10 mg/2.5 mg combination dosage (i.e., Triplixam^® 5 mg + 2.5 mg + 10 mg and Triplixam^® 10 mg + 2.5 mg + 10 mg), in patients undergoing hemodialysis, with bilateral renal artery stenosis, stenosis of the artery to a single kidney.

Use with caution in the presence of only one functioning kidney.

Pediatric Use

The drug is contraindicated in patients under 18 years of age (efficacy and safety not established).

Geriatric Use

Therapy with the drug should be carried out taking into account renal function.

Special Precautions

All precautions associated with the intake of individual components should be considered when using their fixed combination in the composition of a specific drug.

Amlodipine

Chronic heart failure

Treatment of patients with chronic heart failure should be carried out with caution.

When using amlodipine in patients with chronic heart failure of NYHA functional class III and IV, pulmonary edema may develop. Calcium channel blockers, including amlodipine, should be used with caution in patients with chronic heart failure due to a possible increased risk of cardiovascular adverse events and mortality.

In patients with severe chronic heart failure (NYHA functional class IV), treatment should be started with lower doses and under close medical supervision.

Patients with arterial hypertension and coronary artery disease should not discontinue beta-blockers: the ACE inhibitor should be used in combination with beta-blockers.

Hypertensive crisis

The efficacy and safety of amlodipine in hypertensive crisis have not been established.

Indapamide

Hepatic encephalopathy

In the presence of impaired liver function, the use of thiazide and thiazide-like diuretics may lead to the development of hepatic encephalopathy. In this case, the diuretic should be discontinued immediately.

Photosensitivity

Cases of photosensitivity reactions have been reported during the use of thiazide and thiazide-like diuretics. If a photosensitivity reaction occurs during treatment with the drug, treatment should be discontinued. If continuation of diuretic therapy is necessary, it is recommended to protect the skin from exposure to sunlight or artificial ultraviolet rays.

Plasma calcium levels

Thiazide and thiazide-like diuretics may reduce the renal excretion of calcium ions and lead to a slight and transient increase in plasma calcium levels. Marked hypercalcemia may be a consequence of previously undiagnosed hyperparathyroidism. In such cases, diuretic therapy should be discontinued and parathyroid function should be investigated.

Uric Acid

In patients with elevated plasma uric acid concentration, therapy may increase the frequency of gout attacks.

Perindopril

Potassium-sparing diuretics, potassium preparations, potassium-containing salt substitutes and dietary supplements

The simultaneous administration of perindopril and potassium-sparing diuretics, as well as potassium preparations, potassium-containing salt substitutes and dietary supplements is not recommended.

Dual blockade of the RAAS

There is evidence of an increased risk of arterial hypotension, hyperkalemia and impaired renal function (including acute renal failure) with the simultaneous use of ACE inhibitors with ARBs or aliskiren. Therefore, dual blockade of the RAAS resulting from the combination of an ACE inhibitor with an ARB or aliskiren is not recommended. If dual blockade is necessary, it should be performed under strict specialist supervision with regular monitoring of renal function, plasma electrolyte levels and blood pressure.

The simultaneous use of ACE inhibitors with ARBs is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Neutropenia/agranulocytosis/thrombocytopenia/anemia

There are reports of the development of neutropenia/agranulocytosis, thrombocytopenia and anemia during the administration of ACE inhibitors. In patients with normal renal function and in the absence of other aggravating factors, neutropenia rarely develops. Perindopril should be used with particular caution in patients with systemic connective tissue diseases, during treatment with immunosuppressants, allopurinol or procainamide, or their combination, especially in patients with impaired renal function.

Some of these patients developed severe infections, in some cases resistant to intensive antibiotic therapy. When prescribing perindopril to such patients, periodic monitoring of white blood cells is recommended; patients should report any signs of infectious diseases (e.g., sore throat, fever) to their doctor.

Renovascular hypertension

In patients with bilateral renal artery stenosis or stenosis of the artery of a solitary functioning kidney, therapy with ACE inhibitors increases the risk of arterial hypotension and renal failure. The use of diuretics may be an additional risk factor. Deterioration of renal function may be observed even with a slight change in serum creatinine concentration, even in patients with unilateral renal artery stenosis.

Hypersensitivity/angioedema

When taking ACE inhibitors, including perindopril, in rare cases, the development of angioedema of the face, extremities, lips, tongue, glottis and/or larynx may be observed. This can occur at any time during therapy. If symptoms appear, the drug should be discontinued immediately and the patient should be monitored until the signs of edema completely disappear. If the edema affects only the face and lips, its manifestations usually resolve on their own, although antihistamines may be used to treat the symptoms.

Angioedema accompanied by laryngeal edema can be fatal. Swelling of the tongue, glottis, or larynx can lead to airway obstruction; in this case, intensive therapy should be carried out immediately. If such symptoms appear, a 1:1000 solution of epinephrine (adrenaline) (0.3-0.5 ml) should be administered immediately and/or airway patency should be ensured. The patient should be under medical supervision until the symptoms have completely and permanently resolved.

A higher frequency of angioedema was noted in Black patients during treatment with ACE inhibitors compared to patients of other races.

Patients with a history of angioedema not associated with ACE inhibitor use may have an increased risk of its development when taking this combination.

There are reports of rare cases of intestinal angioedema during therapy with ACE inhibitors. In this case, patients experienced abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without preceding facial angioedema and with normal C1-esterase levels. The diagnosis was made using abdominal CT, ultrasound, or at the time of surgery. Symptoms resolved after discontinuation of ACE inhibitors. Therefore, in patients with abdominal pain receiving ACE inhibitors, the possibility of intestinal angioedema should be considered in the differential diagnosis.

Concomitant use with the combination of valsartan + sacubitril

Due to the increased risk of angioedema, simultaneous administration of perindopril with the combination of valsartan + sacubitril is contraindicated. The use of the combination valsartan + sacubitril is possible no earlier than 36 hours after taking the last dose of perindopril. If therapy with the combination valsartan + sacubitril is discontinued, the use of perindopril should not be started earlier than 36 hours after taking the last dose of the combination valsartan + sacubitril. With the simultaneous use of ACE inhibitors with other enkephalinase inhibitors (e.g., racecadotril), the risk of developing angioedema may be increased. In patients receiving perindopril, a thorough risk/benefit assessment should be performed before prescribing enkephalinase inhibitors (e.g., racecadotril).

Concomitant use with mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus)

Concomitant use of an ACE inhibitor and an mTOR inhibitor (e.g., sirolimus, everolimus, temsirolimus) may be associated with an increased risk of developing angioedema (e.g., swelling of the airways or tongue, with or without impaired respiratory function).

Anaphylactoid reactions during desensitization

There are isolated reports of the development of prolonged, 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 a burdened allergic history or a tendency to allergic reactions undergoing desensitization procedures, and the use of ACE inhibitors should be avoided in patients receiving immunotherapy with hymenoptera venom. However, an anaphylactoid reaction can be avoided by temporarily discontinuing the ACE inhibitor at least 24 hours before starting the desensitization procedure.

Anaphylactoid reactions during LDL apheresis

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

Hemodialysis

Anaphylactoid reactions have been observed in patients receiving ACE inhibitors during hemodialysis using high-flux membranes (e.g., AN69^®). Therefore, it is advisable to use a different type of membrane or use an antihypertensive agent of a different pharmacotherapeutic group.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism are generally not susceptible to antihypertensive drugs whose action is based on inhibition of the renin-angiotensin system. Thus, the use of this drug in such patients is not recommended.

Cough

A dry cough may occur during therapy with an ACE inhibitor. The cough persists for a long time during treatment with drugs of this group and disappears after their discontinuation. If a patient develops a dry cough, the possible iatrogenic nature of this symptom should be kept in mind. If the physician believes that ACE inhibitor therapy is necessary for the patient, the possibility of continuing the drug may be considered.

Mitral stenosis/aortic stenosis/hypertrophic obstructive cardiomyopathy

ACE inhibitors should be prescribed with caution to patients with left ventricular outflow tract obstruction.

Ethnic differences

Perindopril, like other ACE inhibitors, apparently has a less pronounced hypotensive effect in Black patients compared to patients of other races. This difference is possibly due to the fact that Black patients with arterial hypertension more often have low renin activity.

Surgery/General anesthesia

The use of ACE inhibitors in patients undergoing surgery with general anesthesia may lead to a pronounced decrease in blood pressure, especially when using general anesthetic agents that have an antihypertensive effect.

It is recommended, if possible, to discontinue long-acting ACE inhibitors, including perindopril, one day before surgery.

Patients with renovascular hypertension

The treatment method for renovascular hypertension is revascularization. Nevertheless, the use of ACE inhibitors has a beneficial effect in patients both awaiting surgery and when surgery is not possible.

When using this combination in patients with existing or suspected renal artery stenosis, treatment should be started in a hospital setting with low doses under constant monitoring of renal status and blood potassium levels, since such patients may develop functional renal failure, which disappears when therapy is discontinued.

Atherosclerosis

The risk of arterial hypotension exists in all patients; however, particular caution should be exercised when using the drug in patients with coronary artery disease and cerebrovascular insufficiency. In such patients, treatment should be started with low doses of the combination components.

Perindopril/Indapamide

Lithium preparations

The simultaneous use of the combination of perindopril and indapamide with lithium preparations is not recommended.

Arterial hypotension and water-electrolyte imbalance

The presence of baseline hyponatremia is associated with the risk of sudden development of arterial hypotension (especially in patients with renal artery stenosis). Therefore, when monitoring patients, attention should be paid to possible symptoms of dehydration and decreased plasma electrolyte levels, for example, after diarrhea or vomiting. Such patients require regular monitoring of plasma electrolyte levels.

In case of severe arterial hypotension, intravenous administration of 0.9% sodium chloride solution may be required.

Transient arterial hypotension is not a contraindication for continuing therapy. After restoration of blood volume and blood pressure, therapy can be resumed using low doses of the combination, or the drug components can be used in monotherapy mode.

Hyponatremia at the initial stage may not be accompanied by clinical symptoms, so regular laboratory monitoring is necessary. More frequent monitoring of sodium ion levels is indicated for elderly patients and patients with liver cirrhosis.

Therapy with any diuretic drugs can cause hyponatremia, sometimes with very serious consequences.

Hyponatremia with hypovolemia can cause dehydration and orthostatic hypotension. Simultaneous loss of chloride ions can lead to secondary compensatory metabolic alkalosis: the frequency and degree of this effect are insignificant.

Patients with diabetes mellitus

In patients with type 1 diabetes (risk of spontaneous increase in potassium ion levels), treatment should be started with lower doses and under careful medical supervision.

When using this combination in patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, regular monitoring of plasma glucose concentration is necessary during the first month of therapy. Blood glucose levels should be monitored in patients with diabetes mellitus, especially in the presence of hypokalemia.

Amlodipine/perindopril

Hepatic insufficiency

In rare cases, cholestatic jaundice occurs during treatment with ACE inhibitors. 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 jaundice or a significant increase in liver enzyme activity appears in patients taking ACE inhibitors, the ACE inhibitor should be discontinued and a doctor should be consulted.

In patients with impaired liver function, the T_1/2 and AUC of amlodipine increase. Amlodipine should be started at the lowest doses and precautions should be taken, both at the beginning of treatment and when increasing the dose. In patients with severe hepatic insufficiency, the dose should be increased gradually, ensuring careful monitoring of the clinical condition.

Considering the effect of each component included in this combination separately, this combination is contraindicated in patients with severe hepatic insufficiency, and also requires special caution if it is necessary to use it in patients with moderate and mild hepatic insufficiency.

Amlodipine/Indapamide/perindopril

Impaired renal function

Use is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 ml/min).

In patients with moderate renal impairment (creatinine clearance 30-60 ml/min), the use of dosages containing 10 mg of perindopril and 2.5 mg of indapamide is contraindicated.

In some patients with arterial hypertension without previous obvious renal impairment, laboratory signs of functional renal failure may appear during therapy. In this case, treatment with the drug should be discontinued with the possibility of subsequently resuming combination therapy using low doses of the drug, or using the combination components in monotherapy mode.

Such patients require regular monitoring of serum potassium ion and creatinine levels – 2 weeks after the start of therapy and then every 2 months. Renal failure occurs more often in patients with severe chronic heart failure or pre-existing renal impairment, including renal artery stenosis.

Not recommended for patients with bilateral renal artery stenosis or stenosis of the artery of a solitary functioning kidney.

There is a risk of arterial hypotension and/or renal failure (including in the presence of chronic heart failure, dehydration and decreased plasma electrolyte levels): in some pathological conditions, significant activation of the RAAS may be noted, especially with severe hypovolemia and decreased plasma electrolyte levels (against 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 failure or liver cirrhosis with edema and ascites.

Blockade of the 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 the combination or during the first 2 weeks of therapy. Sometimes these conditions develop acutely, and their time of onset may vary. In such cases, it is recommended to resume therapy, starting with 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 cerebrovascular accident.

Thiazide and thiazide-like diuretics are fully effective only in patients with normal or slightly impaired renal function (plasma creatinine concentration in adult patients below 25 mg/l or 220 µmol/l). In elderly patients, creatinine levels should be assessed taking into account age, weight and gender.

At the beginning of treatment with diuretics, patients may experience a temporary decrease in GFR and an increase in plasma urea and creatinine concentrations due to hypovolemia and hyponatremia. This transient functional renal failure is not dangerous for patients with unchanged renal function, but in patients with pre-existing renal failure, its severity may increase.

Patients with renal failure can take amlodipine in standard doses.

Changes in plasma concentrations of amlodipine do not correlate with the degree of renal failure.

When using this combination in case of impaired renal function, the effects noted when taking individual components should be taken into account.

Plasma potassium ion levels

Combination therapy with indapamide, perindopril and amlodipine does not prevent the development of hypokalemia, especially in patients with diabetes mellitus or renal failure. As with the use of other antihypertensive agents in combination with a diuretic, regular monitoring of plasma potassium ion levels is necessary.

Hyperkalemia may develop in some patients during treatment with ACE inhibitors, including perindopril. Risk factors for hyperkalemia are renal failure, worsening renal function, old age (>70 years), diabetes mellitus, some concomitant conditions (dehydration, acute decompensation of cardiac activity, metabolic acidosis), simultaneous use of potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene, amiloride), potassium preparations or potassium-containing salt substitutes, as well as the use of other agents that contribute to an increase in plasma potassium ion levels (e.g., heparin, co-trimoxazole, i.e., trimethoprim + sulfamethoxazole). The use of dietary supplements/potassium preparations, potassium-sparing diuretics, potassium-containing salt substitutes can lead to a significant increase in blood potassium levels, especially in patients with reduced renal function. Hyperkalemia can lead to serious, sometimes fatal, cardiac arrhythmias. If combined use of the above agents is necessary, treatment should be carried out with caution, against the background of regular monitoring of serum potassium ion levels.

Therapy with thiazide and thiazide-like diuretics is associated with the risk of developing hypokalemia. Hypokalemia (less than 3.4 mmol/l) must be avoided in the following categories of high-risk patients: elderly and/or debilitated patients (even if they are not receiving combination drug therapy), patients with liver cirrhosis with edema and ascites, patients with coronary artery disease, chronic heart failure. Hypokalemia in these patients enhances the toxic effect of cardiac glycosides and increases the risk of arrhythmia.

The risk group also includes patients with a prolonged QT interval, regardless of whether this increase is caused by congenital causes or the action of drugs.

Hypokalemia, like bradycardia, contributes to the development of severe cardiac arrhythmias, in particular, polymorphic ventricular tachycardia of the “torsades de pointes” type, which can be fatal. In all the cases described above, regular monitoring of plasma potassium ion levels is necessary. The first measurement of potassium ion levels should be performed within the first week of starting therapy.

If hypokalemia is detected, appropriate treatment should be prescribed.

Elderly patients

Before starting the medication, it is necessary to assess the functional activity of the kidneys and the plasma potassium ion concentration. At the beginning of therapy, the dose of the drug is selected taking into account the degree of blood pressure reduction, especially in the case of reduced circulating blood volume and electrolyte loss. Such measures help to avoid a sharp decrease in blood pressure.

In elderly patients, dose increases should be performed with caution.

With caution

Presence of only one functioning kidney, water-electrolyte balance disorders, systemic connective tissue diseases, coronary artery disease, cerebrovascular diseases, renovascular hypertension, diabetes mellitus, chronic heart failure (NYHA functional class III and IV), therapy with immunosuppressants, allopurinol, procainamide (risk of neutropenia, agranulocytosis), acute myocardial infarction (and within 1 month after myocardial infarction), sick sinus syndrome (severe tachy- and bradycardia), mild to moderate renal impairment, bone marrow depression, reduced circulating blood volume (diuretic use, salt-restricted diet, vomiting, diarrhea, hemodialysis), hyperuricemia (especially accompanied by gout and urate nephrolithiasis), aortic stenosis/mitral stenosis/hypertrophic obstructive cardiomyopathy, status after kidney transplantation, concurrent use with inhibitors or inducers of the CYP3A4 isoenzyme, concurrent use of dantrolene, estramustine, labile blood pressure, concurrent use of potassium-sparing diuretics, potassium preparations, potassium-containing salt substitutes and lithium, before the LDL apheresis procedure using dextran sulfate, performing surgical intervention/general anesthesia, performing hemodialysis using high-flux membranes (e.g., AN69^®), concurrent desensitizing therapy with allergens (e.g., hymenoptera venom), patients of Black race, elderly patients.

Effect on the ability to drive vehicles and operate machinery

Due to the possibility of weakness and dizziness during the use of this combination, caution should be exercised when driving vehicles and operating other technical devices requiring increased concentration and speed of psychomotor reactions.

Drug Interactions

Clinical trial data show that dual blockade of the renin-angiotensin-aldosterone system resulting from the simultaneous use of ACE inhibitors, ARBs, or aliskiren leads to an increased incidence of adverse reactions such as arterial hypotension, hyperkalemia, and renal function impairment (including acute renal failure) compared to situations where only one drug affecting the RAAS is used.

Drugs causing hyperkalemia

Some drugs may increase the risk of hyperkalemia: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, heparin, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim. Concurrent use of this combination with these agents increases the risk of hyperkalemia.

Contraindicated drug combinations (see section “Contraindications”)

Aliskiren and medicines containing aliskiren

Concomitant use of ACE inhibitors with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR <60 ml/min/1.73m² body surface area), as it increases the risk of hyperkalemia, worsening of renal function, increased frequency of cardiovascular adverse events and mortality from cardiovascular diseases.

Angiotensin II receptor antagonists

Concomitant use of ACE inhibitors with ARBs is contraindicated in patients with diabetic nephropathy.

Extracorporeal treatments

Extracorporeal treatments leading to contact of blood with negatively charged surfaces, such as dialysis or hemofiltration with certain high-flux membranes (e.g., polyacrylonitrile membranes) and LDL apheresis using dextran sulfate are contraindicated due to an increased risk of severe anaphylactoid reactions. If such treatment is necessary, the possibility of using a different type of dialysis membrane or a different class of antihypertensive drugs should be considered.

Valsartan + sacubitril

Concomitant use of perindopril with the combination valsartan + sacubitril is contraindicated because neprilysin inhibition concurrent with ACE inhibitor use may increase the risk of angioedema. Use of the valsartan + sacubitril combination is possible no earlier than 36 hours after taking the last dose of perindopril. Therapy with perindopril is possible no earlier than 36 hours after taking the last dose of the valsartan + sacubitril combination.

Not recommended drug combinations

Amlodipine

Perindopril

Amlodipine

Indapamide

Perindopril

Perindopril/Indapamide

Amlodipine

Indapamide

Perindopril

Perindopril/Indapamide/Amlodipine

Amlodipine

Sildenafil

No enhancement of the antihypertensive effect of each drug was observed with the simultaneous use of amlodipine and sildenafil.

Cyclosporine

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.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.

Medical Disclaimer

Brand (or Active Substance), Marketing Authorisation Holder, Dosage Form

Triplixam^® [Les Laboratoires Servier (France)]
Film-coated tablets, 5 mg+0.625 mg+2.5 mg: 29 or 30 pcs.
Film-coated tablets, 5 mg+0.625 mg+2.5 mg: 29, 30, or 90 pcs.

Marketing Authorization Holder

Les Laboratoires Servier (France)

Manufactured By

Servier Rus, LLC (Russia)

Servier (Ireland) Industries, Ltd. (Ireland)

Dosage Forms

	Triplixam^®	Film-coated tablets, 5 mg+0.625 mg+2.5 mg: 29 or 30 pcs.
		Film-coated tablets, 5 mg+0.625 mg+2.5 mg: 29, 30, or 90 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, oblong, biconvex, with an engraving on one side and the company logo on the other.

	1 tab.
Amlodipine besylate	6.935 mg,
Equivalent to amlodipine content	5 mg
Indapamide	0.625 mg
Perindopril arginine	2.5 mg

Excipients : calcium carbonate + pregelatinized corn starch, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, pregelatinized starch.

Film coating: glycerol, hypromellose, macrogol-6000, magnesium stearate, titanium dioxide.

29 pcs. – polypropylene bottles equipped with a dispenser and a cap containing a moisture-absorbing gel (silica gel) (1) – cardboard packs with first-opening control.
30 pcs. – polypropylene bottles equipped with a dispenser and a cap containing a moisture-absorbing gel (silica gel) (1) – cardboard packs with first-opening control.

Film-coated tablets white, oblong, biconvex, with an engraving on one side and the company logo on the other.

	1 tab.
Amlodipine besylate	6.935 mg,
Equivalent to amlodipine content	5 mg
Indapamide	0.625 mg
Perindopril arginine	2.5 mg

	1 tab.
Amlodipine besylate	6.935 mg,
Equivalent to amlodipine content	5 mg
Indapamide	1.25 mg
Perindopril arginine	5 mg

Excipients : calcium carbonate + pregelatinized corn starch, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, pregelatinized starch.

Film coating glycerol, hypromellose, macrogol-6000, magnesium stearate, titanium dioxide.

Hospital packaging:
30 pcs. – polypropylene bottles equipped with a dispenser and a cap containing a moisture-absorbing gel (silica gel) (3) – cardboard packs with first-opening control.

Triplixam^® [Les Laboratoires Servier (France)]
Film-coated tablets, 10 mg+1.25 mg+5 mg: 29, 30 or 90 pcs.

Marketing Authorization Holder

Les Laboratoires Servier (France)

Manufactured By

Servier Rus, LLC (Russia)

Dosage Form

Triplixam^®

Film-coated tablets, 10 mg+1.25 mg+5 mg: 29, 30 or 90 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, oblong, biconvex, with an engraving on one side and the company logo on the other.

	1 tab.
Amlodipine besylate	13.87 mg,
Equivalent to amlodipine content	10 mg
Indapamide	1.25 mg
Perindopril arginine	5 mg

Excipients : calcium carbonate + pregelatinized corn starch, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, pregelatinized starch.

Film coating glycerol, hypromellose, macrogol-6000, magnesium stearate, titanium dioxide.

Hospital packaging:
30 pcs. – polypropylene bottles equipped with a dispenser and a cap containing a moisture-absorbing gel (silica gel) (3) – cardboard packs with first-opening control.

Triplixam^® [Les Laboratoires Servier (France)]
Film-coated tablets, 5 mg+2.5 mg+10 mg: 29, 30 or 90 pcs.

Marketing Authorization Holder

Les Laboratoires Servier (France)

Manufactured By

Servier Rus, LLC (Russia)

Dosage Form

Triplixam^®

Film-coated tablets, 5 mg+2.5 mg+10 mg: 29, 30 or 90 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, oblong, biconvex, with an engraving on one side and the company logo on the other.

	1 tab.
Amlodipine besylate	6.935 mg,
Equivalent to amlodipine content	5 mg
Indapamide	2.5 mg
Perindopril arginine	10 mg

Excipients : calcium carbonate + pregelatinized corn starch, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, pregelatinized starch.

Film coating glycerol, hypromellose, macrogol-6000, magnesium stearate, titanium dioxide.

Hospital packaging:
30 pcs. – polypropylene bottles equipped with a dispenser and a cap containing a moisture-absorbing gel (silica gel) (3) – cardboard packs with first-opening control.

Triplixam^® [Les Laboratoires Servier (France)]
Film-coated tablets, 10 mg+2.5 mg+10 mg: 29, 30 or 90 pcs.

Marketing Authorization Holder

Les Laboratoires Servier (France)

Manufactured By

Servier Rus, LLC (Russia)

Dosage Form

Triplixam^®

Film-coated tablets, 10 mg+2.5 mg+10 mg: 29, 30 or 90 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, oblong, biconvex, with an engraving on one side and the company logo on the other.

	1 tab.
Amlodipine besylate	13.87 mg,
Equivalent to amlodipine content	10 mg
Indapamide	2.5 mg
Perindopril arginine	10 mg

Excipients : calcium carbonate + pregelatinized corn starch, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, pregelatinized starch.

Film coating glycerol, hypromellose, macrogol-6000, magnesium stearate, titanium dioxide.

Hospital packaging:
30 pcs. – polypropylene bottles equipped with a dispenser and a cap containing a moisture-absorbing gel (silica gel) (3) – cardboard packs with first-opening control.