TRIPLIXAM instructions for use, description of the drug TRIPLIXAM: contraindications, side effects, dosages, composition - tablets, coating. film-coated in the medicinal reference book

Instructions for use of TRIPLIXAM

All warnings for each ingredient as listed below apply to Triplixam.

Lithium

Concomitant use of lithium and the combination of perindopril/indapamide is usually not recommended.

Double blockade of the RAAS

Hypotension, syncope, stroke, hyperkalemia and renal dysfunction (including acute renal impairment) have been reported in susceptible patients, especially when co-administered with drugs that act on the RAAS. Thus, dual blockade of the RAAS using an ACE inhibitor and an angiotensin II receptor antagonist or aliskiren is not recommended.

Combined use with aliskiren is contraindicated in patients with diabetes mellitus or impaired renal function (GFR <60 ml/min/1.73 m2).

Potassium-sparing medications, potassium supplements, or potassium-containing salt substitutes

The combined use of perindopril and potassium-sparing drugs, potassium supplements, or potassium-containing salt substitutes is generally not recommended.

Neutropenia/agranulocytosis/thrombocytopenia/anemia

Neutropenia, agranulocytosis, thrombocytopenia and anemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia rarely develops. Perindopril should be used with extreme caution in patients with collagen diseases, concomitant use of immunosuppressants, allopurinol or procainamide, as well as in the presence of risk factors, especially if there is a history of impaired renal function. Some of these patients developed severe infections, in some cases untreatable with antibiotics. If such patients are taking perindopril, periodic leukocyte count analysis is recommended. Patients should report any signs of infection (eg, sore throat, fever) to their doctor.

Hypersensitivity/angioedema

Rare cases of angioedema of the face, extremities, lips, tongue, pharynx and/or larynx have been reported in patients treated with ACE inhibitors, including perindopril. These conditions can develop at any time during therapy. In such cases, you should immediately stop taking the drug and monitor the patient's condition until the symptoms disappear completely. In cases where swelling affects only the face and lips, its symptoms usually resolve without special treatment, but antihistamines may be used to relieve symptoms.

Angioedema of the larynx can be fatal. Involvement of the tongue, larynx or pharynx can lead to airway obstruction, appropriate treatment should be started immediately, administer subcutaneous epinephrine solution 1:

1000 (0.3-0.5 ml) and/or take measures to ensure airway patency.

A higher incidence of angioedema has been established in black patients receiving ACE inhibitors.

Patients with a history of angioedema not related to ACE inhibitor therapy may be at increased risk of developing angioedema when treated with ACE inhibitors.

There are rare cases of the development of angioedema of the intestine during therapy with ACE inhibitors. Patients experienced abdominal pain (sometimes with nausea or vomiting); in some cases this was not preceded by angioedema of the face, C-1 esterase activity was normal. Angioedema was diagnosed through procedures including abdominal CT or ultrasound, or during surgery. Symptoms disappeared after stopping the ACE inhibitor. These phenomena should be taken into account when carrying out differential diagnosis in patients with abdominal pain receiving ACE inhibitors.

Anaphylactoid reactions during desensitization

Separately, reports of patients who experienced long-term, life-threatening anaphylactoid reactions when taking ACE inhibitors during desensitizing treatment with hymenoptera venom (bees, wasps) were highlighted. ACE inhibitors should be prescribed with caution to patients prone to allergic reactions and undergoing desensitization. However, these reactions can be prevented by temporarily discontinuing ACE inhibitors at least 24 hours before desensitization.

Anaphylactoid reactions during LDL apheresis

Life-threatening anaphylactoid reactions have been reported rarely in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. These reactions can be avoided by temporarily suspending treatment with ACE inhibitors until apheresis is performed.

Patients on hemodialysis

Anaphylactoid reactions have been reported in patients undergoing hemodialysis using high fluid permeability membranes (eg, AN69®) and concomitantly taking an ACE inhibitor. In such patients, a different type of hemodialysis membrane or a different class of antihypertensive drug should be used.

Hepatic encephalopathy

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

Photosensitivity

Cases of photosensitivity have been reported with the use of thiazide and thiazide-like diuretics. It is recommended to discontinue treatment if a photosensitivity reaction develops during therapy. If it is necessary to restart diuretic therapy, it is recommended to protect areas exposed to sunlight or artificial UVA rays.

Kidney function

In case of severe renal impairment (creatinine clearance <30 ml/min), treatment with the drug is contraindicated.

Patients with moderate renal impairment (creatinine clearance <60 ml/min) are contraindicated in treatment with Triplixam at a dose of 10 mg perindopril/2.5 mg indapamide (i.e. Triplixam 10 mg/2.5 mg/5 mg and 10 mg/2.5 mg/ 10 mg).

Some patients with hypertension who do not have a history of kidney disease, but blood tests indicate functional renal failure, should stop treatment and, if restarted, use a lower dose or only one component of the drug.

In such patients, potassium and creatinine concentrations should be monitored frequently after 2 weeks of treatment and then every 2 months during the period of therapeutic stability.

Renal failure was mainly observed in patients with severe heart failure or underlying renal failure, including renal artery stenosis.

Renovascular hypertension

The drug is not recommended for use in cases of bilateral renal artery stenosis or the presence of one functioning kidney. The use of ACE inhibitors increases the risk of hypotension and renal failure in such patients. Diuretics may worsen this condition. Decreased renal function may be manifested by only a slight decrease in serum creatinine concentration, even in patients with unilateral renal artery stenosis.

When using perindopril, significant stimulation of the RAAS was observed, especially with significant depletion of water and electrolyte reserves (strict sodium-restricted diet or prolonged use of diuretics) in patients with initially low blood pressure, renal artery stenosis, congestive heart failure or cirrhosis with edema and ascites. Blockade of the RAAS by an ACE inhibitor may lead, especially when taking the first dose and during the first 2 weeks of treatment, to an unexpected decrease in blood pressure and/or an increase in plasma creatinine concentrations, indicating functional renal failure. The onset may be acute, although rare; the time until symptoms appear varies. In such cases, treatment should begin with low doses and gradually increase. For patients with coronary artery disease or cerebrovascular disease, excessive hypotension can lead to myocardial infarction or cerebrovascular accident.

Thiazide and thiazide-like diuretics are fully effective only when renal function is not impaired or is mildly impaired (creatinine concentrations in an adult are approximately 25 mg/l lower, i.e. 220 µmol/l). In elderly patients, age, weight and gender should be taken into account when determining plasma creatinine concentrations.

Hypovolemia, which developed secondary to the loss of water and sodium when using a diuretic at the beginning of treatment, leads to a decrease in glomerular filtration. This may cause an increase in the concentration of urea and creatinine in the blood. Such transient functional renal failure has no adverse effects in patients with normal renal function, but may worsen pre-existing renal impairment.

Amlodipine can be used in normal doses in patients with renal failure. Changes in plasma amlodipine concentrations are not associated with the degree of renal dysfunction.

The effect of Triplixam has not been studied in patients with impaired renal function. In case of impaired renal function, the dose of Triplixam should correspond to the doses of its constituent components, used separately.

Hypotension and depletion of water and sodium reserves

There is a risk of developing hypotension in the presence of depleted sodium reserves (especially in patients with renal artery stenosis). Therefore, one should systematically check for signs of water and electrolyte depletion, which may occur with an accompanying episode of diarrhea or vomiting. Plasma electrolyte concentrations should be monitored regularly in such patients.

If hypotension is significant, IV infusion of isotonic saline may be necessary.

Transient hypotension is not a contraindication to continued therapy. After restoration of blood volume and blood pressure, treatment can be resumed using the drug at a lower dose or only one of the components as monotherapy.

The use of any diuretic may result in a decrease in sodium concentration, which can have serious consequences. Hyponatremia may initially be asymptomatic, so it is extremely important to regularly monitor sodium concentrations (more often in elderly patients and patients with cirrhosis).

Potassium concentration

The combination of indapamide with perindopril and amlodipine does not prevent the development of hypokalemia, especially in patients with diabetes mellitus or renal failure. As with any antihypertensive drug used in combination with a diuretic, plasma potassium concentrations should be regularly monitored.

Increased serum potassium concentrations have been reported in some patients receiving ACE inhibitors, including perindopril. Risk factors for the development of hyperkalemia are the following conditions:

renal failure, deterioration of renal function, age (>70 years), diabetes mellitus, concomitant conditions (in particular dehydration, acute cardiac decompensation, metabolic acidosis) and concomitant use of potassium-sparing diuretics (for example, spironolactone, eplerenone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes or other drugs that increase serum potassium concentrations (eg, heparin). The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, especially in patients with impaired renal function, may result in significant increases in serum potassium concentrations. Hyperkalemia can cause serious and sometimes fatal arrhythmias. If concomitant use of the above-mentioned drugs is necessary, such combinations should be used with caution and serum potassium concentrations should be regularly monitored.

Depletion of potassium reserves with the development of hypokalemia is the main risk when using thiazide and thiazide-like diuretics. Decreased potassium levels (<3.4 mmol/L) should be prevented in high-risk groups such as elderly and/or malnourished patients (regardless of how many medications they are taking), patients with liver cirrhosis and edema and ascites, coronary artery disease and cardiac insufficiency. In such cases, hypokalemia increases the toxicity of cardiac glycosides and the risk of developing arrhythmias.

The high-risk group also includes patients with an increased QT interval on the ECG, regardless of the etiology of the disease. Hypokalemia, as well as bradycardia, is a predisposing factor in the development of serious cardiac arrhythmias (especially torsades de pointes), which can be fatal.

In all cases, potassium concentrations should be regularly monitored. The first analysis of plasma potassium should be performed within the first week after starting treatment. If potassium concentration decreases, correction is required.

Calcium concentration

Thiazide and thiazide-like diuretics may reduce urinary excretion of calcium and lead to a slight and temporary increase in plasma calcium. Significant increases in calcium concentrations may be associated with undiagnosed hyperparathyroidism. In such cases, treatment should be stopped until the results of a study of parathyroid function are obtained.

Cough

When using ACE inhibitors, a dry cough was observed, which was persistent and disappeared when treatment was discontinued. If this symptom occurs, an iatrogenic etiology should be considered. If the prescription of an ACE inhibitor is necessary, treatment can be continued.

Atherosclerosis

All patients are at risk of hypotension, but special attention should be paid to patients with coronary artery disease or cerebrovascular insufficiency. In such patients, therapy should be started at a low dose.

Hypertensive crisis

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

Heart failure/severe heart failure

Patients with heart failure should be treated with caution. In a long-term placebo-controlled study in patients with severe heart failure (NYHA class III and IV), the incidence of pulmonary edema was higher in the amlodipine group than in the placebo group. Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure. the risk of cardiovascular complications and mortality may increase.

In patients with severe heart failure (grade IV), treatment should be started under medical supervision with a low dose. Therapy with beta-blockers in patients with arterial hypertension and coronary insufficiency should not be interrupted; ACE inhibitors are added to beta-blockers.

Aortic or mitral valve stenosis/hypertrophic cardiomyopathy

ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction.

Diabetes

In patients with insulin-dependent diabetes mellitus (tendency to hyperkalemia), treatment should be started under medical supervision with a low dose. Glycemic levels should be monitored in patients with diabetes mellitus who have previously received oral hypoglycemic drugs or insulin, namely during the first month of treatment with an ACE inhibitor.

In patients with diabetes mellitus, especially those with low potassium concentrations, it is necessary to monitor the concentration of glucose in the blood.

Ethnic differences

Like other ACE inhibitors, perindopril is less effective in lowering blood pressure in blacks than in other races, possibly due to low renin levels in blacks with high blood pressure.

Surgery/anesthesia

The use of ACE inhibitors may lead to hypotension during anesthesia, especially if the anesthetic used is a drug with hypotensive potential. It is therefore recommended to discontinue treatment with long-acting ACE inhibitors such as perindopril the day before surgery.

Liver dysfunction

In rare cases, the use of ACE inhibitors has been associated with a syndrome that begins with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is unknown. In patients taking ACE inhibitors who experience jaundice or significant increases in liver enzymes, ACE inhibitor therapy should be discontinued and closely monitored.

T1/2 of amlodipine is prolonged and AUC values are higher in patients with impaired liver function; there are no recommendations on dosing of the drug. Therefore, the use of amlodipine should be started with a low dose and with caution both at the beginning of treatment and when increasing the dose. Slow dose titration and close monitoring are necessary in patients with severe hepatic impairment.

The pharmacokinetics of Triplixam in patients with liver dysfunction have not been studied. Taking into account the effects of each individual component of this combination, Triplixam is contraindicated in patients with severe hepatic impairment and should be used with caution in patients with mild to moderate hepatic impairment.

Uric acid

Patients with high levels of uric acid may have an increased risk of gout attacks.

Elderly patients

Before initiating therapy, renal function and potassium concentrations should be assessed. The initial dose is adjusted depending on changes in blood pressure, especially in the case of depletion of water and electrolyte reserves, to avoid the development of hypotension. In elderly patients, the dose of amlodipine should be increased with caution.

Impact on the ability to drive vehicles and operate machinery

The effect of Triplixam on the ability to drive a car and operate machinery has not been studied.

Perindopril and indapamide do not affect the ability to drive a car or use machinery, but some patients may experience individual reactions with a decrease in blood pressure. Amlodipine may have minor to moderate effects on the ability to drive and operate machines.

If patients suffer from dizziness, headache, fatigue, tiredness or nausea, the speed of psychomotor reactions may be reduced, as a result of which the ability to operate a car or operate machinery may be impaired. Patients are advised to exercise caution, especially at the beginning of treatment.

Preclinical safety data

Perindopril.

In chronic oral toxicity studies (rats and monkeys), the target organ was the kidney, which caused reversible damage. Mutagenicity was not observed in in vitro or in vivo studies.

Reproductive toxicity studies (rats, mice, rabbits and monkeys) showed no evidence of embryotoxicity or teratogenicity. However, ACE inhibitors as a class commonly induce adverse effects on late fetal development, leading to fetal death or birth defects in rodents and rabbits:

kidney damage and increased peri- and postnatal mortality. There was no effect on fertility in female or male rats. No carcinogenicity was observed in long-term studies in rats and mice.

Indapamide.

Use in high doses (40-8000 times higher than the therapeutic dose) in various animal species has shown a deterioration in the diuretic properties of indapamide. Serious symptoms of poisoning during acute toxicity studies of indapamide administered intravenously or intraperitoneally were associated with the pharmacological effects of indapamide, such as bradypnea and peripheral vasodilation.

Indapamide did not exhibit mutagenic or carcinogenic properties.

Reproductive toxicity studies revealed no embryotoxicity or teratogenicity in rats, mice or rabbits. No negative effects on fertility were observed in female or male rats.

Perindopril/indapamide.

With the combination of perindopril/indapamide, toxicity increased slightly compared with the administration of the drugs separately. No increased renal reactions were observed in rats. However, gastrointestinal toxicity was observed with this combination in dogs and increased maternal toxicity in rats (compared to perindopril). However, these adverse effects were detected at dose levels that exceeded the safe limit compared to the therapeutic doses used.

Preclinical studies conducted separately for perindopril and indapamide did not reveal genotoxic, carcinogenic or teratogenic potential.

Amlodipine.

Reproductive studies in rats and mice have demonstrated delayed birth, prolonged duration of labor, and decreased neonatal survival at doses approximately 50 times the maximum recommended human dose on a mg/kg basis.

Effect on fertility of rats when administered amlodipine (males - for 64 days, females - for 14 days before mating) at a dose of up to 10 mg/kg/day (8 times* higher than the maximum recommended dose for humans of 10 mg based on mg/m2 ) was missing. In another study, male rats were administered amlodipine besylate for 30 days at a dose comparable to that used in humans at mg/kg; a decrease in plasma FSH and testosterone concentrations was noted, as well as a decrease in the specific gravity of sperm and the number of mature spermatids and Sertoli cells.

In rats and mice receiving amlodipine with food for 2 years at concentrations based on doses of 0.5, 1.25 and 2.5 mg/kg/day, no carcinogenicity was shown. The high dose (similar in mice and twice* in rats higher than the maximum recommended clinical dose of 10 mg mg/m2) was close to the maximum tolerated dose in mice but not in rats.

Mutagenicity studies did not reveal any drug-related effects at the gene or chromosome level.

*Based on the patient’s body weight of 50 kg.

Triplixam®

All precautions associated with taking individual components of the drug should be taken into account when using their fixed combination as part of the drug Triplixam®.

Amlodipine

Chronic heart failure

Patients with chronic heart failure should be treated with caution.

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

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

Patients with arterial hypertension and coronary heart disease should not stop taking beta-blockers: an ACE inhibitor should be used in conjunction with beta-blockers.

Hypertensive crisis

The effectiveness and safety of amlodipine in hypertensive crisis has not been established.

Indapamide

Hepatic encephalopathy

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

Photosensitivity

Cases of photosensitivity reactions have been reported while taking thiazide and thiazide-like diuretics (see section "Side effects"). If a photosensitivity reaction develops while taking the drug, treatment should be discontinued. If it is necessary to continue diuretic therapy, it is recommended to protect the skin from exposure to sunlight or artificial ultraviolet rays.

Content of calcium ions in blood plasma

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

Uric acid

In patients with elevated concentrations of uric acid in the blood plasma, the frequency of gout attacks may increase during therapy.

Perindopril

Potassium-sparing diuretics, potassium supplements, potassium-containing table salt substitutes and food supplements

The simultaneous administration of perindopril and potassium-sparing diuretics, as well as potassium preparations, potassium-containing table salt substitutes and food additives is not recommended (see section “Interaction with other drugs”). Dual 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) when ACE inhibitors are used simultaneously with ARB II or aliskiren. Therefore, double blockade of the RAAS as a result of combining an ACE inhibitor with ARA II or aliskiren is not recommended (see sections “Interaction with other drugs” and “Pharmacodynamics”). If a double blockade is necessary, it should be performed under the strict supervision of a specialist with regular monitoring of renal function, plasma electrolyte levels and blood pressure.

Concomitant use of ACE inhibitors with angiotensin II receptor antagonists 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 while taking ACE inhibitors. In patients with normal renal function and in the absence of other aggravating factors, neutropenia rarely develops. Perindopril should be used with extreme caution in patients with systemic connective tissue diseases, while taking 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, it is recommended to periodically monitor white blood cells in the blood, and patients should report to the doctor any signs of infectious diseases (for example, sore throat, fever) (see section "Side effects").

Renovascular hypertension

In patients with bilateral renal artery stenosis or arterial stenosis of a single functioning kidney during therapy with ACE inhibitors, the risk of developing arterial hypotension and renal failure increases (see section “Contraindications”). The use of diuretics may be an additional risk factor. Deterioration of renal function can be observed with even 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 occur. This can happen at any time during therapy. If symptoms appear, the drug should be stopped immediately and the patient should be observed until signs of edema completely disappear. If the swelling affects only the face and lips, it usually resolves on its own, although antihistamines may be used to treat symptoms.

Angioedema, accompanied by swelling of the larynx, can be fatal. Swelling of the tongue, glottis or larynx can lead to airway obstruction, in which case intensive care should be given immediately. If such symptoms appear, you should immediately administer a solution of epinephrine (adrenaline) 1:1000 (0.3-0.5 ml) and/or ensure airway patency. The patient should be under medical supervision until symptoms disappear completely and permanently.

Patients of the Black race had a higher incidence of angioedema while taking ACE inhibitors compared to other races.

Patients with a history of angioedema not associated with taking ACE inhibitors may have an increased risk of developing it when taking the drug (see section "Contraindications"). There are reports of rare cases of the development of angioedema of the intestine 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 previous angioedema of the face and with normal levels of C1-esterase. The diagnosis was made using abdominal computed tomography, ultrasound, or at the time of surgery. Symptoms resolved after discontinuation of ACE inhibitors. Therefore, in patients with abdominal pain receiving ACE inhibitors. When carrying out differential diagnosis, it is necessary to take into account the possibility of developing angioedema of the intestine.

Combined use with the combination of valsartan + sacubitril

Due to the increased risk of developing angioedema (see section “Contraindications”), simultaneous use of perindopril with the combination of valsartan + sacubitril is contraindicated. The use of the combination of valsartan + sacubitril is possible no earlier than 36 hours after taking the last dose of perindopril. If therapy with the valsartan + sacubitril combination is discontinued, the use of perindopril should not be started earlier than 36 hours after taking the last dose of the valsartan + sacubitril combination (see sections “Contraindications” and “Interaction with other drugs”). When taking ACE inhibitors concomitantly with other enkephalinase inhibitors (for example, racecadotril), the risk of developing angioedema may be increased (see section "Interaction with other drugs"). In patients receiving perindopril, a careful risk/benefit assessment should be performed before prescribing enkephalinase inhibitors (eg racecadotril).

Concomitant use with mTOR inhibitors (for example, sirolimus, everolimus, temsirolimus)

Concomitant use of an ACE inhibitor and an mTOR inhibitor (eg, sirolimus, everolimus, temsirolimus) may be associated with an increased risk of angioedema (eg, swelling of the airways or tongue, with or without impairment of respiratory function) (see Interactions with Other Drugs section) ).

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 history of allergies or a tendency to allergic reactions undergoing desensitization procedures, and the use of an ACE inhibitor 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 the start of the desensitization procedure.

Anaphylactoid reactions during LDL apheresis

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

Hemodialysis

Anaphylactoid reactions have been reported in patients receiving ACE inhibitors during hemodialysis using high-flux membranes (eg, 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 usually not susceptible to antihypertensive drugs whose action is based on inhibition of the renin-angiotensin system. Therefore, the use of this drug in such patients is not recommended.

Pregnancy

Taking ACE inhibitors during pregnancy is contraindicated. If continued therapy with ACE inhibitors is necessary, patients should switch to other types of antihypertensive therapy with an established safety profile when taken during pregnancy. If pregnancy occurs, ACE inhibitors should be stopped immediately and, if necessary, alternative antihypertensive therapy should be started (see sections “Contraindications” and “Use during pregnancy and lactation”).

Cough

During therapy with an ACE inhibitor, a dry cough may occur. The cough persists for a long time while taking drugs of this group and disappears after their discontinuation. If a patient develops a dry cough, one should be aware of the possible iatrogenic nature of this symptom. If the physician believes that ACE inhibitor therapy is necessary for the patient, 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. obviously has a less pronounced hypotensive effect in patients of the Negroid race compared to representatives of other races. This difference may be due to the fact that black patients with arterial hypertension are more likely to have low renin activity.

Surgery/General anesthesia

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

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

Patients with renovascular hypertension

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

When using the drug Triplixam® in patients with existing or suspected renal artery stenosis, treatment should begin in a hospital setting with low doses with constant monitoring of the condition of the kidneys and potassium levels in the blood, since such patients may develop functional renal failure, which disappears with cessation of therapy.

Atherosclerosis

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

Perindopril/Indapamide

Lithium preparations

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

Arterial hypotension and water-electrolyte imbalance

The presence of initial hyponatremia is associated with the risk of sudden development of arterial hypotension (especially in patients with renal artery stenosis). Therefore, clinical signs of dehydration and decreased plasma electrolytes, such as after diarrhea or vomiting, should be systematically assessed. Such patients require regular monitoring of blood 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 continued therapy. After restoration of blood volume and blood pressure, therapy can be resumed using low doses of the combination, or the components of the drug can be used as monotherapy.

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 (see sections “Side effects” and “Overdose”).

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

Hyponatremia with hypovolemia can cause dehydration and orthostatic hypotension. The simultaneous loss of chlorine ions can lead to secondary

compensatory metabolic alkalosis: the frequency and extent of this effect are insignificant.

Patients with diabetes mellitus

In patients with type 1 diabetes mellitus (risk of spontaneous increases in potassium ions), treatment should begin with lower doses and under close medical supervision.

When prescribing the drug to patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, regular monitoring of plasma glucose concentrations is necessary during the first month of therapy. It is necessary to monitor blood glucose levels in patients with diabetes mellitus, especially in the presence of hypokalemia.

Amlodipine/Perindopril

Liver failure

In rare cases, cholestatic jaundice occurs while taking ACE inhibitors. As this syndrome progresses, fulminant liver necrosis develops, sometimes with death. The mechanism of development of this syndrome is unclear. When jaundice or a significant increase in the activity of liver enzymes occurs in patients taking ACE inhibitors. you should stop taking the ACE inhibitor and consult a doctor (see section “Side effects”),

In patients with impaired liver function, T1/2 and AUC of amlodipine are increased. Amlodipine should be started with the lowest doses and precautions should be taken both at the beginning of treatment and when increasing the dose. In patients with severe hepatic impairment, the dose should be increased gradually, ensuring careful monitoring of the clinical condition.

Triplixam® has not been studied in patients with liver failure. Considering the effect of each component included in the drug separately, Triplixam® is contraindicated in patients with severe liver failure, and also requires special caution when prescribed to patients with moderate and mild liver failure.

Amlodipine/Indapamide/Perindopril

Renal dysfunction

The drug is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 ml/min) (see section "Contraindications").

In patients with moderate renal impairment (creatinine clearance 30-60 ml/min), the use of Triplixam® in dosages containing 10 mg of perindopril and 2.5 mg of indapamide is contraindicated (i.e., dosage of Triplixam® 5 mg + 2.5 mg + 10 mg and 10 mg + 2.5 mg + 10 mg).

Such patients require regular monitoring of the content of potassium ions and creatinine in the blood serum - 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 underlying renal dysfunction, including renal artery stenosis.

Triplixam® is not recommended for patients with bilateral renal artery stenosis 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 decreased electrolyte levels in the blood plasma, etc.): in some pathological conditions, significant activation of the RAAS may be observed, especially with severe hypovolemia and decreased electrolyte levels blood plasma (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 cirrhosis of the liver with edema and ascites.

Blockade of the RAAS by ACE inhibitors may 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 when taking the first dose of the drug or during the first two weeks of therapy. Sometimes these conditions develop acutely and the time of their onset may vary. In such cases, it is recommended to resume therapy 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, body weight and gender.

At the beginning of treatment with diuretics, patients may experience a temporary decrease in glomerular filtration rate and an increase in the concentration of urea and creatinine in the blood plasma due to hypovolemia and hyponatremia. This transient functional renal failure is not dangerous for patients with unchanged renal function, but its severity may increase in patients with underlying renal failure. Patients with renal failure can take amlodipine in standard doses.

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

No special studies have been conducted on the use of Triplixam® in renal dysfunction. When using the drug Triplixam® in case of impaired renal function, the effects noted when taking individual components of the drug should be taken into account.

Content of potassium ions in blood plasma

Concomitant 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 drugs in combination with a diuretic, regular monitoring of the content of potassium ions in the blood plasma is necessary.

Hyperkalemia may develop in some patients during treatment with ACE inhibitors, including perindopril. Risk factors for hyperkalemia include renal failure, deterioration of renal function, advanced age (> 70 years), diabetes mellitus, certain concomitant conditions (dehydration, acute cardiac decompensation, metabolic acidosis), concomitant use of potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene, amiloride), potassium preparations or potassium-containing substitutes for table salt, as well as the use of other drugs that increase the content of potassium ions in the blood plasma (for example, heparin, co-trimoxazole, i.e. the combination of trimethoprim + sulfamethoxazole). The use of potassium supplements/preparations, potassium-sparing diuretics, and potassium-containing table salt substitutes can lead to a significant increase in potassium levels 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 above drugs is necessary, treatment should be carried out with caution, against the background of regular monitoring of the content 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. Hypokalemia (less than 3.4 mmol/L) should be avoided in the following high-risk patients: elderly and/or malnourished patients (even if not receiving concomitant drug therapy), patients with cirrhosis with edema and ascites, patients with coronary heart disease, chronic heart failure. Hypokalemia in these patients increases the toxic effect of cardiac glycosides and increases the risk of developing arrhythmia.

The risk group also includes patients with a prolonged QT interval, and it does not matter whether this increase is caused by congenital causes or the effect of drugs.

Hypokalemia, like bradycardia, contributes to the development of severe cardiac arrhythmias, in particular polymorphic ventricular tachycardia of the “pirouette” type, which can be fatal. In all the cases described above, regular monitoring of the content of potassium ions in the blood plasma is necessary. The first measurement of potassium ion content should be carried out within the first week from the start of therapy.

If hypokalemia is detected, appropriate treatment should be prescribed.

Elderly patients

Before starting to take the drug, it is necessary to assess the functional activity of the kidneys and the content of potassium ions in the blood plasma. At the beginning of therapy, the dose of the drug is selected taking into account the degree of reduction in blood pressure, especially in the case of a decrease in circulating blood volume (CBV) and loss of electrolytes. Such measures help to avoid a sharp decrease in blood pressure.

In elderly patients, increasing the dose should be done with caution (see sections “Dosage and Administration” and “Pharmacokinetics”).

Excipients

Sodium level

The sodium content in the drug Triplixam® is insignificant, as it is less than 1 mmol of sodium (23 mg) per tablet.

Triplixam, 10 mg+1.25 mg+5 mg, film-coated tablets, 30 pcs.

All precautions associated with taking individual components of the drug should be taken into account when using their fixed combination as part of the drug Triplixam®.

Amlodipine

Chronic
heart failure
Patients with chronic heart failure should be treated with caution.

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

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

Patients with arterial hypertension and coronary heart disease should not stop taking beta-blockers: an ACE inhibitor should be used in conjunction with beta-blockers.

Hypertensive crisis

The effectiveness and safety of amlodipine in hypertensive crisis has not been established.

Indapamide

Hepatic encephalopathy

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

Photosensitivity

Content of calcium ions in blood plasma

Uric acid

In patients with elevated concentrations of uric acid in the blood plasma, the frequency of gout attacks may increase during therapy.

Perindopril

Potassium-sparing diuretics, potassium supplements, potassium-containing table salt substitutes and food supplements

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

Neutropenia/agranulocytosis/thrombocytopenia/anemia

Hypersensitivity/angioedema

Angioedema, accompanied by swelling of the larynx, can be fatal. Swelling of the tongue, glottis or larynx can lead to airway obstruction, in which case intensive care should be given immediately. If such symptoms appear, you should immediately administer a solution of epinephrine (adrenaline) 1:1000 (0.3–0.5 ml) and/or ensure airway patency. The patient should be under medical supervision until symptoms disappear completely and permanently.

Patients of the Black race had a higher incidence of angioedema while taking ACE inhibitors compared to other races.

In patients with a history of angioedema not associated with taking ACE inhibitors. the risk of its development may be increased when taking the drug (see section “Contraindications”). There are reports of rare cases of the development of angioedema of the intestine 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 previous angioedema of the face and with normal levels of C1-esterase. The diagnosis was made using abdominal computed tomography, ultrasound, or at the time of surgery. Symptoms resolved after discontinuation of ACE inhibitors. Therefore, in patients with abdominal pain receiving ACE inhibitors, when carrying out differential diagnosis, it is necessary to take into account the possibility of developing angioedema of the intestine.

Anaphylactoid reactions during desensitization

Anaphylactoid reactions during LDL apheresis

Hemodialysis

Pregnancy

Cough

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 patients of the Negroid race compared to representatives of other races. Perhaps this difference is due to the fact that black patients with arterial hypertension are more likely to have low renin activity.

Surgery/General anesthesia

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

Patients
with renovascular hypertension
The treatment for renovascular hypertension is revascularization. However, the use of ACE inhibitors has a beneficial effect in patients both awaiting surgery and in cases where surgery is not possible.

Atherosclerosis

Perindopril/indapamide.

Lithium preparations

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

Arterial hypotension and water-electrolyte imbalance

The presence of initial hyponatremia is associated with the risk of sudden development of arterial hypotension (especially in patients with renal artery stenosis). Therefore, when monitoring patients, attention should be paid to possible symptoms of dehydration and decreased plasma electrolytes, for example, after diarrhea or vomiting. Such patients require regular monitoring of blood plasma electrolyte levels. In case of severe arterial hypotension, intravenous administration of 0.9% sodium chloride solution may be required.

All diuretics can cause hyponatremia. 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 ion levels is indicated for elderly patients and patients with liver cirrhosis (see sections “Side effects” and “Overdose”).

Patients with diabetes mellitus

In patients with type 1 diabetes mellitus (risk of spontaneous increases in potassium ions), treatment should begin with lower doses and under close medical supervision.

Amlodipine/perindopril

Liver failure

In rare cases, cholestatic jaundice occurs while taking ACE inhibitors. As this syndrome progresses, fulminant liver necrosis develops, sometimes with death. The mechanism of development of this syndrome is unclear. If jaundice or a significant increase in the activity of liver enzymes occurs in patients taking ACE inhibitors, you should stop taking the ACE inhibitor and consult a doctor (see section “Side Effects”).

In patients with impaired liver function, T½ and AUC of amlodipine are increased. Taking amlodipine should be started with the lowest doses and precautions should be taken both at the beginning of treatment and when increasing the dose. In patients with severe hepatic impairment, the dose should be increased gradually, ensuring careful monitoring of the clinical condition.

Amlodipine/indapamide/perindopril

Renal dysfunction

The drug is contraindicated in patients with severe renal failure (creatinine clearance less than 30 ml/min) (see section "Contraindications").

In patients with moderate renal failure (creatinine clearance 30–60 ml/min), the use of Triplixam® in dosages containing 10 mg of perindopril and 2.5 mg of indapamide is contraindicated (i.e., dosage of Triplixam® 5 mg + 2.5 mg + 10 mg and 10 mg + 2.5 mg + 10 mg).

Some patients with arterial hypertension without previous obvious renal impairment may develop laboratory signs of functional renal failure during therapy. In this case, treatment with the drug should be stopped with the further possibility of resuming combination therapy using low doses of the drug, or using the components of the drug in monotherapy. Such patients require regular monitoring of the content of potassium ions and creatinine in the blood serum - 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 underlying renal impairment, including renal artery stenosis.

Triplixam® is not recommended for patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney.

No special studies have been conducted on the use of Triplixam® in renal failure. When using the drug Triplixam® for renal failure, the effects noted when taking individual components of the drug should be taken into account.

Content of potassium ions in blood plasma

Hyperkalemia may develop in some patients during treatment with ACE inhibitors, including perindopril. Risk factors for hyperkalemia include renal failure, impaired renal function, advanced age (>70 years), diabetes mellitus, certain concomitant conditions (dehydration, acute cardiac decompensation, metabolic acidosis), concomitant use of potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene, amiloride), potassium preparations or potassium-containing table salt substitutes, 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 potassium supplements/preparations, potassium-sparing diuretics, and potassium-containing table salt substitutes can lead to a significant increase in potassium levels 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 above drugs is necessary, treatment should be carried out with caution, against the background of regular monitoring of the content 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. Hypokalemia (less than 3.4 mmol/L) should be avoided in the following high-risk patients: elderly and/or malnourished patients (even if not receiving concomitant drug therapy), patients with cirrhosis with edema and ascites, patients with coronary heart disease, chronic heart failure. Hypokalemia in these patients increases the toxic effect of cardiac glycosides and increases the risk of developing arrhythmia.

The risk group also includes patients with a prolonged QT interval, and it does not matter whether this increase is caused by congenital causes or the effect of drugs.

If hypokalemia is detected, appropriate treatment should be prescribed.

Elderly patients

In elderly patients, increasing the dose should be done with caution (see sections “Dosage and Administration” and “Pharmacokinetics”).

Impact on the ability to drive vehicles and machinery

Due to the possibility of weakness and dizziness while using the drug Triplixam®, care must be taken when driving vehicles and working with other technical devices that require increased concentration and speed of psychomotor reactions.