Triplatenz^® (Tablets) Instructions for Use

Marketing Authorization Holder

Panbio Pharm, LLC (Russia)

Manufactured By

Simpex Pharma, Pvt. Ltd. (India)

ATC Code

C09BX01 (Perindopril and Amlodipine and Indapamide)

Active Substances

Amlodipine (Rec.INN registered by WHO)

Indapamide (Rec.INN registered by WHO)

Perindopril (Rec.INN registered by WHO)

Dosage Forms

	Triplatenz®	Tablets 5 mg+2.5 mg+8 mg
		Tablets 10 mg+1.25 mg+4 mg
		Tablets 10 mg+2.5 mg+8 mg

Dosage Form, Packaging, and Composition

Tablets

10 pcs. – blister packs – cardboard packs (10 pcs.) – Prescription only
10 pcs. – blister packs (2 pcs.) – cardboard packs (20 pcs.) – Prescription only
10 pcs. – blister packs (3 pcs.) – cardboard packs (30 pcs.) – Prescription only
10 pcs. – blister packs (6 pcs.) – cardboard packs (60 pcs.) – Prescription only
10 pcs. – blister packs (9 pcs.) – cardboard packs (90 pcs.) – Prescription only
14 pcs. – blister packs – cardboard packs (14 pcs.) – Prescription only
14 pcs. – blister packs (2 pcs.) – cardboard packs (28 pcs.) – Prescription only
14 pcs. – blister packs (4 pcs.) – cardboard packs (56 pcs.) – Prescription only
14 pcs. – blister packs (6 pcs.) – cardboard packs (84 pcs.) – Prescription only

Tablets

10 pcs. – blister packs – cardboard packs (10 pcs.) – Prescription only
10 pcs. – blister packs (2 pcs.) – cardboard packs (20 pcs.) – Prescription only
10 pcs. – blister packs (3 pcs.) – cardboard packs (30 pcs.) – Prescription only
10 pcs. – blister packs (6 pcs.) – cardboard packs (60 pcs.) – Prescription only
10 pcs. – blister packs (9 pcs.) – cardboard packs (90 pcs.) – Prescription only
14 pcs. – blister packs – cardboard packs (14 pcs.) – Prescription only
14 pcs. – blister packs (2 pcs.) – cardboard packs (28 pcs.) – Prescription only
14 pcs. – blister packs (4 pcs.) – cardboard packs (56 pcs.) – Prescription only
14 pcs. – blister packs (6 pcs.) – cardboard packs (84 pcs.) – Prescription only

Tablets

10 pcs. – blister packs – cardboard packs (10 pcs.) – Prescription only
10 pcs. – blister packs (2 pcs.) – cardboard packs (20 pcs.) – Prescription only
10 pcs. – blister packs (3 pcs.) – cardboard packs (30 pcs.) – Prescription only
10 pcs. – blister packs (6 pcs.) – cardboard packs (60 pcs.) – Prescription only
10 pcs. – blister packs (9 pcs.) – cardboard packs (90 pcs.) – Prescription only
14 pcs. – blister packs – cardboard packs (14 pcs.) – Prescription only
14 pcs. – blister packs (2 pcs.) – cardboard packs (28 pcs.) – Prescription only
14 pcs. – blister packs (4 pcs.) – cardboard packs (56 pcs.) – Prescription only
14 pcs. – blister packs (6 pcs.) – cardboard packs (84 pcs.) – Prescription only

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Agents acting on the renin-angiotensin system; angiotensin-converting enzyme (ACE) inhibitors, combinations; ACE inhibitors, other combinations

Pharmacological Action

A combined antihypertensive drug containing perindopril erbumine (an ACE inhibitor), Indapamide (a thiazide-like diuretic), and Amlodipine (a calcium channel blocker). This combination combines the properties of each of the active substances, which also have a potentiating effect.

Amlodipine is a calcium channel blocker, a dihydropyridine derivative. It has antianginal and antihypertensive effects. Amlodipine inhibits the transmembrane transition of calcium ions into cardiomyocytes and vascular smooth muscle cells. The antihypertensive effect of amlodipine is due to a direct relaxing effect on vascular smooth muscle cells. The mechanism of the antianginal action of amlodipine is not fully understood; it is presumably associated with the following effects: it causes dilation of peripheral arterioles, reducing total peripheral resistance – afterload, which leads to a decrease in myocardial oxygen demand; it causes dilation of coronary arteries and arterioles in both intact and ischemic areas of the myocardium, which increases oxygen delivery to the myocardium, including in patients with Prinzmetal’s angina.

In patients with arterial hypertension, taking amlodipine once a day provides a clinically significant reduction in blood pressure (in supine and standing positions) over 24 hours. The antihypertensive effect develops slowly, so the development of acute arterial hypotension is not typical. In patients with angina, taking amlodipine once a day increases exercise tolerance, time to onset of angina attack and to ‘ischemic’ ST-segment depression, reduces the frequency of angina attacks and the need for nitroglycerin (short-acting forms). Amlodipine does not have an undesirable effect on lipid metabolism and does not cause changes in the plasma lipid profile. Amlodipine can be used in patients with bronchial asthma, diabetes mellitus, and gout.

Indapamide is a sulfonamide derivative. In its pharmacological properties, it is close to thiazide diuretics. Indapamide inhibits the reabsorption of sodium ions in the cortical segment of the loop of Henle, which leads to an increase in the renal excretion of sodium and chloride ions, and to a lesser extent potassium and magnesium ions, thereby enhancing diuresis and reducing blood pressure.

In monotherapy mode, the antihypertensive effect persists for 24 hours and manifests itself when the drug is used in doses that have a minimal diuretic effect. The antihypertensive effect of indapamide is associated with an improvement in the elastic properties of large arteries and a decrease in total peripheral resistance. Against the background of indapamide intake, left ventricular hypertrophy decreases. Indapamide does not affect plasma lipid concentrations (triglycerides, total cholesterol, LDL and HDL), or carbohydrate metabolism parameters (including in patients with diabetes mellitus).

Perindopril is an ACE inhibitor. ACE, or kinase II, is an exopeptidase that converts angiotensin I into the vasoconstrictor substance angiotensin II, and also breaks down bradykinin, which has vasodilating properties, into an inactive heptapeptide. As a result, Perindopril provides the following effects: reduces aldosterone secretion; increases plasma renin activity through the principle of ‘negative’ feedback; with long-term use, reduces total peripheral resistance – cardiac afterload, which is mainly due to its action on muscular and renal vessels. The reduction in total peripheral resistance is not accompanied by sodium and water retention and does not cause reflex tachycardia.

A study of hemodynamic parameters in patients with chronic heart failure revealed: a decrease in filling pressure in the left and right ventricles of the heart; a decrease in total peripheral resistance; an increase in cardiac output and cardiac index; an increase in peripheral muscle blood flow. Furthermore, an improvement in exercise test results was noted.

The action of perindopril is carried out through an active metabolite – perindoprilat. Other metabolites do not have an inhibitory effect on ACE under in vitro conditions. Perindopril is effective in the treatment of arterial hypertension of any severity, reducing both systolic and diastolic blood pressure in the supine and standing positions.

The antihypertensive effect reaches its maximum 4-6 hours after a single oral dose and persists for 24 hours. The antihypertensive effect 24 hours after a single oral dose is about 87-100% of the maximum antihypertensive effect. Perindopril has an antihypertensive effect in patients with both low and normal plasma renin activity. The therapeutic effect occurs in less than 1 month from the start of therapy and is not accompanied by tachyphylaxis. Discontinuation of therapy does not cause withdrawal syndrome.

Perindopril has vasodilating properties and helps restore the elasticity of large arteries, the structure of the vascular wall of small arteries, and also reduces left ventricular hypertrophy. Simultaneous use with a thiazide diuretic enhances the severity of the antihypertensive effect and reduces the risk of hypokalemia during diuretic use.

The combination Perindopril/Indapamide has a dose-dependent antihypertensive effect on both systolic and diastolic blood pressure (in standing and lying positions) regardless of the patient’s age. The antihypertensive effect persists for 24 hours. The therapeutic effect occurs in less than 1 month from the start of therapy and is not accompanied by tachyphylaxis. Discontinuation of therapy does not cause withdrawal syndrome.

In clinical studies, the simultaneous use of perindopril and indapamide enhanced the severity of the antihypertensive effect compared with monotherapy with each drug. The combination of perindopril tert-butylamine (perindopril erbumine)/Indapamide led to a significantly more pronounced reduction in left ventricular hypertrophy than monotherapy with enalapril. The most significant effect on left ventricular hypertrophy is achieved with the use of perindopril tert-butylamine (perindopril erbumine) 8 mg/indapamide 2.5 mg.

Pharmacokinetics

Amlodipine

After oral administration, Amlodipine is slowly absorbed from the gastrointestinal tract. Food intake does not affect the bioavailability of amlodipine. C_max of amlodipine in plasma is reached 6-12 hours after oral administration. Absolute bioavailability is about 64-80%. V_d is approximately 21 L/kg. In in vitro studies, the degree of binding of amlodipine to plasma proteins was about 97.5%. Amlodipine penetrates the blood-brain barrier and placental barrier.

The terminal T_1/2 from plasma is about 35-50 hours, which allows taking Amlodipine once a day. Amlodipine is metabolized in the liver to form inactive metabolites, with 10% of the orally administered dose of amlodipine excreted unchanged, about 60% – by the kidneys as metabolites. Amlodipine is not removed from the body by hemodialysis. Prolongation of T_1/2 in patients with hepatic insufficiency suggests that with long-term use, the accumulation of amlodipine in the body will be higher (increases to 60 hours).

Indapamide

Indapamide is rapidly and completely absorbed from the gastrointestinal tract. Food intake slightly increases the rate of absorption but does not affect the completeness of absorption. C_max in plasma is reached approximately 1 hour after oral administration of the drug. The degree of binding to plasma proteins is 79%. T_1/2 is 14-24 hours (average 18 hours). Repeated administration of indapamide does not lead to its accumulation. It is eliminated mainly by the kidneys (70% of the orally administered dose) and through the intestines (22%) in the form of inactive metabolites.

Perindopril

When taken orally, Perindopril is rapidly absorbed. C_max in plasma is reached 1 hour after oral administration. Perindopril is a prodrug, i.e., it does not have pharmacological activity. About 27% of the orally administered dose of perindopril enters the bloodstream in the form of the active metabolite – perindoprilat. In addition to the active metabolite – perindoprilat, 5 more metabolites are formed, which do not have pharmacological activity. C_max of perindoprilat in plasma is reached 3-4 hours after oral administration. Food intake slows down the conversion of perindopril to perindoprilat, thus affecting bioavailability. Therefore, Perindopril should be taken once a day, in the morning, before meals.

There is a linear relationship between the plasma concentration of perindopril and the orally administered dose. Steady state is reached within 4 days. V_d of free perindoprilat is approximately 0.2 L/kg. The degree of binding of perindoprilat to plasma proteins (mainly with ACE) is about 20% and is dose-dependent. T_1/2 of perindopril from plasma is 1 hour. Perindoprilat is eliminated from the body by the kidneys. The terminal T_1/2 of the free fraction is about 17 hours. The dialysis clearance of perindoprilat is 70 ml/min.

Indications

• Arterial hypertension (when simultaneous therapy with amlodipine, indapamide, and perindopril in doses used in monotherapy of individual components is necessary).

ICD codes

Dosage Regimen

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

The dose of the combination is selected after prior titration of the doses of the individual active components of the drug. The maximum daily dose of the drug is 10 mg amlodipine + 2.5 mg indapamide + 8 mg perindopril.

This combination is contraindicated in patients with moderate and severe renal impairment (CrCl <60 ml/min). The drug can be used in patients with CrCl ≥60 ml/min, however, individual dose selection of amlodipine, indapamide, perindopril is recommended.

No dose adjustment is required in elderly patients, however, dose increase should be carried out with caution, due to age-related changes and prolongation of T_1/2.

The elimination of perindoprilat in elderly patients and patients with renal failure is slowed down. Therefore, in such patients, it is necessary to regularly monitor the concentration of creatinine and the potassium content in plasma. This combination is contraindicated in patients with severe hepatic impairment. Caution should be exercised when using the drug in patients with mild and moderate hepatic impairment.

Adverse Reactions

Classification of the frequency of adverse effects: very common (>1/10), common (from >1/100 to <1/10), uncommon (from >1/1000 to <1/100), rare (from >1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data).

Amlodipine

Blood and lymphatic system disorders very rare – leukopenia/neutropenia, thrombocytopenia.

Immune system disorders very rare – allergic reactions.

Metabolism and nutrition disorders very rare – hyperglycemia.

Psychiatric disorders uncommon – insomnia, mood swings (including anxiety), depression; rare – confusion.

Nervous system disorders common – drowsiness (especially at the beginning of treatment), dizziness (especially at the beginning of treatment), headache; uncommon – tremor, hypoesthesia, paresthesia, taste changes, syncope; very rare – muscle hypertonia, peripheral neuropathy.

Eye disorders uncommon – visual impairment (including diplopia).

Ear and labyrinth disorders uncommon – tinnitus.

Cardiac disorders common – palpitations, sensation of flushing; uncommon – marked decrease in blood pressure (including orthostatic hypotension); very rare – myocardial infarction, possibly due to excessive blood pressure reduction in high-risk patients, cardiac arrhythmias (including bradycardia, ventricular tachycardia, and atrial fibrillation), vasculitis (including hemorrhagic vasculitis).

Respiratory, thoracic and mediastinal disorders uncommon – dyspnea, rhinitis; very rare – cough.

Gastrointestinal disorders common – abdominal pain, nausea; uncommon – vomiting, dyspepsia, changes in bowel habits (including diarrhea, constipation), dry mouth; very rare – gingival hyperplasia, pancreatitis, gastritis, hepatitis, jaundice, increased serum bilirubin concentration, activity of liver enzymes (ALT and AST).

Skin and subcutaneous tissue disorders uncommon – pruritus, rash, exfoliative dermatitis, Stevens-Johnson syndrome, photosensitivity; very rare – erythema multiforme.

Musculoskeletal and connective tissue disorders uncommon – arthralgia, myalgia, muscle cramps.

Renal and urinary disorders uncommon – painful urination, nocturia, frequent urination.

Reproductive system and breast disorders uncommon – impotence, gynecomastia.

Allergic reactions uncommon – urticaria; very rare – angioedema of the face, extremities, lips, tongue mucosa, vocal folds and/or larynx.

General disorders and administration site conditions common – peripheral edema; uncommon – increased or decreased body weight, increased fatigue, asthenia, chest pain, back pain, pain of various localization, general malaise. Isolated rare cases of extrapyramidal syndrome have been observed with the use of amlodipine.

Perindopril/Indapamide

Blood and lymphatic system disorders very rare – leukopenia/neutropenia, agranulocytosis or pancytopenia, thrombocytopenia, aplastic anemia, hemolytic anemia; during treatment with ACE inhibitors in certain situations (after kidney transplantation, during dialysis), the development of anemia has been observed.

Immune system disorders uncommon – hypersensitivity reactions in patients predisposed to bronchospastic and allergic reactions.

Psychiatric disorders uncommon – mood swings (including anxiety), sleep disturbance.

Nervous system disorders common – dizziness (especially at the beginning of treatment), headache, paresthesia, vertigo; frequency not known – syncope.

Eye disorders common – visual impairment (including diplopia).

Ear and labyrinth disorders uncommon – tinnitus (ringing in the ears).

Cardiac disorders uncommon – marked decrease in blood pressure (including orthostatic hypotension), vasculitis (including hemorrhagic vasculitis); very rare – angina pectoris, myocardial infarction, possibly due to excessive blood pressure reduction in high-risk patients, cardiac arrhythmias (including bradycardia, ventricular tachycardia, and atrial fibrillation); frequency not known – polymorphic ventricular tachycardia of the ‘torsades de pointes’ type (possibly fatal).

From the digestive systemfrequently – abdominal pain, nausea, epigastric pain, vomiting, dyspepsia, changes in bowel habits (including diarrhea, constipation), dry mouth, taste disturbance, decreased appetite; very rarely – pancreatitis, intestinal angioedema, jaundice*; frequency unknown – hepatic encephalopathy in patients with hepatic insufficiency.

From the skin and subcutaneous tissuesfrequently – skin itching, rash, maculopapular rash; infrequently – increased sweating; very rarely – erythema multiforme exudativum, Stevens-Johnson syndrome, toxic epidermal necrolysis; frequency unknown – photosensitivity.

From the musculoskeletal systemfrequently – muscle cramps.

From the urinary systeminfrequently – renal failure; very rarely – acute renal failure.

From the reproductive system and mammary glandinfrequently – impotence.

Allergic reactionsinfrequently – urticaria, angioedema of the face, extremities, lips, tongue mucosa, vocal folds and/or larynx.

Laboratory and instrumental datararely – hypercalcemia; frequency unknown – increased serum bilirubin concentration, activity of liver enzymes ALT* and AST*, QT interval prolongation on ECG, increased creatinine concentration in urine and blood plasma, which resolves after discontinuation of therapy, hypokalemia, hyponatremia and hypovolemia leading to dehydration and orthostatic hypotension, increased plasma uric acid and glucose concentration, hyperkalemia.

Otherfrequently – asthenia; infrequently – possible worsening of the acute form of systemic lupus erythematosus.

* In most cases associated with cholestasis.

Contraindications

• History of angioedema associated with the use of ACE inhibitors;
• Hereditary/idiopathic angioedema;
• Renal failure (creatinine clearance less than 60 ml/min);
• Bilateral renal artery stenosis, stenosis of the artery of a solitary kidney;
• Severe hepatic insufficiency, including hepatic encephalopathy;
• Severe arterial hypotension (systolic BP less than 90 mm Hg);
• Shock, including cardiogenic shock;
• Unstable angina (except for Prinzmetal’s angina);
• Left ventricular outflow tract obstruction (e.g., clinically significant aortic stenosis);
• Hemodynamically unstable heart failure after acute myocardial infarction;
• Refractory hypokalemia;
• Concomitant use with drugs capable of causing polymorphic ventricular tachycardia of the ‘torsades de pointes’ type;
• Concomitant use with potassium-sparing diuretics, potassium preparations and lithium, in patients with elevated plasma potassium levels;
• Concomitant use of drugs that prolong the QT interval;
• Concomitant use with aliskiren and aliskiren-containing drugs in patients with diabetes mellitus;
• Pregnancy;
• Lactation period;
• Age under 18 years (efficacy and safety not established);
• Hypersensitivity to amlodipine and other dihydropyridine derivatives, indapamide and other sulfonamide derivatives, perindopril and other ACE inhibitors.

Given the lack of sufficient clinical experience, it should not be used in patients on hemodialysis, as well as in patients with untreated decompensated heart failure.

With caution this combination should be used in mild to moderate hepatic insufficiency, systemic connective tissue diseases (including SLE, scleroderma), therapy with immunosuppressants, allopurinol, procainamide (risk of neutropenia and agranulocytosis), bone marrow depression, reduced blood volume (diuretic intake, salt-restricted diet, vomiting, diarrhea, hemodialysis), coronary artery disease, atherosclerosis, cerebrovascular diseases, renovascular hypertension, diabetes mellitus, chronic heart failure (NYHA class IV), hyperuricemia (especially in combination with gout and urate nephrolithiasis), concomitant use of dantrolene, estramustine, surgical intervention/general anesthesia, labile blood pressure, hemodialysis using high-flux membranes (e.g., AN69^®), before LDL apheresis procedure with dextran sulfate, concomitant desensitizing therapy with allergens (e.g., hymenoptera venom), status after kidney transplantation, aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy, in elderly patients, patients of Black race.

Use in Pregnancy and Lactation

Use during pregnancy and lactation (breastfeeding) is contraindicated.

Use in Hepatic Impairment

Use of this combination is contraindicated in severe hepatic insufficiency, including hepatic encephalopathy.

With caution: mild to moderate hepatic insufficiency.

Use in Renal Impairment

Use of this combination is contraindicated in renal failure (creatinine clearance less than 60 ml/min), bilateral renal artery stenosis, stenosis of the artery of a solitary kidney.

With caution: status after kidney transplantation.

Pediatric Use

Use of this combination is contraindicated in patients under 18 years of age (efficacy and safety not established).

Geriatric Use

No dose adjustment is required in elderly patients, however, dose increase should be performed with caution.

Special Precautions

In some patients with arterial hypertension without prior obvious renal function impairment, laboratory signs of functional renal failure may appear during therapy. In this case, treatment with the drug should be discontinued. Subsequently, combination therapy can be resumed using a combination of perindopril and indapamide in low doses, or these drugs can be used separately. Such patients require regular monitoring of serum potassium and creatinine concentration 2 weeks after the start of therapy and then every 2 months.

Development of renal failure occurs more often in patients with severe chronic heart failure or pre-existing renal function impairment, including renal artery stenosis. The drug is not recommended for use in patients with bilateral renal artery stenosis or stenosis of the artery of a solitary functioning kidney.

In patients with hyponatremia (especially with renal artery stenosis, including bilateral) there is a risk of sudden development of arterial hypotension. Therefore, attention should be paid to possible symptoms of dehydration and decreased plasma electrolyte levels, for example, after diarrhea or vomiting. The use of ACE inhibitors causes blockade of the RAAS and therefore may be accompanied by a sharp decrease in BP 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 drug or during the first 2 weeks of therapy and sometimes develop acutely. 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 BP, treatment can be resumed using low doses of perindopril and indapamide, or used separately.

Before starting the combination, renal function and plasma potassium levels should be assessed. At the beginning of therapy, the drug dose is selected taking into account the degree of BP reduction, especially in case of reduced blood volume and electrolyte loss, which allows avoiding a sharp decrease in BP.

The risk of arterial hypotension exists in all patients, but particular caution should be exercised in patients with coronary artery disease and cerebrovascular diseases. In such patients, treatment is started with low doses of the drug.

Amlodipine

In patients with chronic heart failure (NYHA class III and IV), treatment should be carried out with caution, due to the possibility of pulmonary edema. Calcium channel blockers, including Amlodipine, should be used with caution in patients with chronic heart failure, and due to the possible increased risk of adverse cardiovascular events and mortality.

Amlodipine should be started at the lowest doses and caution should be exercised both at the start of therapy and when increasing the amlodipine dose. In patients with severe hepatic impairment, the dose should be increased gradually, careful monitoring of the clinical condition is necessary.

Indapamide

In the presence of hepatic impairment, taking thiazide and thiazide-like diuretics may lead to the development of hepatic encephalopathy. In this case, the drug should be discontinued immediately.

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

Before starting treatment, plasma sodium levels should be determined. During drug administration, this indicator should be regularly monitored. All diuretics can cause hyponatremia, which sometimes leads to serious complications. At the initial stage of therapy, a decrease in plasma sodium levels may be asymptomatic, so regular laboratory monitoring is necessary. Elderly patients require more frequent monitoring of plasma sodium levels.

Therapy with thiazide and thiazide-like diuretics is associated with the risk of hypokalemia. Hypokalemia (less than 3.4 mmol/l) should be avoided in the following high-risk patient categories: elderly patients, debilitated patients, patients with liver cirrhosis, including those with edema and ascites, patients with coronary artery disease, chronic heart failure. In such patients, hypokalemia enhances the toxic effect of cardiac glycosides and increases the risk of arrhythmia.

The high-risk group also includes patients with prolonged QT interval, both hereditary and drug-induced. Hypokalemia, like bradycardia, contributes to the development of severe cardiac arrhythmias, especially polymorphic ventricular tachycardia of the ‘torsades de pointes’ type, which can be fatal. In all the cases described above, regular monitoring of plasma potassium levels is necessary. Plasma potassium levels should be determined within the first week after starting therapy. If hypokalemia is detected, appropriate therapy should be carried out.

Thiazide and thiazide-like diuretics reduce renal calcium excretion, which can cause a slight temporary increase in plasma calcium levels. Marked hypercalcemia may be associated with previously undiagnosed hyperparathyroidism. In such cases, it is necessary to examine parathyroid function, having previously discontinued diuretic use.

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

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 clearance is calculated taking into account age, weight and sex.

In patients with hypovolemia and hyponatremia at the beginning of diuretic therapy, a temporary decrease in GFR and an increase in plasma urea and creatinine concentrations may be observed. This transient functional renal failure is not dangerous for patients with unchanged renal function, but in patients with renal failure its severity may increase. In such patients, plasma potassium and creatinine concentrations should be regularly monitored.

Indapamide may give a positive reaction during doping control.

Perindopril

During the use of ACE inhibitors, neutropenia/agranulocytosis, thrombocytopenia and anemia may occur. In patients with normal renal function and no other risk factors, neutropenia rarely develops. After discontinuation of the ACE inhibitor, neutropenia and agranulocytosis resolve on their own. Perindopril should be used with particular caution in patients with systemic connective tissue diseases during therapy with immunosuppressants, allopurinol or procainamide, especially in patients with impaired renal function. Some patients developed severe infections, in some cases resistant to intensive antibiotic therapy. When using perindopril in such patients, it is recommended to periodically monitor the white blood cell count in the plasma. If any symptoms of infectious diseases appear (e.g., sore throat, fever), patients should consult a doctor.

During the use of ACE inhibitors, including perindopril, in rare cases, angioedema of the face, extremities, lips, tongue, vocal folds and/or larynx may develop. If symptoms appear, the drug should be discontinued immediately and the patient should be monitored until symptoms completely resolve. As a rule, swelling of the face and lips does not require treatment, although antihistamines may be used to relieve symptoms. Angioedema accompanied by laryngeal edema can be fatal. Swelling of the tongue, vocal folds or larynx can lead to airway obstruction. If such symptoms appear, a solution of epinephrine (adrenaline) 1:1000 (0.3-0.5 ml) should be administered subcutaneously immediately and/or airway patency should be ensured. In patients with a history of angioedema not associated with ACE inhibitor use, the risk of its development when taking drugs of this group may be increased.

In rare cases, intestinal angioedema develops during therapy with ACE inhibitors. In this case, patients complain of abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without preceding facial angioedema and with normal C-1 esterase levels. The diagnosis was established using CT, ultrasound of the abdominal organs or during surgery. Symptoms disappear after discontinuation of ACE inhibitors. Therefore, in patients complaining of abdominal pain who are taking ACE inhibitors, the possibility of intestinal angioedema should be considered in the differential diagnosis.

There are isolated reports of anaphylactoid reactions in patients taking ACE inhibitors during desensitizing therapy (e.g., with hymenoptera venom: bees, wasps). Such reactions were avoided by temporarily discontinuing ACE inhibitors (at least 24 hours before desensitization); with accidental intake of an ACE inhibitor, the anaphylactoid reaction recurred.

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

In rare cases, in patients receiving ACE inhibitors, anaphylactoid reactions developed during hemodialysis using high-flux membranes (e.g., AN69^®). Therefore, it is recommended to use a membrane of a different type or to use an antihypertensive drug of another pharmacotherapeutic group.

During therapy with ACE inhibitors, a dry cough may occur. The cough persists for a long time during the use of drugs of this group and disappears after their discontinuation. If a patient develops a dry cough, the possibility of its occurrence due to the use of an ACE inhibitor should be remembered. If it is necessary to use drugs of this group, the ACE inhibitor may be continued.

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

In patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, regular monitoring of plasma glucose concentration is necessary during the first month of treatment with an ACE inhibitor.

The use of ACE inhibitors in patients undergoing surgery with general anesthesia may lead to a marked decrease in BP, especially when using general anesthetic agents that have an antihypertensive effect. It is recommended to discontinue long-acting ACE inhibitors, including perindopril, 24 hours before surgery.

In patients of Black race, angioedema develops more often during the use of ACE inhibitors than in representatives of other races. Perindopril, like other ACE inhibitors, apparently has a less pronounced antihypertensive effect in patients of Black race compared to representatives of other races. Perhaps this difference is due to the fact that Black patients with arterial hypertension more often have low plasma renin activity.

In rare cases, cholestatic jaundice occurs during the use of 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 a significant increase in liver enzyme activity or the appearance of jaundice occurs during the use of ACE inhibitors, the drug should be discontinued and the patient should continue to be monitored.

Hyperkalemia may develop during the use of an ACE inhibitor. Risk factors for hyperkalemia are renal failure, old age (over 70 years), diabetes mellitus, some concomitant conditions (dehydration, acute decompensation of chronic heart failure, metabolic acidosis), simultaneous use of potassium-sparing diuretics (spironolactone, eplerenone, triamterene, amiloride), potassium preparations, potassium-containing salt substitutes, as well as other agents that contribute to an increase in plasma potassium levels (e.g., heparin) (especially in patients with reduced renal function). Hyperkalemia can lead to serious, sometimes fatal, cardiac arrhythmias. If simultaneous use of the drug with the above agents is necessary, caution should be exercised and plasma potassium levels should be regularly monitored.

The method of treatment for renovascular hypertension is revascularization. Nevertheless, the use of ACE inhibitors may be effective in patients with renovascular hypertension, both those awaiting surgery and when it is impossible to perform it.

In patients with diagnosed or suspected renal artery stenosis, treatment should be started with lower doses of the combination. In some patients, functional renal failure may develop, which resolves after discontinuation of the drug.

Effect on ability to drive vehicles and operate machinery

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

Drug Interactions

Amlodipine

Cases of fatal ventricular fibrillation and collapse have been observed in laboratory animals with the use of verapamil and intravenous dantrolene, accompanied by hyperkalemia. Due to the risk of hyperkalemia, it is recommended to avoid the concomitant use of amlodipine and dantrolene in patients susceptible to malignant hyperthermia, as well as during the treatment of malignant hyperthermia.

The concomitant use of inducers of the CYP3A4 isoenzyme (rifampicin, St. John’s wort preparations) may lead to a decrease in the plasma concentration of amlodipine. Caution should be exercised when amlodipine is used concomitantly with inducers of the CYP3A4 isoenzyme.

The concomitant use of amlodipine with strong or moderate inhibitors of the CYP3A4 isoenzyme (protease inhibitors, azole antifungals, macrolide antibiotics (e.g., erythromycin or clarithromycin), verapamil or diltiazem) may lead to a significant increase in the concentration of amlodipine. The clinical manifestations of these pharmacokinetic deviations may be more pronounced in elderly patients. Therefore, clinical monitoring and dose adjustment may be required.

Amlodipine enhances the antihypertensive effect of antihypertensive therapy drugs.

Concomitant intake of amlodipine and consumption of grapefruit or grapefruit juice is not recommended due to a possible increase in the bioavailability of amlodipine in some patients, which may lead to an enhancement of the antihypertensive effect.

Indapamide

Given the risk of hypokalemia, caution should be exercised when indapamide is used concomitantly with drugs capable of causing polymorphic ventricular tachycardia of the ‘torsades de pointes’ type, for example, antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide, amiodarone, dofetilide, ibutilide, bretylium tosilate, sotalol), some neuroleptics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidol, haloperidol), other neuroleptics (pimozide), other drugs such as bepridil, cisapride, difemanil methyl sulfate, intravenous erythromycin, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, intravenous vincamine, methadone, astemizole, terfenadine. Concomitant use with the above-mentioned drugs should be avoided if hypokalemia develops; it should be corrected, and ECG (QT interval) should be monitored.

Concomitant use with intravenous amphotericin B, systemic glucocorticoids and mineralocorticoids, tetracosactide, laxatives that stimulate gastrointestinal motility increases the risk of hypokalemia (additive effect). Monitoring of plasma potassium levels is necessary, and correction of hypokalemia if required. Particular caution should be exercised with concomitant use of cardiac glycosides. Laxatives that do not stimulate gastrointestinal motility should be used.

Hypokalemia enhances the toxic effect of cardiac glycosides. During concomitant use, plasma potassium levels and ECG parameters should be monitored, and if necessary, the advisability of continuing therapy should be considered.

Functional renal failure, which may occur during the use of diuretics, especially ‘loop’ diuretics, when used concomitantly with metformin, increases the risk of lactic acidosis. Metformin should not be used if plasma creatinine clearance exceeds 15 mg/l (135 µmol/l) in men and 12 mg/l (110 µmol/l) in women.

Dehydration during diuretic use increases the risk of acute renal failure, especially when high doses of iodine-containing contrast agents are administered. Hypovolemia must be corrected before using iodine-containing contrast agents.

Concomitant use may lead to hypercalcemia due to reduced renal excretion of calcium.

An increase in plasma creatinine may occur without a change in the concentration of cyclosporine, even with normal water and sodium levels.

Perindopril

Concomitant use of perindopril with aliskiren is contraindicated in patients with diabetes mellitus or moderate or severe renal impairment (creatinine clearance less than 60 ml/min).

During therapy with ACE inhibitors, plasma potassium levels generally remain within the normal range, but hyperkalemia may develop. Concomitant use of potassium-sparing diuretics (spironolactone, triamterene, amiloride, eplerenone), potassium preparations, and potassium-containing salt substitutes may lead to a significant increase in plasma potassium levels. If concomitant use of an ACE inhibitor with the above-mentioned drugs is necessary (in case of hypokalemia), caution should be exercised and regular monitoring of plasma potassium levels and ECG parameters should be performed.

Concomitant use of ACE inhibitors with estramustine is associated with a risk of angioedema.

Dual blockade of the RAAS in patients with atherosclerosis, chronic heart failure, or diabetes mellitus with target organ damage is associated with a higher frequency of arterial hypotension, syncope, hyperkalemia, and renal dysfunction (including the development of acute renal failure) compared to the use of a drug from one of the listed groups. Dual blockade of the RAAS is possible only in individual cases under careful monitoring of renal function.

Concomitant use of ACE inhibitors with NSAIDs (including acetylsalicylic acid at a dose exerting an anti-inflammatory effect, COX-2 inhibitors, and non-selective NSAIDs) may lead to a reduction in the antihypertensive effect, as well as a deterioration in renal function, including the development of acute renal failure, and an increase in plasma potassium levels, especially in patients with reduced renal function. Caution should be exercised when using this combination, especially in elderly patients. Patients should compensate for fluid loss and undergo regular monitoring of renal function, both at the beginning of treatment and during treatment.

ACE inhibitors may enhance the hypoglycemic effect of insulin and sulfonylurea derivatives in patients with diabetes mellitus. The development of hypoglycemia is observed very rarely (probably due to increased glucose tolerance and reduced insulin requirement).

In patients receiving diuretics, especially with excessive fluid and/or electrolyte loss, a significant decrease in blood pressure may be observed at the beginning of therapy with an ACE inhibitor. The risk of arterial hypotension can be reduced by discontinuing the diuretic, correcting hypovolemia and electrolyte balance, and by prescribing Perindopril at a low dose (2 mg/day), gradually increasing it.

Concomitant use of allopurinol, cytostatic and immunosuppressive drugs, systemic corticosteroids and procainamide with ACE inhibitors may increase the risk of leukopenia.

Concomitant use of ACE inhibitors and agents for general anesthesia may lead to an enhancement of the antihypertensive effect.

When using ACE inhibitors, including perindopril, in patients receiving intravenous gold (sodium aurothiomalate), a symptom complex including facial flushing, nausea, vomiting, and arterial hypotension has been described.

Concomitant use of gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin) with ACE inhibitors may increase the risk of angioedema due to suppression of dipeptidyl peptidase IV activity by the gliptin.

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Amlodipine+Indapamide+Perindopril

Concomitant use of ACE inhibitors with lithium preparations may cause a reversible increase in plasma lithium concentration with the development of intoxication.

Concomitant use with thiazide diuretics may contribute to an additional increase in lithium concentration and an increased risk of intoxication. Concomitant use of the perindopril and indapamide combination with lithium preparations is not recommended. If such therapy is carried out, regular monitoring of plasma lithium concentration is necessary.

Concomitant use with baclofen may enhance the antihypertensive effect. Blood pressure and renal function should be monitored, and if necessary, the dose of antihypertensive drugs should be adjusted.

Concomitant use with antihypertensive medicinal products (for example, beta-blockers) may enhance the antihypertensive effect. Caution should be exercised when used concomitantly with nitroglycerin, other nitrates, or other vasodilators, as this may cause an additional decrease in blood pressure.

Concomitant use with corticosteroids (mineralo- and glucocorticoids), tetracosactide may reduce the antihypertensive effect (fluid and sodium retention as a result of the action of corticosteroids).

Concomitant use with alpha-blockers (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin) causes an enhancement of the antihypertensive effect and an increased risk of orthostatic hypotension.

Concomitant use with amifostine may enhance the antihypertensive effect of amlodipine.

Tricyclic antidepressants/neuroleptics/agents for general anesthesia enhance the antihypertensive effect and increase the risk of orthostatic hypotension (additive effect).

Storage Conditions

Store at 2°C (36°F) to 25°C (77°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.